TextBook of Cardiology History

Textbook of
CARDIOLOGY
Textbook of
CARDIOLOGY
A Clinical and Historical Perspective
Editors
HK Chopra MD
Senior Consultant Cardiologist
Moolchand Medcity, New Delhi, India
Chairman, WHA, WWF
Editor, Book on Heart Protection
Formerly Editor, Indian Heart Journal
Journal of Indian Academy of Echocardiography
Vice President, JROP Institute of Echocardiography and National CSI
Navin C Nanda MD
Distinguished Professor of Medicine and Cardiovascular Disease
Director, Heart Station/Echocardiography Laboratories
University of Alabama, Birmingham, Alabama, USA
Director, Echocardiography Laboratory, The Kirklin Clinic
University of Alabama Health Services Foundation, Birmingham, Alabama, USA
Editor in Chief, Echocardiography
Founding President, American Association of Cardiologists of Indian Origin
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Textbook of Cardiology: A Clinical and Historical Perspective
First Edition : 2013
ISBN 978-93-5090-081-9
Printed at
Dedicated to
Our parents, teachers, families, friends and
patients for their kind support
and constant inspiration
Contributors
Adji A Bahl VK
St. Vincent’s Clinic; Australian School of Head, Department of Cardiology
Advanced Medicine AIIMS, New Delhi, India
Macquarie University
Sydney, Australia
Agarwal SK
Senior Consultant Banerjee AK
Internal Medicine Senior Consultant and Intervention Cardiologist
Indraprastha Apollo Hospitals AMRI Hospital, Salt Lake
New Delhi, India Kolkata, West Bengal, India
Former, National President, CSI and API
President, SAARC Cardiac Society
Aggarwal KK
Bansal M
Padma Shri and Dr B C Roy National Awardee
Senior Consultant Physician
Medanta: The Medcity
Cardiologist and Dean Medical Education
Gurgaon, Haryana, India
Moolchand Medcity, New Delhi, India
Editor, IJCP Group of Publication
Bhan A
Director, Cardiovascular Surgery
Arora R
Medanta: The Medcity
Chief Cardiologist
Metro Hospitals and Heart Institute
Noida, Uttar Pradesh
India
Bhandari S
Director Cardiology and Cath Labs
Asirvatham SJ Escorts Heart Institute and Research Centre
Consultant New Delhi, India
Division of Cardiovascular Diseases
and Internal Medicine
Division of Pediatric Cardiology Bharani A
Professor of Medicine and Pediatrics Division of Cardiology, Department of Medicine
Mayo Clinic College of Medicine, Vice Chairman, MGM Medical College and
Cardiovascular Division - Innovations Maharaja Yeshwant Rao Hospital
Program Director, EP Fellowship Program Indore, Madhya Pradesh, India
Mayo Clinic, Rochester, MN, USA
Bhargava B
Bahl A Professor of Cardiology
Assistant Professor, Department of Cardiology Cardiothoracic Sciences Centre
Postgraduate Institute of Medical Education Executive Director
and Research Stanford India Biodesign Centre
Chandigarh, India AIIMS, New Delhi, India
viii Textbook of Cardiology: A Clinical and Historical Perspective
Bhatnagar A Chopra HK
Sr. Consultant Cardiologist
Moolchand Medcity, New Delhi
Bhat KSS
Chairman, WHA, WWF
Consulatant Cadiologist and Director
Editor, Book on Heart Protection
Clinical Cardiology
Formerly Editor, Indian Heart Journal
Manipal Heart Institute and Heart Lung Clinic
Journal of Indian Academy of Echocardiography
Bengaluru, Karnataka, India
Vice President
JROP Institute of Echocardiography and National CSI
C Venkata S Ram
Director, Texas Blood Pressure Institute
Director, Medical Education and Chouhan NS
Clinical Research, DNA Consultant Interventional Cardiologist
Clinical Professor of Internal Medicine Medanta: The Medicity
University of Texas Southwestern Medical School Gurgaon, Haryana, India
Global Liason
American Society of Hypertension
Dallas, Texas, USA Cruickshank JM
Consultant Cardiologist
Chaddha V Madingley Hall
Consultant Fetal and Genetic Medicine Cambridge University, Cambridge, UK
Moolchand Medcity
New Delhi, India
Chahal NS Das MK
Cardiology Specialist Registrar Consultant Interventional Cardiologist
Northwick Park Hospital, UK BM Birla Heart Research Institute
Kothari Medical Centre and Calcutta
Medical Research Institute
Kolkata, West Bengal, India
Chandra KS
Additional Professor Deb PK
Department of Cardiology Consultant Cardiologist
Nizam’s Institute of Medical Sciences ESI Hospital
Punjagutta, Hyderabad, India Manciktolla, Kolkata
President Elect., National CSI
Chandra P
Chairman
Division of Interventional Cardiology Deedwania PC
Medanta: The Medicity Chief, Cardiology Division
Gurgaon, Haryana, India VACCHCS/UCSF, Fresno, Ca, USA
Professor of Medicine, UCSF School of Medicine
San Francisco, Ca, USA
Chatterjee A Director of Cardiovascular Research
Consultant Cardiologist UCSF Program, Fresno, Ca, USA
Rabindranath Tagore Clinical Professor of Medicine
International Institute of Cardiac Sciences Stanford University
Kolkata PaloAlto, Ca, USA
Choo WK
Specialty Registrar in Cardiology Deepesh R
Basildon University Hospital Registrar Cardiology
Basildon SS16 5NL, UK Westfort Hi-Tech Hospital Pvt. Ltd.
Contributors ix
Deshpande NV Hage FG
Director Cardiac Cath-Lab Section of Cardiology
Spandan Heart Institute and Research Center Birmingham Veteran’s Administration Medical Center
Nagpur, Maharashtra, India Birmingham, AL
Dhir U Hegde BM
Associate Consultant Editor-in-Chief
Medanta Heart Institute Journal of the Science of Healing Outcomes
The Medcity, Gurgaon, Haryana, India Emeritus International Adviser
Royal Colleges of London and Edinburgh, UK
Enas AE
CEO and Founder President
Henkin Y
Coronary Artery Disease among Asian
Associate Professor of Cardiology
Indians (CADI) Research Foundation
Cardiology Department
Illinois, USA
Soroka University Medical Center
Beer Sheva, Israel
Guha S Hotchandani R
Professor and Head Director Nephrology
Department of Cardiology Moolchand Medcity Hospital
Medical College, Kolkata New Delhi, India
West Bengal, India
Hon. Secretary, National CSI
Iyengar SS
Consultant and Head, Department of Cardiology
Gulati P Manipal Hospital
Director Bengaluru, Karnataka, India
Dr Gulati Imaging Institute
Director, Imaging Pushpanjali Crosslay Hospital
New Delhi, India
Iyer KS
Director
Pediatric and Congenital Heart Surgery
Gupta R Fortis-Escorts Heart Institute
Director, JROP Health Care New Delhi, India
Senior Consultant Cardiologist, Max Hospital
Editor
Journal of Indian Academy of
Jain P
Echocardiography
Principal Consultant Cardiologist and Head
Associate Editor
Department of Preventive and
Indian Heart Journal (IHJ)
Rehabilitative Cardiology
New Delhi, India
Fortis-Escorts Heart Institute
New Delhi, India
Gupta S Jain V
Consultant Cardiologist Consultant Cardiologist
Whipps Cross and St. Bartholomews Hospitals Choithram Hospital, Indore
London, UK Madhya Pradesh, India
x Textbook of Cardiology: A Clinical and Historical Perspective
Jariwala P Kaushal S
Professor and Head, Pharmacology
Jaswal A Hero DMC Heart Institute
Senior Consultant Cardiologist Dayanand Medical College and Hospital
and Electrophysiologist Ludhiana, Punjab, India
Escorts Heart Institute and Research Centre
New Delhi, India
Khaira A
Consultant Nephrologist
Moolchand Medcity Hospital
Kapoor PM
Delhi, India
Additional Professor
Department of Cardiac Anaesthesiology
CN Centre
All India Institute of Medical Sciences (AIIMS)
New Delhi, India
Khanna NN
Senior Consultant Interventional Cardiology
Kapur KK Senior Consultant Vascular Interventions
Senior Consultant Cardiologist Coordinator - Vascular Services
Indraprastha Apollo Hospital Advisor - Apollo Group of Hospitals
New Delhi, India Indraprastha Apollo Hospitals
Karmakar RN
Kohli V
Kasliwal RR Director, Cardiac Surgery
Chairman, Clinical and Preventive Cardiology Medanta Heart Institute
Editor: Journal of Clinical and Gurgaon, Haryana, India
Preventive Cardiology (JCPC)
Medanta: The Medcity, Gurgaon
Haryana, India
Kohli V
Katariya K
Director, Delhi Child Heart Center and
CEO and MD
Senior Consultant
Cardiothoracic Surgeon
Department of Pediatric Cardiology
Oncor Healthcare Pvt. Ltd.
Indraprastha Apollo Hospital
New Delhi, India
Katikireddy CK
Clinical Fellow, Cardiovascular Division
Stony Brook University Medical Center
Stony Brook, NY, USA Kort S
Professor of Medicine
Director, Noninvasive Cardiac Imaging
Director, Echocardiography
Kaul U Stony Brook University Medical Center
Executive Director and Dean Cardiology New York, USA
Fortis Escorts Heart Institute and
Fortis Vasant Kunj
New Delhi, India Krishan K
Consultant Cardiac Surgeon
Department of Cardiothoracic Surgery
Kaur H Medanta: The Medcity
Associate Professor Gurgaon
Medicine Department Haryana, India
Contributors xi
Krishna BA Late Sharma KB
Chief and Consultant Formerly, Regional Advisor
Department of Nuclear Medicine Health Laboratory Services, WHO/SEARO
PD Hinduja National Hospital New Delhi, India
and Medical Research Centre Deputy Director General Health Services
Mumbai, Maharashtra, India Govt. of India, New Delhi, India
Dean
Maulana Azad Medical College
New Delhi, India
Krishna CK
Senior Fellow
Department of Cardiology and Medicine
Moolchand Medcity Mahapatra GN
New Delhi, India Consultant
Department of Nuclear Medicine
Fortis Raheja hospital and
Bhatia General Hospital
Raju PK Mumbai
Dean of Medical Studies
Chairman, Care Foundation and
Telemedical Services
Hyderabad, Andhra Pradesh, India
Maheshwari S
Senior Consultant Pediatric Cardiologist
RXDX and Narayana Hrudayalaya
Kumar A Bengaluru, Karnataka, India
Professor and Head of Cardiology Department
Government Medical College
Amritsar, Punjab, India Makhija A
Associate Consultant Cardiologist
Department of Cardiology
Sir Ganga Ram Hospital
Kumar S New Delhi, India
Professor
Department of Medicine (Division of Cardiology)
Vivekananda Institute of Medical Sciences
Malhotra R
Kolkata, West Bengal, India
Associate Director
Chief Co-ordinator
Medanta Heart Institute
(Academic Services – Cardiology)
The Medcity, Gurgaon
Rabindranath Tagore International Institute
Haryana, India
of Cardiac Sciences, Kolkata, West Bengal, India
Kuppuswamy V Malik M
Specialist Registrar Resident
Basildon and Thurrock University Hospital Department of Dermatology
NHS Trust Lady Hardinge Medical College
Basildon New Delhi, India
Essex SS16 5NL, UK
Manchanda SC
Lal P Senior Consultant Cardiologist
Director, Interventional Cardiology Sir Ganga Ram Hospital, New Delhi
Metro Hospitals and Heart Institute Formerly, HOD Department of Cardiology
Noida, Uttar Pradesh, India AIIMS, New Delhi, India
Awarded Padma Bhushan Editor
Padma Vibhushan and Dr BC Roy National Award Journal of Preventive Cardiology
xii Textbook of Cardiology: A Clinical and Historical Perspective
Manjuran RJ Mendiratta V
Head, Department of Cardiology and Director Professor
Pushpagiri Heart Institute Department of Dermatology
Formerly National President of CSI Lady Hardinge Medical College
Kerala, India New Delhi, India
Rourke MO’
Manoria P
Professor
Chief Interventional Cardiologist
University of New South Wales/
Manoria Heart Care and Intervention Center
Victor Chang Cardiac Research Institute
Bhopal, Madhya Pradesh, India
and St. Vincent’s Clinic, Australia
Manoria P
Clinical Assistant
Jaipur Golden Hospital Mishra S
New Delhi, India Senior Interventional Cardiologist
Additional Professor of Cardiology
AIIMS, New Delhi, India
Manoria PC
Director
Manoria Heart Care and Intervention Center
Bhopal, Madhya Pradesh, India Mishra YK
Formerly, National President, CSI Director, Department of Cardiovascular Surgery
Fortis Escorts Heart Institute
New Delhi, India
Mathur MR
Research Fellow Mohan V
Public Health Foundation of India and SGRD Medical Institute
Doctoral Student Amritsar, Punjab, India
University College
London, UK Mohanan PP
Director and Head of Department Cardiology
Westfort Hi-Tech Hospital Pvt. Ltd.
Mehrotra R
Medanta: The Medcity Mukherjee S
Mullasari AS
Director - Cardiology
Mehta NP Institute of Cardio-Vascular Diseases
Senior Registrar Madras Medical Mission
Jaslok Hospital Chennai, Tamil Nadu, India
Mumbai, Maharashtra
India Nahar U
Associate Professor
Department of Histopathology
Postgraduate Institute of Medical Education
Mehta S and Research, Chandigarh, India
Associate Clinical Professor of Medicine
Miller School of Medicine Namasivayam M
University of Miami Faculty of Medicine
Florida, USA University of New South Wales
Course Director, Lumen Sydney, Australia
Contributors xiii
Nanda NC Parikh A
Distinguished Professor of Medicine and Resident, Department of Cardiology
Cardiovascular Disease Nanavati Heart Institute
Director, Heart Station/ Mumbai, Maharashtra, India
Echocardiography Laboratories
University of Alabama Patel A
Birmingham, Alabama, USA Assistant Professor
Director, Echocardiography Laboratory Department of Medicine
The Kirklin Clinic MGM Medical College
University of Alabama Health Services Foundation, Indore, Madhya Pradesh, India
Birmingham, Alabama, USA
Editor in Chief, Echocardiography
Founding President, American Association of Cardiologists of
Indian Origin Pathak LA
Head, Department of Cardiology
Nanavati Heart Institute
Mumbai, Maharashtra, India
Nath RK
Dr Ram Manohar Lohia Hospital
New Delhi, India
Prabhakaran D
Executive Director
Centre for Chronic Disease Control
Executive Director
Initiative for Cardiovascular Health Research
Padmavati S in the Developing Countries
President, All India Heart Foundation Prof. Chronic Disease Epidemiology
New Delhi Public Health Foundation of India
Prakash A
Associate Professor of Medicine
Pain P Lady Hardinge Medical College and
Resident, Department of Cardiology Smt. Sucheta Kriplani Hospital
Nanavati Heart Institute New Delhi, India
Mumbai, Maharashtra, India
Prasad SG
Pancholia AK Chief of Telemedicine
Head Care Foundation
Department of Clinical and Hyderabad, Andhra Pradesh, India
Preventive Cardiology
Arihant Hospital and RC Gokuldas Heart Hospital
Indore, Madhya Pradesh, India
Raghothaman S
Parakh N Assistant Professor of Cardiology
Assistant Professor of Cardiology Madras Medical College and
GB Pant Hospital Government General Hospital
New Delhi, India Chennai
Tamil Nadu, India
Parashar SK
Chief Cardiologist Rao BH
Metro Heart Institute Senior Consultant Cardiologist and
New Delhi, India Electrophysiologist
Formerly, National President, CSI Care Hospitals, Hyderabad
President, JROP Institute Echocardiography Andhra Pradesh, India
xiv Textbook of Cardiology: A Clinical and Historical Perspective
Ray S Shah SN
Professor and Senior Consultant Consulting Physician and Diabetologist
Interventional Cardiologist Bhata Hospital, SL Raheja Hospital
Vivekananda Institute of Medical Sciences HN Hospital, Saifee Hospital
Kolkata, West Bengal, India Mumbai, Maharashtra, India
Saini L
Sr. Consultant Radiologist
Gulati Imaging Institute Shah VK
New Delhi, India Interventional Cardiologist
Sir HN Hospital and Research Centre
Sambi RS Mumbai, Maharashtra, India
Senior Fellow
National Heart Institute
Shalia KK
New Delhi, India Research Scientist
Sir HN Medical Research Society
Sir HN Hospital and Research Centre
Sawhney JPS Mumbai, Maharashtra, India
Chairman
Sir Ganga Ram Hospital Sharma MK
New Delhi, India DNB (Senior Resident) Cardiology
Sir Ganga Ram Hospital
New Delhi, India
Sahgal V
Professor of Medicine
Case Western University School of Medicine Sharma V
University Hospitals Case Medical Center Vice CEO and Head, Cardiology Services
National Heart Institute
New Delhi, India
Sengottuvelu G
Sharma VK
Senior Consultant and
Fortis Escorts Heart Institute
Interventional Cardiologist
New Delhi
Apollo Hospitals
Chennai, Tamil Nadu, India
Shrivastava S
Senior R Associate Director
Professor of Clinical Cardiology Noninvasive Cardiology
National Heart and Lung Institute Fortis Escorts Heart Institute
Imperial College, London, UK New Delhi, India
Consultant Cardiologist and
Director of Echocardiography
Royal Brompton Hospital Sindhe P
London and Northwick Park Hospital, Harrow Postgraduate Trainee
UK (Diplomate of National Board, Medicine)
Seth A
President, National CSI
Awarded ‘Padma Shri’ Shad S
Chief Cardiologist and Senior Consultant Cardiac Surgeon
Chairman, Cardiology Council Director Heart Transplant
Fortis Group of Hospitals, New Delhi Sir Ganga Ram Hospital, New Delhi
Contributors xv
Singh MM Upasani PT
Chief Cardiologist Senior Interventional Cardiologist
Punjab Institute of Heart Diseases Metro Hospitals and Heart Institute
Amar Hospital, Patiala Noida, Uttar Pradesh, India
Punjab, India
President, Punjab Medical Council Vikranth V
Manipal Heart Institute and Manipal Hospitals
Sinha AK
Bengaluru, Karnataka, India
Magadh Hospital, HMRI, Cardiac Care
Patna, Bihar, India Veeranna V
Dept of Cardiology and Internal Medicine
Wayne State, University of Detroit
Michigan, USA
Somasundaram M
Venugopal K
Formerly Professor of Cardiology
Madras Medical College and
Amrita Institute of Medical Sciences
Government General Hospital
Cochin, Kerala, India
Verma RK
Srikanth S
Medical Specialist
Civil Hospital, Sehore
Srivastava S Madhya Pradesh, India
Director
Pediatric and Congenital Heart Disease
Fortis Escorts Heart Institute Vijayalakshmi IB
New Delhi Professor of Pediatric Cardiology
Sri Jayadeva Institute of Cardiovascular
Subban VK Sciences and Research
Consultant Cardiologist Bengaluru, Karnataka, India
Institute of Cardiovascular Diseases
Madras Medical Mission
Wander GS
Talwar KK
Professor and Head of Cardiology
Formerly Director, Professor and Head
Dayanand Medical College and Hospital
Punjab, India
Postgraduate Institute of Medical Education
and Research, Chandigarh, India
President, Medical Council of India
Wardhan H
Tewari S Head, Department of Cardiology
Additional Professor Dr Ram Manohar Lohia Hospital
Department of Cardiology New Delhi, India
Sanjay Gandhi Postgraduate Institute
of Medical Sciences
Lucknow, Uttar Pradesh, India
Trehan N Yadava OP
Chairman CEO and Chief Cardiac Surgeon
Medanta: The Medcity National Heart Institute
Gurgaon, Haryana, India New Delhi, India
Preface
The textbook provides an insight into the clinical perspectives of cardiology and at the same time dwells into the
historical aspects highlighting the evolution of various discoveries, innovations and therapies in cardiology from their
first introduction to the present. We salute and pay tribute to all the pioneers and fathers of cardiology who have served as
a source of inspiration to all of us in the pursuit of not only excellence but also compassion in patient care. These masters
have contributed enormously to the understanding diagnosis and management of various cardiac disease entities. It is
interesting to note that some of these discoveries and innovations were completely serendipitous, while others resulted
from relentless efforts and amazing perseverance and tenacity in the face of frustrations, failed experiments and ridicule
from peers. Also, some of the previously discarded concepts and therapies have come into vogue again! Many of the
advances in cardiology have occurred because of cooperation among basic scientists, pathologists, clinical researchers
and bedside clinicians resulting in patient management based on sound basic investigations. Both bench research
and clinical trials are ongoing and never ending leading to ever-changing diagnostic and management guidelines
and decisions and preventive strategies which promise to provide the best in patient care. It is thus imperative to keep
abreast of all the current trends, emerging issues and the newest advances and this book amply fulfills that need. All
the chapters are written by experts, who are well-known in their fields and they have provided the most up-to-date
available information. This book will, therefore, be of interest to not only practicing cardiologists, cardiac surgeons,
pediatric cardiologists, cardiac anesthetists but also to fellows and residents in training and research institutions,
medical students and paramedical personnel as well as medical practitioners of all specialties to whom it will serve as
a useful reference guide.
The book is organized into several sections dealing with clinical cardiology, noninvasive cardiology, interventional
cardiology, cardiac surgery and the future frontiers. The section on clinical cardiology begins with various chapters
dealing with preventive, diagnostic and management aspects of coronary artery disease and myocardial infarction.
Epidemiology and risk factors, such as diet, physical activity, tobacco use, obesity, stress, homocysteine, dyslipidemia
and hypertension and their interrelationships are described. Management issues including the role of agents like
aspirin, statins, polypill, nitrates, carotenoid lycopene, beta blockers and calcium-channel blockers. ACE inhibitors
and ARBS are extensively discussed. Evolving concepts in acute coronary syndrome and medical management of acute
myocardial infarction are also covered with a full discussion of anticoagulants and antithrombotic and antiplatelet
agents. Next, various types of cardiomyopathies, myocarditis and pericarditis are delineated in detail as well as a full
coverage of antiarrhythmic drugs. Other chapters cover various facets of cardiac syncope, sudden cardiac death and
cardiopulmonary resuscitation. The pros and cons of the use of enhanced external counter pulsation technique are also
given. Deep vein thrombosis, pulmonary embolism and newer therapies in the treatment of pulmonary hypertension
are also covered. Other important chapters deal with rheumatic heart disease, cardiocutaneous diseases, congenital
heart disease and cardiac rehabilitation.
The second section of the book deals with noninvasive cardiology. The evolution of echocardiography as the most cost-
effective noninvasive tool in cardiac assessment is described in this section which also covers stress echocardiography,
myocardial contrast echocardiography, role of echocardiography in catheter interventions in congenital heart disease
as well as echo evaluation of tricuspid and pulmonary valves. Other chapters deal with nuclear cardiology, cardiac
magnetic resonance, computed tomography, fetal cardiology and telemedicine in cardiology.
The third section of the book deals with the important topic of interventional cardiology. Topics which are covered in
this section include coronary intervention, left main percutaneous coronary intervention, interventions using the radial
artery approach, intravascular ultrasound, saphenous venous graft angioplasty and peripheral vascular interventions.
Wide QRS tachycardias, catheter ablation and cardiac resynchronization therapy are also prominently detailed. The
use of intracardiac echocardiography in various interventions performed in the cardiac catheterization laboratory
is also included in this section. The next section deals with all aspects of cardiac surgery. Surgery for ischemic heart
disease, valve surgery, aortic surgery, robotically assisted cardiac surgery, surgery for congenital heart disease and
xviii Textbook of Cardiology: A Clinical and Historical Perspective
cardiac transplantation are covered by well-known experts. The last section points to expected refinements and future
developments in cardiology, such as stem cell therapy, newer thrombolytics, new frontiers in balloon valvotomy and
cardiac transplantation and artificial hearts. There is no question of newer developments are occurring at a very rapid
pace and crystal gazing into the future points to exciting prospects.
We are most grateful to all the well-known experts in cardiology and cardiac surgery who have taken valuable time
from their busy schedule to contribute to this work. We are also most thankful to Drs Sambi RS, and Krishna CK, and
Dianne Blizzard and Lindy Chapman from the University of Alabama, Birmingham, USA for providing valuable editorial
assistance.
H K Chopra MD
Navin C Nanda MD
Editors
Acknowledgments
We express our gratitude and thanks to all our contributors for their help and support especially Dr S Padmavati,
Dr Naresh Trehan, Dr SC Manchanda, Dr Savitri Srivastava, Dr U Kaul, Dr SK Parashar, Dr RJ Manjuran,
Dr Ashok Seth, Dr Ramesh Arora, Dr VK Bahl, Dr Amal Banerjee, Dr PK Deb, Dr Santanu Guha, Dr OP Yadava, Dr Ravi
R Kasliwal, Dr KK Aggarwal and Dr Rakesh Gupta for their constant advice and guidance.
We also express our thanks to the M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, including
Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Managing Director), Mr Tarun Duneja (Director-Publishing) and
Ms Samina Khan (PA to Director-Publishing) for their help, guidance and timely active intervention.
We also express our thanks to Soban Singh for working hard for helping in timely publication of this book.
H K Chopra MD
Navin C Nanda MD
Contents
SECTION 1: CLINICAL CARDIOLOGY
1. Development of Cardiology in India: Are We on the Right Track?________________________________________ 3
Padmavati S
Cardiac Society and Foundation 3
Funding of Health Care 3
Preventive Programs 3
Research 4
Lack of International Recognition 4
2. History of Thrombolysis______________________________________________________________________________ 5
Chopra HK, Sambi RS, Krishna CK
Development of Thrombolytic Therapy 5
Advantages of Newer Agents Over the Older Agents 8
Trends in Thrombolysis 8
3. Epicardial Reperfusion______________________________________________________________________________ 10
Importance of Epicardial Reperfusion 10
No-Reflow Phenomenon 10
Measures of Epicardial Reperfusion 11
Reperfusion Strategies 12
4. History of Beta-Blockers_____________________________________________________________________________ 15
Cruickshank JM
The Very Early Days 15
The Pharmacology and Adverse Reactions of Different β-Blockers 15
Coronary Artery Disease; Peripheral Arterial Disease; Arrhythmias; The Atheromatous Process 21
Beta-Blockers in Hypertension 23
Beta-Blockers and Heart Failure 26
Other Indications 28
5. History of Antithrombotics Agents____________________________________________________________________ 31
Jariwala P, Chandra KS
Antiplatelet Agents 31
Anticoagulants 38
Thrombolytic Agents 45
6. History of Statins____________________________________________________________________________________ 49
Manchanda SC, Makhija A, Sharma MK
The Discovery of Compactin—Initial Molecule 49
Mechanism of Action 50
Pharmacology 50
Adverse Effects and Drug Interactions 50
Safety Results 52
Current Indications of Statins 52
Statin Trials—Primary Prevention 52
Statin Trials—Stable Coronary Heart Disease 55
xxii Textbook of Cardiology: A Clinical and Historical Perspective
Statin Trials—Acute Coronary Syndromes 55
Utility of Statins in Special Populations 56
Statins in Combination with Other Lipid-Lowering Drugs 56
Which Statin and What Dose to Start with—Indian Scenario 56
Future Directions 57
7. History of Angiotensin Receptor Blockers_____________________________________________________________ 59
Pancholia AK, Jain V, Tewari S
The Angiotensin II Receptor 59
Functions beyond Hypertension Control 60
The Renin-Angiotensin Cascade and Angiotensin II Receptor Subtypes 61
Development of Saralasin 61
Development from Losartan to Other Drugs 62
The ARB Controversy—Myocardial Infarction 62
Cardiovascular Protection—A Breakthrough for High-Risk Patients 62
The New Challenge—ARBs as a Cancer Risk Factor 65
Time Line of Landmark Trials with ARBs 65
ARBs Under Development 65
Selected Abbreviations and Acronyms 65
8. History of Heparin and Cardiovascular Disease Protection_____________________________________________ 68
Banerjee AK, Ray S
Early Days 68
Research Escalates 68
Heparin in Clinical Domain 69
Postwar Resurrection 69
Procreation 70
Heparin in Cardiovascular Disease 70
Sibling Rivalry 71
Epilogue 71
9. History of ACE-Inhibitors____________________________________________________________________________ 73
Sawhney JPS
10. Antibiotics in Cardiology____________________________________________________________________________ 76
Sharma KB
Emerging Relationships of Infections and the Cardiovascular System 76
Cardiovascular Infections 76
Acute Rheumatic Fever 76
Infective Endocarditis 77
11. Polypill in Cardiovascular Disease: Current Evidence and Future Promises______________________________ 80
Kuppuswamy V, Choo WK, Gupta S
Current Strategies in Reducing Cardiovascular Risk 80
The Birth of Polypill 80
Failure of Current Preventive Strategies 81
Components of a Polypill 82
Polypill in Primary Prevention 85
Polypill in Secondary Prevention 85
Limitations of the Polypill 85
12. The History of Acute Coronary Syndrome_____________________________________________________________ 87
Bansal M, Mehrotra R, Kasliwal RR
Anatomy and Physiology of Circulation 87
Understanding the Pathophysiology of Acute Coronary Syndrome 88
Contents xxiii
Evaluation of Acute Coronary Syndrome 89

Management of Acute Coronary Syndrome 90
13. History of AMI: A Saga of Transition from Tortoise Walks to Rabbit Run_________________________________ 92
Chouhan NS, Chandra P
Stethoscope Era 92
Era of Electrocardiography 93
Concept of Coronary Care Units 95
Pharmacotherapy Era 95
Reperfusion Era 95
Primary Angioplasty Era 96
The Platelet Inhibitors 96
Stenting Era 96
14. History of Nitrates___________________________________________________________________________________ 99
Gupta R, Mangla S, Bhatnagar A, Chopra HK, Parashar SK
History 99
Wartime Production Rates 99
Instability and Desensitization 100
Detonation 100
Manufacturing 100
Use as an Explosive and a Propellant 100
Nitroglycerin and Dynamite 101
Industrial Exposure 102
15. History of Calcium Channel Blockers________________________________________________________________103
Guha S, Mukherjee S, Karmakar RN
16. Antiplatelet Therapy—History and Future Trends, with Special Reference to Prasugrel__________________107
Singh M, Sharma V, Singh A
Historic Milestones in Antiplatelet Therapy 107
Classification of Antiplatelet Drugs 107
Pathophysiology of Atherothrombosis—Role of Platelets 107
Antiplatelet Therapy 109
ADP Receptor Blockers—Thienopyridines 109
Glycoprotein IIA/IIIB Receptor Blockers 110
Novel Drugs—Special Reference to Prasugrel 110
Prasugrel 110
Future Trends 111
17. History of Antiarrhythmic Drugs____________________________________________________________________113
Wander GS, Kaushal S
Quinidine 113
Procainamide 113
Lidocaine 114
Phenytoin 114
Sparteine 114
Ajmaline 115
Moricizine 115
Bretylium 115
Amiodarone 115
Flecainide and Others 115
β-Blockers 116
Calcium Blockers 116
xxiv Textbook of Cardiology: A Clinical and Historical Perspective
Atropine and Others 116
Classification 117
Recent Studies 117
18. Enhanced External Counterpulsation and Its Clinical Applications____________________________________120
Chopra HK, Krishna CK, Sambi RS, Aggarwal KK, Parashar SK, Manjuran RJ, Gupta R, Bansal M,
Kasliwal RR, Mittal S, Srivastava S, Nanda NC
Historical Background and Development 120
Researchers in the 1970s and Late 1980s 121
What is the Principle of Mechanism? 127
Enhanced External Counterpulsation 127
What are the Effects of EECP? 128
What are the Indications? 128
What are the Contraindications? 128
19. Lycopene and Related Tomato Carotenoids in Coronary Heart Disease_________________________________130
Henkin Y
Bioavailability and Absorption of Lycopene 130
Role of Oxidation in the Pathogenesis of Coronary Heart Disease 131
Antioxidant Properties of Lycopene 131
Additional Potential Mechanisms for Inhibition of Atherosclerosis by Lycopene 131
Epidemiological Studies 132
20. History of Oils, Fats and Coronary Heart Disease_____________________________________________________135
Jain P
The Beginnings 135
Protein Toxicity Versus Lipid Hypothesis 135
Observations in Familial Hypercholesterolemia 135
Diet and the Heart 136
A Note on the Saga of Trans-Fats 138
21. History of Cardiac Fitness___________________________________________________________________________140
Somasundaram M, Raghothaman S
History of Cardiac Fitness Programs 140
Rehabilitation/Maintaining Fitness after Discharge 142
Aerobics for Cardiac Fitness—Its History 143
Other Advantages of a Fit Lifestyle—History of Its Discovery 144
22. History of Blood Pressure and Its Measurement______________________________________________________147
Hegde BM
The Beginning 147
Later Developments 148
What is The Future? 148
23. History of Blood Pressure Amplification between the Heart and Peripheral Arteries_____________________149
Rourke MO’, Adji A, Namasivayam M
24. The History of Cardiac Rehabilitation: An Evolutionary Perspective____________________________________156
Sahgal V
Prehistoric 156
Modern Times 157
25. A Brief Historical Chronicle of Hypertension_________________________________________________________160
C Venkata S Ram
Systemic Hypertension as a Risk Factor for the Global Disease Burden 160
Hypertension and Target Organ Damage 160
History of Blood Pressure Measurement 162
Contents xxv
Reducing the Burden of Cardiovascular Disease 163

History of Anti-Hypertensive Drugs—From Reserpine to Aliskiren 163
26. History of Risk Factor Stratification of Hypertension__________________________________________________168
Mehta NP, Shah SN
United States Guidelines (1977–2003) 168
Indian Hypertension Guidelines (2001–2007) 171
World Health Organization/International Society of Hypertension Guidelines (1986–2003) 173
European Society of Hypertension (ESH) and European Society of Cardiology (ESC) Guidelines—
(2003–2007) 176
British Hypertension Society Guidelines (1989–2004) 178
27. Retracing the Heroic Steps from Lipid Hypothesis to Aggressive Treatment
of Blood Cholesterol—A Revolution in Preventive Cardiology_________________________________________180
Enas EA, Kuruvila AT, Lulla S
Atherosclerotic Cardiovascular Disease 180
Cardiovascular Epidemic and Cholesterol Wars 180
Nicholai N Anitschkow—The Father of Atherosclerosis 180
The Lipid Hypothesis 182
Genetic Evidence of High Cholesterol Producing Heart Attacks in Children 182
Familial Hypercholesterolemia 182
Goldstein Brown and LDL Receptor 182
Cholesterol-Year Score and Coronary Atherosclerosis 183
John Gofman—The Father of Clinical Lipidology 183
LDL-C and Lipoproteins 183
Oxidized LDL 184
Low HDL—The Body Armor against Atherosclerosis 184
Lipoprotein (A)—A Dangerous Genetic Variant of LDL 184
Donald Fredrickson and Classification of Lipoproteins 184
How High is High Blood Cholesterol? 184
Ancel Keys and International Comparison of Cholesterol Levels 185
The Framingham Heart Study—The Mother of All Epidemiological Studies 185
Diet-Heart Disease Versus Diet-Blood Cholesterol-Heart Disease Paradigm 185
Impact of Dietary Cholesterol on Blood Cholesterol 185
Cholesterol Agnostics 186
Dietary Intervention Trials 186
Dramatic Reduction in Blood Cholesterol with Intestinal Bypass Surgery 187
How to Lower the Blood Cholesterol? 188
Jeremiah Stamler and American Heart Association (AHA) 188
Lipid Research Clinics 189
LRC-CPPT (Coronary Primary Prevention Trial) 189
The 1984 NIH Consensus Development Conference 190
The National Cholesterol Education Program 190
Akira Endo and the Era of Statins—The Underused Wonder Drugs 190
Statin Mega Trials and Revolution in Preventive Cardiology 191
Blood Cholesterol, Stroke and Statins 191
How Safe are Statins? 191
How Low is Low LDL-C? 191
Does Low Cholesterol Increase Non-CVD Mortality? 192
When to Start LDL-C Lowering Therapy? 192
28. Past, Present and Future of Cardiovascular Dysmetabolic Syndrome___________________________________195
Srikanth S, Deedwania P
Historical Perspective 195
xxvi Textbook of Cardiology: A Clinical and Historical Perspective
Evolution of the Definition 195
Prevalence 196
Clinical Implications 197
Understanding Pathophysiology of CDS 197
Identification 199
Therapy 200
Lifestyle Modification 200
Pharmacological Options 201
Surgical Management 205
Current Controversies and Future Direction 205
29. History of Obesity and Cardiovascular Disorder______________________________________________________209
Manoria PC, Pankaj M, Verma RK, Manoria P
Obesity and Relation with Various Diseases 209
Different Body Shapes and Obesity Risk 209
Obesity and Syndrome X 210
Treatment of Obesity in the Early Days 210
The Situation Today 210
30. History of Dilated Cardiomyopathy__________________________________________________________________211
Bahl A, Nahar U, Talwar KK
Dilated Cardiomyopathy 211
The Genetics of Dilated Cardiomyopathy 212
Treatment 212
31. History of Hypertrophic Cardiomyopathy____________________________________________________________215
Parakh N, Bhargava B
The First Citation 215
History before History 216
The Journey after Teare 216
The First Surgery 216
Journey to Golden Jubilee 216
32. History of Restrictive Cardiomyopathy_______________________________________________________________219
Venugopal K
The Enigma of Endomyocardial Fibrosis 219
Geographical Distribution 219
History of Endomyocardial Fibrosis 219
Endomyocardial Fibrosis in India 220
Cardiac Amyloidosis 220
Other Infiltrative and Storage Disorders 221
33. Peripartum Cardiomyopathy_______________________________________________________________________224
Deshpande NV
Epidemiology 224
Etiology and Pathogenesis 224
Clinical Presentation 225
Management 225
Natural History and Prognosis 226
34. History and Clinical Implications of Myocarditis and Pericarditis______________________________________229
Tewari S, Jain V, Pancholia AK
Myocardium 229
Myocarditis 229
Etiology 229
Contents xxvii
Pathogenesis 230
Clinical Presentation 231
Diagnostic Evaluation 231
Natural History and Prognosis 232
Treatment 232
Pericarditis 233
Pericardial Effusion 234
Laboratory Investigations 235
35. History of Infective Endocarditis and Future Directions_______________________________________________238
Sankardas MA, Subban VK
Historical Perspective 238
Pathophysiology of Endocarditis—Infectious or Inflammatory 239
Birth of Blood Culture 239
Experimental Reproduction of Endocarditis 240
Classification of Endocarditis 240
Antibiotic Era 241
Antibiotic Prophylaxis 241
Echocardiography and Infective Endocarditis 241
Diagnostic Criteria 241
Current Trends and Future Challenges 241
New Developments 242
36. The History of Deep Vein Thrombosis and Pulmonary Thromboembolism______________________________244
Deb PK, Chatterjee A
Etiology 244
Clinical Picture 245
Investigations 245
Medical Management 246
Surgical Management 247
Prevention 247
Epilogue 247
37. Lessons Learnt from History of Rheumatic Heart Diseases____________________________________________249
Vijayalakshmi IB
History in the 18th Century 249
Rheumatism’s New Face 251
Death From Acute Rheumatism: A New Outcome 251
Wells and “Rheumatism of the Heart” 252
Acute Rheumatism Changes again with Chorea 253
Patients and Doctors 253
Social Setting of Acute Rheumatism 255
Therapy for Rheumatism in the Early 19th Century 255
History of Drugs in Acute Rheumatic Fever 256
Treatment for Congestive Heart Failure 257
Molecular Biology 258
Adrenocorticotropic Hormone and Cortisone 258
Penicillin 259
Inadequacy of Public Health Programs 261
Sorting Out Therapy 262
xxviii Textbook of Cardiology: A Clinical and Historical Perspective
Variation of Virulence of Strains in a Single M Type 263
The Return of Rheumatic Fever and Invasive Gas Disease 264
Experimental Studies of the Capsule’s Relation to Adherence, Epithelial Internalization, Colonization and
Mucosal Invasion 264
Surgery for Rheumatic Fever 264
38. History of Pediatric Cardiology: From the “Untouchable” Heart to the Brave New Era___________________270
Maheshwari S, Kiran VS
Legacy of a Young Branch 270
Prehistoric Era—Babylonian Clay Tablets 270
The Contributions from Greece—Galen 270
Renaissance Period—Leonardo Da Vinci 270
European Contribution—Steno and Tetralogy 271
Masterpiece Work—Morgagni 271
Account of a Blue Boy—Sandifort 271
Cyanotic Spells—Hunter 272
The Debate on Cyanosis—19th Century Europe 272
Works of a Seer—Sir Thomas Bevill Peacock 273
Cardiac Septal Defects—Rokitansky 273
Tetralogy Defined—Fallot 273
The Godmother Arrived 274
Mother of Pediatric Cardiology 274
Tombstone of Paget’s Views 275
Surgical Victory over the Arterial Duct—Robert Gross 275
New Ideas, New Directions 275
Success of Teamwork—Alfred Blalock and Vivien Thomas 276
Lateral Thinking—Other Paths for Tetralogy of Fallot Palliation 277
Structuring Pediatric Cardiology—Fellowship Programs 277
New Angles to Diagnosis—Catheterization Techniques 277
Conquering Valvular Lesions—Percutaneous Techniques 278
Devising the Devices—The Amplatzer Era 278
From No One’s Child to A World Class Entity—Progress to World Congress 278
Dreams of Correction—Evolution of Definitive Surgery 278
Heart-Lung Machine—Saga of Gibbon 279
Story of a Single Pump—Glenn and Fontan 279
Changing Hearts—Quest for Pediatric Heart Transplants 280
Other Correlations—Genetics, Therapeutics, Nosology and Epidemiology 281
The Future: Dare to Try—No Star is Too High! 281
39. History of Pulmonary Embolism____________________________________________________________________283
Pathak LA, Pravin P, Parikh A
Pathogenesis of Pulmonary Embolism 283
Diagnosis of Deep Venous Thrombosis and Pulmonary Embolism 283
Management of Pulmonary Embolism 285
40. History of Stroke in Cardiac Patients_________________________________________________________________289
Patel A, Bharani A
Hypertension and Stroke 291
Myocardial Infarction and Stroke 291
Heart Failure and Stroke 291
Mitral Stenosis and Stroke 291
Prosthetic Heart Valve and Stroke 292
Atrial Fibrillation and Stroke 292
Contents xxix
Infective Endocarditis and Stroke 292

Paradoxical Embolism and Stroke 293
41. Tobacco and Heart: A Historical Perspective_________________________________________________________296
Mathur MR, Prabhakaran D
Historical Overview of Journey of Tobacco Across the World 297
Anti-Tobacco Movements and Sentiments—A Historical Snapshot 298
A Historical Synopsis of Establishment of Relationship between Tobacco Consumption and
Cardiovascular Disease 299
Anti-Tobacco Policies—A Historical Synopsis 301
42. History of Stress and Heart Disease Relationship_____________________________________________________306
Bhat KSS, Vikranth V, Veeranna V
The Brain Heart Connection 306
43. History of Cardiorenal Connectors__________________________________________________________________314
Hotchandani R, Khaira A
History of Cardiorenal Connectors 314
44. History of Oxidative Stress and Cardiovascular Disease Protection_____________________________________321
Prakash A, Agarwal SK
History 321
45. History of Hormone Replacement Therapy and the Heart_____________________________________________325
Nath RK
Menopausal Symptoms 325
Discovery of Estrogen 326
Progesterone 326
Hormone Replacement Therapy 326
The Protective Effects of Estrogen on the Cardiovascular System 327
Hormone Replacement Therapy and Heart Disease 327
Hormone Replacement Therapy and Stroke 328
Hormone Replacement Therapy and Cancer 328
Hormone Replacement Therapy and Thromboembolic Disease 328
46. Tuberculosis and Heart_____________________________________________________________________________330
Kumar S, Sindhe P
Tuberculosis of Heart 330
Tuberculosis and Myocardium 332
Tuberculosis and Atherosclerosis 333
Tuberculosis in Heart Transplant Recipients 333
47. History of Cardiac Syncope_________________________________________________________________________336
Das MK
Historical Landmarks 336
48. History of Markers of Sudden Cardiac Death_________________________________________________________340
Sinha AK
Arrhythmias During Sudden Cardiac Death 341
Pathophysiology of SCD—How do Noninvasive Tests Help Us 342
Markers of Sudden Cardiac Death 344
Scientists Reveal The Mystery of Sudden Cardiac Death 355
Markers of SCD in Individual Patients 355
Future Direction and My Point of View 356
xxx Textbook of Cardiology: A Clinical and Historical Perspective
49. History of Women and Heart Disease________________________________________________________________359
Vinod S, Tsering TP
Clinical Assessment and Chest Pain History 360
Enormity of Coronary Artery Disease in Women in Global Context 361
Gender Differences in Selecting the Appropriate Diagnostic Test 364
Medical Management for Coronary Artery Disease in Women 366
Final Interpretation 366
50. History of Heart and Trans-Fat Relationship_________________________________________________________370
Kumar A, Kaur H, Mohan V
Chemistry 370
Sources 370
Potential Molecular Mechanisms of Cardiovascular Effects of Trans-Fatty Acids 371
History of Trans-Fat Development and Progress in Food Industry 372
Trials Showing Increased Risk of Coronary Artery Disease with Intake of Trans-Fats 372
Ban on Trans-Fats 374
51. Coronary Artery Disease and Homocysteine Relationship_____________________________________________380
Mohanan PP, Deepesh R
Homocysteine Metabolism 380
52. Savitri Satyawana: The First Described Cardiac Revival of the Vedic Times______________________________390
Aggarwal KK
International Scenario In Brief (uptodate.com) 390
53. History of Sildenafil: From Angina to Erectile Dysfunction_____________________________________________393
Shrivastava S, Sharma VK
History of Sildenafil 393
The Success Story of Sildenafil 394
Controversies 394
Expanding Uses beyond Treatment for Erectile Dysfunction 394
54. Cardiocutaneous Diseases__________________________________________________________________________396
Mendiratta V, Malik M
Genetic Disorders 396
Disorders of Keratinization 401
Autoimmune Diseases 402
Inherited Disorders of Elastin and Collagen 402
Disorders of Lipid Metabolism 403
Immunological and Infective Disorders 404
Inborn Errors of Metabolism 404
Infiltrative Disorders 405
55. ARBs and CVD Protection___________________________________________________________________________408
Ray S
History of Development of Angiotensin Receptor Blockers 408
Mode of Action of ARB 408
The Members of ARB Class 408
Role of ARB in Hypertension 409
ARB in Heart Failure 409
Post-MI Set-Up 409
Combination Therapy with ACE-I and ARB 409
ARB and Coronary Artery Disease 410
ARB and Stroke 410
ARB and Nephropathy 410
Contents xxxi
ARB and Diabetes 410

ARB and AF 410
SECTION 2: NONINVASIVE CARDIOLOGY

56. Echocardiography: A History and Perspective________________________________________________________413
Hage FG, Nanda NC
The History of Ultrasound 413
Development of Clinical Cardiac Ultrasound: A-Mode and M-Mode Echocardiography 414
Two-Dimensional Echocardiography 417
Conventional Doppler Ultrasound 417
Color Doppler Ultrasound 419
Contrast Echocardiography 420
Transesophageal Echocardiography 423
Tissue Doppler and Speckle Tracking Imaging 423
Three-Dimensional Echocardiography 423
Perspective 425
57. History of Cardiac Imaging_________________________________________________________________________432
Krishna BA
X-ray Imaging 432
Angiocardiography 432
Ultrasound Imaging 432
Two-Dimensional Echocardiography 433
Doppler Echocardiography 433
Intracardiac Intracoronary Ultrasound 433
Nuclear Imaging 433
Positron Emission Tomography 433
Computed Tomography 434
Magnetic Resonance Imaging 434
Fusion Imaging 434
58. History of Myocardial Contrast Echocardiography____________________________________________________436
Chahal NS, Senior R
Opacifying The Myocardium 436
Advances in Contrast Agents 436
Improving Microbubble Visualization 437
From Bench to Bedside 437
Quantifying Myocardial Perfusion 438
Safety of Ultrasound Contrast Agents 439
59. History of Stress Echocardiography__________________________________________________________________442
Upadhyayula S, Kapur KK
Historical Perspectives 442
Stress Echocardiography 443
Exercise-Induced Mitral Regurgitation 449
Real-Time Three-Dimensional Dobutamine Stress Echocardiography 456
Real-Time Myocardial Contrast Echocardiography + Three-Dimensional Stress Echocardiography 456
Two-Dimensional and Three-Dimensional Echocardiography in Non-Coronary Heart Diseases 456
Hemodynamic Two-Dimensional Stress Echocardiography 456
Preload Two-Dimensional Stress Echocardiography 457
Diastolic Two-Dimensional Stress Echocardiography 457
Evaluation of Cardiac Resynchronization Therapy Responders by Two-Dimensional Low-Dose Dobutamine
Echocardiography + Myocardial Contrast Echocardiography 457
xxxii Textbook of Cardiology: A Clinical and Historical Perspective
60. Role of Echocardiography in Congenital Heart Disease—Catheter Interventions________________________463
Awasthy N, Shrivastava S
Role of Echocardiography in Congenital Heart Disease—Catheter Interventions 463
Evaluation of Atrial Septum by Transesophageal Echocardiography 465
Patent Foramen Ovale 466
Patent Ductus Arteriosus 469
Percutaneous Closure of Ductus Arteriosus 470
Valvuloplasty: Pulmonary and Aortic 471
Infundibular Stenosis 474
Left Ventricular Outflow Tract Obstruction 475
Coarctation of Aorta 476
Pericardiocentesis 478
61. History of Fetal Cardiology__________________________________________________________________________480
Chadha V, Kapoor N
The History of The Four-Chamber View 480
62. Cardiac MRI: Present Status________________________________________________________________________494
Gulati P, Saini L
Applications of Cardiac MRI 495
Obstructive Disorders 497
Anatomic Disorders 498
Valvular Lesions 499
Cardiomyopathies 500
Cardiac Tumors 501
Neoplastic Diseases 505
Coronary MR Angiography 505
Transplanted Heart 506
History of MRI 508
63. History of Nuclear Cardiology_______________________________________________________________________509
Mahapatra GN
Various Nuclear Cardiology Procedures 510
64. Telemedicine and Cardiology in India_______________________________________________________________539
Raju PK, Prasad SG
History 539
Indian Scenario 540
Burden in India—Coronary Heart Disease 541
Telemedicine as a Process 542
Methodologies 542
Application Software 543
Our Experiences 545
Obstacles and Challenges 551
65. Echocardiographic Evaluation of Tricuspid and Pulmonic Valve_______________________________________553
Malhotra P
Tricuspid Valve Anatomy 553
Transesophageal ECHO Examination of The Tricuspid Valve—Different Views 555
Abnormalities of the Tricuspid Valve 558
Tricuspid Stenosis 562
Pulmonary Regurgitation 565
Pulmonary Stenosis 568
Contents xxxiii
Grading Pulmonic Stenosis 569

Historical Aspects of Echocardiography of Tricuspid and Pulmonary Valve 570
SECTION 3: INTERVENTIONAL CARDIOLOGY

66. History of Interventional Cardiology________________________________________________________________575
Bhatia V, Kaul U
The Development of Right and Left Heart Catheterization 575
Unravelling the Coronary Vasculature 576
Moving into the Peripheral and Coronary Tree 577
The Stent Era—Stents and Other Devices 578
History of Some Other Devices and Concepts 579
67. History of Saphenous Vein Grafts Intervention_______________________________________________________581
Kumar V, Rastogi V, Seth A
Nature of Vein Graft Disease and its Pathophysiology 581
68. History of Left Main Percutaneous Coronary Intervention_____________________________________________588
Mishra S, Bahl VK
69. History and Future of Coronary Angioplasties by Radial Approach_____________________________________594
Sengottuvelu G
History 594
Limitations of The Radial Approach 595
Future 595
70. History of Cardiac Interventions and Future Directions_______________________________________________597
Upasani PT, Lal P
Cardiac Catheterization 597
Angioplasty and Related Catheter Interventions 599
High-Risk Angioplasty and Related Procedures 601
Adjunctive Equipment and Therapies Used in Angioplasty 601
The Discipline of Interventional Cardiology 602
A Note of Caution 603
71. History of Catheter Ablation________________________________________________________________________605
Chen FC, Tester GA, Bisco SE, Gard JJ, Asirvatham SJ
History of The Prerequisites: Setting the Table 605
The His Bundle Electrogram 606
Surgery and Catheter Ablation 606
Supraventricular Tachycardia 606
Typical Atrial Flutter 607
Atrial Fibrillation 608
Ventricular Tachycardia 608
Past History 608
Future History 608
Summary—Back to the Future 609
72. Cardiac Resynchronization Therapy_________________________________________________________________613
Rao BH
Pacing for Heart Failure 613
The Era of Randomized Trials 613
Do All Heart Failure Patients Need Cardiac Resynchronization Therapy-D? 616
Nonconventional Indications for Cardiac Resynchronization Therapy 616
xxxiv Textbook of Cardiology: A Clinical and Historical Perspective
Patients without Overt Heart Failure 617
Dyssynchrony and Cardiac Resynchronization Therapy 617
The Issue of Response and Nonresponse 618
Reasons For Non-response to Cardiac Resynchronization Therapy 618
Etiology of Heart Failure 619
Optimal Programming of Cardiac Resynchronization Therapy Parameters 619
Future 620
73. History of Intravascular Ultrasound_________________________________________________________________622
Garg N, Bhandari S
Development of Intravascular Ultrasound 622
Preliminary Studies 623
Therapeutic Studies of Intravascular Ultrasound 623
74. History of Intervention for Congenital Heart Disease_________________________________________________625
Kohli V
History of Angiography 625
History of Balloon Atrial Septostomy 626
History of Valvuloplasty 627
History of Device Closure 628
History of Coil Closure 629
History of Stent Use 630
Timeline of Interventions of Congenital Heart Disease 630
75. Wide QRS Tachycardias Diagnosis and Management__________________________________________________631
Singhal R, Jaswal A
Classification of Tachycardias with a Broad QRS Complex 631
Electrophysiology of Ventricular Tachycardia 631
Criterias to Differentiate Wide QRS Tachycardia 632
Etiology of Ventricular Tachycardia 632
Value of the Electrocardiogram during Sinus Rhythm 634
Value and Limitations of the Electrocardiogram in Broad QRS Tachycardia 635
Management of Wide QRS Tachycardia 635
76. History of Periphral Vascular Interventions__________________________________________________________638
Rao SS, Khanna NN
Carotid Angioplasty 639
Advancement—The Age of Cerebral Protection 640
Renal Angioplasty 640
Angioplasty for Aortoiliac Occlusive Diseases 641
Angioplasty for Infrainguinal Peripheral Vascular Disease 641
Endovascular Repair of Aortic Aneurysm 641
History of IVC Filters 642
77. Intracardiac Echocardiography: Historical Perspective, Current Applications and Future Directions_____643
Katikireddy CK, Kort S
History 643
Types of Ice Catheters and Transducers 643
Ice Applications 645
Ice in the Pediatric Population 649
Accuracy of Ice 650
Complications of Ice 650
Limitations of Ice 650
Contents xxxv
SECTION 4: CARDIAC SURGERY

78. History and Advances in Cardiac Surgery____________________________________________________________655
Trehan N, Malhotra R, Dhir U
Coronary Artery Disease 655
Percutaneous Valve Repair and Replacement 660
Surgery for Heart Failure 661
79. History of Valvular Heart Surgery___________________________________________________________________667
Yadava OP
Surgery for Mitral Stenosis 667
Surgery for Aortic Stenosis 668
Mitral Regurgitation 669
Artificial Heart Valve 669
Aortic Homograft 670
Development of Tissue Valves 671
Pulmonary and Tricuspid Valves—Poor Cousins 672
Percutaneous Approaches to Valvular Heart Diseases 673
Robotic Valve Surgery 673
80. History of Surgery for Ischemic Heart Disease________________________________________________________676
Katariya K
Surgical Treatment of Ischemic Heart Disease: The First Era (Pre 1935) 677
The Second (Pre Heart-Lung Machine) Era (1932-1954) 679
Post Heart-Lung Machine Era (After 1954) 681
81. History of Robotically Assisted Cardiac Surgery______________________________________________________688
Mishra YK, Collison SP
Historical Aspects of The Development of Current Robotic Technology 688
Development of Robotic Cardiac Surgery 689
Laparoscopic Surgery 689
The Development of Telepresence Surgery 690
Milestones in The Development of Robotic Cardiac Surgery 692
Robotic Coronary Artery Bypass 693
Mitral Valve Surgery 693
Atrial Fibrillation Surgery 693
Time Line of Salient Events in the Development of Robotic Cardiac Surgery 694
Left Ventricular Lead Placement 695
Congenital Heart Disease 695
82. History of Aortic Surgery___________________________________________________________________________697
Bhan A
Arterial Aneurysmal Disease 697
Arterial Occlusive Disease 699
Development of Vascular Grafts 700
Development of Imaging 701
Pioneers of Present Day Aortic Surgery 701
Landmarks in Aortic Surgery 702
83. History of Heart Transplantation and Its Future______________________________________________________705
Kohli V, Krishan K
Mechanical Circulatory Support 708
The Future of Heart Transplant 708
xxxvi Textbook of Cardiology: A Clinical and Historical Perspective
84. The History of Congenital Heart Surgery_____________________________________________________________710
Iyer KS
The Precardiopulmonary Bypass Era 710
The Era of Cardiopulmonary Bypass 712
Landmark Moments in the Development of Surgery 712
Origins of Congenital Heart Surgery in India 713
SECTION 5: FUTURE OF CARDIOLOGY

85. Future of Thrombolytics____________________________________________________________________________717
Oliveros E, Dahya Z, Ishmael A, Peña C, Mehta S
History and Evolution of Fibrinolytic Therapy 717
Role of Thrombolytics for Acute Myocardial Infarction 717
Clinical Trials Relevant to the Development of Tenecteplase 719
Assent-3 Plus 722
Assent-4 PCI 722
Future Horizons of Thrombolytics Therapy 723
86. Future of Thrombus, Thrombolytic Therapy and PCI in Cardiovascular Disorders in India_______________726
Iyengar SS
St Elevation Myocardial Infarction 726
Thrombolytic Therapy in Acute Ischemic Stroke 727
Thrombolytic Therapy in Acute Pulmonary Embolism 728
Thrombolytic Therapy in Other Situations 728
87. Future of Balloon Valvotomy—Newer Aspects________________________________________________________730
Arora R
Mitral Stenosis 730
Tricuspid Stenosis 733
Pulmonary Valve Stenosis 734
Aortic Stenosis 735
Special Situations 736
Fetal Balloon Dilatation 736
88. History of Stem Cell Therapy and its Future in Cardiovascular Diseases________________________________739
Shah VK, Shalia KK
Preclinical Data Evidence towards Regeneration 739
Animal Experiments 740
Human Trials 742
Specific Set-Up Required for Clinical Cell Therapy to Ensure Quality Control and Safety 747
89. Future of Heart Transplant in India__________________________________________________________________750
Shad S
Heart Transplant as the Definitive Treatment for Heart Failure 750
Indian Scenario 750
Essentials of Good Results of Heart Transplant 751
Factors Limiting Modern Therapies in India 751
Opportunities and the Way Forward 752
Index______________________________________________________________________________________________753
19. Lycopene and Related Tomato Carotenoids in Coronary Heart Disease
20. History of Oils, Fats and Coronary Heart Disease
21. History of Cardiac Fitness
22. History of Blood Pressure and its Measurement
23. History of Blood Pressure Amplification between the Heart and Peripheral Arteries
24. The History of Cardiac Rehabilitation: An Evolutionary Perspective
25. A Brief Historical Chronicle of Hypertension
26. History of Risk Factor Stratification of Hypertension
27. Retracing the Heroic Steps from Lipid Hypothesis to Aggressive Treatment of Blood
Cholesterol—A Revolution in Preventive Cardiology
28. Past, Present and Future of Cardiovascular Dysmetabolic Syndrome
29. History of Obesity and Cardiovascular Disorder
30. History of Dilated Cardiomyopathy
31. History of Hypertrophic Cardiomyopathy
32. History of Restrictive Cardiomyopathy
33. Peripartum Cardiomyopathy
34. History and Clinical Implications of Myocarditis and Pericarditis
35. History of Infective Endocarditis and Future Directions
36. The History of Deep Vein Thrombosis and Pulmonary Thromboembolism
37. Lessons Learnt from History of Rheumatic Heart Diseases
38. History of Pediatric Cardiology: From the “Untouchable” Heart to the Brave New Era
39. History of Pulmonary Embolism
40. History of Stroke in Cardiac Patients
41. Tobacco and Heart: A Historical Perspective
42. History of Stress and Heart Disease Relationship
43. History of Cardiorenal Connectors
44. History of Oxidative Stress and Cardiovascular Disease Protection
45. History of Hormone Replacement Therapy and the Heart
46. Tuberculosis and Heart
47. History of Cardiac Syncope
48. History of Markers of Sudden Cardiac Death
49. History of Women and Heart Disease
50. History of Heart and Trans-Fat Relationship
51. Coronary Artery Disease and Homocysteine Relationship
52. Savitri Satyawana: The First Described Cardiac Revival of the Vedic Times
53. History of Sildenafil: From Angina to Erectile Dysfunction
54. Cardiocutaneous Diseases
55. ARBs and CVD Protection
Development of Cardiology
1 in India: Are We on the
Right Track?
Padmavati S
I was amazed at the member of specialists who have contributed ar- to safe sanitation to mention a few. The indices are far lower than
ticles for this volume. Dr HK Chopra must be congratulated on his Bangladesh or Pakistan and just above Sub Saharan Africa Primary
powers of persuasion in obtaining articles from just about every car- Health Care in the rural areas is in the doldrums.
diologist in India. And the number of contributors is immense. The numbers under below poverty line (BPL) is the subject of
In the following paragraph the positive and negative aspects of hot debate depending on the criteria used from 30 to 70%. Reason-
this phenomenal growth are reviewed. able estimates are around 45% of the population. How can these be
accommodated in the 85% private sector? Its motive all said and
CARDIAC SOCIETY AND FOUNDATION done is profit. As their beds cannot be filled with Indian patients,
there is a big drive to attract foreigners the so allied “health tourism”,
Modern Cardiology as a super specialty came into existence only af- combining surgery and medical treatment with tourism. The govern-
ter World War II. Earlier “Cardiologists “were merely internists who ment has secured beds for its patients [in the ECHS, (CGHS) from
had a special interest in the subject. No less a person than Braunwald private hospitals at low cost], but this only helps a minority. Hospitals
testifies to this.1 According to World Health Organization (WHO) which have been given government land at discounted prices have
(2005)2 30% of all deaths in India are due to heart disease and stroke. been the target with mixed success.
The risk factors are high blood pressure, diabetes and smoking in the It is agreed that modern medicine including cardiology is largely
majority. The numbers are likely to increase phenomenally by 2020. technology oriented and technology is expensive. One cannot avoid
India jumped on the bandwagon much earlier than most in- it in this day and age of mind boggling scientific expansion. The gov-
dustrialized countries. The Cardiological Society of India (CSI) ernment is dedicated to right to food, right to education and right to
was formed in 1948 [earlier than the American College of Cardiol- information. It should also ensure a right to health. There should be
ogy (ACC) 1949] and many others. The All India Heart Foundation significant facilities in the public sector for the poor. There are many
(AIHF) was founded in 1962, one of the first in Asia. Both these so- models from Western countries to choose from.
cieties are affiliated to the World Heart Federation (WHF), which in Professor Jayati Ghosh of the Jawaharlal Nehru University in
its earlier incarnation; the International Society of Cardiology was her 2011 UCL Lancet lecture in London has found the situation
formed in 1946. The CSI has held regular annual meetings and has disturbing.
chapters throughout India. The AIHF equally active has not yet es- Instead of investing in a national publically funded health ser-
tablished centers all over the India. Through the WHF they are con- vice which would undermine the private sectors ability to create a
nected to the Asian Pacific Society of Cardiology (APSC) and Asian market in health, according to her India’s economic model destroys
Pacific Heart Network and to all Asian countries. There are now over health that is health considered as a public good. She has suggested
1,000 cardiologist listed as members of the CSI. It has Councils in var- as alternatives a wage employment based health strategy, combined
ious subspecialties. In short it is very well organized and is far ahead with substantial investments in the public sector health system. Her
of cardiac societies in most developing countries. ideas need consideration.3
FUNDING OF HEALTH CARE PREVENTIVE PROGRAMS

And yet there are many short comings one cannot ignore. First Indi-
an health care is 85% in the private sector. The government is concen- Ischemic Heart Disease
trating on “growth” and its trickle effect, which is in effect helping the Preventive Programs are conspicuous by their absence. In industri-
private sector to thrive. In spite of 9% growth until last year its health alized countries today there have been substantial gains in labeling
indices are some of the worst in the world, e.g. under 5 years mortal- food, nonsmoking campaigns and provision for exercise by provid-
ity, appalling number of maternal deaths in child birth and access ing parks and cycle paths all done by the government.
4 Section 1  Clinical Cardiology
Cardiac Societies/Foundations in the USA, UK, Western Europe, is expensive particularly of newborns and infants. The facilities for
Australia, New Zealand, and Canada have used guide lines on the pediatric cardiology and cardiac surgery are restricted to about three
three important aspects for preventive heart disease viz diet, exer- or four private centers in the whole country. There has been no at-
cise and nonsmoking. In India apart from conflicting messages in tempt to build such centers in the public sector. Research also needs
the newspapers from time to time, nothing has been done. Although, to be done in prevention in this group.
India has joined the Framework Convention on Tobacco Control
(FCTC) in 2004, which makes its mandatory to control tobacco, there RESEARCH
is a big gap in the implementation. The observance of World Health
Day (Sept. 29th) World Diabetes Day (Nov. 14th), which will help in Although every heart center in India has the label of “research
creating awareness, has just begun in India. center” following it, research is conspicuous by its absence. There is
much scope for research in India in conditions peculiar to this coun-
try, both basic and operational. A scrutiny of peer reviewed journals
Rheumatic Heart Disease
makes this abundantly clear.
Rheumatic heart disease (RHD) has been eliminated in all industri-
alized countries, but still takes a large toll of lives of young individuals LACK OF INTERNATIONAL RECOGNITION
in India. It is entirely preventable as shown by an Indian Council of
Medical Research (ICMR) project (1994) utilizing the School Health Lastly why have big international conferences on heart disease by
Services and Primary Health Centers. Rheumatic heart disease re- passed India? The Fifth World Congress of Cardiology was the only
ceived mention in the Fifth Five-Year Plan (1966–71), but no succes- World Congress held in India so far in 1966. It has been held two or
sive plan make any mention of heart disease prevention.4,5 three times in many smaller countries since the first one in 1950. The
APSC founded 1956 has held only one meeting in Mumbai in 2005.
These conferences are now held once in 2 years. Exposure to World
Pediatric Cardiology
Cardiology of a large number of Indian doctors would be an inspira-
There are no hard data on the number of children with congenital tion. Why has it not been done?
heart malformation, but extrapolating the data from elsewhere it is It seems, in spite of a well-organized society, the fruits of
8 per 1,000 live births 130,000–270,000 children are born each year research in modern cardiology, although available in India in large
with congenital heart defects of whom some 80,000 need same form measure is denied to the majority of Indians. Something should be
of intervention in infancy. It is a resource intensive specialty and done and quickly to reverse this trend.
REFERENCES
1. Braunwald E. Shattuck Lecture Cardiovascular Medicine at the turn of the Millennium Triunaphs, concerns and opportunities. N Engl J Med.
1997;337:1360-9.
2. World Health Organization (2005) Preventing chronic diseases-a vital investment. [online] WHO website. Available from http://www.who.int/
chp/chronic_disease_report/en/ [Accessed July 2012]
3. Ghosh Jayanti. 2011 UCL Lancet Lecture. The Lancet. 2011;378:1986.
4. Padmavati S, Bhatia D. Control of rheumatic fever and rheumatic heart disease in India through School Health Services. ICMR Pilot Project.
1984–1990. [online] ICMR website. Available from www.icmr.nic.in Accessed July 2012]
5. Sharma KB, Prakash Kunti. Community control of Rheumatic Fever and Rheumatic Heart Disease. 1982/1990.ICMR 1994.
2 History of Thrombolysis
adsorb the fibrinogen and prevent the formation of a clot. However,

INTRODUCTION
the results of this experiment were uniformly negative: there was a
Physiological thrombosis is an important part of the normal hemo- clot formation in all the tubes, regardless of the presence of Strepto-
static response that limits hemorrhage caused by microscopic or cocci. Dejected with the results of this experiment, he left the tubes in
macroscopic vascular injury. This is counterbalanced by intrinsic the tray without cleaning.1
antithrombotic properties and fibrinolysis. However, under patho- After some time, to his surprise, he found that there was a clot
logical conditions, a thrombus can partially or completely obliterate lysis in the tubes containing streptococcal cultures. This led him to
a vessel lumen or propagate into an otherwise normal vessel. The conclude that the Streptococci had synthesized a fibrinolytic agent
principal clinical syndromes the result of which are acute myocardial that was responsible for dissolving the clots (Figs 2.2A to C). This
infarction (AMI), deep vein thrombosis (DVT), pulmonary embolism was the probable mechanism for clot lysis, rather than adsorption of
(PE), acute ischemic stroke, acute peripheral arterial occlusion and fibrinogen, as he had presumed earlier. He confirmed these findings
occlusion of indwelling catheters. on larger scale and on June 27, 1933, Tillett and Garner submitted
Over the last century, thrombolytic therapy has gained promi- their findings as “Fibrinolytic activity of hemolytic streptococci”. The
nence in the management of thrombo-embolic phenomena and has agent was termed as streptococcal fibrinolysin, which was crude and
helped hundreds of physicians in reanalyzing cardinal vessel occlu- impure, thus could not be used clinically.1,2
sions. This chapter reviews major milestones in the history of throm-
bolysis. Mechanism of Action of Streptokinase
In 1941, Milstone reported the existence of a substance, normal-
DEVELOPMENT OF THROMBOLYTIC
ly present in plasma that was required for dissolution of clot. He
THERAPY
termed it the “lytic factor”. Christensen and Kaplan independently
determined that the lytic factor was a proteolytic enzyme normally
Streptokinase
The Discovery of Streptokinase

The first thrombolytic, streptokinase (SK) was discovered by Dr
William Smith Tillett (Fig. 2.1) in 1933 by sheer serendipity. He was
Associate Professor of Medicine and Director of the Biological Di-
vision at Johns Hopkins University, at that time. He observed that
Streptococci agglutinated in test tubes that contained human plasma,
but not in those that contained human serum. He hypothesized that
the agglutination of Streptococci is caused by fibrinogen in plasma
that is deficient in serum. The fibrinogen probably is adsorbed onto
the surface of Streptococci, rendering the plasma devoid of free fi-
brinogen. In order to prove his hypothesis, Tillett devised a simple
experiment. He took oxalated human plasma containing fibrinogen,
which would not clot due to calcium depletion. He added calcium to
the control test tubes and hemolytic streptococci and calcium to the
rest of the test tubes, hoping that the hemolytic streptococci would Figure 2.1: Dr William Smith Tillett (1882–1974)
A B C
Figures 2.2A to C: WS Tillett’s experiment. (A) Oxalated human plasma alone in test tubes i–v and with cultures of Streptococci in test tubes iv
and v; (B) Clot formation in all of the test tubes, upon adding calcium; (C) Dissolution of clots, after the passage of time, in test tubes iv and v, which
contained cultures of Streptococci
present in plasma as an inactive precursor. The streptococcal sub- zation results and frequent bleeding complications. Despite this fact,
stance (fibrinolysin) activates the proteinase precursor, converting he must be credited with the first use of thrombolytic agents for the
it to an active enzyme in a manner analogous to the conversion of treatment of pathological thrombi, as well as with the first catheter-
trypsinogen to trypsin by enterokinase. The active serum proteinase directed administration of a thrombolytic agent.8
then lyses the fibrin clot. Christensen and MacLeod proposed the In late 1950s, Fletcher and associates performed new studies re-
term “streptokinase” in 1945 to replace the term fibrinolysin origi- garding an intravenous approach to the treatment of AMI patients.
nally applied to the streptococcal component of the system. They fur- Their patients were infused with SK in massive doses and for pro-
ther suggested the name “plasminogen” for the inactive form of the longed periods after myocardial infarction (MI). Except for the de-
serum proteinase and “plasmin” for the active enzyme.2 velopment of a hemorrhagic diathesis in a few patients, there were
no significant complications and the mortality rate was significantly
The Source for Streptokinase lower in patients who had received SK, in comparison with other
treatments. This proved that SK infusion via the intravenous route
Evans reported the discovery of fibrinolytic properties in certain was a promising therapeutic approach to MI.9,10
strains of Streptococcus equisimilis.3 Christensen reported that the After the success of intravascular thrombolysis with SK, Rueg-
strain S. equisimilis H46A can act as a commercial source for SK as it segger and colleagues successfully dissolved intracoronary clots for
does not produce erythrogenic toxins, is less fastidious in its growth the first time in various animal models. With serial angiography, they
requirements than are most other Group A strains and could be clearly showed dissolution of clots in high proportion of animals.
grown on semi-synthetic media. This was a discovery of immense An important finding of this study was that the heart muscle could
importance as till date, the commercial SK used for thrombolytic not be saved from death if more than a few hours passed between
therapy is derived from S. equisimilis (Lancefield Group C). clotting and lysis, which has now emerged as the concept of golden
hour in the management of AMI. The earlier thrombolysis resulted in
Human Studies on Streptokinase smaller area of infarction as compared to controls in this study.11
In spite of the success spurts, the production of SK in the United
In late 1940s, Tillett and Sherry successfully used SK to treat fibrin- States was stopped due to the inefficiency in production of less pyro-
ous, purulent and sanguineous pleural exudations, hemothorax genic preparations. It still remained the drug of choice in Europe and
and tuberculous meningitis.4,5 In these studies, SK was associated Australia for several decades. However, in the United States the focus
with few side-effects, such as a pyrogenic reaction with associated was shifted to another thrombolytic molecule, urokinase (UK).
malaise, headache, arthralgia, and occasionally nausea and febrile Several small scale trials conducted in on SK during 1960s and
responses.6,7 This was probably due to impurities in the existing for- 1970s failed to establish the therapeutic superiority of SK till 1979
mulation. Later on, further purification of SK was taken up by Lederle when European Cooperative Study Group for Streptokinase Treat-
Laboratories. ment in Acute Myocardial Infarction published its findings from a
The first report on intravascular thrombolysis in humans came large scale trial. The trial conducted in 2,388 patients found that the
up in 1956 by Cliffton EE at the Cornell University Medical College, overall mortality rates within 6 months of SK therapy after AMI were
New York, who used SK in 40 patients with intravascular thrombosis significantly lower (P < 0.01) in the SK group (15.6%) than in the con-
of diverse etiology. His study was associated with nonuniform canali- trol group (30.6%).12 In 1980s, several trials demonstrated that use of
Chapter 2  History of Thrombolysis 7
SK within 1.5–3 hours of infarction was associated with high reperfu- nogen activation. At the site of the thrombus, however, the binding of
sion rates. Still, these results were not sufficient to establish practice tPA and plasminogen to the fibrin surface induces a conformational
guidelines.2 change in both molecules, greatly facilitating the conversion of plas-
Finally, in 1986, a landmark trial, GISSI (Gruppo Italiano per la minogen to plasmin and dissolution of the clot. tPA also manifests
Sperimentazione della Streptochinasi nell’Infarto Miocardico) in the property of fibrin affinity, that is, it binds strongly to fibrin. Other
11,806 patients in 176 coronary care units dissipitated the confusion. fibrinolytic agents, such as prourokinase, do not demonstrate fibrin
There was a significant difference in mortality rates between the affinity.17
SK group and the nonstreptokinase group (controls) at 12 months Recombinant tPA (rtPA or alteplase) was produced in the 1980s
(17.2% in the SK group vs 19.0% in controls, P = 0.008; relative risk, after molecular cloning techniques were used to express human tPA
0.90), especially in the 0–3 and 3–6 hour groups (relative risks, 0.89 DNA. A predominantly single-chain form of rtPA, was eventually
and 0.87, respectively). Thus, GISSI succeeded in firmly establishing approved for the indications of AMI and massive PE. rtPA has been
the efficacy of intravenously administered SK.13-16 However, devel- studied extensively in the setting of coronary occlusion.17
opment of antibodies against SK remains as a major hindrance for In the GUSTO I study of 41,000 patients with AMI; rtPA was more
reuse of SK in a patient. effective than SK in achieving vascular patency. Despite a slightly
Today, SK although superseded in efficacy and safety by newer greater risk of intracranial hemorrhage with rtPA, overall mortality
thrombolytics still remains a widely used affordable drug for throm- was significantly reduced.18
bolysis in developing countries.
Reteplase Plasminogen Activator
Urokinase
Reteplase plasminogen activator (rPA) was developed as a second-
The fibrinolytic potential of human urine was first described by Mac- generation recombinant tissue-type plasminogen activator. It is
farlane and Pilling in 1947. The active molecule was extracted, isolat- a deletion mutant of tPA, which has a longer half-life (14-min) as
ed and named ‘‘Urokinase’’ in 1952. Unlike SK, UK directly activates compared to alteplase and greater thrombolytic potency. It is a
plasminogen to form plasmin; prior binding to plasminogen or plas- direct plasminogen activator, but was found to cause more fibrino-
min is not necessary for activity. Also in contrast to SK, preformed gen depletion than alteplase, which could result in a higher frequen-
antibodies to UK are not observed. The agent is nonantigenic and cy of bleeding complications.19
untoward reactions of fever or hypotension are rare. The most com- Reteplase was developed with the goal of avoiding the necessity
monly employed UK has been of tissue-culture origin, manufactured of a continuous intravenous infusion, thereby simplifying the ease of
from human neonatal kidney cells. administration. Reteplase produced in Escherichia coli cells, is non-
A recombinant form of urokinase (rUK) was tested in a single tri- glycosylated, demonstrating a lower fibrin-binding activity and a di-
al of patients with AMI and in two multicenter trials of patients with minished affinity to hepatocytes. This latter property accounts for a
peripheral arterial occlusion. It had a higher molecular-weight and a longer half-life than rtPA, potentially enabling bolus injection versus
shorter half-life than its low molecular-weight counterpart. Despite prolonged infusion. Similar to UK, the fibrin affinity of reteplase was
these differences, however, the clinical effects of the two agents have only 30% of that exhibited with tPA. The decrease in fibrin affinity was
been quite similar. McNamara and Fischer were the first to describe hypothesized to reduce the incidence of distant bleeding complica-
the use of UK for local thrombolytic treatment, using a high-dose tions in a manner similar to that of SK over rtPA in the GUSTO trial.
protocol featuring graded, stepwise reductions in dose as the infu- In fact, several properties of reteplase may account for a decreased
sion progressed.17 risk of hemorrhage, including poor lysis of older, platelet-rich clots.
Reteplase has been studied in several small trials, and its safety and
efficacy appear to be similar to alteplase.17
Alteplase
Tissue Plasminogen Activator Tenecteplase

Tissue plasminogen activator (tPA), originally developed in the mid- Tenecteplase (TNK-tPA) molecule was bioengineered in an effort to
1980s for acute coronary artery occlusion, is a naturally occurring lengthen the duration of bioavailability of tPA. Three regions in kring-
fibrinolytic agent produced by endothelial cells and is intimately le-1 and the protease portion of tPA, which mediated hepatic clear-
involved in the balance between intravascular thrombogenesis and ance, fibrin specificity, and resistance to plasminogen activator and
thrombolysis. Natural tPA is a single-chain (527 amino acid) serine inhibitor were identified. These three sites were modified to create
protease and in contrast to most serine proteases (e.g. urokinase), TNK-tPA, a novel molecule with a greater half-life and fibrin speci-
the single-chain form has significant activity. tPA exhibits significant ficity. The longer half-life of TNK-tPA allowed successful administra-
fibrin specificity. In plasma, the agent is associated with little plasmi- tion as a single bolus, in contrast to the infusion required for rtPA. In
addition, TNK-tPA manifests greater fibrin specificity than rtPA, within minutes of symptom onset and prehospital thormbolysis is ef-
resulting in less fibrinogen depletion. In studies of acute coronary fective in saving lives.22
occlusion, TNK-tPA performed at least, as well as rtPA, concurrent Although, primary percutaneous coronary intervention (P-PCI)
with greater ease of administration.20 It had received US Food and within first 6 hours of chest pain is suggested as the most preferred
Drug Administration (FDA) approval for the management of AMI in therapy for AMI, it is not feasible in routine clinical settings due to
the year 2000. The first biosimilar tenecteplase (Elaxim) was indig- delays in transfer, unavailability of catheterization facility and scar-
enously developed in India by Gennova Biopharmaceuticals at Pune. city of skilled personnel.20 Five-year follow-up of a multi-centric trial
CAPTIM (Comparison of Angioplasty and Prehospital Thrombolysis
in Acute Myocardial Infarction) shows that prehospital fibrinolysis
ADVANTAGES OF NEWER AGENTS
with immediate transfer for rescue angioplasty, if needed, is associ-
OVER THE OLDER AGENTS
ated with similar mortality as compared to primary percutaneous
Urokinase is found to be safer, nonpyrogenic and nonantigenic than coronary intervention (P-PCI) if managed within 6 hours of onset
SK. The thrombolysis with UK is in fact safer than alteplase. However, of chest pain and improved long-term mortality when administered
it is less specific and less effective fibrinolytic-thrombolytic agent within first 2 hours.23,24
than human tissue plasminogen activation. Since the beginning of
tissue plasminogen era, they have largely replaced SK and UK in the
For Peripheral Arterial Occlusion
developed countries.
Alteplase was found to be a more favorable mortality results than Three multicenter trials designed to compare thrombolytic therapy
SK in GUSTO study.15 It had better thrombolytic /fibrinolytic ration with surgical revascularization established the routine use of throm-
than UK. The disadvantages were higher bleeding risk and lack of bolytics in this area. In the first study amongst 114 patients with
resistance to plasminogen activator inhibitor (PAI-1). Reteplase, al- hyperacute ischemia, 84% of patients randomized to UK were alive
though was more potent than alteplase, was associated with higher compared to only 58% of patients allocated to primary operation at
bleeding risk. The advantage associated with reteplase was that it the end of 1 year. By contrast, the rate of limb salvage was identical at
could be given in form of bolus injection rather than continuous in- 80%. This variable mortality was due to the development of cardio-
fusion. With the introduction of tenecteplase, we now have a throm- pulmonary complications during the periprocedural period.17
bolytic that can be given as a bolus injection, is more fibrin specific The second prospective, randomized analysis of thrombolysis
and resistant to plasminogen activator inhibitor.19 versus surgery was the surgery or thrombolysis (with rtPA or UK) for
the ischemic lower extremity (STILE) trial in 393 patients. The results
TRENDS IN THROMBOLYSIS indicated that the endpoints of amputation and death were equiva-
lent in all treatment groups, but subgroup analysis suggested that the
thrombolysis appeared more effective in patients with graft occlu-
For Acute Myocardial Infarction
sions. In thrombolysis or peripheral arterial surgery (TOPAS), 30,544
Although, the first thrombolytic was discovered in 1933. The clini- patients were randomized to a recombinant form of UK or primary
cal use of thrombolytics in the management of AMI was delayed till operative intervention. This trial failed to show superiority of UK
1980s. This was due to the controversies in the pathogenesis of MI. It over surgical intervention. Nevertheless, the findings confirmed that
was earlier that coronary thrombosis is a consequence rather than the acute limb ischemia could be managed with catheter-directed
cause of MI. This confusion was resolved in 1980, when DeWood and thrombolysis, achieving amputation and mortality rates similar to
his collegues showed that 87% of patients presenting within 4 hours surgery, but avoiding the need for open procedures in a significant
of AMI had total coronary occlusion. He showed the angiographic percentage of patients. Till today, SK is the only FDA approved agent
evidence for coronary thrombosis in AMI patients for the first time for peripheral arterial thrombolysis.17
and was able to retrieve the thrombus using Fograty catheter in 88%
of these patients. DeWood’s paper led to credence to the concept of
For Pulmonary Thromboembolism
endogenous fibrinolysis and ushered the era of fibrinolytics.21
By the end of 1980s, large randomized trials had been con- Streptokinase, UK and rtPA are FDA approved agents for the treat-
ducted in this area. The meta-analysis of these trials suggested that ment of acute PE. From an randomized controlled trials done on
the sooner the thrombolytic given after the onset of chest pain, the UK [Urokinase Pulmonary Embolism Trial (UPET)] and four rand-
greater the survival benefit. This led to the concept of “golden hour” omized trials on rtPA, it was evident that thrombolytic therapy only
in myocardial thrombolysis, which was later lengthened to a period led to early resolution of PE in lung scans as compared with heparin
of 3 hours. The findings of GREAR trial suggested that modest delays and anticoagulant therapy. However, within 2 weeks the percentage
in the treatment may be detrimental as myocardial cell death starts improvement in scans was no different than the comparator. In fact,
Chapter 2  History of Thrombolysis 9
rtPA for PE was associated with 8.4% incidence of major hemorrhage thrombolytic therapy in the treatment of PE, it probably remains un-
and 2.2% incidence of fatal hemorrhage.25 derutilized in clinical practice due to fears of hemorrhagic complica-
Due to this fact, American College of Chest Physicians (ACCP) tions and complicated regimes of thrombolytics.26 Recently, Becat-
guidelines recommended the use of thrombolytics only in massive tini et al. demonstrated the efficacy of tenecteplase against heparin
PE associated with circulatory collapse considering that mortality of in 58 hemodynamically stable patients of PE with right ventricular
PE in patients without shock treated with heparin and oral antico- dysfunction.27 Despite this, large scale trials demonstrating mortality
agulants is in the range of 2%. (In spite of the regulatory approval for benefits would be needed to establish the use of thrombolytics in PE.
REFERENCES
1. Tillett WS. The fibrinolytic activity of hemolytic streptococci in relation to the source of strains and to cultural reactions. J Bacteriol. 1935;29:111-
30.
2. Sikri N, Bardia A. A history of streptokinase use in acute myocardial infarction. Tex Heart Inst J. 2007;34:318-27.
3. Evans AC. Studies on hemolytic streptococci: VIII. Streptococcus equisimilis. J Bacteriol. 1944;48:267-84.
4. Tillett WS, Sherry S. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal desoxyribonuclease on fibrinous, puru-
lent and sanguinous pleural exudations. J Clin Invest. 1949;28:173-90.
5. Sherry S, Tillett WS, Read CT. The use of streptokinase-streptodornase in the treatment of hemothorax. J Thorac Surg. 1950;20:393-417.
6. Hubbard WN. The systemic toxic responses of patients to treatment with streptokinase streptodornase. J Clin Invest. 1951;30:1171-4.
7. Sherry S. The fibrinolytic activity of streptokinase activated human plasmin. J Clin Invest. 1954;33:1054-63.
8. Cliffton EE, Grunnet M. Investigations of intravenous plasmin (fibrinolysin) in humans. Circulation. 1956;14:919.
9. Fletcher AP, Alkjaersig N, Sherry S. The maintenance of a sustained thrombolytic state in man. I. Induction and effects. J Clin Invest. 1959;38:1096-
110.
10. Fletcher AP, Sherry S, Alkjaersig N, et al. The maintenance of a sustained thrombolytic state in man. II. Clinical observations on patients with
myocardial infarction and other thromboembolic disorders. J Clin Invest. 1959;38:1111-9.
11. Ruegsegger P, Nydick I, Hutter RC, et al. Fibrinolytic (plasmin) therapy of experimental coronary thrombi with alteration of the evolution of myo-
cardial infarction. Circulation. 1959;19:7-13.
12. Streptokinase in acute myocardial infarction. European Cooperative Study Group for Streptokinase Treatment in Acute Myocardial Infarction. N
Engl J Med. 1979;301:797-802.
13. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto
Miocardico (GISSI). Lancet. 1986;1:397-402.
14. Chopra HK, Chopra KL, Aggarwal KK, et al. Intravenous streptokinase and oral nifedipine in evolving myocardial infarction—a pilot study. Indian
Heart J. 1984;36(6):347-51.
15. Chopra HK, Chopra KL, Aggarwal KK, et al. Specific reperfusion arrhythmias with high dose short term IV streptokinase therapy in acute myocar-
dial infarction. Indian Heart J. 1988;40(4):232-6.
16. Chopra HK, Chopra KL, Aggarwal KK. et al. Intravenous streptokinase in acute evolving myocardial infarction-six to thirty-six months follow-up.
Indian Heart J. 1990;42(1):13-25.
17. Ouriel K. A history of thrombolytic therapy. J Endovascular Ther. 2004;11(Suppl 2):128-33.
18. The GUSTO Investigators. An international randomized trial comparing four thrombolytic therapies for acute myocardial infarction. N Engl J Med.
1993;329:673-82.
19. Baruah DB, Dash RN, Chaudhari MR, et al. Plasminogen activators: A comparison. Vascular Pharmacology. 2006;44(1):1-9.
20. Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myo-
cardial Infarction (TIMI) 10A dose-ranging trial. Circulation. 1997;95:351-6.
21. Maroo A, Topol EJ. The early history and development of thrombolysis in acute myocardial infarction. J Thromb Haemost. 2004;2:1867-70.
22. Gray D. Thrombolysis: Past, present and future. Postgraduate Med J. 2006;82:372-5.
23. Kushner FG, Hand M, Smith SC, et al. 2009 Focused Updates: ACC/AHA guidelines for the management of patients with ST-Elevation myocardial
infarction. J Am Coll Cardiol. 2009;54:2205-41.
24. Bonnefoy E, Steg PG, Boutitie F, et al. Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM)
trial: a 5-year follow-up. Eur Heart J. 2009;30:1598-606.
25. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: Is it effective? Is it safe? When is it indicated? Arch Intern Med.
1997;157:2550-6.
26. Büller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the seventh ACCP Conference on Antithrom-
botic and Thrombolytic Therapy. Chest. 2004;126(3):401S-8S.
27. Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embo-
lism. Thromb Res. 2010;125:e82-e86.
3 Epicardial Reperfusion
The importance of early reperfusion therapy in reducing the

INTRODUCTION
short-term, as well as long-term mortality in AMI patients has been
Restoration of blood flow in the thrombosed epicardial blood ves- highlighted in many studies and meta-analyses.5 Early mechanical
sels is termed as epicardial reperfusion. As Lee et al. in 1995 stated reperfusion and maintenance of antegrade or collateral flow inde-
that reperfusion therapy has become so central to the modern treat- pendently preserve myocardial salvage primarily through a reduc-
ment of acute myocardial infarction (AMI), that we are said to be tion in infarct transmurality.5
in the reperfusion era.1,2 Patients who present with suspected AMI Hence, the current guidelines for management of acute STEMI
and ST segment elevation (STEMI) usually have an occlusive throm- have recommended primary coronary intervention with door to bal-
bosis in an epicardial coronary artery and are therefore candidates loon time of less than 90 minutes in PCI-capable hospitals and door
for immediate reperfusion, either with thrombolytic therapy, per- to needle time of less than 30 minutes for administration of fibrino-
cutaneous coronary intervention (PCI) or when these therapies are lytics in hospitals not capable of providing immediate PCI.6
unsuccessful, bypass surgery. Individuals with unstable angina (UA)
or non ST segment elevation myocardial infarction (NSTEMI) also NO-REFLOW PHENOMENON
need to undergo coronary angiography or noninvasive stress testing
to determine if there is significant ischemia that would benefit from The “no-reflow” phenomenon can be defined as an acute and severe
revascularization. reduction of coronary flow (Thrombolysis in myocardial infarction:
TIMI 0 to 2) after removal of an arterial occlusion, in the absence of
IMPORTANCE OF EPICARDIAL spasm, thrombi, severe residual lesions and arterial dissection. It is
not to be confused with slow flow, which is a much less critical situa-
REPERFUSION
tion that is more frequently observed and usually reversible.7
Coronary atherosclerosis is the major etiology for myocardial in- In some patients, despite achievement of normal epicardial flow
farction (MI), with more than 90% cases associated with superim- at the end of reperfusion therapy, the tissue level perfusion may be
posed luminal thrombus on a ruptured plaque. The biochemical and inadequate. Ito et al. have shown that many patients with successful
functional abnormalities begin almost immediately at the onset of epicardial reperfusion have “no-reflow” at the level of myocardium
ischemia and severe loss of myocardial contractility occurs within and coronary microcirculation by using myocardial contrast echo-
60 seconds. The loss of viability (irreversible injury) occurs at least cardiography.8 Such patients with poor tissue reperfusion have poor
20–40 minutes after total occlusion of blood flow as demonstrated recovery of left ventricular function after MI and are at high-risk for
in preclinical canine models of myocardial ischemia. Early reperfu- the development of congestive heart failure and death.
sion results in limitation of infarct to the subendocardial area and Patients with “no-reflow” have a higher level of creatine kinase
prevents progression to transmural infarct, which is associated with and have more severe wall motion abnormalities on ventriculogra-
ventricular remodeling and decreased survival rate in the long run.3 phy. Patients with “no-reflow” phenomenon have a higher incidence
Further, acute coronary thrombosis may result into the embo- of myocardial wall or ventricular septal wall rupture, as compared to
lization of microparticles, including fragments of fibrin–platelet those who do not.9
thrombus and necrotic core. Coronary microembolization has been The mechanisms of “no-reflow” are not completely understood.
associated with arrhythmias, contractile dysfunction, microinfarcts The most accepted hypothesis is probably due to embolism, arterial
and reduced coronary reserve. Autopsy studies have shown a 13% thrombosis, microvasculature dysfunction, platelet action, endothe-
rate of microembolization in cardiac disease, often associated with lial injury mediated by leukocytes or regional myocardial contrac-
focal myocyte necrosis. The rate of coronary microembolization is ture. The “no-reflow” phenomenon is associated with a mortality
the highest in documented epicardial coronary thrombosis, reach- rate of up to 15%, an incidence 10 times greater than that in an or-
ing 30–54% and even higher (79%) in AMI.3,4 dinary interventional procedure. Considering that the phenomenon
Chapter 3  Epicardial Reperfusion 11
worsens with time, the earlier the diagnosis and the onset of the tent chest pain in spite of thrombolytic therapy or revascularization
therapy, the better and faster the reversion. Additional therapy with was found be associated with slow coronary flow (TIMI grade 2)
antiplatelet agents like glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitors rather than total coronary occlusion. Thus, persistent chest pain for
and clopiogrel, have shown benefits in the treatment of “no reflow”. 90 minutes after epicardial reperfusion can be considered as one of
Though therapy with other drugs like adenosine, verapamil and the noninvasive criterion for epicardial reperfusion. But alone it is
papaverine has been studied, however, prevention remains as the not sufficient to guide decisions about catheterization or rescue in-
best treatment for this phenomenon.7 tervention.12
MEASURES OF EPICARDIAL REPERFUSION Resolution of ST Elevation in ECG
Thrombolysis in Myocardial Infarction Flow Maroko et al. in 1972 for the first time analyzed ST resolution as a
noninvasive tool for evaluating the efficacy of therapy for AMI.13 Sev-
The TIMI study group developed a grading scale for coronary blood eral large trials have evaluated the relationship between ST resolu-
flow based on visual assessment of the rate of contrast opacification tion and subsequent mortality. Schroder et al. have demonstrated
of the infarct artery. The TIMI flow grade has become the standard that patients with complete ST resolution (≥ 70%) 180 minutes after
for semiquantitative evaluation of myocardial perfusion before and thrombolysis had a mortality of 2.2% versus 3.4% in patients with
after coronary reperfusion therapies (Table 3.1).10 partial resolution (30–70%) and 8.8% in patients with no ST resolu-
Determination of TIMI flow grade after coronary reperfusion tion (≤ 30%). Early resolution (at 60 min) of ST segment is a greater
yields important prognostic information in patients with AMI. Pa- predictor of survival.14,15
tients with TIMI flow grade 3 show improved regional and global left A large study done in 2000 has shown that there is a highly sig-
ventricular function, lower enzyme peaks, and reduced morbidity nificant stepwise correlation between greater ST resolution and
and mortality rates compared with patients with TIMI flow grades 0, higher rates of infarct related artery patency and TIMI grade 3 flow.
1 or 2.11 More than or equal to 70% ST resolution at 90 minutes has 94% prob-
ability of a patent infarct related artery. However, more than 50% of
Resolution of Chest Pain patients with no ST resolution may have patent infarct related artery
(Fig. 3.1). This probably indicates poor myocardial reperfusion in
Chest pain is a common clinical symptom associated with acute spite of achieving complete epicardial reperfusion.
coronary syndrome and coronary reperfusion with thrombolysis or In fact, ST resolution is an independent predictor of mortality in
PCI is associated with resolution of chest pain. Per se, the criterion MI than epicardial flow. Incomplete (< 70%) ST resolution has a ten-
of chest pain has several limitations. Chest pain due to acid peptic fold increase in mortality versus those with complete (> 70%) ST res-
disorder, acute costochondritis often mimics that due to MI. Also, MI olution.14 According to the recent American College of Cardiology/
without chest pain (silent MI) is commonly seen in diabetic patients American Heart Association (ACC/AHA) guidelines, less than 50% of
and patients with autonomic neuropathy, due to other reasons. ST resolution in the lead showing the greatest degree of ST-segment
The resolution of chest pain after reperfusion alone is not a reli- elevation at presentation is considered to be failure of fibrinolytic
able indicator for successful reperfusion. A study done by de Lemos therapy.5 ST resolution correlates well with the myocardial blush
et al. has shown that patients who had resolution of chest pain still (perfusion) as shown by a multivariate analysis, however is shown to
had 13% probability of having an occluded coronary artery. Persis- be a better prognostic variable than myocardial blush.16
TABLE 3.1 TIMI-Grading system for coronary flow9

Grade Coronary Flow
Grade 0 (no perfusion) There is no antegrade flow beyond the point of occlusion.
Grade 1 (penetration without The contrast material passes beyond the area of obstruction, but “hangs up” and fails to opacify the entire
perfusion) coronary bed distal to the obstruction for the duration of the cineangiographic filming sequence.
Grade 2 (partial perfusion) The contrast material passes across the obstruction and opacifies the coronary bed distal to the obstruction.
However, the rate of entry of contrast material into the vessel distal to the obstruction or its rate of clearance
from the distal bed (or both) is perceptibly slower than its entry into or clearance from comparable areas not
perfused by the previously occluded vessel (e.g. the opposite coronary artery or the coronary bed proximal to the
obstruction).
Grade 3 (complete perfusion) Antegrade flow into the bed distal to the obstruction occurs as promptly as antegrade flow into the bed from the
involved bed and is as rapid as clearance from an uninvolved bed in the same vessel or the opposite artery.
Combined Indicator for Reperfusion

Assessment of Chest Pain, ST Resolution
and Myoglobin Levels
Since individually chest pain resolution, ST resolution and myoglo-
bin are not adequate to predict the success of reperfusion. A com-
bined criteria of ≤ 50% ST resolution at 90 minutes, persistent chest
pain at the time of angiography and a ratio smaller than 4 of serum
myoglobin at 60 minutes/baseline is used to identify candidates for
rescue PCI. Patients satisfying all the three criteria have 70% prob-
ability of achieving less than TIMI grade 3 flow, a more than 50%
probability of an occluded infarct related artery and a greater than
10-fold increase in the risk for 30-day mortality versus those with 0
or 1 criteria present.11
Figure 3.1: ST Resolution versus TIMI flow grade8 p <0.001 for the These are important noninvasive criteria for deciding whether to
correlation between ST resolution and TIMI 3 flow and p <0.001 for go for rescue operation in patients with TIMI grade 2 flow. This be-
correlation of ST resolution with patency (TIMI 2+3 flow) cause, TIMI grade 2 flow is not a good predictor of reperfusion unlike
TIMI grade 3. In many patients with TIMI grade 2 flow, increased mi-
crovascular resistance, rather than residual stenosis and thrombosis,
Thus ST resolution is an important predictor of myocardial, as appears to be the cause of reduced blood flow.21
well as epicardial reperfusion and it is simple and easily available as
compared to other measures of tissue perfusion like cardiac magnet- Combined Assessment of Epicardial
ic resonance imaging (CMRI), nuclear scintigraphy, position emis-
and Myocardial Reperfusion
sion tomography (PET) scanning and Doppler Flow-Wire studies.
Gibson et al. evaluated an angiographic score, i.e. a combination of
Cardiac Enzymes and Biomarkers TIMI Myocardial Perfusion Grade (TMPG) and TIMI flow grade in
the infarct related artery, before and after a PCI.22
A rapid increase in the serum concentration of cardiac biomarkers TMPG was used to assess tissue-level perfusion and has been
over the first 60–90 minutes after fibrinolysis can help to identify pa- previously defined as: grade 0, no or minimal angiographic blush;
tients who have achieved successful epicardial reperfusion. Of the grade 1, stain or prolonged persistence of dye on next contrast injec-
serum markers studied myoglobin appears to be superior to creatine tion; grade 2, dye bright at the end of injection, gone by next injec-
kinase-MB and the cardiac troponins for this purpose. The ratios of tion; and grade 3, normal ground glass appearance of blush. Patients
plasma concentration at the end of 60 minutes to basal concentra- with TIMI grade 3 flow with absent or near absent myocardial perfu-
tion of ≥ 4.0 for myoglobin, ≥ 3.3 for CK-MB and ≥ 2.0 for cTnI yielded sion (TMPG 0/1) after fibrinolytic administration had a mortality rate
a probability of patency of 90%, 88% and 87%, respectively.17 of 5.0%, which is as high as that in patients with unsuccessful restora-
However, measurement of serum myoglobin has similar limitation of optimal epicardial artery patency (TIMI 0–2), but preserva-
tions to measurement of ST resolution; although a rapid increase in tion of myocardial perfusion (TMPG 3; 4.7%). Conversely, restoration
myoglobin is highly predictive of a patent IRA, the absence of rapid of both TIMI grade 3 epicardial and myocardial flow was associated
myoglobin “washout” is not indicative of an occluded IRA.17,18 with a seven-fold reduction in mortality rate, to 0.7%. This just proves
The myoglobin criterion is an independent predictor of infarct that both epicardial, as well as myocardial reperfusion are equally
related artery occlusion, but not of the presence or absence of TIMI important predictors of survival after coronary intervention.22
grade 3 flow as early serum myoglobin ratios cannot distinguish Another combined indicator studied in literature is simultane-
TIMI grade 2 from TIMI grade 3 flow.19 ous assessment at 60 minutes of epicardial flow (measured by TIMI
flow grade), myocardial perfusion (measured by myocradial perfu-
Coronary Flow Velocity Pattern sion grade) and ST resolution. This was found to be a powerful prog-
nostic tool in patients with STEMI treated with fibrinolytic therapy.23
Coronary flow velocity pattern (CFVP) recorded within 3 days of
PCI has been reported to be useful in predicting left ventricular (LV) REPERFUSION STRATEGIES
function. CFVP in the left anterior descending artery occlusion can
be used, within 4 weeks after PCI, to predict the recovery of regional Regardless of the mode of reperfusion, the emphasis of the reperfu-
LV function in patients with reperfused anterior-wall AMI.20 sion concept is to minimize total ischemic time, which is defined as
Chapter 3  Epicardial Reperfusion 13
the time from the onset of symptoms of STEMI to the initiation of minutes and (C) bleeding risk is low (younger age, absence of poorly
reperfusion therapy. We can classify the reperfusion strategies in fol- controlled hypertension, normal body weight).6
lowing categories:
Pharmacological Reperfusion and Rescue PCI
Primary Coronary Intervention
Pharmacological reperfusion with full-dose fibrinolysis may not al-
According to the recent ACC guidelines, STEMI patients presenting ways be successful in restoring antegrade flow in the infarct artery.
to a hospital with PCI capability should be treated with primary PCI In such situations, a prompt coronary angiography with intent to
within 90 minutes of first medical contact as a systems goal.6 perform PCI is advised. In patients with cardiogenic shock (espe-
cially those less than 75 years of age), severe congestive heart failure/
Fibrinolysis pulmonary edema, or hemodynamically compromising ventricular
arrhythmias (regardless of age) this approach has demonstrated sur-
STEMI patients presenting to a hospital without PCI capability vival benefits. Another group of patients in whom rescue PCI can be
and who cannot be transferred to a PCI center and undergo PCI undertaken are the patients with failure of fibrinolysis.6
within 90 minutes of first medical contact should be treated with
fibrinolytic therapy within 30 minutes of hospital presentation Pharmacoinvasive Approach
as a systems goal unless fibrinolytic therapy is contraindicated.5
The emerging concept of pre-hospital fibrinolysis may offer a vi- A pharmaco-invasive strategy can be defined as pharmacological fi-
able option for effective and timely reperfusion of MI patients brinolysis followed by PCI after 4–6 hours. Unlike the facilitated PCI,
when the adavanced clinical setups are not easily approachable. in pharmacoinvasive strategy, PCI is delayed for 6 hours, so that it can
Newer fibrinolytics like tenecteplase may be of special impor- be performed with GpIIb/IIIa inhibitors, heparin and a loading dose
tance in this case, which is highly fibrin selective, can be given of clopidogrel without increasing the risk of hemorrhage. The recent
a single bolus injection and is resistant to plasminogen activator TRANSFER-AMI trial using pharmacoinvasive strategy has shown
inhibitor.24 reduction in 30-day mortality, reinfarction, recurrent ischemia, con-
gestive heart failure as compared to the standard fibrinolytic therapy
Facilitated PCI followed by rescue PCI if indicated. This strategy was not associated
with increase in bleeding risk.25
This is a planned immediate PCI after administration of an initial Results from GRACIA-2 indicates that the pharmacoinvasive
pharmacological regimen of high dose heparin, Gp IIb/IIIa inhibi- therapy is associated with better TIMI flow grade and better rate of ST
tor and full- or partial-dose fibrinolytic intended to improve coro- resolution than primary angioplasty indicating better microvascular
nary patency before the procedure. However, the facilitated PCI with perfusion.26
full-dose fibrinolytic is associated with higher rate of abrupt vessel
closure, reinfarction, and death versus primary PCI alone in patients Ancillary Therapy
with only modest treatment delays and treated with low-dose hepa-
rin probably due to early prothrombotic state following fibrinolytic Prolonged anticoagulant therapy more effectively with low molecu-
therapy that may increase PCI risk. Facilitated PCI using regimens lar weight heparins has been associated with improved outcomes
other than full-dose fibrinolytic therapy might be considered as a following acute coronary syndromes. Addition of aspirin and clopi-
reperfusion strategy when all of the following are present: (A) pa- dogrel should be considered in all patients regardless of the choice of
tients are at high risk, (B) PCI is not immediately available within 90 reperfusion strategy.
REFERENCES
1. Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an inter-
national trial of 41,021 patients. GUSTO-I Investigators. Circulation. 1995;91:1659-68.
2. Chopra HK, Chopra KL, Aggarwal KK, et al. Specific reperfusion arrhythmias with high dose short term IV streptokinase therapy in acute myocar-
dial infarction. Indian Heart J. 1988;40(4):232-6.
3. Burke AP, Virmani R. Pathophysiology of acute myocardial infarction. Med Clin N Am. 2007;91:553-72.
4. Björklund E, Stenestrand U, Lindback J, et al. Pre-hospital thrombolysis delivered by paramedics is associated with reduced time delay and mor-
tality in ambulance-transported real-life patients with ST-elevation myocardial infarction. Eur Heart J. 2006;27:1146-52.
5. Ortiz-Pérez JT, Lee DC, Meyers SN, et al. Determinants of myocardial salvage during acute myocardial infarction. J Am Coll Cardiol Img. 2010;3:491-
500.
6. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the management of patients with ST-
Elevation myocardial infarction. Circulation. 2008;117:296-329.
7. Esteves A, Garcia DP, Martinez EE. The “No-Reflow” phenomenon in the coronary arteries. Arq Bras Cardiol. 1999;72(1):104-8.
8. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perlusion immediately after successful thrombolysis: A predictor of poor recovery of left ven-
tricular function in anterior myocardial infarction. Circulation. 1992;85:1699-705.
9. de Lemos JA. ST-Segment resolution as a marker of epicardial and myocardial reperfusion after thrombolysis: Insights from the TIMI 14 and In
TIME-II Trials. J Electrocardiol. 2000;33:67-72.
10. Battler A, Brindis RG, Cox JL, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and
outcomes of patients with acute coronary syndromes. J Am Coll Cardiol. 2001;38(7):2115-29.
11. Kern MJ, Moore JA, Aguirre FV, et al. Determination of angiographic (TIMI Grade) blood flow by intracoronary doppler flow velocity during acute
myocardial infarction. Circulation. 1996;94:1545-52.
12. de Lemos JA, Morrow DA, Gibson CM, et al. Early noninvasive detection of failed epicardial reperfusion after fibrinolytic therapy. Am J Cardiol.
2001;88:353-8.
13. Maroko PR, Libby P, Bloor CM, et al. Reduction by hyaluronidase of myocardial necrosis following coronary artery occlusion. Circulation.
1972;46;430-7.
14. Schroder R, Dissmann R, Bruggemann T, et al. Extent of early ST segment elevation resolution: a simple but strong predictor of outcome in pa-
tients with acute myocardial infarction. J Am Coil Cardiol. 1994;24:384-91.
15. de Lemos JA, Antman EM, McCabe CH, et al. ST segment resolution and infarct related artery patency and flow after thrombolytic therapy. Am J
Cardiol. 2000;85:299-304.
16. Sorajja P, Gersh BJ, Costantini C, et al. Combined prognostic utility of ST-segment recovery and myocardial blush after primary percutaneous
coronary intervention in acute myocardial infarction. Eur Heart J. 2005;26:667-74.
17. Tanasijevic MJ, Cannon CP, Antman EM, et al. Myoglobin creatinekinase-MB and cardiac troponin-I 60-minute ratios predict infarct-related ar-
tery patency after thrombolysis for acute myocardial infarction: results from the thrombolysis in myocardial infarction study (TIMI) 10B. J Am Coll
Cardiol. 1999;34:739-47.
18. Ohman EM, Christenson RH, Califf RM, George BS, Samaha JK, Kereiakes DJ, Worley SJ, Wall TC, Berrios E, Sigmon KN, for the TAMI 7 Study
Group. Noninvasive detection of reperfusion after thrombolysis based on serum creatine kinase MB changes and clinical variables. Am Heart J.
1993;126:819-26.
19. Laperche T, Golmard J, Steg P. Early behavior of biochemical markers in patients with thrombolysis in myocardial infarction grade 2 flow in the
infarct artery as opposed to other flow grades after intravenous thrombolysis for acute myocardial infarction. Am Heart J. 1997;134:1044-51.
20. Zhang YL, Wei M, Han BB, et al. Coronary flow velocity pattern and recovery of regional left ventricular function. Tex Heart Inst J. 2010;37(2):166-
71.
21. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary
angioplasty in patients with acute anterior myocardial infarction. Circulation. 1996;93:1993-9.
22. Gibson CM, Murphy SA, Morrow DA, et al. Angiographic perfusion score: An angiographic variable that integrates both epicardial and tissue level
perfusion before and after facilitated percutaneous coronary intervention in acute myocardial infarction. Am Heart J. 2004;148:336-40.
23. Giugliano R, Sabatine MS, Gibson CM, et al. Combined assessment of thrombolysis in myocardial infarction flow grade, myocardial perfusion
grade, and ST segment resolution to evaluate epicardial and myocardial reperfusion. Am J Cardiol. 2004;93:1362-7.
24. Baruah DB, Dash RN, Chaudhari MR, et al. Plasminogen activators: A comparison. Vascular Pharmacology. 2006;44:1-9.
25. Cantor WJ, Fitchett D, Borgundvaag B, et al. Rationale and design of the trial of routine angioplasty and stenting after fibrinolysis to enhance rep-
erfusion in acute myocardial infarction (TRANSFER-AMI). Am Heart J. 2008;155:19-25.
26. Fernandez-Avile´s F, Alonso JJ, Pena A, et al. Primary angioplasty vs. early routine post-fibrinolysis angioplasty for acute myocardial infarction
with ST-segment elevation: the GRACIA-2 non-inferiority, randomized, controlled trial. Eur Heart J. 2007;28:949-60.
4 History of Beta-Blockers
Cruickshank JM
Beta-Receptor Occupancy, Selectivity

THE VERY EARLY DAYS
and the Concept of ISA
The Concept of the Adrenoceptor
The “lock and key” relationship between full β-1 (noradrenaline) and
Ahlquist,1 in 1948, described two types of adrenoceptor. The term al- β-2 (pirbuterol) stimulation and The β-1 and β-2 receptor is shown in
pha (α) to those receptors, which is the most sensitive to adrenaline Figures 4.2A and B.6 A tissue-response will occur only if the coupling
and noradrenaline and the least to isoprenaline; and the term beta mechanism (involving stimulatory guanine nucleotide regulatory
(β) to those showing the reverse pattern being the most sensitive to protein) between stimulus and response is efficient. The β-1 and β-2
isoprenaline and l-adrenaline. Lands,2 in 1967, was to demonstrate receptors could be competitively occupied by a molecule similar to
two types of β-adrenoceptor, β-1 and β-2; a β-3 receptor has now also noradrenaline and pirbuterol, but does not couple with the guanine
been demonstrated. Table 4.1 illustrates the distribution of adreno- stimulatory nucleotide regulating protein, e.g. propranolol, resulting
ceptor sub-types and the physiological effects of stimulation. in no tissue-response (Fig. 4.3).6
Some molecules will act in a similar way to propranolol, but par-
The Concept of β-Blockade tially “couple” with guanine nucleotide regulatory protein, effecting
a “partial stimulation”. This is known as partial agonist activity or ISA.
While an academic physiologist at Glasgow University Veterinary Different β-blocking molecules with ISA will stimulate to different
School James Black became aware of the harmful effects of stress degrees (Fig. 4.4).7
upon the heart and how angina pectoris and some arrhythmias Some β-blocking molecules exert a marked preference for either
could be exacerbated. He thus developed the notion that a synthetic the β-1 or β-2 receptor. ICI 118551 is a highly β-2 selective molecule
compound similar to adrenaline might act as a false key, binding while bisoprolol is a highly β-1 selective molecule. These proper-
onto so-called β-receptor sites in the heart, thus antagonising the ties can be expressed as a β-1/β-2 selectivity ratio (Fig. 4.5),8 with
effects of adrenaline and reducing the oxygen requirements of the ICI 118551 and bisoprolol at the two extremes, propranolol blocking
heart. He took these ideas to Imperial Chemical Industries’ (ICI) both receptors equally (non β-1 selective) and agents like atenolol
pharmaceutical division at Alderley Park, Cheshire in 1958 and was and metoprolol being only moderately β-1 selective.
invited to form a team dedicated to develop the concepts further. The
first β-blocker, dichloroisoprenaline, had too much intrinsic sympa- THE PHARMACOLOGY AND ADVERSE
thomimetic activity (ISA) to be of any value.3 This was followed by
REACTIONS OF DIFFERENT β-BLOCKERS
a β-blocker with much less ISA, pronetholol,4 but this project was
halted due to toxic effects in animals. Eventually, in 1964, proprano- Pharmacodynamics
lol with no ISA arrived. Propranolol was to fulfil all of James Black’s
ideas as an antianginal and antiarrhythmic agent and was also found Hemodynamics
by Brian Prichard in 19645 to lower blood pressure. During the 10 years, following the appearance of propranolol (1964)
The structural similarities of adrenalin, noradrenaline, isoprena- many different types of the β-blockers appeared on the market.
line, dichlorisoprenaline, pronetholol and propranolol are shown in Some, like propranolol, were nonselective without ISA (timolol, so-
Figure 4.1. talolol and nadolol). Others were: (A) nonselective with ISA (oxpre-
For his massive contribution to medicine, James Black was to be nolol, pindolol, alprenolol, pirbutolol, carteolol); (B) nonselective
knighted in 1981 and was awarded the Nobel Prize for Medicine in plus β-blockade (labetalol, carvedilol); (C) moderately β-1 selective
1988. Sadly both he and Brian Prichard were died within 2 weeks of without ISA (atenolol and metoprolol); (D) moderately β-1 selec-
each other in the Spring of 2010. tive plus ISA (practolol, acebutolol). These differing properties can
TABLE 4.1 Distribution of adrenoceptor sub-types and the physiological effects of stimulation
Organ Predominant Adrenoceptor Physiological Effect of Stimulation
Myocardium β-1 > β-2 Increased of contractility and heart-rate
β-3 Cardiodepression
Smooth muscle—bronchi β-2 Bronchodilatation
Smooth muscle—blood vessels α-1 Vasoconstriction
α-2 Vasoconstriction
β-2 Vasodilatation
β-3 Vasodilatation
β-1 Vasodilatation (coronary)
Smooth muscle—genitourinary α-1 Muscle contraction
β-2 Muscle relaxation
β-3 Muscle relaxation
Smooth muscle—large bowel β-2 Relaxation
β-3 Relaxation
Fat tissue α-2 Inhibition of lipolysis
β-2 > β-1 Stimulation of lipolysis
β-3 Stimulation of lipolysis and thermogenesis
Platelets α-2 Aggregation
Liver α-1 Glycogenolysis
β-2 Glycogenolysis and gluconeogenesis
Pancreas α-2 Inhibition of insulin release
β-2 Stimulation of insulin release
Sympathetic terminals α-2 Inhibition of noradrenaline release
β-2 Stimulation of noradrenaline release
Skeletal muscle (slow-twitch fibres) β-2 Less fatigue (aerobic)
Increase in tremor
Blood lipids β-2 Low triglycerides
High HDL
Kidney β-1 Renin release increase
Eye β-2 Increase in intraocular pressure
have a marked effect on the pharmacodynamic profile9 (Table 4.1). Respiratory Effects
While all agents decrease the exercise heart rate, the possession of ISA
(oxprenolol, carteolol) can abolish the fall in resting heart rate, as can Bronchial muscle contains primarily β-2 receptors. Subjects with
β-blockade (labetalol) or even increase resting heart rate (pindolol) normal respiratory function suffer no inconvenience when given
Table 4.2. All β-blockers decrease the blood pressure, but not always none or poorly β-1, selective agents. This is not so for patients with
in the same way. Agents without ISA or β-blockade lower the blood reversible airways disease10 (Fig. 4.6), where none or poorly β-1,
pressure via a fall in cardiac output (propranolol, timolol, sotalol, na- selective agents not only induced bronchospasm, but inhibited the
dolol, atenolol, metoprolol) while the possession of high nonselective bronchodilatory effects of β-2 stimulation. Here, there are marked
ISA (pindolol, carteolol) or β-blockade (labetalol) means that much of benefits for high β-1 selectivity (bisoprolol) over moderately β-1 se-
the antihypertensive action is via a fall in peripheral resistance. lective agents like atenolol.11
Chapter 4  History of Beta-Blockers 17
Figure 4.2A: Agonist activity and the β-1 receptor

Full β-1, agonist activity (efficacy), e.g. Noradrenaline
Figure 4.2B: Agonist activity and the β-2 receptor

Figure 4.1: Chemical structures of catecholamine and β-blocker Full β-2, agonist activity (efficacy), e.g. Purbuteroi
Metabolic Effects
These were shown to be a function of β-2 blockade and comprised
mainly an increase in plasma blood sugar and triglycerides and a
fall in high density lipoprotein (HDL) levels.9 Such changes could be
avoided by ISA or high β-1 selectivity, e.g. bisoprolol.12
Pharmacokinetics
Probably the major determinant of pharmacokinetic profile of Figure 4.3: Effect of full antagonist, e.g. propranolol,
a β-blocker is its lipid solubility as expressed by distribution at the β-1 and β-2 receptor
Figure 4.4: Relative degree of ISA of various β-blockers Figure 4.5: β-1 and β-2 selectivity ratios
Source: Wellstein et al. Euro Heart J. 1987
TABLE 4.2 Some of the older β-blocker hemodynamic values

Type Agent Heart Rate Blood Pressure Cardiac Output Peripheral
at Rest Resistance
Rest Exercise Rest Exercise
Non-β-1 selective with NO ISA Propranolol ↓ ↓ ↓ ↓ ↓ ↑
Timolol ↓ ↓ ↓ ↓ ↓ ↑
Sotalol ↓ ↓ ↓ ↓ ↓ ↑
Nadolol ↓ ↓ ↓ ↓ ↓ ↑
Non-β-1 selective + ISA Oxprenolol ↓↔ ↓ ↓ ↓↔ ↓↔ ↑↔
Pindolol ↓↔ ↓ ↓ ↓↔ ↓↔ ↑↔
Alprenolol ↓ ↓ ↓ ↓↔ ↓↔ ↑↔
Penbutalol ↓ ↓ ↓ ↓ ↓↔ ↑↔
Carteolol ↓↔ ↓ ↓ ↓↔ ↓↔ ↑↔↓
Non-β-1 selective + α-blockade Labetaolol ↓↔ ↓ ↓ ↓ ↔↓ ↔↑
β-1 selective with NO ISA Atenolol ↓ ↓ ↓ ↓ ↓↔ ↑↔
Metoprolol ↓ ↓ ↓ ↓ ↓↔ ↑↔
Bisoprolol ↓ ↓ ↓ ↓ ↔ ↑↔
β-1↔selective + ISA Practolol ↓↔ ↓ ↓ ↓↔ ↓↔ ↑↔
Acebutolol ↓ ↓ ↓ ↓↔ ↓↔ ↑↔
Abbreviation: ISA: Intrinsic sympathomimetic activity
Figure 4.6: Effects of different β-blockers on airways function in labile asthmatics

Source: Decalmer et al. 1978
TABLE 4.3 Beta-blocker distribution coefficients in octanol/water (high

coefficients (high = liphophilic) (Table 4.3). As a general rule highly
value = lipophilic)
liphophilic agents (e.g. propranolol) will be (A) rapidly and complete-
β-Blocker Distribution Coefficients at pH 7.4 and 37 ly absorbed for the gut, (B) heavily metabolized in the liver, (C) high-
Atenolol 0.015 ly bound to plasma proteins, (D) be widely distributed in the body
Sotalol 0.039 tissues and compartments, and (E) have short plasma half-lives. The
pharmacokinetic profiles of some of the most-used β-blockers are
Practolol 0.060
shown in Table 4.4. Some metabolized β-blockers, e.g. metoprolol,
Nadolol 0.066
are vulnerable to genetic polymorphism. About 10% of Caucasians
Acebutolol 0.68 and possibly 30% of Chinese13 are poor metabolizers of metoprolol
Pindolol 0.82 and experience very high blood-levels of drug14 (Fig. 4.7). In such
Metoprolol 0.98 patients metoprolol would lose its relative β-1 selectivity and a
Timolol 1.16 higher level of adverse reactions might be experienced.
Oxprenolol 2.28
Labetalol 11.50 Adverse Reactions
Propranolol 20.20 Beta-blockers were shown to have a high benefit/risk-ratio. Being
Penbutolol 179.0 a nonhomogeneous class of drugs adverse reactions would vary
TABLE 4.4 Pharmacokinetic profiles of some commonly used β-blockers

β-Blocker Lipid Solubility Extent Time to Peak Plasma Half- First-Pass Systemic Bio- Metabolized Active
x= water sol Absorbed Blood Level Life (hr) (liver) availability (%) (Hepatic) Metabolite
xxxx=lipid sol (% dose) (hr) Elimination
(%)
Atenolol x 40–60 2–4 6–10 0 50 No No
Bisoprolol xx > 90% 2–3 10–12 < 10 90 Yes (50%) No
Carvedilol xxx 85 1.5 6–7 60–75 25 Yes No
Labetalol xxxx > 90 1–2 3–6 60–70 30–40 Yes No
Metoprolol tartrate xxx > 90 1–3 3–4 25–50 50–75 Yes Yes (weak)
slow release 12–24
= CR/ZOK; OROs;
succinate)
Nebivolol xxxx 90 1–4 13 70 12–96 Yes yes
Oxprenolol xxx 90 1–1.5 1–2 25-80 20–75 Yes No
Pindolol xx > 90 0.5–1 2–5 20 80 Yes No
Propranolol slow xxxx > 90 1–3 3–4 70 30 Yes Yes
release 10–12
Sotalol x > 90 2–3 7–15 0 > 90 No No
Timolol xxx > 90 1–4 2–5 50-60 40–50 Yes No
Relating to β-1 Blockade
All β-blockers on the market possess, to a greater or lesser extent,

β-1 blocking properties. Adverse reactions that may be associated
with β-1 blockade are: (A) bradycardia, which is rarely symptomatic,
(B) fatigue, which tends to diminish with time (and is exacerbated
by β-2 blockade), (C) cold peripheries (via reduced cardiac output),
worse if β-2 blockade present (via vasoconstriction) and (D) very
rarely left-ventricular dysfunction (where cardiac function is criti-
cally dependent on high sympathetic nerve activity).
Relating to β-2 Blockade

As mentioned above β-2 blockade can exacerbate fatigue and cold-
peripheries observed occasionally with β-1 blockade. This is prob-
ably due to blockade of β-2 receptors in muscle and peripheral
vasoconstriction.
Beta-2 blockade can reduce renal blood flow and impair renal
function. In vulnerable patients bronchoconstriction can be induced.
Figure 4.7: Effect of oxidation phenotype on
Metabolic disturbance can occur, involving increased insulin
the metabolism of metoprolol
resistance, high blood sugar or HbA1-c, high plasma triglycerides
and low HDL levels.
according to the degree of β-1 selectivity: the presence of ISA; the Adverse reactions relating to the central nervous system are
presence of β-blocking activity, e.g. labetalol or carvedilol; the rare. Under blind, placebo-controlled conditions depression is not
presence of Class III antiarrhythmic activity, e.g. sotalol; the degree observed. Sleep disturbance and nightmares can occur with highly
of lipophilicity; unpredictale metabolism, e.g. metoprolol. liphophilic agents like propranolol and metoprolol that cross the
Figure 4.8: β-blocker brain concentrations Figure 4.9: Effect of bisoprolol and nifedipine on circadian
distribution of silent ischemia
blood-brain barrier and enter brain tissue in high concentration15 angina episodes and nitrate consumption and markedly increasing
(Fig. 4.8). Motor performance and reaction times are unaffected on effort tolerance.7
chronic dosage. Patients with chronic angina pectoris were shown to exhibit
Sexual dysfunction can occasionally occur. Under blind, place- many ischemic episodes (ST-segment reduction) on the 24-hour
bo-controlled conditions sexual dysfunction is most likely with the ECG, 85% of which were “silent”. β-blockade was shown to be highly
combination of β-1, β-2 and β-blocking properties (e.g. labetalol, effective in reducing the number of ischemic episodes, being more
carvedilol) followed by nonselective (e.g. propranolol) and mod- effective than the calcium antagonist nifedipine.18 β-1 blockade
erately β-1 selective (e.g. atenolol and metoprolol) with problems (bisoprolol) was particularly effective (vs nifedipine) in reducing
occurring at placebo-level with highly β-1 selective bisoprolol.15a ischemic episodes during the “vulnerable period” between 6.0–9.0
Weight-gain (average 1.2 kg) can occur with none or poorly β-1 am19 (Fig. 4.9) and this benefit was translated into fewer deaths,
selective β-blockers.15a myocardial infarction (MI) and hospitilization (than nifedipine) at
Skin rashes can occur rarely and psoriasis may be worsened. The 1 year.19a
occulomucocutaneous syndrome is unique to practolol (necessitat-
ing its removal from the market) and comprised: (A) psoriasiform Myocardial Infarction
rash with hyperkeratosis of the palms and soles, (B) keratoconjunc-
tivitis sicca leading to corneal opacification and ulceration, (C) otitis As for ischemic episodes on the ECG MI peaks at the vulnerable pe-
media and (D) sclerosing peritonitis. Immunological mechanisms riod between 6.0 am and noon (time of maximal sympathetic nerve
are responsible.16 Arrhyhthmias (ventricular tachycardia) can be activity), and this pattern was abolished in those receiving
induced by sotalol, which contains Class III antiarrhythmic activity; β-blockers.20
2–4% of patients experience “torsades de pointes”, which can result in A β-blocker (atenolol) given intravenously, followed by oral
death.15a therapy within 12 hours of onset of pain, was associated with a
15% significant reduction in in-hospital deaths, as shown in the
CORONARY ARTERY DISEASE; PERIPHERAL ISIS-1 study.21 However, this benefit was not seen, if thrombolysis
was administered pre-β-blocker, as shown with metoprolol in the
ARTERIAL DISEASE; ARRHYTHMIAS;
large COMMIT (Community Intervention Opidogreland Metoprolol
THE ATHEROMATOUS PROCESS in MI) trial;22 indeed there was a 30% excess of cardiogenic shock in
the β-blocker group. Thus, early (intravenous) blockade should be
Angina Pectoris
given only when the hemodynamic state is stable.
Black’s ideas were soon to be proven correct. By the mid-1960s, it was Late intervention (3–4 days post MI) with oral β-blockers had
apparent that intravenous propranolol increased the work perfor- proven highly effective23 (Fig. 4.10). β-blockers without ISA reduced
mance, as did chronic oral therapy,17 in patients with chronic angina death by about 30%, the active ingredient being β-1 blockade. The
pectoris. Propranolol was shown to be superior to nifedipine, with benefits of reduced mortality, reinfarction and infarct size were all
the combination of the two agents being highly effective in reducing positively related to the reduction in heart rate.24
Figure 4.10: Secondary prevention of myocardial infarction with Figure 4.11: Decrease Study – 112 high-risk cases for noncardiac
different types of b-blockers surgery; 3-year follow-up. Source: Poldermans et al. 2001
Source: Yusuf S et al. Progress Cardiovasc. Diseases 1985;5:335-71
Peripheral Arterial Disease Thus, exercise/stress-induced supraventricular arrhythmias,

Even to this day many, mistakenly, are of the opinion that β-blockers including post-MI, can be prevented or treated (with intravenous or
are contraindicated in patients with peripheral arterial disease oral therapy), though Wolff-Parkinson-White often does not respond
(PAD). Traditional β-blockers have little or no effect on resting/exer- to β-blockade.
cise muscle blood flow and do not reduce walking distance.9 Indeed, Paroxysmal atrial fibrillation (AF) often responds well to β-1
counter-intuitively, it is β-blockers with vasodilatory properties, such blockade in terms of prevention. Sustained AF can sometimes be
as β-blockade (labetalol) or high ISA (pindolol) that reduce walking converted into sinus rhythm, but more often a lower sustained rate
distance,25 probably via a “vascular-steal effect”. of AF is achieved. Postoperative AF can often be prevented by pro-
High-risk patients with PAD coming to nonvascular surgery ben- phylactic β-blockade as can AF associated with heart failure.
efit (improved event-free survival) from perioperative β-1 blockade The prevalence of post-MI or percuteous coronary intervention
(bisoprolol) started on low-dose 3–4 weeks presurgery and contin- (PCI) induced ventricular tachycardia or fibrillation can be
ued postsurgery26 (Fig. 4.11). Starting the β-blocker (metoprolol) the significantly decreased by prophylactic β-blockade.15a This befit can
day before surgery at too high a dose may result in an increase in be attributed to β-1 blockade.
stroke-rate.27 β-blockade (atenolol) in high risk middle-aged hyper- Ventricular arrhythmias associated with mitral valve prolapse,
tensives can reduce (by approximately 60%) the appearance of PAD long Q-Tc syndrome, hypertrophic cardiomyopathy, anesthesia/sur-
end-points.18 gery or pacemakers, often respond well to β-1 blockade.15a
Patients with dissecting aneurysms may benefit from
β-blockade.15a Aortic aneurysms coming to surgery benefit from β-1 Atheroma Progression/Regression
blockade (bisoprolol).26 Dissecting aneurysms often require urgent
surgery, but for those managed conservatively the β-blockers are the In stressed animals fed atheromatous diets coronary atheroma can
cornerstone of treatment.15a be reduced by about 60% by propranolol.28
In humans, the atheromatous process has an underlying
Arrhythmias inflammatory process and the siting of the atheromatous lesions is
dependent on blood flow patterns.15a Lesions are common at sites of
Many arrhythmias are linked to either underlying coronary artery flow-disturbance, e.g. oscillatory flow, and absent where endothelial
disease or increased sympathetic nerve activity; such arrhythmias shear-forces are high, e.g. laminar blood flow. β-blockade encourages
often can be prevented or respond excellently to β-blockade.15a laminar blood flow, probably related to their bradycardic effect.15a
All this was to change in 2006 when [primarily as a result of two

negative results for the first-line atenolol in two studies of elderly
hypertensives [LIFE (Losartan intervention for Endpoint reduction
in hypertension study) and ASCOT (Anglo-Scandinavian Cardiac
Outcomes Trial)] the UK NICE Committee, supported by the
British Hypertension Society30 recommended that: (1) β-blockers
were no longer to be a preferred the first-line choice, (2) that the
combination of β-blocker and a diuretic was to be discouraged
due to the increased risk of Type-2 diabetes; (3) in patients aged
55 years or less the first-choice for initial therapy should be an
ACE-inhibitor [or angiotensin receptor blocker (ARB) if an ACE-
inhibitor was not tolerated].
Could so many experts have got it wrong? The author of
this chapter strongly disagreed with the NICE Committee
Figure 4.12: Decrease in coronary atheromatous volume (mm3) by BBs recommendations,15a,31 for reasons set out below.
over 1 year (independent of statins, ACE inhibitors, other drugs, LDL Conc. HR
Source: Sipahi I, et al. 2007
The Pathophysiology of Essential/
Primary Hypertension
It thus came as no surprise that β-blockers actually regressed Several large studies have described a link between the development
the coronary atheromatous volume in humans as assessed by intra- of diastolic hypertension in the young/middle-aged and a high
vascular ultra sound (Fig. 4.12).29 body mass index (BMI). The Framingham group32 was one of the
groups, who also showed that the development of isolated systolic
BETA-BLOCKERS IN HYPERTENSION hypertension (wide pulse-pressure) was a function of ageing, stiff
arteries (Table 4.5).
As already mentioned propranolol was first noted to lower blood The development of diastolic hypertension in young/middle-
pressure in 1964.5 β-blockers were to become a cornerstone in aged was linked not only to central obesity, but also to a high heart
the treatment of hypertension. The UK adopted the AB/CD rule, rate and cardiac output,33 suggesting high sympathetic nerve activ-
with either angiotensin-converting-enzyme (ACE)-inhibitors ity. This was indeed the case,15a,31 indicating (in theory at least) a
(A) or β-blockers (B) as first-line therapy in the young/middle- perfect scenario for the first-line β-blockade. What was the evidence
aged hypertension (high renin) and in the elderly (low renin) (hard end-points) from large, randomized, controlled clinical trials
first line calcium blocker (C) or diuretic (D) was recommended. in younger hypertensives.
TABLE 4.5 The Framingham Heart Study—different predictors of diastolic hypertension (IDH ± systolic hypertension) and isolated systolic hypertension
Predictors of IDH (± systolic hypertension) = DBP > 90 mm Hg Predictors of ISH-SBP > 140 mm Hg + < 90 mm Hg
(± SBP > 140 mm Hg)
Young age Older age
Male sex Female sex
High BMI at baseline Increasing BMI during follow-up (but much weaker than in young)
Increasing BMI during follow-up ISH arises more commonly from normal and high normal BP than “burned
out” diastolic hypertension
Main mechanism of IDH is raised peripheral resistance Only 18% with new-onset ISH had a previous DBP > 95 mm Hg
Main mechanism of ISH is increased arterial stiffness (poor vascular
compliance)
Abbreviations: N, 3915 untreated normal subjects, mean age 48.5 years, followed-up for 10 years; IDH: Isolated diastolic hypertension; ISH: Isolated
systolic hypertension; BMI: body mass index
TABLE 4.6 Randomized, controlled, hard-endpoint studies in younger/middle-aged diastolic hypertensives (± diabetes) involving 1st line β-blocker
therapy
Trial β-Blockers (vs comparator) Mean Age (y) Initial β-Blockers (mm Hg) Pulpse-Pressure (mm Hg)
IPPPSH Oxprenolol (vs diuretic) 52 173/108 65
MRC Mild Propranolol (vs diuretic vs placebo) 51 161/98 63
Hypertension
MAPHY Metoprolol (vs diuretic) 52 167/108 59
UKPDS Atenolol (vs captopril) 56 159/94 65
Abbreviations: IPPSH: International prospective primary prevention study in hypertension; MRC: Medical Research Council; MAPHY: the metoprolol
atherosclerosis prevention in hypertensives; UKPDS: UK prospective diabetes study
Figure 4.13: β-Blockers in hypertension – MRC-1 Figure 4.14: β-blockers/Smoking interaction (MI) in
young/mid-age hypertensives
First-Line β-Blockers in the Young/Middle- middle-aged, being 2–3 more common than stroke) it is apparent
Aged Hypertensive; Major Randomized, that the 35–50% reduction in MI by the β-blockers relative to placebo
or diuretic therapy is nullified by smoking (Fig. 4.14). What is the
Controlled, Harden-Point Studies
mechanism of the smoking interaction? Smoking is associated with
The four major hard-end-point studies involving the first-line a 2–3 fold increase in adrenaline secretion37 lasting for at least 30
β-blockers are outlined in Table 4.6.15a In order to appreciate the minutes. Adrenaline stimulates β-1, β-2 and β-receptors, so that in
strengths and weaknesses of β-blockers, it is important to view the the presence of nonselective (oxprenolol, propranolol) or moderately
results in terms of cigarette-smoking status, as vividly illustrated in β-1 selective (metoprolol, atenolol) there would be unopposed
the Medical Research Council (MRC) Mild Hypertension Study34 (total or partial) β-constriction resulting in a marked hypertensive
(Fig. 4.13). About 30% of the study population were smokers, and response. This is vividly illustrated in Figure 4.1538 where, in the
it is clear that the 33% reduction in MI and 54% reduction in stroke presence of raised adrenaline levels, the increase in mean blood
by propranolol versus placebo seen in nonsmokers are totally pressure (vs control) is marked with nonselective β-blockers (about
cancelled by smoking. The smoking issue was also addressed in 30 mm Hg) moderate with modestly β-1 selective metoprolol (9–10
the IPPPSH (International prospective primary prevention study in mm Hg) and absent with highly β-1 selective bisoprolol.
hypertension) and MAPHY (metoprolol atherosclerosis prevention The fourth study in Table 4.6 is the UKPDS study,39 which did
in hypertensives).35,36 studies involving oxprenolol and metoprolol not address the smoking issue. It examined the effect of tight hyper-
respectively. Concentrating on MI (number one killer in young/ tension control (with randomized first-line atenolol or captopril,
Figure 4.15: Perioperative interaction between adrenaline and Figure 4.16: UKPDS – all primary end-point trends favor atenolol
β-blockers. Source: Tarnow J, Muller R 1991 versus captopril
second-line diuretics) versus less-tight control (acting as surrogate primary care after 10 years of follow-up) exhibited a significant 23%
placebo), in obese (men BMI = 30) hypertensives with Type 2 diabe- reduction in all-cause death compared to those randomized to the
tes. The difference between tight and less-tight control was 10/5 mm ACE-inhibitor (may be the ability of the β-blocker to regress athero-
Hg. After 9–10 years follow-up all seven primary end-point trends ma is relevant here).
(plus heart failure prevention) favored the β-blocker; Figure 4.1615a
shows the contribution of atenolol and captopril in reducing the sev- First-Line β-Blockers in the Elderly Systolic
en primary end-point (plus heart failure) versus less-tight control of
Hypertensive; Major Randomized, Controlled,
blood pressure. Worthy of note is: (A) the approximate 50% reduction
stroke by atenolol, (B) the approximate 60% reduction in PAD and
Hard-End-Point Studies
heart-failure end-points by atenolol and (C) the absence of special The results of the major hard-end-point studies have not been fa-
renoprotection (microvascular) by captopril.40 At 20-year follow- vorable to first-line β-blockade15a (Table 4.7). All involved atenolol
up41 those originally randomized to atenolol (patients discharged to which did not compare well versus placebo and diuretic therapy—
TABLE 4.7 First-line β-blockers (atenolol) perform poorly in elderly systolic hypertension (wide pulse-pressure)
Trial β-Blocker (vs Mean Age (y) Initial BP (mm Hg) Pulse-Pressure Result
comparator agent) (mm Hg)
MRC Elderly Atenolol (vs placebo vs 70 185/91 94 Only diuretics differed from placebo in stroke
diuretic) prevention; diuretic superior to atenolol in
reducing coronary events
HEP Atenolol (vs non- 69 196/99 97 Significant reduction in stroke but no effect on
treatment) coronary events by atenolol
LIFE Atenolol (vs losartan) 67 174/98 76 Losartan superior to atenolol in reducing CV
mortality and non-fatal and fatal stroke
ASCOT Atenolol ± Diuretic 63 164/94 70 Amlodipine ± perindopril was superior to
(vs amlodipine ± atenolol ± diuretic in reducing all-cause mortality
perindopril) and all coronary and stroke end-points
Abbreviations: MRC: Medical Research Council; LIFE: Losartan intervention for Endpoint reduction in hypertension study; ASCOT: Anglo-Scandinavian
Cardiac Outcomes Trial; CV: Cardiovascular
MRC elderly study,42 angiotensin receptor antagonist—LIFE Study43 cause death at 20-year follow-up; ARBs may not prevent MI
and amlodipine—ASCOT Study.44 Only when coronary artery dis- in younger hypertensives.
ease was also present—INVEST Study,45 did first-line atenolol per- • Nonappreciation of the powerful smoking-interaction, which di-
form, as well (and better at preventing heart failure) as the calcium lutes the marked benefits of first-line nonselective and modestly
blocker verapamil. β-1 selective β-blockers in nonsmoking younger hypertensives.
Why do first-line β-blockers perform so poorly in the elderly
systolic hypertensive without coronary artery disease? The answer Beta-Blocker and Left Ventricular Hypertrophy
lies in the central, aortic blood pressure, which in the elderly is more
potent than peripheral pressures in predicting cardiovascular (CV) Meta-analyses that do not take age into account age usually conclude
events. Due to the stiff arteries the reflected wave (from periphery that β-blockers, compared to ACE-inhibitors, are not very effective
back to the heart) is speeded up, so that it arrives during systole (un- in reversing left ventricular hypertrophy (LVH).15a However, in the
like the younger patient where it arrives during diastole, thus aid- young/middle-aged hypertensive LVH is dependent on both blood
ing coronary artery filling) causing augmentation of central systolic pressure and high sympathetic nerve activity15a and should be effec-
pressure and a widening of the pulse-pressure. First-line β-blocker tively reversed by β-1 blockade. This is indeed the case, with highly
(atenolol) is ineffective in lowering central systolic pressures, unlike β-1 selective bisoprolol being at least as effective as ACE-inhibition
diuretic and calcium blocker therapy which are effective.46 This poor in reducing all parameters of LVH.49
effect of classic β-blockers like atenolol probably arises due to an By contrast, in the elderly systolic hypertensive β-blockade is
absence of vasodilatation. relatively ineffective in reducing LVH15a undoubtedly due to the rela-
So, where do β-blockers belong in the treatment of the elderly? tively minor effects on central systolic pressure.15a,46
The answer is second-line to either diuretic or calcium blocker
therapy. First-line diuretic and second-line β-blocker therapy was BETA-BLOCKERS AND HEART FAILURE
shown to be particularly effective in preventing CV end-points in
the MRC elderly study versus placebo,42 the SHEP study versus
History
placebo47 and the vast ALLHAT study versus first-line β-blocker,
calcium blocker and ACE-inhibitor.48 The likely reason for this is It is counter-intuitive that β-blockers should be beneficial to patients
that a diuretic improves vascular compliance and raises plasma with systolic heart failure or heart failure with reduced ejection
renin and sympathetic nerve activity, thus creating a hemodynamic fraction (HFREF), due to their acute action resulting in a fall in left-
scenario similar to younger diastolic hypertensive where β-blockers ventricular contractility and cardiac output.9 Indeed even very low
do well. As the smoking interaction is observed with second-line doses of propranolol are known to sometimes to precipitate severe
atenolol42 the best choice would be highly β-1 selective bisoprolol, low-output heart failure in frail elderly patients with ischemia.50
thus avoiding the adrenaline/β-blocker hypertensive response.39 However, chronic dosing of β-blockers in HFREF results in
favorable hemodynamic changes (increased ejection fraction) and
So How Did the UK NICE Committee improved effort tolerance.15a,51 The first indication that β-blockers
might benefit morbidity/mortality came from postinfarction studies
Get It So Wrong?15a
where patients with heart failure did better on propranolol (BHAT) or
• Failure to appreciate that younger diastolic hypertension is timolol than patients without heart failure versus placebo.15a Exciting
closely linked to central obesity, high sympathetic nerve activity results also arose from a placebo-controlled study in patients with
and a high cardiac output; a scenario ideal for β-1 blockade. idiopathic dilated cardiomyopathy where only two patients receiving
• Inappropriate attention to the poor results of first-line β-blockade metoprolol, compared to 19 on placebo, required an eventual cardiac
(atenolol) in the elderly hypertensive. transplant.52 The scene was thus set for large, placebo-controlled
• Inappropriate attention to surrogate end-points, such as blood hard-endpoint studies.
sugar levels and uncontrolled observational data regarding drug-
induced (β-blocker and diuretic) diabetes and CV events, at the Placebo-Controlled, Hard-Endpoint Studies
expense of long-term (15–20 years) randomized, prospective,
in Patients with HFREF on Background
placebo (or surrogate placebo)—controlled studies (i.e. UKPDS.
SHEP), which indicate that drug-induced metabolic changes are
of ACE-Inhibition
not harmful to the patient. Results in relation to all-cause death are shown in Table 4.8 and
– Ignoring the facts that (A) in the only comparison between Figure 4.17.15a It is noteworthy that significant positive results were
β-blocker and ACE-inhibition in the young/middle-aged observed only with β-blockers without ISA (carvedilol, metoprolol
(UKPDS) all trends (for the 7 primary end-points) over 10 succinate, bisoprolol) where the reduction in all-cause death was
years favored the β-blocker, becoming significant for all- 34.5%. The common property of the three effective agents was
TABLE 4.8 Placebo-controlled heart-failure trials involving β-blockers–effects on all-cause death

Study β-Blockers ISA HF Severity Number of All-Cause Statistic
Patients Mortality Significance
Positive Trials CIBIS II Bisoprolol (high β-1 selective) No Mod—severe 2,649 ↓34% Yes
MERIT Metoprolol succinate (mod β-1 No Mild—moderate 3,991 ↓34% Yes
selective)
COPERNICUS Carvedilol (non-selective + No Severe 2,289 ↓35% Yes
α-blocker)
Negative Trials Xamoterol Xamoterol (β-1 selective) 43% β-1 ISA Mod—severe 516 ↑249% Yes
BEST Bucindolol (weak α-blocker + 25% ISA Mod—severe 2,708 ↓10% No
non selective)
SENIORS Nebivolol (β-1 selective) Both β-2 and Mod—severe 2,128 ↓12% No
β-3 ISA
Abbreviations: CIBIS: Cardiac Insufficiency Bisoprolol Study; COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival; BEST: Beta Blocker
Stroke Trials; SENIORS: Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure; ISA: Intrinsic
sympathomimetic activity
Figure 4.17: β-blockers and hard end-point placebo-controlled trials Figure 4.18: CIBIS III – prevention of sudden death with bisoprolol
in heart failure; ISA reduces efficacy (all-cause death) Source: Results of the CIBIS III study: Circulation, 2005;112:121.
β-1 blockade, indicating that this was the active ingredient. In Mechanisms of Benefit
contrast, negative or nonsignificant results (in reducing all-cause
death) occurred with the agents with ISA (xamoterol, bucindolol, These include: (A) bradycardia (reduced cardiac work and prolonged
nebivolol). diastolic filling-time, (B) antiarrhythmic activity, (C) up-regulation
of β-receptors, (D) inhibition of renin-angiotensin system, (E) inhi-
First-Line β-Blockade versus bition of catecholamine-induced necrosis/apoptosis/inflammation,
(F) restoration of calcium-release channel/cardiac ryanodin recep-
First-Line ACE-Inhibition
tor function.
The Cardiac Insufficiency Bisoprolol Study (CIBIS) III study
addressed this issue.53 Bisoprolol was “not inferior” to ACE inhibi- Heart Failure Primary Prevention
tion in reducing the primary end-point of all-cause mortality or
hospitalization, and was significantly superior in reducing sudden The two main causes of heart failure are MI and hypertension.
death (46% less common in the β-blocker group) (Fig. 4.18). Surprisingly, there are no convincing data from randomized con-
trolled studies in postinfarction patients that heart failure can be Pharmacology and Adverse Reactions
prevented by β-blockade. This is not the case in hypertension.
The best example of heart failure prevention with first-line All β-blockers lower the exercise heart rate and cardiac output
β-blockade in hypertension is from the UKPDS study38 (Fig. 4.16). (mainly via β-1 blockade), but those with ISA or β-blocking
When the components of “tight control” (i.e. atenolol and capto- properties less so. Likewise, all β-blockers without ISA or
pril) are compared to “less-tight control” (10/5 mm Hg less) it is β-blocking properties lower blood pressure via lowering cardiac
apparent that atenolol is associated with an approximate 65% re- output, but others with ISA or β-blocking properties also reduce
duction in the appearance of heart failure (vs about 50–55% on peripheral resistance. Blockade of the β-2 receptors increases
captopril). peripheral resistance, can induce bronchospasm, causes
metabolic changes, e.g. increase in triglycerides and lowering of
OTHER INDICATIONS HDL levels and can induce sexual dysfunction (particularly when
combined with β-blockade, e.g. labetalol and carvedilol). The fall
Space does not permit a discussion on the many other probable or in cardiac output can sometimes cause fatigue or cold peripheries
possible indications for β-blockade that have appeared over the last (as can β-2 blockade).
45 years or so, other than to list the main disease areas. These topics
have been covered in detail elsewhere.54 Coronary and Peripheral Artery
Disease and Arrhythmias
Cardiovascular Disease
Beta-blockers were shown to be effective antianginal agents and
Pheochromocytoma; Fallot’s tetralogy; hypertrophic obstructive benefitted patients in the post-MI period; the benefit being via β-1
cardiomyopathy (HOCM); dissecting aneurysm; hyperkinetic heart blockade, with ISA lessening efficacy. Patients with PAD can ben-
syndrome; idiopathic orthostatic hypotension; portal hypertension. efit from β-1 blockade, particularly in the perioperative period. The
atheromatous process can be reversed by β-blockade. Arrhythimias
Metabolic Disorders (both supraventricular and ventricular), particularly if stress/emo-
tion-induced, often respond well to β-1 blockade.
Thyrotoxicosis, hyperparathyroidism, acute porphyrias, the dumping
syndrome (postgastrectomy hypoglycemia) and carcinoid syndrome. Hypertension
Neurological (Including Eye) and Psychiatric A major set-back for β-blockers was the UK NICE Committee’s rec-
ommendation that these agents should no longer be a preferred
Anxiety/stress; schizophrenia and psychosis; drug-addiction; alco- first-line choice (based mainly on two negative studies with first-
holism; tremors; migraine; narcolepsy/cataplexy/sleep paralysis; line atenolol in elderly hypertensives (LIFE and ASCOT). However,
restless leg (akathisia); head injury/trauma; subarachnoid hemor- the age-factor was ignored. Younger/middle-aged diastolic hy-
rhage; glaucoma. pertension is closely linked to central obesity, a high cardiac out-
put and sympathetic nerve activity, in contrast to elderly systolic
SUMMARY AND CONCLUSIONS hypertension, which is a reflection of ageing, stiff/noncompliant
arteries.
In younger hypertensives nonselective (propranolol and ox-
The Very Early Days
prenolol) and moderately β-1 selective (metoprolol) agents were
Alpha and beta-receptors were first described by Ahlquist in 1948, highly effective in preventing MI (number one killer) in non-
the β-receptors being subdivided into β-1 and β-2 by Lands in 1967. smokers; this benefit was negated in smokers (smoking induces
It was James Black who, in the late 1950s, developed the concept high adrenaline concentration and in the presence of β-1 and
of β-blockade arising from his observations that stress (adrenaline β-2 blockade there is uninhibited β-constriction with marked in-
and noradrenaline) could induce angina and MI. Propranolol (ICI) creases in blood pressure avoided by high β-1 selectivity, e.g. biso-
was the first β-blocker to reach the market in 1964 and was soon prolol). In the UKPDS study involving middle-aged, over-weight
shown to be not only a highly effective antianginal agent, but also hypertensives with Type 2 diabetes, over a 10-year follow-up pe-
an antiarrhythmic and antihypertensive agent. In the next few years riod the trends in reduction of all seven primary end-points all fa-
β-blockers that could partially stimulate (ISA), as well as block the vored atenolol over the ACE-inhibitor captopril, achieving signifi-
β-receptor appeared (e.g. practolol) or selectively block either the cance at 20 years follow-up for all-cause death. Thus β-1 blockade
β-1 (e.g. bisoprolol) or β-2 receptors (e.g. ICI 118551) or block both should be the first-line treatment of choice in young/middle-aged
(e.g. propranolol). patients.
By contrast in elderly systolic hypertension first-line atenolol the hemodynamic situation, reducing the need for cardiac trans-
performed poorly versus diuretic, calcium blocker and angiotensin plantation. Hard-end point, placebo-controlled studies (on ACE-
receptor blocker therapy, due to the fact that β-blockade is poor at inhibitor background) showed that all cause of death could be re-
lowering central systolic pressures. β-blockers are best given second- duced by a significant 35% by β-blockers without ISA (carvedilol,
line to either diuretics of calcium blockers, unless coronary artery metoprolol succinate, bisoprolol). First-line β-blocker (bisoprolol)
disease is also present (indicating first-line β-blockade). was shown to be at least as good as first-line ACE-inhibitor in reduc-
ing death/hospitalization and probably better in reducing sudden
death.
Heart Failure In young/middle-aged hypertensives β-blockade (UKPDS) is
In the early days, β-blockers were considered to be contraindicated highly effective in preventing heart failure.
in heart failure. However, chronic therapy was noted to improve
REFERENCES
1. Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586-600.
2. Lands AM, Arnold A, McAuliff JP, et al. Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967; 214:597-8.
3. Moran NC, Perkins ME. Adrenergic blockade of the mammalian heart by a dichloro analogue of isoproterenol. J Pharmacol Exp Ther. 1958;124:223-
37.
4. Black JW, Stevenson JS. Pharmacology of a new adrenergic beta-receptor blocking compound (Nethalide). Lancet. 1962;2:311-4.
5. Prichard BNC, Gillum PMS. Use of propranolol on the treatment of hypertension. BMJ. 1964;2:725.
6. Cruickshank JM. Measurement and cardiovascular relevance of partial agonist activity (PAA) involving beta-1 and beta-2 adrenoceptors. Pharma-
col Ther. 1990;46:199-242.
7. Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice, 2nd edition. Edinburgh: Churchill Livingstone; 1994. P. 95.
8. Wellstein A, Palm D, Belz GG. Affinity and selectivity of beta-adrenoceptor antagonists in vitro. J Cardiovasc Pharmacol. 1986;8(suppl):S36-40.
9. Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice. 2nd editition. Edinburgh: Churchill Livingstone; 1994. pp. 87-257.
10. Decalmer PB, Chatterjee SS, Cruickshank JM, et al. Beta-blockers and asthma. Br Heart J. 1978;40:184-9.
11. Dorow P, Bethge M, Tonnesmann V. Effects of single oral doses of bisoprolol and atenolol on airways function in non-asthmatic chronic obstruc-
tive lung disease and angina pectoris. Eur J Clin Pharmacol. 1986;31:143-7.
12. Fogari R, Zoppi A. The clinical benefits of beta-1 selectivity. Rev Contemp Pharmacother. 1997;8:45-54.
13. Kalow W. The metabolism of xenobiotics in different populations. Can J Physiol Pharmacol. 1982;60:1-12.
14. Lennard MS, Silas JH, Freestone S, et al. Oxidation phenotype—a major determinant of metoprolol metabolism and response. N Engl J Med.
1982;307:1558-60.
15. Neil-Dwyer G, Bartlett J, McAinsh J, et al. Beta-blockers and the blood brain barrier. Br J Clin Pharmacol. 1981;11:549-53.
15a. Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. Shelton Ct, PMPH-USA; 2010.
16. Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice, 2nd editition. Edinburgh: Churchill Livingstone; 1994. pp. 962-4.
18. Lynch P, Dargie H, Krikler S, et al. Objective assessment of anti-anginal treatment: a double-blind comparison of propranolol, nifedipine and their
combination. BMJ. 1980:281:184-7.
19. Von Arnim T. Medical treatment to reduce total ischemic burden: Total Ischemic Burden Bisoprolol Study (TIBBS), a multicentric trial comparing
bisoprolol and nifedipine. J Am Coll Cardiol. 1995;25:231-8.
19a. Von Arnim. Prognostic significance of transient ischemic episodes: response to treatment shows improved prognosis results of the TIBBS follow-
up. J Am Coll Cardiol. 1995:25 (suppl); 88A.
20. Muller JE, Stone PH, Turi ZG, et al. and the MILIS Study Group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl
J Med. 1985;313:1315-22.
21. ISIS-1 (First International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous atenolol among 16,027 cases of sus-
pected acute myocardial infarction. Lancet. 1986;2:57-66.
22. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial). Early intravenous and oral metoprolol in 45,852 patients with acute myo-
cardial infarction; randomised, placebo-controlled trial. Lancet. 2005;366:1622-32.
23. Yusuf S, Peto R, Lewis J, et al. Beta-blockade during and after myocardial infarction; an overview of the randomised trials. Prog Cardiovasc Dis.
1985;27:335-71.
24. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials.
Am J Cardiol. 1986;57:43F-49F.
25. Roberts DH, Tsao Y, Mc Loughlin GA, et al. Placebo-controlled comparison of captopril, atenolol and pindolol in hypertension complicated by
intermittent claudication. Lancet. 1987;2:650-3.
26. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high risk patients undergo-
ing vascular surgery. N Engl J Med. 1999;341:1789-94.
27. POISE Study Group, Devereaux PJ, Yang H, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery
(POISE trial) : a randomised controlled trial. Lancet. 2008;371:1839-47.
28. Cruickshank JM, Smith JC. The beta-receptor, atheroma and cardiovascular damage. Pharm Ther. 1989;42:385-404.
29. Sipahi I, Tuzcu EM, Woski KE, et al. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography
trials. Am Intern Med. 2007;147:10-8.
30. NICE clinical guidelines 34. Hypertension management of hypertension in primary care. [online] Available from www.nice.org.uk, ISBN 1-84629-
222-0. [Accessed June 212].
31. Cruickshank JM. Are we misunderstanding beta-blockers. Internat J Cardiol. 2007;120:10-27.
32. Franklin SS, Pio JR, Wong ND, et al. Predictors of new-onset diastolic and systolic hypertension.The Framingham Heart Study. Circulation.
2005;111:1121-7.
33. Drukteinis JS, Roman MJ, Fabsitz RR, et al. Cardiac and systemic haemodynamic characteristics of hypertension and prehypertension in adoles-
cents and young adults. The Strong Heart Study. Circulation. 2007;115:221-7.
34. Medical Research Council Working Party. MRC trial of treatment of mild hypertension principal results. BMJ. 1985;291:97-104.
35. IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomised trial of treatment-based on the beta-blocker oxprenolol. J Hy-
pertens. 1985;3:379-92.
36. Wikstrand J, Warnold T, Tuomilehto J, et al. Metoprolol versus diuretics in hypertension. Morbidity results from MAPHY study. Hypertension.
1991;17:579-88.
37. Cryer PE, Haymond MW, Satiago JV, et al. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated haemody-
namic and metabolic events. N Engl J Med. 1976;295:573-7.
38. Tarnow J, Muller RK. Cardiovascular effects of low-dose epinephrine infusions in relation to the extent of pre-operative beta-blockade. Anaesthe-
siology. 1991;74:1035-43.
39. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type-2 diabe-
tes. UKPDS 38. BMJ. 1998:317:703-13.
40. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in
type-2 diabetes: UKPDS 39. BMJ. 1998;317:713-20
41. Holman RR, Paul SK, Bethel MA, et al. Long-term follow-up after tight control of blood pressure in type-2 diabetes. N Engl J Med. 2008;359:1565-
76.
42. Medical Research Council working party. MRC trial of treatment of hypertension in older adults: principal results. BMJ. 1992;304:405-12.
43. Kjeldsen SE, Dahlof B, Devereux RB, et al. Effect of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hyperten-
sion and left-ventricular hypertrophy (LIFE). JAMA. 2002;288:1491-8.
44. Dahlof B, Sever P, Poulter N, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as
required versus atenolol adding bendroflumethzide, as required (ASCOT-BPLA); a multicentre randomised controlled trial. Lancet. 2005;366:895-
906.
45. Pepine CJ, Handberg EM, Cooper-Dehoff RM, et al. A calcium antagonist vs non-calcium antagonist hypertension treatment strategy for patients
with coronary artery disease (INVEST). JAMA. 2003;290:2805-16.
46. Morgan T, Lauri J, Bertram D, et al. Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens. 2004;17:118-23.
47. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension.
JAMA. 1991;265:3255-64.
48. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients ran-
domised to ACE-inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288:2981-97.
49. Goss P, Routaut R, Herreo G, et al. Beta-blockers vs ACE-inhibition in hypertension: effects on left-ventricular hypertrophy. J Cardiovasc Pharma-
col. 1990;16:S 145-50.
50. Greenblatt DJ, Koch-Weser J. Adverse reactions of propranolol in hospitalised medical patients: a report from the Boston Collaborative Drug Sur-
veillance Program. Am Heart J. 1973;86:478-84.
51. Dubach P, Myers J, Bonetti P, et al. Effects of bisoprolol fumarate on left-ventricular size, function and exercise capacity in patients with heart fail-
ure. Am Heart J. 2002;143:676-83.
52. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metolpolol in Dilated Cardio-
myopathy (MDC) Trial Study Group. Lancet. 1993;342:1441-6.
53. Willenheimer R. The current role of beta-blockers in chronic heart failure: with special emphasis on the CIBIS III trial. Eur Heart J. 2009;11(suppl
A):A 15-20.
5 History of Antithrombotic
Agents
Jariwala P, Chandra KS
ders (antiplatelet agents, anticoagulants and thrombolytics) is rich in

INTRODUCTION
historical lessons. This review highlights the historical perspective of
Vaso-occlusive disorders due to arterial thrombosis which include important antithrombotic agents.
unstable angina, myocardial infarction (MI), transient ischemic
attacks (TIAs), stroke and peripheral vascular disease remain major ANTIPLATELET AGENTS
sources of morbidity and mortality throughout the world.1 Platelet
activation and aggregation play a major role in the pathogenesis of
Aspirin
these thromboembolic diseases. Recognition of the contribution of
platelets to the pathophysiology of cardiovascular disease (CVD) The year, 1997 marks the centenary of the first and the most com-
has provided impetus for the continued search for new antiplatelet mercially successful synthetic drug the world has seen: acetylsali-
agents. Hence, over the past 2 decades many strategies have been cylic acid (aspirin).8 Acetylsalicylic acid is obtained by acetylation of
evaluated in the search for efficacious mechanisms to reduce plate- salicylic acid. The name of this acid comes from Latin Salix means
let function.2,3 willow. This fatty acid has been isolated for the first time in the bark of
Heparin and the vitamin K antagonist warfarin have been in clin- this tree. The brand name aspirin was introduced in 1899 by the com-
ical use for more than 50 years. Importantly, all of the discoveries in pany Bayer. The name was composed of “a” (referring to the acetyla-
antithrombotic agents led to important advances in our understand- tion), and “Spirin” (which refers to the acid spirique). The acid was
ing not only of antithrombotic processes, but also of procoagulant extracted from the spirique Spiraea ulmaria, Latin name given at that
systems.4 There have been tremendous growth in our understanding time to Queen-of-Pres.
of the molecular mechanisms of platelet aggregation and coagula- Salicin is found in the willow, poplar trees and the black haw
tion cascade and several new antithrombotic agents emerged in the plant. Other salicylates, such as methyl salicylate can be derived from
last recent years. Several well-designed clinical trials have been car- birch trees, coffee, liquorice, olive, wintergreen, and various shrubs
ried out in the prevention or treatment of vascular thrombosis with and grasses. In addition, smaller amounts of salicylates also occur in
already known or newly developed agents. The efficacy of antiplate- orange, apple, strawberry, cherry, plum, raspberry and grape plants,
let agents has been established after several years of uncertainty but, as well as other plants and shrubs. Salicylates can also be derived
since 1983, several studies have demonstrated the therapeutic value from animals, for example, a glandular beaver secretion (beaver cas-
of aspirin and ticlopidine in the prevention of arterial thrombosis.5 tor) contains salicylates.9 It was soon realized that spirique acid and
There are two classes of antithrombotic agents: antiplatelets and salicylic acid were one and the same substance. Bark willow is known
anticoagulants. Antiplatelet molecules block the physical process since antiquity for its healing powers. Decoction of willow leaves in
(traditionally referred to as the cellular process), whereas anticoagu- an Egyptian papyrus dating 1550 Ave. AD. The famous Greek physi-
lants inhibit the chemical process (also referred to as the humeral cian Hippocrates (460–377 Ave. AD) recommended already a prepa-
process).6 ration from the white willow bark to relieve pain and fever. The Ro-
Compounds originally came from plant, animal, human urine, mans also knew of its properties, the Latin name for willow is Salix.
cell culture or bacterial sources. The current versions are prepared by The Reverend Edward Stone, from Chipping Norton, Oxford
simple chemical synthesis (e.g. aspirin, warfarin), purification from shire, UK, is generally recognized as giving the first scientific de-
animal tissues (e.g. heparin and related compounds), bacterial cul- scription in 1763 of the beneficial effects of willow bark in a letter to
tures [e.g. streptokinase (SK)], human cell cultures (e.g. urokinase) the Earl of Macclesfield, President of The Royal Society, (Fig. 5.1) in
or by recombinant deoxyribonucleic acid (DNA) technology (e.g. which he describes successfully treating patients with ague (fever,
tissue-type plasminogen activator).7 The history of the discovery usually taken to be malaria) with 20 grains (about 1 g) of powdered
and development of agents for the treatment of thrombotic disor- willow bark in a dram of water every 4 hours. In his report, Stone
making acetylsalicylic acid but, again, it was ignored. In 1860, Kolbe

and Lautemann at Marburg University developed a practical method
to prepare salicylic acid from phenol in large quantities. Kolbe was
later to join the Bayer Company and, in 1874, one of his students, von
Heyden, set up in Dresden the first large factory for synthetic produc-
tion of salicylic acid.9
Felix Hoffmann, German chemist, joined the Bayer laborato-
ries in 1894, which in October 1897, incorporating the earlier work
of Charles Frederic Gerhardt, found a way to get pure acetylsalicylic
acid and realize its industrial production. He used primarily to treat
his father, who suffered from chronic rheumatism.12
Finally, the patent and trade mark of aspirin are filed by Bayer
in 1899 under the name “Aspirin”. Preparation arrives in France in
1908 (Figs 5.2A and B) and is marketed by the Company Rhone
chemical plants. However after the World War I, the Treaty of Ver-
sailles banned the brand and its manufacturing process in a number
Figure 5.1: Reverend Edwards Stone’s original letter on ‘An account of countries like France and US, but they persisted in other countries
of the success of the bark of the willow tree in the cure of agues’ in the like Canada.12
Philosophical Transactions of the Royal Society, 25 April 17639
The next step was taken by Craven, an otorhinolaryngologist
with a private practice in California who, in 1948, began treating all
described 6 years of experience with the use of a willow bark extract his older male patients with acetylsalicylic acid to prevent MI. He
in the treatment of a variety of fevers. He also associated the sur- reported in a brief letter to the Annals of Western Medicine and
roundings where the willow grows with the development of fevers.9 Surgery in 1950 that none of his 400 patients taking acetylsalicylic
In 1829, Pierre-Joseph Leroux, a French pharmacist, after boil- acid had developed an MI. Craven extended his studies to more
ing the powdered bark of white willow in water while trying to con- than 8,000 patients and, interestingly, he also described a subset of
centrate its preparation produced soluble crystals, which he called patients whom he had treated with acetylsalicylic acid as secondary
salicyline (from Salix). Then German scientists purified the active prevention. These patients were protected from developing MI and,
substance, first called salicyline and then salicylic acid.9 in addition, Craven also reported complete protection from major
In 1835, Karl Löwing showed that the acid spirique extracted strokes in his cohort of patients treated with acetylsalicylic acid.9
from the Queen-of-Pres is chemically similar to salicylic acid and But the mechanism how aspirin works was not known till Quick
thus became the first to prepare salicylic acid. He not only indicated had shown that a small oral dose of aspirin, but not sodium salicy-
to use this preparation to bring down the fever, relieve pain and rheu- late, may prolong the bleeding time even in normal subjects in 1968.
matism, but cautioned that it causes heartburn. Moreover, several investigators had shown that aspirin, but not
In Paris, salicylic acid was isolated by Piria in 1838 from the wil- sodium salicylate, when taken orally or added to platelet-rich plasma
low bark glycoside salicin5 and a year later Dumas showed that Low- inhibited platelet aggregation and blocked the release of adenosine
ing’s and Piria’s compounds were identical. Both scientists had pre- diphosphate (ADP) from these cells. It was suggested at the time that
pared salicylic acid, one working with salicin from willow bark and the unique capacity of aspirin to form acetyl derivatives of human
the other working with salicylaldehyde from meadowsweet.9 proteins might well play a role in these phenomena, but no mecha-
In 1853, the analyst Strasbourg Charles Frederic Gerhardt ex- nism of action had been proposed.13 In 1971, two graduate students
periments the synthesis of acetylsalicylic acid and filed a patent. He working in the Department of Pharmacology of the Royal College of
died 3 years later and his work fell into oblivion. The first reports on Surgeons of England in London, Bryan Smith working with Gustav
the clinical use of salicylic acid in rheumatic disorders were made Born and Jim Willis working with the Sir John Vane reported that
independently by the two German physicians Stricher and Reiss in aspirin added in vitro to human platelet-rich plasma or administered
1876. Stricher, working as the staff physician, reported in Berliner orally to three healthy volunteers selectively inhibited the release of
Klinische Wochenschrift, January 3, 1876, on the successful treatment prostaglandin (PG)E2-like bioactivity from platelets, under experi-
of four patients with joint rheumatism at the Traube Clinic.9 The mental conditions, in which the release reaction was unimpaired,
same year Maclagan in Dundee10 described the successful treatment and suggested that one action of aspirin on platelets is inhibition
with Salicin of patients with acute and sub-acute rheumatism. In the of the conversion of arachidonic acid into PGs.14 As a result of
report by Maclagan published in the Lancet on March 4, 1876.11 these findings, Sir John Vane received the Nobel Prize in Medicine
In spite of the achievement of Gerhardt, the invention was in 1982.
ignored until 1859 when it was prepared again by von Glim. Ten years Chronological historical events leading to development of aspi-
later the German Karl Kraut found an improved synthetic method of rin and its mechanism are shown in Table 5.1.
Chapter 5  History of Antithrombotic Agents 33
In concert with the two accompanying papers, the paper of

Smith and Willis suggested that ‘‘the clinical effectiveness of aspirin
and indomethacin as anti-inflammatory agents could be explained
by the inhibition of the production of PGs’’. It is perhaps not surpris-
ing that no mechanistic link between PG synthesis and platelet func-
tion was established at the time of this fundamental discovery.15 In as
much as the only two PGs then known, that is PGE2 and PGF2a, had
no obvious effects on platelet aggregation.
The fundamental work of Nobel Laureate Bengt Samuelsson and
his associates at the Karolinska Institute in Stockholm elucidated
platelet arachidonic acid metabolism with the discovery of unsta-
ble biosynthetic intermediates, the cyclic endoperoxides PGG2 and
PGH2, and with the trapping of an extremely potent, but evanescent
platelet-aggregating prostanoid named thromboxane TXA2.
Further insight into the molecular mechanism of action of aspi-
rin was provided by Gerry Roth and Phil Majerus at the Washington
University in St Louis, who used aspirin labeled with 3H at the acetyl
group to demonstrate acetylation of PG-synthase and its irreversible
inactivation by the drug.16
Figure 5.3 showing historical development of understanding of
antiplatelet effect of aspirin in brief.
FitzGerald made other important contributions to platelet phar-
macology, including the presystemic nature of platelet inactivation
by low-dose aspirin.17
FitzGerald and Patrono together demonstrated the extremely
A low rate of TXA2 biosynthesis in humans under physiological condi-
tions and characterized episodic increases in TXA2 biosynthesis in
acute coronary and cerebrovascular syndromes, as well as persistent
platelet activation in the presence of major cardiovascular (CV) risk
factors and myeloproliferative disorders. These findings provided a
rationale for exploring the efficacy and safety of low-dose aspirin in
these settings.18 The concordant findings of Majerus, Patrono and
FitzGerald in demonstrating immediate and virtually complete acet-
ylation of platelet COX1, suppression of platelet TXA2 production
and negligible TXM excretion produced by 160 mg of aspirin.19
Clinical Trial Service Unit at Oxford University, directed by Sir
Richard Peto, to test this daily dose of aspirin in the first large-scale,
placebo-controlled randomized trial for efficacy and safety in the
short-term treatment of patients with acute myocardial infarction
(AMI) (ISIS-2 Collaborative Group, 1988).
Also in landmark trial of Second International Study of Infarct
Survival (ISIS-2) sought to determine if benefits would accrue if as-
pirin was given within the first 24 hours of suspected evolving MI.
The aspirin group experienced a significant 23% reduction in five-
week vascular mortality compared with those receiving placebo.20
The benefit of aspirin has been proved for secondary prevention.
In patients with unstable angina, aspirin reduced the occurrence of
fatal and nonfatal MI by approximately 50%. In patients with a previ-
B
ous history of MI, aspirin reduced the occurrence of subsequent CV
Figures 5.2A and B: Aspirine Usines du Rhône. (A) Advertisement events (fatal or nonfatal) by approximately 20%.
in France; (B) Early glass bottle with aspirin powder from Friedrich Bayer Also given alone or in combination with dipyridamole, aspirin
and Co. in Elberfeld, Germany12 significantly reduced the frequency of occlusion of coronary artery
TABLE 5.1 Chronological investigations of willow tree for establishment of aspirin development
Period Figure in the Field Clinical/Chemical Perspective
4000 BC Assyrians Used the extract of willow leaves for painful musculoskeletal joint pain conditions, as well as
antipyretic drug
3500 BC Sumerian Described the use of willow leaves for various ailments such as antipyretic drug
1300 BC Egyptians Used willow leaves for joint pain and for the relief of pain and inflammation associated with
wounds and antipyretic drug
605 BC Babylonians Used the willow tree for treatment for fever, pain and inflammation
400 BC Hippocrates A Greek Physician Relieve pain in childbirth and for fever
1763 Edward Stone an Oxford shire Carried the first clinical trial of willow bark and used willow powder to treat ague
Reverend
1828 Johann Buchner Extracted and purified salicin from willow bark
Professor of Pharmacology,
University of Munich
1829 Henri Leroux a French Pharmacist Improved the purification process and obtained salicin in crystalline form for the first time
1830 Gay-Lussac and Magendie They showed that salicin was non-nitrogenous compound
1838 Raffaele Piria Italian Chemist Resolved the chemical structure of salicin as a glucosidic salicyl alcohol. Then oxidized salicyl
alcohol into salicylic acid
1852 Garland H First to prepare salicylic acid
1853 Charles von Gerhardt Gave evidence that salicylic acid structure comprises phenol and carboxylic group. He also
Professor of Chemistry at developed acetylsalicylic acid, or aspirin
Montpellier University
1859/1860 Hermann Kolbe and Lautemann Discovered the chemical structure of salicyl alcohol and synthesized salicylic acid
E A German Chemists at Marburg
University
1874 Hermann Kolbe and Lautemann Industrial scale production of salicylic acid and end of willow powder era use as remedy
E A German Chemists at Marburg
University
1876 Thomas MacLagan Tried willow extract powder on himself before administration of a patient with acute rheumatism
A Scottish Physician
1893 Felix Hoffman Synthesized aspirin by acetylating the hydroxyl group of salicylic acid at the ortho position
1971 Sir John Vane He proved the anticoagulant properties of aspirin by blocking the biosynthesis of prostaglandin,
A British Pharmacologist the pain messengers. He suggested that aspirin may reduce the risk of cardiovascular disease
which led to use low-dose aspirin as a preventative measure in various cardiac conditions
Figure 5.3: Main historical steps in understanding aspirin’s mechanism of action in inhibiting platelet biochemistry and function18
bypass grafts over the year following surgery without however reduc- potent antiplatelet drugs that can be used safely, especially in high-
ing intimal hyperplasia.7 risk patients.27
Aspirin was also studied in the primary prevention of coronary A family of oral antiplatelet agents known as the thienopyridines,
artery disease in a double-blind, placebo-controlled clinical trial which inhibit platelet activation and aggregation processes through
where more than 22,000 male US physicians were included (US Phy- adenosine 5’-diphosphate receptor blockade, became one of the
sicians’ Health Study) over an average period of 5 years. Aspirin use, most investigated areas in CV pharmacology.28
reduced the incidence of MI (fatal or nonfatal) by 44%, but did not Ticlopidine was synthesized in 1972 as a potential substitute for
reduce total CV mortality (irrespective of the CV disorder) or total another thienopyridine, tinoridine, the anti-inflammatory proper-
mortality. Moreover, the treatment proved beneficial only in patients ties of which were published in 1970 by a Japanese team. According
over 50 years.5,21 Important trials investigating the use of aspirin as to Jean-Pierre Maffrand, the Sanofi scientist responsible for synthe-
primary prevention are shown in Table 5.2. sising the molecule, the Company’s subsequent good fortune was
By 1988 there had been 25 published trials of antiplatelet therapy, due to their ability to test the molecule in vivo where an unstable
principally with aspirin, in the secondary prevention or treatment metabolite is responsible for its activity, ticlopidine being inactive in
of prior MI, prior occlusive stroke, TIA or unstable angina.22 These vitro. Equally fortunate was the use of ADP to induce aggregation,
trials randomized approximately 25,000 patients and demonstrated because it was shown later that the active metabolite blocks an ADP-
that those receiving aspirin experienced a significant 25% reduction receptor on platelets.
in the occurrence of “important vascular events,” an endpoint that Aspirin (1,300 mg daily) and ticlopidine (500 mg daily) were
combines non-fatal MI, non-fatal stroke and CV death.23 compared in a large multicenter double-blind study, which includ-
The ability of low-dose aspirin to irreversibly inhibit platelet- ed 3,069 patients with a TIA or a reversible ischemic neurological
dependent cyclooxygenase provides a biologic mechanism to deficit (RIND) or a minor stroke. Over an average period of 3 years,
explain why this drug may decrease the risk of thrombotic CV events. ticlopidine reduced significantly the rate of recurrence of fatal or
Observational epidemiologic studies, both case-control and cohort nonfatal ischemic attacks (related to cerebrovascular atherosclero-
have suggested that aspirin might reduce the risk of CVD by approxi- sis) by 21% and total mortality related to nonfatal ischemic attacks
mately 20–30%.23 This led to its use in primary prevention. by 12%. This superiority of ticlopidine over aspirin was recorded
Regarding the role of aspirin in primary prevention, several in patients and could be demonstrated from the first year of treat-
meta-analyses have described the benefits of aspirin in patients with ment.29
multiple risk factors (diabetes, stroke, peripheral arterial disease).24,25 In the Canadian American Ticlopidine Study (CATS), ticlopi-
Differences in efficacy in man and woman were also found.26 The dine (500 mg daily) was given double-blind versus placebo to 1,072
results are more mixed for other studies; although they are made patients with a recent history of major ischemic cerebral event (re-
in people who are at “high-risk”. Despite the absence of convincing lated to atherosclerosis). This antiplatelet agent reduced CV events
evidence, the medical recommendations advocate the use of aspirin (ischemic cerebral event related to atherosclerosis, MI or vascular
in primary prevention in high-risk patients.15 mortality) by 30% in patients; aspirin did not demonstrate a similar
effect in this group of population.30
Thienopyridines Ticlopidine has also shown its beneficial effect by both increas-
ing the walking distance of patients with peripheral vascular disease
Although aspirin is a cost-effective therapy, a considerable number and reducing, in this high-risk population, CV morbidity and mortal-
of patients who take aspirin continue to experience atherothrom- ity by 60%. In this population again, no evidence of efficacy of aspirin
botic complications. This led to continued search to identify more has been shown to date.31
TABLE 5.2 Primary prevention trials of aspirin

Trial Population No. of Aspirin Dose (mg) Follow-up Placebo Event Relative Risk of
Patients (yrs) Rate (%/yr) Treatment Group
Physicians’ health study Healthy men 22,071 325 every other day 5 0.7 0.82
Primary prevention project High-risk men and women 4,495 100 daily 3.6 0.8 0.71
Hypertension optimal treatment Hypertensive patients 18,790 75 daily 3.8 1.1 0.85
UK doctors Healthy men 5,139 500 daily 5.8 1.4 1.03
Thrombosis prevention trial High-risk men 5,085 75 daily 6.3 1.6 0.83
Swedish angina pectoris aspirin trial Stable angina patients 2,035 75 daily 4.2 3.7 0.71
Women’s health study Healthy women 39,876 100 every other day 10.1 0.26 0.91
Ticlopidine is a first-generation thienopyridine that, in combina- independent and complementary action of these two agents (both
tion with aspirin, enhances platelet inhibition. This enhanced effect ADP-induced platelet aggregation and TXA2 inhibited) that provide
is due to the additive effects on platelet inhibition achieved with the the clinical benefits of this combination in ACS patients undergoing
blockade of the COX1 and P2Y12 pathways.5 PCI (especially patients undergoing stent implantation).38
Thienopyridine, the first FDA-approved thienopyridine, have In addition, long-term (up to 12 months) dual antiplatelet ther-
a well-established role in the treatment of coronary artery disease, apy with clopidogrel and aspirin is more effective than aspirin alone
especially in the setting of acute coronary syndromes (ACS) and perin preventing major CV events in patients with ACS, including those
cutaneous coronary interventions (PCI).22 treated with PCI.39
There were two major limitations with the use of ticlopidine: its More recently, the spectrum of clinical benefit of clopidogrel has
safety profile (neutropenia, thrombocytopenia, rash and adverse been extended to patients with ST-segment elevation MI, including
gastrointestinal effects) and its inability to induce platelet inhibition those undergoing PCI.40,41
rapidly. This led researchers to the development of an antiplatelet On the other hand, results of the Clopidogrel for High Athero-
agent with the same beneficial properties of ticlopidine, but without thrombotic Risk and Ischemic Stabilization, Management, and
its limitations. Thus, clopidogrel, a second-generation thienopyri- Avoidance (CHARISMA) trial showed that in 15,603 high-risk, but
dine, was developed. Today, clopidogrel has largely replaced ticlopi- nonacute patients with clinically evident CVD or multiple risk fac-
dine.32 tors, long-term treatment (median 28 months) with clopidogrel plus
The P2Y12 receptor that was identified post hoc as the molecular aspirin was not significantly more effective than aspirin alone in
target of ticlopidine and clopidogrel has become the target for novel reducing the rate of MI, stroke or death from CV causes, but patients
reversible antagonists that are being developed by several drug com- with a greater thrombotic burden (e.g. history of plaque rupture and
panies.5 thrombosis) are most likely to derive benefit from an extended dura-
Dual antiplatelet therapy was first explored in the emerging clin- tion of dual antiplatelet therapy.42
ical setting of coronary stenting. In fact, in the initial era of coronary Clopidogrel has a number of significant limitations. (1) A sig-
stenting, the antithrombotic regimen of choice for the prevention of nificant increase in bleeding risk in patients requiring surgery who
stent thrombosis was still not established; and various combinations have not been withheld clopidogrel treatment for at least 5–7 days.
of antiplatelet agents and anticoagulants were used with elevated (2) Platelet inhibition variability, may explain why the antiplatelet ef-
complication rates. The lack of a safe and efficacious antithrombotic fects achieved with a loading dose of clopidogrel are not always rapid
drug regimen for patients undergoing coronary stenting significantly and why elevated platelet reactivity may persist in some patients
limited the growth of coronary interventions.28 Landmark clinical tri- despite the adjunctive use of this antiplatelet drug. (3) Its inefficient
al in patients undergoing coronary stenting, better clinical outcomes conversion to the active metabolite, which may, in part, account for
was achieved with the combined use of aspirin and ticlopidine than the variable and sometimes inadequate antiplatelet effects of clopi-
with aspirin alone or aspirin plus warfarin.25 dogrel, as well as its delayed onset of action.43 Limited intestinal
Antiplatelet therapy is the current criterion standard for the absorption and interactions with such frequently used drugs as ome-
treatment of patients undergoing PCI and patients who have ACS. prazole, lipophilic statins and calcium channel blockers.44
Clopidogrel in combination with aspirin is the current standard of Five agents (prasugrel, cangrelor, ticagrelor, SCH 530348 and ter-
care for reducing CV events in these patients.33,34 The long-term utroban), that are in the most advanced phases of clinical develop-
clinical benefit associated with dual antiplatelet therapy has been ment.45
observed overall in patients with non-ST-segment elevation ACS Thus it lead to discovery of novel, third generation thienopyri-
(unstable angina and non-ST-segment elevation MI) independent of dines, prasugrel which as compared to clopidogrel has demonstrated
coronary revascularization.34,35 lower inter-patient response variability and a reduced incidence of
The milestone Clopidogrel Versus Aspirin in Patients at Risk of Is- ischemic events.24 Compared to the standard dose of clopidogrel, the
chemic Events (CAPRIE) study confirmed the antiplatelet efficacy of metabolization of prasugrel is more efficient (requiring a single met-
clopidogrel versus aspirin. This study demonstrated that, in patients abolic step) and thus at lower doses more effectively inhibits platelet
with history of MI, stroke, or peripheral arterial disease, clopidogrel activity with less variability of response.46
reduced ischemic event recurrence by 8.7% compared to aspirin.36 The Joint Utilization of Medications to Block Platelets Optimal-
Furthermore, 2 hours after administering a 600 mg loading dose, a ly—Thrombolysis in Myocardial Infarction (JUMBO-TIMI)-26 study
significant reduction was observed in platelet aggregation, reaching assessed the safety of prasugrel versus clopidogrel in patients sched-
its peak at 6-hour (40–60% reduction).37 uled for PCI. The study concluded that, during the first 30 days after
In patients with ACS, the Clopidogrel in Unstable angina to pre- intervention, there were no significant differences between the two
vent Recurrent Events (CURE) trial demonstrated the superiority of drugs regarding bleeding rates, but there were lower incidences of ad-
clopidogrel combined with aspirin versus monotherapy with aspirin, verse cardiac events in patients treated with prasugrel, as well as lower
with a 20% reduction in relative risk. In fact, it is thought that it is the incidences of MI, recurrent ischemia and venous thrombosis.47
The Trial to Assess Improvement in Therapeutic Outcomes by the parasites, which rely on salvage pathways for purines. The trypa-
Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myo- nosome genome project has revealed a large number of transporters
cardial Infarction (TRITON TIMI)-38 study directly compared the with different substrate specificities. The intention is to exploit dif-
effects of prasugrel (60 mg loading dose and 10 mg maintenance ferences between mammalian and trypanosome transporters, either
dose) and clopidogrel (300 mg loading dose and 75 mg mainte- by finding drugs capable of blocking the latter or by using them to
nance dose) on patients with ACS scheduled for PCI.48 Compared to introduce novel drugs into the cells. These advances can therefore be
clopidogrel, prasugrel was associated with a reduction in ischemic traced to work on platelet aggregation inhibitors.50
events, including stent thrombosis, although it has the drawback of
higher bleeding rates, including fatal bleeding, in elderly patients, Glycoprotein IIb/IIIa Receptor Antagonists
underweight patients, or those with stroke or transitory ischemic
attacks.24 Given the redundancy of discrete pathways leading to platelet aggre-
AZD6140 is not a member of the thienopyridine family. Cur- gation, it is not surprising that the clinical efficacy of aspirin, ticlopi-
rently, several studies are continuing to test new direct P2Y12 recep- dine and clopidogrel is only partial. Balloon angioplasty generated
tor antagonists, such as cangrelor and AZD6140, characterized by a locally injured surfaces that could be highly attractive to platelets
faster reversal of platelet inhibition.45 and carried the risk of rapid vessel closure. The available antiplate-
let agents, such as aspirin, were generally weak and non-specific and
Dipyridamole were inadequate to fully protect against this new type of provocation.
Glanzmann thrombasthenia was first noted in 1918, a hereditary
Dipyridamole was synthesized half a century ago and introduced disorder which has defective platelet-fibrinogen interaction second-
clinically in the early 1960s as a coronary vasodilator. Dipyridamole ary to absent platelet membrane glycoprotein called Integrins. These
was shown to inhibit platelet adhesiveness to glass ex vivo in patients receptors are the final common pathway of platelet aggregation. Cor-
with coronary artery disease and to reduce thrombus formation in relation of all these findings suggested that blockade of GP IIb/IIIa
experimental models. These findings led Boehringer Ingelheim to receptors could be a particularly desirable therapeutic strategy.51
develop dipyridamole as an antithrombotic agent.16 Although the The search for selective antagonists of GP IIb/IIIa and platelet
clinical efficacy of dipyridamole, alone or in combination with as- aggregation led to the development of a potent monoclonal antibody
pirin, has been questioned on the basis of earlier randomized tri- and small-molecule competitive antagonists that mimic the natural
als, the issue has been reopened by the reformulation of the drug ligand(s) of the receptor.18
to improve its relatively low bioavailability and the positive results Table 5.3 showing different classes of GP IIb/IIIa inhibitors dis-
with the new preparation of the European Stroke Prevention Study-2 covered used clinically or in early stage of research.
(ESPS-2) on 6,602 patients with cerebrovascular disease.18 Unexpect-
edly, dipyridamole did not increase the bleeding complications in
these patients, raising the possibility that other properties of the drug TABLE 5.3 Discovery of different classes of glycoprotein IIb/IIIa
may have contributed to its beneficial effects on stroke prevention. inhibitors
Steve Prescott at the University of Utah has recently reported that Chemical Nature
dipyridamole inhibits the inflammatory gene expression in human • Monoclonal antibody—c7E3, YM337
platelet-monocyte interactions, which may be involved in athero- • RGD, cyclic analogs—integrilin, DMP728
sclerosis and in its thrombotic complications. The inhibitory action • Non-peptide—tirofiban, lamifiban, xemilofiban, lefradafiban,
of adenosine on platelet aggregation is potentiated by dipyridamole, roxifiban, lotrafiban
which inhibits the uptake of adenosine by platelets, increasing the
Route of Administration
concentration of adenosine in the plasma. The observation that
• Intravenous—c7E3, Integrilin, tirofiban, lamifiban
dipyridamole inhibits adenosine uptake by platelets led to an unex-
pected, but important development in an entirely different field.49 • Oral—xemilofiban, lefradafiban, DMP754
It is known that the trypanosome parasite responsible for African • Other routes: intranasal—DMP755
sleeping sickness is incapable of synthesising nucleotides de novo, Binding Kinetics
but needs to take up nucleosides like adenosine from surrounding • Selectivity for activated versus resting platelets—DMP728 versus
tissue fluids. This raised the idea of the development of trypanocidal c7E3, XV454, DMP802
drugs acting as inhibitors of the uptake of adenosine by these organ- Platelet Dissociation Rate (Duration of Action)
isms. The demonstration of a weak effect of this kind on Trypano-
• Fast: Integrilin, tirofiban, lamifiban, orbofiban
soma brucei by dipyridamole initiated extensive research on purine
acquisition by these organisms. This has shown that dipyridamole • Intermediate: DMP754 (roxifiban)
and similar compounds are unlikely to block nucleoside uptake by • Slow: c7E3, DMP802, XV454
A solution to this problem was thought to have been found with ing PCI, with and without later stent implantation (the EPIC, EPI-
the development of the oral GP IIb/IIIa inhibitors. Despite the prom- LOG, EPISTENT trials).57
ising rationale behind the use of oral GP IIb/IIIa inhibitors, clinical In contrast, its clinical efficacy in patients with unstable angina
trials failed to show any benefit of these agents; and a pooled analysis not scheduled for PCI is less clear. Whereas several clinical trials
from trials of oral GP IIb/IIIa antagonists showed increased mortality (CAPTURE, PRISM,PRISM-PLUS, PURSUIT, TACTICS-TIMI 18, PAR-
when these agents were given.52 Thus oral GP IIb/IIIa inhibitors were AGON A, PARAGON B) have demonstrated a clear benefit, differing
fallen behind the scene and emergence of intravenous GP IIb/IIIa results were obtained in the GUSTO IV study.58-60
inhibitors with its proven efficacy in the setting of ACS particularly All the major clinical trials of intravenous GP IIb/IIIa inhibitors
after primary angioplasty lead to establishing their role as a short- are shown in Table 5.4.
term third antiplatelet agent.24 The ability of GP Ilb/IIIa inhibitors The advantages of eptifibatide and tirofiban are: (1) they are
to reduce adverse ischemic events was first demonstrated in high- small synthetic molecules and less immunogenic, (2) They are
risk patients (those with AMI, unstable angina or high-risk coronary reversibly and competitively bind to fibrinogen receptor and (3) Both
morphology) scheduled for PCI.53 have a short half-life (2 hours) and, due to the reversibility of their
The pathway leading to the development of abciximab began effect, their antithrombotic properties rapidly dissipate after stop-
in the laboratory of Dr Barry Coller. In 1985, Dr Coller reported the ping treatment. Various clinical trials have defended their efficacy
isolation of a mouse-derived monoclonal Immunoglobulin G (IgG) in the treatment of ACS without PCI and in high-risk patients with
antibody against the human GP IIb/IIIa receptor, dubbed 7E3.54 The diabetes mellitus or high troponin levels. Despite of these abciximab
use of platelet GP IIb/IIIa-receptor inhibition in cardiology began in has demonstrated its superiority to these two agents in patients with
1994 with the publication of the results of the Evaluation of 7E3 for ACS undergoing PCI. It is thought that its greatest efficacy is due to
the Prevention of Ischemic Complications (EPIC) trial. the additional capacity of abciximab to block vitronectin receptor
The initial trials of Abciximab (marketed as ReoPro by Eli Lilly and leukocyte integrin Mac-1.61
Company) made the drug hugely popular. All over the world the drug The initial enthusiasm about the use of these drugs has con-
was used in a variety of clinical circumstances including ACS, pri- siderably come down in the recent years with the knowledge that
mary angioplasty, elective angioplasty which involved high risk situ- when these drugs are used in combination with dual antiplatelet
ations like diabetes and complex lesions. Naturally this led to further therapy (aspirin and clopidogrel) they do not show a great clini-
increase in the cost of angioplasty. cal advantage. Most of the initial trials like the EPIC and EPILOG
Almost simultaneous research led to the development of two did not use clopidogrel in combination with aspirin. However in
more drugs in the same category namely eptifibatide and tirofiban. the recent years a number of trials have been published could not
However these are not antibodies, but are chemically synthesized, demonstrate significant advantage over and above combination
eptifibatide being a peptide inhibitor and tirofiban non-peptide antiplatelet therapy.
inhibitor of GP IIb/IIIa receptor. Table 5.5 showing the summery of key milestones in the devel-
Key to the design of eptifibatide was the recognition of naturally opment of antiplatelet agents in brief.
occurring inhibitors of the GP IIb/IIIa receptor, particularly among
the snake venoms. Scarborough and colleagues are credited with ANTICOAGULANTS
screening and sequencing many of these proteins, including the
protein barbourin from the venom of the south eastern pygmy rat- Anticoagulants include direct and indirect inhibitors of enzymes
tlesnake Sistrurus miliaris barbouri.55 Also they identified the mo- involved in the coagulation pathways, primarily thrombin and factor
lecular basis (an amino acid substitution of lysine for arginine) for Xa. Direct inhibitors interact with the procoagulant enzyme’s active
the greater selectivity and specificity of barbourin for GP IIb/IIIa site or an exosite blocking its proteinase activity. Direct inhibitors of
over other snake venoms and directly led to the design of eptifiba- coagulation being clinically tested include thrombin inhibitors, hiru-
tide. In creating eptifibatide, the conservative substitution of lysine din, bivalirudin, argatroban, efegatran and inogratran, and factor Xa
for arginine in the arginine-glycine-asparate (RGD) sequence was inhibitors, tick anticoagulant peptide (TAP) and antistasin.
retained.55 In contrast, indirect inhibitors enhance the proteinase inhibito-
The same groundwork also provided the basis for the creation of ry activity of natural anticoagulants, antithrombin (AT) and heparin
tirofiban. Nuclear magnetic resonance studies identified the key spa- co-factor II. Indirect inhibitors currently available include unfrac-
tial determinants of the RGD sequence, and led to a directed search tionated heparin (UFH), low-molecular-weight heparins (LMWHs)
for compounds with the same distance and charge configuration as and heparin pentasaccharide.
exists between the basic guanidine and the acidic carboxylate groups Another major category of anticoagulant that works in an
of RGD.56 indirect manner includes the coumarins and 1, 3-indanediones,
In clinical terms, abciximab has demonstrated its efficacy (up to which prevent the biosynthesis of active forms of procoagulant
50% reduction of cardiac death or AMI) in patients with ACS requir- proteinases.6
TABLE 5.4 Major clinical trials of glycoprotein IIb/IIIa inhibitors

Acronym IIb/IIIa Trial Number of
Subjects
Percutaneous Coronary Intervention
EPIC Abciximab Evaluation of 7E3 for the Prevention of Ischemic Complications 2,099
EPILOG Abciximab Evaluation in PTCA to Improve Long-Term Outcome with Abciximab Glycoprotein IIb/IIIa Blockade 2,792
CAPTURE Abciximab c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina 1,265
IMPACT-II Eptifibatide Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis-II 4,010
RESTORE Tirofiban Randomized Efficacy Study of Tirofiban for outcomes and Restenosis 2,141
EPISTENT Abciximab Evaluation of Platelet IIb/IIIa Inhibitor for Stenting 2,399
ESPRIT Eptifibatide Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy 2,064
Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction
RAPPORT Abciximab ReoPro in Acute Myocardial Infarction and Primary PTCA Organization and Randomized Trial 483
ISAR-2 Abciximab Intracoronary Stenting and Antithrombotic Regimen 401
ADMIRAL Abciximab Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and 300
Long-term Follow-up
CADILLAC Abciximab Abciximab Controlled Abciximab and Device Investigation to Lower Late 2,625
Angioplasty Complications
Non–ST-Elevation Acute Coronary Syndrome
PURSUIT Eptifibatide Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy 10,948
PRISM Tirofiban Platelet Receptor Inhibition in Ischemic Syndrome Management 3,232
PRISM-PLUS Tirofiban Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable 1,915
Signs and Symptoms
PARAGON A and B Lamifiban Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndromes in a Global Organization 2,282
Network 5,225
GUSTO IV Abciximab GUSTO IV Acute Coronary Syndrome without ST-Elevation 7,800
Thrombolysis
TIMI 14 Abciximab Thrombolysis in Myocardial Infarction-14 888
SPEED Abciximab Strategies for Patency Enhancement in the Emergency Department 305
IMPACT-AMI Eptifibatide Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis-Acute Myocardial 180
Infarction
INTRO-AMI Eptifibatide Integrilin and Reduced Dose Thrombolytic in Acute Myocardial Infarction 268
GUSTO IV Abciximab GUSTO IV Acute Myocardial Infarction Ongoing
TABLE 5.5 Key milestones behind recent advances in the development Oral Anticoagulants
of antiplatelet agents
The source of the oral anticoagulant is again a plant, but it was the
• Platelets—Bizzizro, 1882 animals consuming, which brought to scientists’ attention. As the
• Light transmittance aggregometry—Born, 1962 over farmed soil and harsh climate would not support standard
• Aspirin—antiplatelet trials—1960s—present animal feed crops any longer so around the turn of the century,
• Ticlopidine—late 1980s; clopidogrel—1990s (ADP-inhibitors) resourceful farmers in Northern Prairie States began planting me-
lilots or sweet clover plants (Melilotus alba, M officinalis) imported
• Platelet GPIIb/IIIa integrin—1980s
from Europe. Sweet clover provided abundant silage for cattle but
• GPIIb/IIIa monoclonal antibody—B. Coller, 1980s
within 2 decades brought a new disease that decimated cattle herds
• RGD mimetics (cyclic peptides, peptidomimetics, nonpeptides)—1980s and horrified farmers: sweet clover disease, in which affected cattle
• Clinical trials intravenous/oral—1990s developed relentless and fatal spontaneous bleeding.
It was first thought to represent “hemorrhagic septicemia.” Scho- Table 5.6 showing in brief the chronology of historical events
field, a veterinary pathologist in Alberta, first observed the myste- leading to development of warfarin.
rious condition in 1921 and reported it in 1922. He found that the Nichol, in 1942, was the first to propose treating patients with
disease was due to neither pathogens nor nutritional deficiency, AMI with dicumarol, though the role of thrombosis in MI was contro-
but instead traced it to the consumption of spoiled (not fresh) sweet versial at that time. With the final results of a landmark randomized
clover hay and noted a prolonged clotting time. He also showed that study sponsored by the American Heart Association in 1948, oral an-
the disease could be cured by immediate withdrawal of the spoiled ticoagulant treatment of MI became widespread in the 1950s. Link
clover feed and with transfusions from healthy cattle.7 Also in 1929, developed tuberculosis in 1945 and retreated to a sanatorium. Away
Dam reported another strange disease: dietary hemorrhagic chick from his laboratory, he occupied himself by reading about the his-
disease, associated with chicken feed prepared by a process that tory of rodent control. Returning to the laboratory in 1946, he was
extracts all sterols. determined to develop the ideal rat poison. As dicumarol was weak
Karl Paul Link, PhD (an agriculturalist) was offered a job in late and unreliable rodenticide, he developed a new agent whose patent
1932 at the University of Minnesota by Ross Gortner, a project to rights were given to the Wisconsin Alumni Research Foundation and
study the new cattle’s sweet clover disease and to develop a strain of was named “warfarin” (from the first letters of the foundation, with
sweet clover free from coumarin.7 No one suspected that the sweet- the suffix—arin) by Link.62
smelling, bitter-tasting coumarin was related to spoiled sweet clover In 1948, warfarin was launched as the ideal rat poison, not as
disease. In February 1933, a farmer named Ed Carlson with his cattle a human therapeutic agent. In 1951, a navy recruit unsuccessfully
affected by the same disease was told to go to the Agricultural Experi- attempted suicide with warfarin. His surprising full recovery induced
ment Station to get advice. Accidently, he found it closed and that Shapiro and Meyer to test warfarin in human volunteers in 1953 and
by chance led him to Link’s Biochemistry Building, where Carlson reported it to be superior to dicumarol.
produced a dead cow and a milk can containing blood that would not Clinicians quickly discarded dicumarol in favor of the rat poi-
clot. Link could only tell the desolate Carlson to avoid the hay and son warfarin. It was introduced commercially in 1954 and Pollock
transfuse the ill cows. He told him that nothing else could be done.
The poor farmer went back home without any remedy found for his
problem.
In 1935, Quick et al. developed the prothrombin time (PT) test,
which was important development. In 1937, he showed the PT to be
elevated in both the sweet clover and hemorrhagic chick diseases.
At dawn on June 28, 1939, Link’s associate Harold Campbell saw a
pure, crystalline hemorrhagic agent on a microscope slide.7 Link was
confident of his associate’s work and the successes mounted. They
reported the hemorrhagic agent to the world in 1940. Late his own
colleague Huebner solved the hemorrhagic agent’s structure as 3,
3’-methylenebis-(4-hydroxycoumarin) as shown in Figure 5.4. The
compound received the name “dicumarol,” which would serve in the
United States as both generic and trade name.62 Link first gave dicu-
marol to Meyer at Wisconsin General Hospital in late 1940 and by
January 1941 he documented its anticoagulant effects in human vol-
unteers. Dr Wright became the first to use dicumarol therapeutically Figure 5.4: Photomicrograph of crystalline “hemorrhagic agent”
by treating his one of his patient who was suffering from thrombotic [3, 3’methylenebis-(4-hydroxycoumarin) or dicumarol] isolated from
disorder successfully. With further reports of its successful trials in spoiled sweet clover hay by Campbell of Link’s University of Wisconsin
human, the drug became widely available in 1944.62 team7
TABLE 5.6 Brief history of warfarin

1929 Moldy sweet clover hay Leads to hemorrhagic disease in cattle
1935 Henrick Dam Postulates vitamin K (coagulation) depletion, to explain hemorrhagic disease in chicks fed fat-free diet; awarded
Nobel prize for this work
1935 Armand Quick Describes Prothrombin Time test, unchanged for 60 years
1941 Link et al. Isolated “dicoumarol” from moldy sweet clover, marketed as rat poison by Wisconsin Alumni Research Foundation,
later developed into Warfarin for human use
reported the first clinical series using warfarin in 1955. The precise
mechanism of warfarin was not elucidated until 1974, when Sten-
flo et al. described the post-translational carboxylation of vitamin
K-dependent clotting factors. In 1978, Whitlon et al. and Bell inde-
pendently found that warfarin acts by inhibiting the enzyme vita-
min K epoxide reductase, thereby closing the historical loop begun
by observations on cattle and chickens killed by lethal feed that
completely blocked the action of vitamin K.7
Despite the search for newer and better oral anticoagulants,
warfarin still does not have effective replacement and used world-
wide as an oral anticoagulant in treatment and prophylactic agent for
thromboembolic diseases.
Hirudin and Its Analog

Most thrombin inhibitors reported to date can be divided into three
Figure 5.5: Structure of hirudin in complex with thrombin
major subtypes: covalent; noncovalent, peptide-based; and non-
covalent, nonpeptide-based inhibitors.63 Many newer agents are
undergoing clinical trials presently.
Hirudin itself has a long, fascinating history. Medicinal leech-
es (Hirudo medicinalis) have been used throughout history; their Though parentally administered Hirudin is clinically effective,
saliva contains hirudin, a direct and potent selective thrombin inhib- but it experiences a setback on requirement of a long-term oral dos-
itor that allow the leech to feed on flowing blood. It was discovered ing.
by Haycraft in 1884 (decades before the discovery of the standard AT Class of inhibitors incorporate an electrophilic moiety referred
agent heparin). Jacoby coined the name hirudin in 1904.64 to as serine traps that binds covalently to the active site of the en-
Its action as an AT and its peptide nature were described in 1957 zyme, especially to the neucleophilic serine hydroxyl of the catalytic
by Markwardt. The amino acid sequence was reported by Petersen in triad. Leupeptin, a natural peptide aldehyde isolated in 1969 was
1976. Full length, hirudin is made up of 65 amino acids. These amino the first peptide derivative with an electrophilic carbonyl that would
acids are organized into a compact N-terminal domain containing reversibly inhibit the mammalian serine protease. Since then, vari-
three disulfide bonds and a C-terminal domain which is completely ous workers have developed a number of reversible covalent inhibi-
disordered, when the protein is un-complexed in solution.65 Natural tors which are under various steps of clinical evaluation.
hirudin contains a mixture of various isoforms of the protein.66 How- The first prototypes of this sub class, NAPAP and argatroban
ever, recombinant techniques can be used to produce homogeneous derive their origin from arginine derivative N-a-tosylarginine me-
preparations of hirudin. It was subsequently prepared by recombi- thyl ester (TAME) which in itself was a poor substrate. Argatroban
nant DNA.67 Hirugen is a C-terminal fragment of hirudin that binds derived from TAME has advanced to phase III clinical trials in US
the fibrinogen-binding site of thrombin and hirulogs are synthetic and has been approved in Japan under the name of Novastan as an
bifunctional fragments with the C-terminal fragment of hirudin and intravenous anticoagulant.69 In 1985, AstraZeneca R and D, Molndal,
its N-terminal fragment that binds to and blocks thrombin’s catalytic Sweden, undertook new research aimed at the development of
site as shown in Figure 5.5. Hirudin and its derivatives are being thrombin inhibitors with a direct mode of action that could be
shown to be effective anticoagulants (usually safer and more effec- administered orally. Some of this early research—on experimen-
tive than heparin) in a variety of venous and arterial thrombotic distal and parenteral thrombin inhibitors—has now been published.
orders.7,64 Continued research led to the discovery of the oral direct thrombin
It is difficult to extract large amounts of hirudin from natu- inhibitor (oral DTI) ximelagatran (Exantak, AstraZeneca) and its
ral sources, so a method for producing and purifying this protein active metabolite melagatran.70
using recombinant biotechnology has been developed. This has led Deletion of serine trap from covalent thrombin inhibitors led
to the development and marketing of a number of hirudin based to inogatran and melagatran which have entered clinical trials.
anticoagulant pharmaceutical products several other direct throm- Inogatran is administered intravenously whereas melagatran is
bin inhibitors are derived chemically from hirudin. administered orally in the form of its prodrug, ximelagatran. L372,460
Triabin, isolated from the saliva of a bug Triatoma pallidipen- has been found to be efficacious and orally bioavailable in dogs and
nis is another natural peptide inhibitor. Another naturally occurring monkeys.68
thrombin inhibitor published recently is Bothroalternin, a bothrojar- Optimization of these important parameters has been attained
acin-like protein, isolated from Bothrops alternatus venom.68 in a few of these compounds, such as in DPC423, razaxaban, apixa-
ban, LY517717, betrixaban eribaxaban, otamixaban, edoxaban and In 1880, Schmidt-Mulheim reported on “peptone shock,” an early
rivaroxaban, which have been advanced into clinical development. experimental model for the study of hemostasis. An endogenous
anticoagulant originating in the liver was released after experimen-
Heparin tal injection of peptone in the dog; later workers would identify the
water-soluble substance as heparin. Pavlov also described a water-
The story of the discovery and development of heparin and related soluble tissue extract as an anticoagulant in 1887, but was unable to
glycosaminoglycan anticoagulants is not as old as that of ASA, but it characterize it further.72
is very fascinating.7 Morawitz noted in 1905 that extractions of tissues by organic sol-
Unlike aspirin, heparin involves a natural animal source rather vents yielded procoagulant, whereas aqueous extracts of the residue
than a plant source and early workers were studying hemostatic after extraction with organic solvents showed anticoagulant activ-
effects rather than other properties, such as antipyresis or analge- ity.73 Biedl and Kraus reported in 1909 that similar to peptone shock,
sia. However, since 1936, heparin has been used in clinics for the the blood became incoagulable in anaphylactic shock due to release
prevention and treatment of thrombosis.33 Its main antithrombotic of an endogenous anticoagulant. In 1911, Doyon et al. also isolated a
activity is explained by its ability to potentiate the activity of the ser- water-soluble dog liver anticoagulant after peptone shock.74 In 1912,
ine protease inhibitor ATIII, which inactivates a number of serine William Howell of Johns Hopkins was the world’s most prominent
proteases, such as thrombin and factor Xa in the coagulation cascad- expert in coagulation and he was studying the procoagulant effects
ed. Jay McLean (Fig. 5.6) had the insight and perseverance to pursue of a dog brain thromboplastin extract he called cephalin. The stage
strange leads.71 was set for a fortuitous, historic chain of events. Perhaps the most
What he discovered as a medical student working in William important step was the first; medical student Jay McLean, a San
Howell’s laboratory at Johns Hopkins in 1915–1916 was a power- Francisco native, decided to leave the University of California and
ful, natural anticoagulant that is still used universally for a variety of transfer to Johns Hopkins to prepare for a planned career as an
venous and arterial thrombotic disorders and is today under great academic surgeon. Despite being denied admission to Johns
scrutiny for its promise as a cellular growth factor modulator in a Hopkins, McLean left California, worked at several menial jobs to
variety of vascular cell types. earn money, made the long journey to Baltimore and presented
The heparin story begins decades before McLean’s historic med- himself to a stunned admissions office at Johns Hopkins requesting
ical student laboratory project with early studies on the physiology admission to his chosen school.
of hemostasis in the late 1800s. The basic details of hemostasis were He offered to work in a research laboratory for a year awaiting
just beginning to emerge and most attention was first placed on pro- admission to the medical school; this offer was accepted the next
coagulant systems; endogenous anticoagulant systems were to be day. McLean immediately called on Howell and announced his
discovered and exploited later.7 desire for an academic career in surgery and for a year (1915–1916) of
physiological research in Howell’s laboratory. He was given the job of
isolating the true active thromboplastic principle of the crude brain
mixture cephalin.
Cephalin was a mixture of phospholipids; McLean found that
when it aged, it lost its procoagulant activity. He prepared phosphati-
des from other tissues, including Erlandsen’s courin (from dog heart)
and Baskoff’s heparphosphatide (from dog liver) in an effort to find a
purer procoagulant from which to start his isolations.
In the 1930s, several researchers were investigating heparin. Erik
Jorpes at Karolinska Institute published his research on the structure
of heparin in 1935, which made it possible for the Swedish company
Vitrum AB to launch the first heparin product for intravenous use in
1936.75 Between 1933 and 1936, Connaught Medical Research Labo-
ratories, then a part of the University of Toronto, perfected a tech-
nique for producing safe, non-toxic heparin that could be adminis-
tered to patients in a salt solution.
The first human trials of heparin began in May 1935, and, by
1937, it was clear that Connaught’s heparin was a safe, easily-avail-
able, and effective blood anticoagulant. Prior to 1933, heparin was
available, but in small amounts, and was extremely expensive, toxic
Figure 5.6: Jay McLean discovered heparin in 1916 and as a consequence, of no medical value.76
The use of heparin for a variety of venous or arterial thrombot- After they had shown that AT was the major heparin cofactor
ic disorders became standard in the 1940s; large randomized and and had purified this protein in reasonable amounts from plasma,
controlled clinical trials followed later and established the role of Rosenberg and his collaborators executed an essential experi-
heparin in thromboembolic disease.7 ment, the results of which were submitted for publication in Febru-
But need for APTT for its monitoring effect and continuous infu- ary 1976. By centrifuging a mixture of heparin and AT on a sucrose
sion leads to search for agent which does not need monitoring. Also density gradient they found that approximately one-third of the
heparin has problem of developing heparin induced thrombocyto- heparin migrated together with AT, while two-thirds of the material
penia. remained at its original position. This result was surprising since a
two to three fold molar excess of AT was present in the original reac-
Low-Molecular-Weight Heparins tion mixture. According to the authors “the data suggested that hepa-
rin bound to the inhibitor might represent an active species while
However, it was not until 1939 that heparin was shown to be an heparin unable to complex to AT-heparin cofactor could signify a
efficient anticoagulant only in the presence of a plasma component, chemically similar, but inactive form of this polysaccharide”.81
initially called heparin-cofactor. The link between heparin cofactor Shortly after publication of these findings, Lindahl and co-work-
and AT was made in the 1950s.77 At the same time it was suggested ers reported the fractionation of a standard heparin preparation by
that the activity of AT was accelerated by heparin. This postulate was affinity chromatography on a column of agarose AT. Thrombin in-
confirmed in 1968 by Abildgaard who isolated for the first time pure hibition by AT required a heparin fragment having a relatively large
AT and definitively settled in 1973 by Rosenberg and his collabora- size, factor Xa inhibition seemed to be independent of molecular
tors, who also devised a procedure to obtain the large amounts of weight.82 Because of the Choay company’s involvement in LMWH
AT required for the forthcoming studies.78,79 While coagulation bio- research, and the critical role then assigned to factor Xa inhibition
chemists were penetrating the mode of action of heparin, structural in the antithrombotic properties of heparin, Jean Choay decided
chemists were seeking the structure of the basic oligosaccharide unit to launch a research program with the ambitious objectives to first
(di-, tetra-, octasaccharide) of the heparin polysaccharide that they identify the shortest sequence able to inhibit factor Xa, and then to
imagined at that time as a “homopolymer” constituted of repeated synthesize it.77
oligosaccharide units as shown in Figure 5.7. Lindahl and co-workers published a detailed study of com-
Enoxaparin (Lovenox, Clexane, PK 10169, RP 54563, Rhone- pounds obtained by affinity chromatography following partial
Poulenc Rorer, Collegeville, PA) is prepared by benzylation followed nitrous acid fragmentation of heparin. For the first time a complete
by alkaline hydrolysis to achieve depolymerization of porcine hepa- sequence was proposed for the oligosaccharide as shown in Figure
rin. It contains a mixture of heparin molecules ranging from 4,000 to 5.8, involved in AT binding, and this sequence included the tetra
5,000 (average—4,500) with a saccharide length of 8–18. It was soon saccharide previously found by Rosenberg. However, Lindahl et al.
clearly established that the carbohydrate backbone was a repetition emphasized the nonsulphated iduronic acid as the functionally
of glucosamine and uronic acid moieties, but researchers were stuck important unit of the tetra saccharide structure, while they noted
for quite a long period of time by the nature of the uronic acid (D- that the N-acetyl group of the glucosamine moiety could be replaced
glucuronic or L-iduronic), as well as the content and the position of by an N-sulfonyl group.83
the various sulfonate groups. Up to the middle of the 1970s, when Meanwhile, the Choay group pursued their objective to identify
heparin was still considered essentially a homopolymer, all studies the smallest heparin fragment able to catalyze factor Xa inhibition by
tried to relate the anticoagulant potency of heparin preparations to AT. The approach included preparation of heparin fragments, affinity
structural parameters like molecular size, degree of sulfation, con- chromatography to select compounds able to bind to AT, size frac-
tent in N-sulfonate, O-sulfonate and N-acetyl groups, content in L- tionation of the fragments obtained and determination of the factor
iduronic and D-glucuronic acids.80 Xa inhibitory potency of the products.84 Several oligosaccharide frac-
Figure 5.7: Heparin was initially viewed as a homopolymer of basic oligosaccharide units.
Here is shown the basic octasaccharide unit proposed by Velluz et al80
Figure 5.8: The structure of the antithrombin binding site of pig mucosal heparin as viewed by Lindahl et al.
in 1979. X stands for either a sulfonate group or a hydrogen atom83
Figure 5.9: Structure of the antithrombin binding site of heparin. Circled groups play a critical role in binding to the protein; removal
of either of them decreases the affinity by several orders of magnitude while removal of the others hardly affects the affinity87
tions thus were prepared, either by direct extraction from standard thesized the pentasaccharide sequence DEFGH (the variant N-sul-
heparin, after enzymatic fragmentation of the polysaccharide by fonated at D and later its N-acetylated counterpart). This compound
heparinase or else after partial nitrous acid fragmentation of heparin. bound to AT with high affinity. The two tetrasaccharides DEFG and
Following affinity chromatography on AT-agarose and gel filtration, EFGH were also obtained and their ability to interact with AT was
several couples of active and inactive oligosaccharide fractions were evaluated. The results clearly indicated for the first time that the
thus obtained.77 entire pentasaccharide sequence is required to observe high
affinity binding. Biosynthetic experiments further confirmed the
Pentasaccharides conclusions regarding the functional roles of various O-sulfonate
groups in the AT-binding region of heparin.86
The inhibition of FXa by small molecules has been aggressively pur- In past decades, extensive research has been conducted on
sued by the pharmaceutical industry. Initial successes have led to the understanding the biochemistry of hemostasis and on the search
clinical development of low-molecular-weight heparins and fonda- for oral anticoagulants. Among the many enzymes in the coagula-
parinux.85 tion cascade, thrombin (factor IIa; fIIa) and factor FXa are two par-
From these studies it was deduced in 1981 that a unique penta- ticularly attractive targets. This research effort has yielded many new
saccharide fragment, which occurs in about one-third of the heparin anticoagulants, such as low-molecular-weight heparin (LMWH),
polysaccharide chains, constitutes the minimal binding domain for heparinoid, specific indirect FXa inhibitors and specific direct
ATIII. The pentasaccharide fragment (also known as the DEFGH part thrombin inhibitors.77
of heparin as shown in Figure 5.9) was synthesized a couple of years The slightly modified synthetic pentasaccharide fragment 1
later to confirm the earlier proposal. The above consistent experi- (ORG31540/SR90107) was found to elicit a very selective antithrom-
ments established the structure of the AT-binding site. However, they botic mode of action, in that it only accelerates the ATIII mediated
were extrapolations from structural data obtained by degradation of inhibition of coagulation factor Xa, but not that of thrombin. The
heparin, and they were not based on binding analysis of a true pen- results of four Phase III clinical trials show that the pentasaccharide
tasaccharide, hence the “soft” wording used by the authors in their 1 provides a superior benefit over a low-molecular-weight hepa-
formulations. rin.87
To go further, a true pentasaccharide was eagerly requested, and The replacement of the long-standing antithrombotic warfarin
the only way to obtain it (at least from a practical point of view) was for the treatment and prophylaxis of primary and secondary venous
chemical synthesis. In collaboration with Sinaÿ the Choay group syn- and arterial thromboembolisms is needed.
tree.89 In 1958, Sherry, Fletcher and Alkjaersig et al. reported the first
THROMBOLYTIC AGENTS
administration of SK (by intravenous infusion) to patients with AMI,
All of the thrombolytics are large proteins and their current sources with variable clinical success.90
are diverse: SK from bacterial cultures, urokinase from human kid- Because of the temporary lack of a source of SK, Sherry’s team
ney cell tissue cultures and tissue plasminogen activator (TPA) from turned to developing the recently described urokinase. They report-
recombinant DNA expressed in Chinese hamster ovary cell cultures. ed its successful use in maintaining a fibrinolytic state with intrave-
The history of thrombolytic agents begins in 1861 with the report by nous infusion in human volunteers in 1965, paving the way for later
von Brucke on the proteolytic activity of human urine. In 1886, Sahli use in AMI by others. The first studies of intravenous urokinase in
noted urinary proteolytic activity with some specificity for fibrin. pulmonary embolism began in 1967, and large, randomized, con-
Purification and isolation of the fibrinolytic enzyme in urine came trolled trials demonstrated the efficacy of thrombolytics in pulmo-
much later, in 1947 by MacFarlane and Pilling. Sobel et al. coined the nary embolism beginning with the 1970 report from the Urokinase
name “urokinase” in 1952. They demonstrated that urokinase is not Pulmonary Embolism Trial (UPET) study.91
a direct fibrin-digesting enzyme, but rather an activator of endog- Streptokinase was resuscitated in the 1960s by the drug firms
enous plasminogen, thereby generating plasmin, which then con- Behringwerke AG and Kabi Pharmacia. As a result, between 1960 and
sumes fibrin, fibrinogen and other coagulation proteins. In the early 1979, 18 trials of intravenous SK in AMI were published, and meta-
1930s, William Tillett, a bacteriologist and Chief of Medicine at the analyses by Stampfer et al. and Yusuf et al. revealed that these early,
New York University School of Medicine and its division at Bellevue small, primitive studies provided unequivocal evidence of SK’s effect
Hospital, was studying acute-phase reactants.7 on reducing MI mortality. The famed GISSI and ISIS-2 studies of the
Noting that plasma from patients with an acute febrile illness 1980s provided the final convincing proof of the great usefulness of
could agglutinate hemolytic streptococci but serum could not, Til- intravenous SK in AMI.92
lett suspected that fibrinogen was the mediator of agglutination. He Despite the demonstration by Herrick as early as 1912 of the cen-
reasoned that if plasma (containing fibrinogen) was added to strep- tral role of thrombosis in AMI, doubt lingered about the issue until
tococci, the fibrinogen would be tied up in agglutinating the bacte- the landmark angiographic demonstration of DeWood et al. in 1980
ria. To Tillett’s initial disappointment, the treated plasma from the of acute thrombosis in most cases of AMI.93
acute phase patient clotted, as well as the plasma from normal sub- Despite the success of early experience with intravenous SK for
jects. Just before discarding the test tubes, Tillett happened to look at AMI in the 1960s, clinicians used it rarely due to the paucity of large-
them again. Strangely, the tube with the added culture had liquefied, scale trials of efficacy. Concern over the significant bleeding inci-
although it had clotted initially.7 Tillett called it “fibrinolysin.”88 dence encountered with early, very long infusion protocols; confu-
Milstone and colleague showed in 1941 that the streptococcal sion over widely differing dosing regimens and prevailing scepticism
fibrinolysin did not directly dissolve fibrin in vitro; rather it required about the role of thrombosis in AMI.7
a plasma protein cofactor he called “plasma lysing factor”. This fac- The much better known report of Rentrop et al. in 1979 of intra-
tor later proved to be plasminogen, of course. In 1944, Christensen coronary SK led to a number of reports of uncontrolled small series
and MacLeod from New York University and Kaplan independently of intracoronary SK, which would be followed by larger, randomized,
discovered this. Christensen coined the terms “plasminogen” and controlled studies of intracoronary and then intravenous SK.94
“plasmin” and renamed fibrinolysin “streptokinase”. They also par- Tissue slices were shown by Astrup and Permin to lyse fibrin in
tially purified both plasminogen and SK. In 1946, Tillett recruited 1947. Sherry’s group briefly dabbled with TPA, reporting in 1964 the
one of Bellevue’s residents, Sol Sherry, to join the team researching partial purification of TPA from pig heart. Fully purified TPA was pre-
SK.7 pared by Rijken et al. first from uterine tissue in 1979 and then from
He would become a pivotal figure in the development of not only human melanoma cell cultures in 1981.95 Pennica et al. reported the
SK, but urokinase and even TPA in ensuing years. His team became cloning of TPA DNA derived from human melanoma cells and its ex-
the first to administer crude SK to humans in early 1947. They treated pression by Escherichia coli in 1983.96 Clinical use evolved rapidly,
patients with chronic empyemas, hemothorax, loculated effusions seizing on the new preparations. Van de Werf et al. reported the first
with intrapleural injections of SK with dramatic results (break-up use of natural TPA (harvested from the Bowes human melanoma tis-
of fibrin septations, allowing for easy aspiration of fluid). They also sue culture) in an uncontrolled series of AMI patients in 1984, with
treated chronic abscess cavities with local injections of SK, reporting clinical and angiographic success. The same group also became the
their results in 1949. New York University SK was crude and too toxic first to use recombinant TPA (this time in dogs) with experimental
for systemic use. Lederle Laboratories assisted by supplying them MI, also in 1984.97 The same year, Collen et al. pioneered the use of
with improved preparations that were pure enough for intravenous recombinant TPA in patients with AMI. Randomized, controlled tri-
use.7 By 1952, Johnson and Tillett reported that experimental rabbit als followed, with striking success, leading to the US Food and Drug
ear vein thrombi were lysed by peripheral intravenous administra- Administration (FDA) approval of intravenous TPA for AMI in 1987
tion of the purer SK, thus pioneering the use of SK in the vascular and for pulmonary embolism in 1990.98
CONCLUSION
The stories of history of antithrombotic agents are very fascinating and landmarks in medicine. The cooperation and competition lead to
discovery of agents for the cure of diseases in mankind.
REFERENCES
1. Gonzalez ER. Antiplatelet therapy in atherosclerotic cardiovascular disease. Clinical Therapeutics. 1988;20(Suppl B):B18-41.
2. Kam PC, Nethery CM. The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical develop-
ments. Anaesthesia. 2003;58:28-35.
3. Kuzniatsova N, Shantsila E, Lip GY. Future directions in antiplatelet therapy: efficacy versus safety. Future Prescriber. 2009;10:20-3.
4. Hirsh J. Current anticoagulant therapy—unmet clinical needs. Thromb Res. 2003;109:S1-8.
5. Savi P, Herbert JM. ADP receptors on platelets and ADP-selective antiaggregating agents. Semin Thromb Hemost. 1996;16:159-79.
6. Desai UR. New antithrombin-based anticoagulants. Med Res Rev. 2004;24:151-81.
7. Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation. 1994;89:432-49.
8. Jack DB. One hundred years of aspirin. Lancet. 1997;350:437-9.
9. Bellanger A, Reboux G, Botterel F, et al. Original Article New evidence of the involvement of Lichtheimia corymbifera in farmer’s lung disease.
Medical Mycology: Official Publication of The International Society for Human and Animal Mycology. 2010.
10. Miner J, Hoffhines A. The discovery of aspirin’s antithrombotic effects. Tex Heart Inst J. 2007;34:179-86.
11. Maclagan T. The treatment of acute rheumatism by salicin. Lancet. 1876;1:342-343,383-384.
12. Jeffries D. The remarkable story of a wonder drug: aspirin, New York: Bloomsbury Publishing; 2005.
13. Quick AJ. Bleeding time after aspirin ingestion. Lancet. 1968;1:50.
14. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232-5.
15. Smith and Willis. Aspirin selectively inhibits prostaglandin production in human platelets, Nat New Biol. 1971;231:235-7.
16. Hamberg B, Svensson M, Samuelsson J. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperox-
ides. Proc Nat Acad Sci. 1975;72:2994-8.
17. Penderson AK, Fitzgerald GA. Dose-related kinetics of aspirin: pre-systemic acetylation of platelet cyclo-oxygenase. N Engl J Med. 1984;311:1206-
11.
18. Patrono C, Coller B, FitzGerald GA, et al. Platelet-active drugs: the relationship among dose, effectiveness, and side effects: the seventh ACCP
conference on antithrombotic and thrombolytic: Chest. 2004;126:234S-64S.
19. Born G. Antiplatelet drugs. BMJ. 2001;322:329.
20. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2,
Lancet. 1988;2:349.
21. Preliminary report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1988;318:262-4.
22. Collaboration AT. Secondary prevention of vascular disease by prolonged anti-platelet treatment. BMJ. 1988;296:320-31.
23. Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010;9:154-69.
24. Badimon L, Vilahur G. Coronary Atherothrombotic Disease: Progress in Antiplatelet Therapy, Revista Española De Cardiología (English edition).
2008;61:501-13.
25. Bertrand ME, Legrand V, Boland J. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned
and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation. 1998;98:1597-603.
26. Ridker P, Cook N. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New Eng J Med.
2005;352:1293-304.
27. Cheng X, Chen W, Simon D. Aspirin Resistance or variable response or both? AJ Cardiol. 2006;98:11N-7N.
28. Angiolillo DJ, Guzman LA, Bass TA. Current antiplatelet therapies: benefits and limitations. Am Heart J. 2008;156:S3-9.
29. Hass WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk
patients. N Engl J Med. 1989;321:501-7.
30. Gent M, Easton JD, Hachinski V, et al. The Canadian American ticlopidine study (CATS) in thromboembolic stroke. Lancet. 1989;1:1215-20.
31. Boissel JP, Peyrieux JC, Destors JM. Is it possible to reduce the risk of cardiovascular events in subjects suffering from intermittent claudication of
the lower limbs? Throm Hemost. 1989;62:681-5.
32. Bertrand ME, Rupprecht HJ, Urban P. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin
compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study
(CLASSICS). Circulation. 2000;102:624-9.
33. Abuhajir M, Mazzeo A. The pharmacology of antithrombotic and antiplatelet agents. Anesthesiol Clin North Am. 1999;17:749-86.
34. Yusuf S, Zhao F, Mehta S. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The
New England. 2001;345: 494-502.
35. CAPRIE Steering Committee (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
Lancet. 1996;348:1329-39.
36. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-39.
37. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600 mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-
ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol. 2006;48:1339-45.
38. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE). Effects of clopidogrel in addition to aspirin in patients
with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.
39. Mehta S, Yusuf S, Peters R, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percu-
taneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527-33.
40. Sabatine M, Cannon C, Gibson C, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment eleva-
tion. CLARITY-TIMI 28 Investigators. N Engl J Med. 2005;352:1179-89.
41. Chen ZM, Jiang LX, Chen YP. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo con-
trolled trial. Lancet. 2005;366:1607-21.
42. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New Eng J Med.
2006;354:1706-17.
43. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and
future perspectives. J Am Coll Cardiol. 2007;49:1505-16.
44. Rich JD, Wiviott SD. New antiplatelet therapies for acute coronary syndromes. Curr Cardiol Rep. 2007;9:303-11.
45. Franchini M, Mannucci PM. New antiplatelet agents: why they are needed. Eur J Inter Med. 2009;20:733-8.
46. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibi-
tion is related to active metabolite formation. Am Heart J. 2007;153:e9-16.
47. Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (cs-747, ly640315), a novel thienopyridine p2Y12 antagonist, with
clopidogrel in percutaneous coronary intervention: Results of the joint utilization of medications to block platelets optimally (JUMBO)-TIMI 26
trial. Circulation. 2005;111: 3366-73.
48. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. New Eng J Med. 2007;357:2001-
15.
49. Weyrich AS, Denis MM, Kuhlmann-Eyre JR, et al. Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggre-
gates. Circulation. 2005;111:633-42.
50. James DM, Born GV. Uptake of purine bases and nucleosides in African trypanosomes. Parasitology. 2009;81:383-93.
51. Coller BS. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic strategy. Circulation. 1995;92:2373-80.
52. Chew DP, Bhatt DL, Sapp S, et al. Topol, Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III mul-
ticenter randomized trials. Circulation. 2001;103:201-6.
53. Cohen M, Ferguson JJ, Harrington RA. Trials of glycoprotein IIb-IIIa inhibitors in non-ST-segment elevation acute coronary syndromes: applica-
bility to the practice of medicine in the United States. Clin Cardiol. 1999;22(Suppl 6):VI2-12.
54. Coller BS. A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the
platelet glycoprotein IIb/IIIa complex. J Clin Invest. 1985;76:101-8.
55. Scarborough RM, Naughton MA, Teng W, et al. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for
glycoprotein IIb-IIIa. J Biol Chem. 1993;268:1066-73.
56. Chen Y, Pitzenberger SM, Garsky VM, et al. Proton NMR assignments and secondary structure of the snake venom protein echistatin, Biochemis-
try. 1991;30:11625-36.
57. Topol EJ, Lincoff AM, Kereiakes DJ, et al. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutane-
ous coronary revascularization. Am J Med. 2002;113:1-6.
58. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary
syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Eng J Med. 2001;344:1879-87.
59. Peterson ED, Pollack CV, Roe MT, et al. Early use of glycoprotein IIb/IIIa inhibitors in non-ST-elevation acute myocardial infarction: Observations
from the National Registry of Myocardial Infarction 4. J Am Coll Cardiol. 2003;42:45-53.
60. Simoons ML, GUSTO IV-ACS Investigators. Effect of GP IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndrome
without early coronary revascularization: The GUSTO IV-ACS trial. Lancet. 2001;357:1915-24.
61. Yamanaka T, Ohkubo M, Kuroda S, et al. Design, synthesis, and structure-activity relationships of potent GPIIb/IIIa antagonists: discovery of
FK419. Bioorg Med Chem. 2005;13:4343-52.
62. Link KP. The discovery of dicumarol and its sequels. Circulation. 1959;19:97-107.
63. Vacca JP. New advances in the discovery of thrombin and factor Xa inhibitors. Curr Opin Chem Biol. 2000;4:394-400.
64. Fink E. Comparison of hirudins, Semin Thromb and Hemost. 1989;15:283-7.
65. Folkers PJ, Clore GM, Driscoll PC, et al. Gronenborn, Solution structure of recombinant hirudin and the Lys-47. fwdarw. Glu mutants: a nuclear
magnetic resonance and hybrid distance geometry-dynamical simulated annealing study. Biochemistry. 1989;28:2601-17.
66. Haruyama H, Wüthrich K. Conformation of recombinant desulfatohirudin in aqueous solution determined by nuclear magnetic resonance. Bio-
chemistry. 1989;28:4301-12.
67. Rydel TJ, Tulinsky A, Bode W, et al. Refined structure of the hirudin-thrombin complex. J Mol Biol. 1991;221:583-601.
68. Srivastava S, Goswami LN, Dikshit DK. Progress in the design of low molecular weight thrombin inhibitors. Med Res Rev. 2005;25:66-92.
69. Stürzebecher J, Markwardt F, Voigt B, Wagner G, Walsmann P. Cyclic amides of N-a-arylsulfonyl- aminoacylated 4-amidinophenylalanine-tight
binding inhibitors of thrombin. Thromb Res. 1983;29:635-42.
70. Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite
melagatran: a mini-review. Thromb Res. 2003;109:S9-15.
71. Björk I, Lindahl U. Mechanism of the anticoagulant action of heparin. Mol Cell Biochem. 1982;48:161-82.
72. Belik PI. Reprinted OTS Washington, February 1959. US Joint Publications Research Service.
73. Morawitz P. Die chemie der blutgerinnung, Monatsschrift Kinderheilkunde. 1905;4:307-422.
74. Doyon M, Morel A. Estraition directe de l’an- tithrombine du foie: influence de la congelation. C R Soc Biol (Paris). 1911;70:341-4.
75. Jorpes E. The chemistry of heparin Biochem J. 1935;29:1817-30.
76. Rutty C. Miracle blood lubricant: connaught and the story of heparin, 1928–1937, Health Heritage Research Services.
77. Petitou M, Casu B, Lindahl U. 1976-1983, a critical period in the history of heparin: the discovery of the antithrombin binding site. Biochimie.
2003;85:83-9.
78. Abildgaard U. Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest. 1968;21:89-
90.
79. Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem. 1973;248:6490-505.
80. Velluz L, Nomine G, Mathieu J. Recherches sur l’héparine. Les héparides antilipémiques. Bull Soc Chim Biol. 1959;41:415-35.
81. Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forks of heparin. Biochem Biophys Res Commun. 1976;69:570-7.
82. Höök M, Björk I, Hopwood J, et al. Anticoagulant activity of heparin: separation of high-activity and low-activity heparin species by affinity chro-
matography on immobilized antithrombin. FEBS Letters. 1976;66:90-3.
83. Lindahl U. Structure of the antithrombin-binding site in heparin, proceedings of The National Academy of Sciences. 1979;76:3198-202.
84. Choay J, Lormeau JC, Petitou M, et al. Anti-Xa active heparin oligosaccharides. Thromb Res. 1980;8:573-8.
85. Kohrt JT, Filipski KJ, Cody WL, et al. The discovery of glycine and related amino acid-based factor Xa inhibitors. Bioorg Med Chem. 2006;14:4379-
92.
86. Choay J, Lormeau JC, Petitou M, et al. Structurally studies on a biologically active hexasaccharide obtained from heparin. Ann N Y Acad Sci.
1981;370:644-9.
87. Codee J, Overkleeft H, Vandermarel G, et al. The synthesis of well-defined heparin and heparan sulfate fragments, Drug Discovery Today: Tech-
nologies. 2004;1:317-26.
88. Tillett WS. The fibrinolytic activity of streptococci. J Exp Med. 1933;58:485-502.
89. Johnson AJ, Tillett WS. The lysis in rabbits of intravascular blood clots by the streptococcal fibrinolytic system (streptokinase). J Exp Med.
1952;95:449-64.
90. Sherry S, Fletcher AP, Alkajersig N, et al. An approach to intravascular fibrinolysis in man. Transactions Assoc Am Physicians. 1957;70:288-96.
91. Sherry S. Personal reflections on the development of thrombolytic therapy and its application to acute coronary thrombosis. Am Heart J.
1981;102:1134-9.
92. Stampfer MJ, Goldhaber SZ, Yusuf S, et al. Effects of intravenous streptokinase on acute myocardial infarction: results pooled from randomized
trials. N Eng J Med. 1982;307:1180-2.
93. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J
Med. 1980;303:897-902.
94. Rentrop KP, Blanke H, Karsch KR, et al. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase in combination
with transluminal recanalization. Clin Cardiol. 1979;2:354-63.
95. Rijken DC, Collen D. Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J Biol Chem.
1981;256:7035-41.
96. Pennica D, Holmes WE, Kohr WJ, et al. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature. 1983;301:214-
21.
97. Van de Werf F, Ludbrook PA, Bergmann SR, et al. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocar-
dial infarction. N Engl J Med. 1984;310:609-13.
98. Collen D, Topol EJ, Tiefenbrunn AJ, et al. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, ran-
domized, placebo-controlled trial. Circulation. 1984;70:1012-7.
6 History of Statins
Manchanda SC, Makhija A, Sharma MK
acted via competitive inhibition of the enzyme HMG CoA reductase.

INTRODUCTION
Initially known as compactin (ML-236 B), this compound was later
According to World health report 2002, cardiovascular disease (CVD) called mevastatin.5
will be the largest cause of death and disability by 2020 in India. In The first clinical studies with compactin were carried in 1977
2020 AD, 2.6 million, Indians are predicted to die due to coronary in Osaka by Yamamoto and Sudo in collaboration with Endo. They
heart disease (CHD), which constitutes 54.1% of all CV deaths. Near- showed that the compactin in doses of 50–150 mg/day reduced the
ly half of these are likely to occur in young and middle aged individu- serum cholesterol by 27% on average in patients with heterozygous
als (30–39%).1 familial hypercholesterolemia (FH) or combined hyperlipidemia,
Dyslipidemia is undoubtedly the most important modifiable risk most of decrease being in LDL.6 In 1980, Sankyo suddenly suspended
factor for CVD, particularly for CHD.1 The link between lowering high their clinical trial program reputedly because of the perceived car-
total and especially low-density lipoprotein cholesterol (LDL-C) and cinogenicity (lymphoma) of high doses of compactin in dogs.7 As a
therefore reduction of CVD risk is today established as “the lower— consequence, it was never licensed for use in man.
the better” paradigm in hypercholesterolemia management.2
The cornerstone of CHD risk reduction therapy is the treat- Development of Lovastatin
ment of elevated lLDL-C levels. Since their introduction in 1987, hy-
droxymethyl glutaryl-coenzyme A (HMG CoA) reductase inhibitors In 1966, Sankyo had provided Merck with samples of compactin and
(statins) have become the preferred drugs for reducing LDL-C. pharmacological data on the drug as a part of a confidential agree-
Statins are now one of the most widely prescribed medica- ment. Over a decade later, in 1978 after carrying out independent
tions worldwide, with an estimated two million people in the UK3 studies with compactin, Merck independently isolated a new HMG
and more than 18 million people in the USA currently taking a CoA reductase inhibitor, lovastatin (then called mevinolin), from an
statin.4 By inhibiting HMG-CoA reductase, the rate limiting step Aspergillus species. At much the same time, Endo, now working at
in cholesterol biosynthesis, statins lower LDL-C levels by approxi- Tokyo Noko University, had also isolated a compactin analogue with
mately 21–63%. a slightly greater efficacy, which he called monacolin K.8
Although the development of this drug was also halted in 1980
THE DISCOVERY OF COMPACTIN— following the compactin toxicity study findings, some small-scale
clinical investigations by US physicians and additional toxicity stud-
INITIAL MOLECULE
ies (which suggested that the ‘lymphomas’ were actually histological
In 1968, Akira Endo, a Japanese microbiologist, working for phar- changes due to massive drug doses rather than malignancies)5 led
maceutical company Sankyo, started searching for microbial me- to Merck resuming the development of lovastatin, which was finally
tabolites that would inhibit, HMG CoA reductase, the key enzyme given the US Food and Drug Administration approval in 1987, nine
of cholesterol biosynthesis. His hope that this would provide a novel years after its discovery.
means of lowering plasma cholesterol were vindicated when after
testing more than 6,000 microbial strains over two years, he and his Development of Other Statins
colleagues isolated a potent inhibitor of HMG CoA reductase from
Penicillium citrinum, which lowered serum cholesterol in experi- In 1988, Merck team developed a more potent semi-synthetic
mental animals. The molecule contained a portion with a chemical derivative of lovastatin, which differed only by an additional side-
structure very similar to mevalonate, the product of the HMG CoA chain methyl group. This was named simvastatin and subsequently
reductase reaction. This finding fitted well with the theory that it marketed worldwide.
In 1991, pravastatin, derived by a biotransformation of compac-

ADVERSE EFFECTS AND DRUG
tin, was developed by Sankyo. Four more statins followed: fluvastatin
(1994), atorvastatin (1997), cerivastatin (1998), rosuvastatin (2003),
INTERACTIONS
and pitavastatin (2003—available in Japan and India only), all of As a class, statins are well tolerated and there are no known differ-
which are synthetic products. Cerivastatin was eventually discontin- ences in safety. Mild gastrointestinal disturbances and headaches
ued in 2001 following several deaths from rhabdomyolysis.9 are reported by about 10% of patients treated with either statins or
placebo. The most important adverse effects are liver and muscle
MECHANISM OF ACTION toxicity. The incidence of transaminase increases greater than 3-fold
is 1% for all statins and is dose-related.18-20 If this occurs, the drug
Statins inhibit the rate-determining step of endogenous cholesterol should be stopped; transaminase levels generally return to baseline
synthesis, i.e. the deacylation of HMG-CoA to mevalonic acid, which within 2–3 months.19 The major adverse effect of statins is myopathy,
is catalyzed by the enzyme HMG-CoA reductase.10 The resultant redefined as muscle pain or weakness associated with creatine kinase
duction in hepatocyte cholesterol concentration triggers increased (CK) levels higher than 10 times the upper limit of normal. Symp-
expression of hepatic LDL receptors, which clear LDL and LDL pre- toms may include fever and malaise, and cases have been associated
cursors from the circulation. Statins may inhibit hepatic synthesis of with elevated serum statin drug levels. Rhabdomyolysis and acute
apo-lipoprotein B-100 and decrease the synthesis and secretion of renal failure may result if myopathy is not recognized and the drug
triglyceride-rich lipoproteins.11 Although the primary mechanism of is continued.21 If recognized promptly and the drug is stopped, the
action for LDL lowering is enhanced clearance of LDL via LDL recep- myopathy is reversible, and acute renal failure is unlikely to ensue.
tors, reduced hepatic production and secretion of lipoproteins may Some patients (e.g, those with renal impairment, hypothyroidism,
explain the observation that the atorvastatin and simvastatin are ca- serious debility or those who are older than 80 years) are more sus-
pable of lowering LDL in patients with homozygous familial hyper- ceptible than others to myopathy. A systematic review of randomized
cholesterolemia, who have no functional LDL receptors.12 statin trials and cohort studies provides an overall estimated risk of
myopathy with statin use of 11 per 100,000 person-years of follow-
PHARMACOLOGY up, with the risk of rhabdomyolysis about one-third of this (3–4 per
100,000 person-years).22 The drugs that interact with statins are given
Lovastatin, pravastatin and simvastatin are derived from fungal fer- in the Box 6.1.23
mentation. Fluvastatin, atorvastatin, cerivastatin and rosuvastatin The combination of statins with certain drugs that are CYP3A4
are entirely synthetic. inhibitors or substrates increases the risk of myopathy, presumably
Atorvastatin, lovastatin and simvastatin are metabolized through by inhibiting the metabolism of the statin and increasing its blood
the catalyzing action of the cytochrome P450 isoenzyme 3A4.13 Flu- concentration. Fibrates and niacin also increase the risk of statin-
vastatin is mainly metabolized through the catalyzing action of iso- induced myopathy via a mechanism that does not increase plasma
enzyme CYP 2C9, while pravastatin is eliminated, independently statin concentrations.24 A further rare undesired effect is severe
of both 3A4 and 2C9, by means of the “organic anion transporting hepatotoxicity. Statins are therefore contraindicated in patients with
polypeptide” (OATP) and MRP2 transport proteins (MRP = “multi- active hepatic disease, cholestasis or myopathy, as well as in preg-
drug resistance protein”).14 Inhibition of cytochrome P450, e.g. by nant women and nursing mothers (because of a lack of data about
concomitant use of other medications, elevates the concentration of possible harmful effects in these situations). Creatine kinase activity
3A4-dependent statins. Special caution is required, therefore, when
3A4-dependent statins are used in combination with macrolide an-
Box 6.1 Drugs that might interact with statins23
tibiotics, azole antimycotic agents, HIV-protease inhibitors, cyclo-
sporine or grapefruit juice (Text Box). Although the addition of a • Cyclosporin
statin to gemfibrozil or niacin increases the risk of myopathy, statins • Fibrates
– Gemfi brozil, bezafi brate, fenofi brate and ciprofi brate
administered in low doses have been found to be safe in combination
• Azol anti-fungal
with other fibrates15 and with niacin.16 The newer, synthetic statins
– Itraconazole, ketoconazole and miconazole
(e.g. atorvastatin and rosuvastatin), in comparison to the older prep-
• Macrolide antibiotics
arations (such as lovastatin), are characterized by tighter binding – Erythromycin, telithromycin and clarithromycin
in the HMG binding pocket and they therefore inhibit the binding • Anti-arrhthymics
of HMG-CoA with greater potency.17 Statins thus differ in the rela- – Verapamil, amiodarone
tive strength of their effects for a given quantity of their active agent. • Nefazodone
Though they all have the same mechanism of action. They differ too • Protease inhibitors
with respect to their solubility in water and their pharmacokinetics – Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfi
(Table 6.1). navir, ritonavir, and tipranavir
TABLE 6.1 Pharmacological Properties of Statins
Characteristic Lovastatin Pravastatin Slmvastatin Fluvastatin Atorvastatin Rosuvastatin
Usual starting dose (mg/ 20 mg 40 mg 20–40 mg 20–40 mg 10 mg 10 mg (in Asians: 5 mg)
day)
Expected LDL fall, this 24% 34% 38% 25% (40 mg) 39% 52%
dose
Elderly starting dose Not stated 40 mg start 20 mg or less Dose unchanged Dose unchanged 5 mg
Timing of dose Evening meal Any time Evening Bedtime Any time Any time
Maximum daily dose 80 mg 80 mg 80 mg 80 mg 80 mg 40 mg
LDL reduction, max dose 40% 37% 47% 36% 60% 63%
HDL-C increase, max 9.5% 13% 8% 5.6% 5% 14.7%
dose
Mortality reduction in No data Yes Yes No data No data No data
trials
CV end point reduction Yes Yes Yes Probable Probable Yes (atheroma)
Stroke reduction No data Yes Yes No data Probable No data
Elimination route, chief Hepatic and biliary Hepatic and biliary Hepatic and biliary Hepatic and biliary Hepatic and biliary Hepatic and biliary
Renal excretion of 10 20 13 <6 <2 28
absorbed dose (%)
Chapter 6  History of Statins
Dose in severe renal 20 mg 10 mg 5 mg Dose unchanged Dose unchanged 5 mg

failure
Dose with cyclosporine 10 mg 10 mg 5 mg Dose unchanged Reduce 5 mg
Digoxin effect None None Small increase Small increase 20% increase None
Mechanism of hepatic CYP3A4 Not by CYP, by sulfation CYP3A4 CYP2C9 CYP3A4 CYP2C9
metabolism
Hepatic interactions Erythromycin No Erythromycin Clearance decrease, by Erythromycin Clearance decrease, by
Ketoconozole Ketoconozole cimetidine, ranitidine; Ketoconozale cyclosporine, gemfibrozil
Antiretrovirals Antiretrovirals Clearance increase by Antiretrovirais
Verapamil Verapamil rifampicin Verapamil
Abbreviations: LDL, Low-density lipoprotein; HDL, High-density lipoprotein
51
and serum transaminase levels should be measured in the first few

CURRENT INDICATIONS OF STATINS
months of statin treatment, whenever the dose is raised, and when-
ever there are potential interactions with other medications.25 The effect of statin therapy on CV events has now been studied in
numerous major randomized controlled trials, as summarized in
Risk of Incident Diabetes Table 6.3.
Statin therapy is associated with a slightly increased risk of develop- STATIN TRIALS—PRIMARY PREVENTION
ment of diabetes but the risk is low both in absolute terms and when
compared with the reduction in coronary events. These trials cover a broad spectrum of patient populations. Six in-
In a recent meta-analysis, 13 statin trials with 91,140 partici- volved populations with no clinically evident CHD: the West of
pants, of whom 4,278 (2,226 assigned statins and 2,052 assigned con- Scotland Coronary Prevention Study (WOSCOPS)20 in hypercholes-
trol treatment) developed diabetes during a mean of 4 years. Statin terolemic men, the Air Force/Texas Coronary Atherosclerosis Pre-
therapy was associated with a 9% increased risk for incident diabetes vention Study (AFCAPS/TexCAPS)34 in men and women with low
[odds ratio (OR) 109; 95% CI 102–117]. Meta-regression showed HDL-cholesterol levels, the Anglo-Scandinavian Cardiac Outcomes
that risk of development of diabetes with statins was the highest in Trial-Lipid Lowering Arm (ASCOTLLA)35 and the Antihypertensive
trials with older participants, but neither baseline body-mass index, and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALL-
nor change in LDL-C concentrations accounted for residual varia- HAT)36 in subjects with hypertension, the Collaborative Atorvastatin
tion in risk. Treatment of 255 (95% CI 150–852) patients with statins Diabetes Study (CARDS)37 in diabetics and the Prospective Study of
for 4 years resulted in one extra case of diabetes. So, clinical practice Pravastatin in the Elderly at Risk (PROSPER)38 study.
for statin therapy does not need to change for patients with moderate Recently, results from the Justification for the Use of Statins in
or high CV risk or existing CVD.26 Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPI-
TER)39 demonstrated significant benefit with statin therapy in a
SAFETY RESULTS population of 17,802 healthy individuals with low to moderate lev-
els of LDL-cholesterol (< 130 mg/dL C-reactive protein and elevated
Almost 27,000 patients have been randomized into trials compar- (CRP, > 2 mg/L). The trial compared the effects of 20 mg rosuvasta-
ing atorvastatin 80 mg daily with various standard statin regimens or tin versus placebo on a combined primary end point of myocardial
placebo. No excess risk of myopathy was reported among those al- infarction (MI) hospitalization for unstable angina, and CV death.
located this dose of atorvastatin neither in these trials, nor in pooled After a median follow-up of 1.9 years, the trial was stopped due to
data from earlier trials (Table 6.2). early evidence of efficacy. The treatment group demonstrated a
TABLE 6.2 Safety results from large randomized trials of intensive statin therapy
Trial Statin Medical Alanine Creatine Kinase Rhabdomyolysis Non-Vascular Death
Comparison Condition of Transaminase Ten Times Upper Higher vs Lower Higher vs Lower
Higher vs Lower Participants Three Times Upper Limit of Normal, or
Limit of Normal Myopathy Higher vs
Higher vs Lower Lower
PROVE– A 80 mg vs Acute coronary 69 (33%) vs 2 (01%) vs 0 (0%) vs 0 (0%) 17 (08%) vs 27 (13%)
IT27,28 (4162) P 40 mg syndromes 23 (11%) 3 (015%)
Phase Z of S 80 mg vs Acute coronary 19 (09%) vs 9 (04%) vs 3 (01%) vs 0 (0%) 21 (09%) vs 21 (09%)
the A to Z S 20 mg syndromes 8 (04%) 1 (004%)
Trial29 (4497)
TNT30,31 (10 A 80 mg vs Stable CHD 60 (12%) vs (00%) vs (00%) 2 (004%) vs 3 (006%) 158 (32%) vs 127 (25%)
001) A10 mg 9 (02%)
IDEAL32 A 80 mg vs Stable CHD 43 (097%) vs 6 (014%) vs 2 (005%) vs 3 (007%) 143 (32%) vs 156 (35%)
(8888) S 20–40 mg 5 (011%) 11 (025%)
SPARCL33 A 80 mg vs Post stroke or 51 (22%) vs 7 (03%) vs 7 (03%) 2 (01%) vs 3 (01%) 117 (49%) vs 94 (39%)
(4731) placebo TIA (no CHD%) 11 (05%)
Abbreviations: CHD, Coronary heart disease; TIA, Transient ischemic attack; A, atorvastatin; P, pravastatin; S, Simvastatin
TABLE 6.3 Randomized controlled trials of statins with clinical endpoints
Trial Year Drug and Dose Control Patients LDL-Cholestrol Primary Endpoint Event rate HR (95% CI)
(%) Therapy P Value
Vs Control
Follow-up Therapy Control Difference (%)
(yrs) (mg/dL) (mg/dL)
Primary prevention
WOSCOPS20 1995 Pravastatin Placebo 6,595 men 4.9 142 192 26 CHD death plus 5.5 vs 7.9 0.69 (0.57-
(high LDL-C) 40 mg MI 0.83) P < .001
AFCAPS/ 1998 Lovastatin Placebo 6,605 5.2 115 156 26 CHD death, MI 6.8 vs 10.9 0.63 (0.50-
TexCAPS34 (low 20–40 mg or UA 0.79) P < .001
HDL-C)
ASCOT-LLA 2003 Atorvastatin Placebo 10,305 3.3 87 133 35 CHD death or MI 6.0 vs 9.4 0.64 (0.50-
(BP)35 10 mg 0.83)
P = .0005
ALLHAT-LLT 2002 Pravastatin, Placebo 10,355 4.8 111 135 17 All-cause 12.2 vs 12.4 0.99 (0.89-
(BP)36 40 mg mortality 1.11) P = .88
CARDS 2004 Atorvastatin Placebo 2,838 3.9 72 120 40 CHD death, 5.8 vs 9.0 0.63 (0.48-
(diabetes)37 10 mg MI, UA, cardiac 0.83) P < .001
arrest, CABG, PCI,
or stroke
PROSPER 2002 Pravastatin Placebo 5,804 3.2 107 147 27 CHD death, MI, 14.1 vs 16.2 0.85 (0.74-
(elderly)38 40 mg or stroke 0.97) P = .014
JUPITER 2003 Rosuvastatin Placebo 17,802 1.9 55 110 MI, stroke, 0.77/100 0.56 (0.46-
Chapter 6  History of Statins
(hscRP)39 Revascularization Person/y vs 0.69)

VA, CVD death 1.36/100 P < .00001
Person/y
Stable CAD
4S41 1994 Simvastatin Placebo 4,444 5.4 122 188 36 Total mortality 8.2 vs 11.5 0.70
20–40 mg (0.58–0.85)
P = .0003
CARE42 1996 Pravastatin Placebo 4,159 5.0 97 125 28 CHD death or MI 10.2 vs 13.2 0.76
40 mg (0.64–0.91)
P = .003
LIPID43 1998 Pravastatin Placebo 9,014 6.1 113 150 25 CHD death 6.4 vs 8.3 0.76
40 mg (0.65–0.88)
P < .001
(Contd….)
53
(Contd….)
54
Trial Year Drug and Dose Control Patients LDL-Cholestrol Primary Endpoint Event rate HR (95% CI)
(%) Therapy P Value
Vs Control
Follow-up Therapy Control Difference
(yrs) (mg/dL) (mg/dL) (%)
TNT 2005 Atorvastatin Atorvastatin 10,001 4.9 77 101 24 CHD death, MI 8.7 vs 10.9 0.78 (0.69-
80 mg 10 mg stroke, cardiac 0.89)
arrest P = 0.0002
IDEAL32 2005 Atorvastatin Simvastatin, 8,888 4.8 81 104 22 CHD death, MI or 9.3 vs 10.4 0.89 (0.78-
80 mg 20 mg cardiac arrest 1.01) P =.07
Post-ACS
MIRACL44 2001 Atorvastatin Placebo 3,086 16 weeks 72 135 40 Death, MI, 14.8 vs 17.4 0.84 (0.70-
80 mg cardiac arrest, 1.0) P = .048
UA requiring
hospitalization
PROVE-IT27 2004 Atorvastatin Pravastatin 4,162 2.0 62 95 35 Death, MI, UA, 22.4 vs 26.3 0.84 (0.74-
80 mg 40 mg PCI, CABG or 0.95)
stroke
A to Z29 2004 High-dose Placebo 4,497 2.0 Varied Varied Variable CHD death, MI, 14.4 vs 16.7 0.89 (0.76-
simvastatin followed by ACS, or stroke 1.04) P =.14
low dose
simvastatin
Special
Population
Heart 2002 Simvastatin Placebo 20,536 5 89 127 29 All-cause 12.9 vs 14.7 0.82 (0.77-
Protection 40 mg mortality 0.87)
Study (high P = .0003
risk)
Section 1  Clinical Cardiology
4D (diabetes + 2005 Atorvastatin Placebo 1,255 4 72 120 41 All-cause 37 vs 38 0.92 (0.77-

ESRD)45 20 mg mortality MI or 1.10) P = .37
stroke
SPARCL 2006 Atorvastatin Placebo 4,731 4.9 73 129 43 Stroke 11.2 vs 13.1 0.84 (0.71-
(stroke)33 80 mg 0.99) P = .03
CORONA (heart 2007 Rosuvastatin, Placebo 5,011 2.7 76 136 45 All-cause 11.4 vs 12.3 0.92 (0.83-
failure)46 10 mg mortality, MI, or 1.02) P = .12
stroke
Abbreviations: ACS, Acute coronary syndrome; BP, Blood pressure; CABG, Coronary artery bypass grafting; CAD, Coronary artery disease; CHD, Coronary heart disease; ESRD, End-stage
renal disease; HDL-C, High-density lipoprotein cholesterol; HR, Hazard rate; LDL-C, Low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention;
UA, Unstable angina
Chapter 6  History of Statins 55
50% reduction in LDL-cholesterol and the mean level was near 50 (20 or 40 mg/day) or placebo and observed for a median of 5.4 years.
mg/dL. This translated into a relative 44% reduction in the primary LDL-C was reduced by 35%. The primary endpoint, all-cause mor-
end point, 54% reduction in the risk for MI, 48% reduction in the risk tality, was reduced by 30% (P = .0003), major coronary events were
for stroke, 47% reduction for revascularization or unstable angina reduced by 34%, and the need for revascularization was lowered by
and 20% reduction for all-cause mortality. Benefit was consistent 37% with simvastatin relative to placebo.
across all subgroups. The results from JUPITER suggest statins may In the CARE trial (1996),42 4,159 post-MI patients with average
be beneficial in the primary prevention in men over 50 years and total and LDL-C levels of 209 mg/dL and 139 mg/dL, respectively,
women over 60 years that are at risk. were randomized to pravastatin (40 mg/day) or to placebo. During
In all but one of these primary prevention trials, the primary end- 5 years of follow-up, LDL-C levels were 28% lower in the pravastatin
point was significantly lower in the statin group compared with the group, and the primary endpoint, nonfatal MI and CHD death, was
placebo group. The one exception, ALLHAT, was impacted by a high reduced by 24% (P = .003). The Long-Term Intervention with Pravas-
crossover rate of placebo patients to unblinded statin therapy so that tatin in Ischemic Disease, (LIPID) trial43 (1998) randomized 9,014
the difference in LDL-C levels between the pravastatin and placebo men and women with CHD to pravastatin (40 mg/day) or to placebo
groups was only 17%. On the other hand, both the ASCOTLLA and and observed them for 6.1 years. Pravastatin reduced CHD mortality
the CARDS trials were stopped early because of a statistically signifi- by 24%, overall mortality by 22%, MI by 29%, coronary revasculariza-
cant benefit in the atorvastatin groups compared with the placebo tion by 20% and stroke by 19%, with all of the differences being statis-
groups. In PROSPER, nearly half of the patients had a history of vas- tically significant.
cular disease at baseline. Although pravastatin significantly reduced In the Treating to New Targets (TNT) trial (2005),30 10,001
events in the entire study population, the benefit was not statistically patients with stable CHD were randomized to 10 or 80 mg/day of
significant among patients with no history of vascular disease. atorvastatin and observed for 4.9 years. The study was designed so
The Heart Protection Study (2002)40 recruited 20,536 men and that patients receiving 10 mg would have a mean LDL-C level of 100
women at high risk because of either a history of CHD (secondary mg/dL and those receiving 80 mg would have LDL-C in the range
prevention) or risk factors (primary prevention). Patients had to be of 75–80 mg/dL. The primary endpoint, CHD death, MI, resuscitated
40–80 years old and to have the baseline total cholesterol level of only cardiac arrest, or stroke, occurred in 8.7% of the group receiving 80
135 mg/dL or greater. Patients were randomly assigned to placebo mg and 10.9% of the group receiving 10 mg, a relative risk reduction
or simvastatin (40 mg/day) and were observed for 5 years. Com- of 22% (P < .001).
pared with placebo, treatment with simvastatin was associated with The Incremental Decrease in End Points Through Aggressive
significant reductions in all-cause mortality (13%), CV death (17%), Lipid Lowering (IDEAL) study32 (2005) randomized 8,888 CHD
stroke (25%), and major CV events (24% relative reduction, 5.4% patients to atorvastatin (80 mg) or to simvastatin (20–40 mg/day)
absolute reduction). Importantly, the reduction in events was uni- and observed them for 4.8 years. Mean LDL-C levels were 81 mg/dL
form across all patient groups, including women and patients up in the atorvastatin group and 104 mg/dL in the simvastatin group.
to the age of 80 years and was not related to baseline LDL-C levels. The primary endpoint, CHD death, MI or resuscitated cardiac arrest,
Even among the 3,421 patients whose baseline LDL-C level was less occurred in 9.3% of atorvastatin patients and 10.4% of simvastatin
than 100 mg/dL, simvastatin reduced events, with a rate of 16.4% patients (P = .07). Myocardial infarction (P = .02), coronary revascu-
compared with 21.0% in the placebo group (p = .0006). larization (P < .001), and any CHD event (P < .001) were reduced in
This result from the Heart Protection Study has shifted the target the atorvastatin group.
for statin therapy. Patients should be treated if they are at high risk, The results of TNT and IDEAL indicate that in patients with
irrespective of their cholesterol level. Lowering of LDL-C, even when stable CHD, lower LDL-C levels on treatment are associated with
it is already within the average range, reduces the events in patients lower event rates, even below the LDL-C target of 100 mg/dL.
at high risk. This approach was confirmed in ASCOT and CARDS, in
which hypertensives and diabetics, respectively, experienced benefit STATIN TRIALS—ACUTE CORONARY
irrespective of baseline cholesterol level.
SYNDROMES
STATIN TRIALS—STABLE CORONARY The Myocardial Ischemia Reduction with Aggressive Choles
terol Lowering (MIRACL) study44 (2001) randomly assigned 3,086
HEART DISEASE
patients to receive 16 weeks of treatment with atorvastatin (80 mg/
Five large randomized trials of statins have been completed in day) or placebo starting 24–96 hours after hospital admission for
patients with stable CHD, as summarized in Table 6.3. The first of unstable angina or non-Q wave acute MI. LDL-C levels at the end of
these (1994), the Scandinavian Simvastatin Survival Study (4S),41 the treatment period were 125 mg/dL in the placebo group and 72
included 4,444 patients with angina pectoris or previous MI and with mg/dL in the atorvastatin group. The composite primary endpoint
total cholesterol levels between 212 and 309 mg/dL and triglycerides (death, MI, resuscitated cardiac arrest, and worsening angina with
less than 220 mg/dL. Participants were randomized to simvastatin new objective evidence of ischemia requiring hospitalization) oc-
curred in 17.4% of the placebo group and 14.8% of the atorvastatin Trial in Heart Failure (CORONA)46 (2007) included 5,011 patients at
group (P = .048). least 60 years of age with systolic heart failure and coronary disease.
The Pravastatin or Atorvastatin Evaluation and Infection Thera- They were randomized to rosuvastatin (10 mg/day) or to placebo
py (PROVE-IT) trial27 (2004) randomized 4,162 patients hospitalized and observed for a mean of nearly 3 years. The primary outcome (CV
with an acute coronary syndrome within 10 days to pravastatin (40 death, MI or stroke) occurred in 11.4% of rosuvastatin patients and
mg) or atorvastatin (80 mg/day).26 LDL-C averaged 95 mg/dL in the 12.3% of placebo patients, a nonsignificant reduction (P = .12). Total
pravastatin group and 62 mg/dL in the atorvastatin group. During hospitalizations and hospitalizations for heart failure were signifi-
a mean follow-up of 24 months, the primary composite endpoint cantly reduced in the rosuvastatin group.
(death, MI, stroke, unstable angina requiring hospitalization and Taken together, the results of the major statin trials provided con-
coronary revascularization) occurred in 26.3% of the pravastatin clusive evidence for cholesterol lowering in the prevention of clinical
group and 22.4% of the atorvastatin group (P = .005). CVD in diverse populations, including patients at risk with average
In the Aggrastat to Zocor (A to Z) tria129 (2004), 4,497 patients LDL-C levels. Overall, the statins were well tolerated. Although the
stabilized after an acute coronary syndrome were randomized to absolute risk reduction is greater in the highest risk patients (e.g. 4S),
simvastatin (40 mg increasing to 80 mg/day after 1 month) or to pla- statins have been shown to be cost-effective for both primary and
cebo for 4 months followed by simvastatin (20 mg/day). At 1 month, secondary prevention.
LDL-C levels were 68 mg/dL in the placebo group. The primary end-
point (CV death, MI, stroke, or readmission for an acute coronary STATINS IN COMBINATION WITH OTHER
syndrome) was reduced by 11% during the 2 years of follow-up but
LIPID-LOWERING DRUGS
the difference was not statistically significant (P = .14).
Statins, in combination with the bile acid-binding resins “cholesty-
UTILITY OF STATINS IN SPECIAL ramine” and “colestipol”, produce 20–30% greater reductions in LDL-
C than can be achieved with statins alone. Niacin also can enhance
POPULATIONS
the effect of statins, but the occurrence of myopathy increases when
The utility of statins has also been assessed in special populations. statin doses greater than 25% of maximum (e.g. 20 mg of simvastatin
The German Diabetes and Dialysis Study (4D) investigators45 (2005) or atorvastatin) are used with niacin. The combination of a fibrate
randomized 1,255 patients with diabetes and end-stage renal disease (clofibrate, gemfibrozil or fenofibrate) with a statin is particularly
undergoing hemodialysis to atorvastatin (20 mg/day) or placebo and useful in patients with hypertriglyceridemia and high LDL-C levels.
observed them for 4 years. LDL-C levels were reduced by 42% in This combination increases the risk of myopathy, but usually is safe
atorvastatin-treated patients, to a mean of 72 mg/dL. However, the with a fibrate at its usual maximal dose and a statin at no more than
primary composite endpoint (cardiac death, MI or stroke) occurred 25% of its maximal dose.47 Fenofibrate, which is least likely to inter-
in 37% of atorvastatin patients and 38% of placebo patients, a non- fere with statin metabolism, appears to be the safest fibrate to use
significant difference. All cardiac events combined were reduced by with statins.48
18% in the atorvastatin group (P = .03), and there was a trend toward In a recently completed ACCORD LIPID study49 (5518 pts.)
a lower all-cause mortality (20% vs 23%; P = .08). combination therapy with a statin (simvastatin) plus a fibrate, was
The Stroke Prevention by Aggressive Reduction in Cholester- compared with statin monotherapy, with aim to investigate whether
ol Levels (SPARCL) trial33 (2006) included 4,731 patients without combination therapy would reduce the risk of CVD in patients with
known coronary disease, but with a stroke or transient ischemic at- Type 2 diabetes mellitus who were at high risk for CVD.
tack within 6 months, randomized to atorvasta tin (80 mg/day) or to The mean follow-up was 4.7 years. The annual rate of the pri-
placebo. LDL-C decreased by an average of 53% to 61 mg/dL in the mary outcome (the first occurrence of nonfatal MI, nonfatal stroke
atorvastatin group. During 4.9 years of follow-up, the primary end- or death from CV causes) was similar in both groups of pts. (2.2% vs
point, fatal or nonfatal stroke, occurred in 11.2% of patients in the 2.4%, P = 0.32).
atorvastatin group compared with 13.1% in the placebo group (ad-
justed P = .03), a 16% relative risk reduction. Despite the reduction WHICH STATIN AND WHAT DOSE TO
in overall stroke, hemorrhagic stroke, although rare, occurred more
START WITH—INDIAN SCENARIO
frequently in the atorvastatin group. Major coronary events were
reduced by 35% (P = .003). Thus, statins are indicated for secondary It has been recommended that starting dose of statin should be
prevention of ischemic stroke, just as they are indicated for second- aimed at reducing the LDL-C level up to 35–40% of baseline LDL
ary prevention of coronary disease. values. This level of reduction can be achieved by available range of
Patients with heart failure were either excluded or under-repre- statins (Table 6.1). Still due to nonavailability of Indian guidelines
sented in most of the major statin trials; yet experimental evidence controversy exists regarding which statin and what dose to start with?
from a variety of sources suggests that these drugs might be benefi- The IRIS study group50 compared “Rosuvastatin (10 or 20
cial for this condition. The Controlled Rosuvastatin Multinational mg) versus Atorvastatin (10 or 20 mg)” in patients (N = 680) of
Chapter 6  History of Statins 57
South-Asian origin with hypercholesterolemia. The primary outcome clinical coronary events. Thus, although, LDL-C remains the primary
measure was percentage change from baseline in LDL-C at 6 weeks. “bad actor” atherogenesis and is the first lipid target of therapy, re-
Secondary outcome measures included proportions of patients reach- search has moved beyond LDL alone to include other lipid fractions
ing NCEP ATP III LDL-C goals. After 6 weeks, LDL-C decreased signifi- that may be contributing to the risk, such as HDL-C and TGs. The
cantly more with rosuvastatin 10 mg than with atorvastatin 10 mg (45% Framingham Heart Study was one of the to observe the inverse cor-
vs 40%, p = 0.0023). But there was no significant difference in reduction relation between HDL-C and, coronary risk: the higher the HDL-C,
of LDL-C with rosuvastatin 20 mg vs atorvastatin 20 mg (50% vs 47% the lower the risk for an event, to the extent that a 1-mg/dl incre-
p = NS). Most patients in all treatment groups reached ATP III LDL-C ment in HDL-C corresponded with 1% decrement in CHD risk. There
goals (79% and 89% with rosuvastatin 10 and 20 mg, respectively, 76% are number of trials with fibric acid derivatives, the lipidifying drug
and 85% with atorvastatin 10 and 20 mg, respectively). Rosuvastatin class with primary HDL-C-raising and TG-lowering effects. None of
brought 76–88% of high-risk patients to the LDL-C goal of less than 100 these trials were powered to look at all-cause mortality. However, in
mg/dL. After this study was started, an updated ATP III treatment algo- recently completed ACCORD LIPID study49 addition of fibric acid
rithm for “very high-risk” patients with established CVD plus multiple, derivatives failed to achieve significantly lower rate first occurrence
severe or poorly controlled risk factors suggested an optional, very ag- of nonfatal MI, nonfatal stroke, or death from CV causes.
gressive LDL-C goal of less than 70 mg/dL. An exploratory analysis of Torcetrapib is a CETP inhibitor which was shown to increase
high-risk patients in this study found that 42 and 56% reached this goal HDL-cholesterol significantly. The ILLUMINATE trial compared
at 6 weeks with rosuvastatin 10 mg and 20 mg compared with 18 and atorvastatin plus torcetrapib with atorvastatin plus placebo for clini-
42% with atorvastatin 10 mg and 20 mg, respectively. cal endpoints. It found the torcetrapib arm had 72% increased HDL
Based on the results of IRIS study group, it may be concluded and 25% decreased LDL, but increased CV and CV deaths due to
that rosuvastatin 10 mg is sufficient to achieve the desired LDL goals which the trial was stopped prematurely.51 The effect of torcetrapib
in vast majority of patients, but very high risk patients require at least on atherosclerosis was evaluated in the ILLUSTRATE, RADIANCE-1
20 mg of rosuvastatin to achieve desired LDL level. Still we require RADIANCE-2 trials. In spite of increased HDL levels, there was no
large scale studies and Indian guidelines to solve this issue. beneficial effect of torcetrapib on atherosclerosis. In all these trials, it
was found that the torcetrapib produces an increase in mean blood
FUTURE DIRECTIONS pressure by 3–4 mm Hg.
Currently other fibric acid derivatives (ABT-335) and JTT-705 (a
Although the clinical trials of statins have established that targeting CETP inhibitor which does not produce hypertension), Phosphatidyl
LDL-C yields coronary benefit, statin treatment does not completely inositol (increase reverse cholesterol transport) are being developed
abolish CHD risk, and many receive statins nevertheless proceed to to address the issue of mixed dyslipidemia.
REFERENCES
1. World Health organization. World health report: reducing risks, promoting healthy life. Geneva: WHO 2002 report. [online] WHO website. Avail-
able from http://www.who.int/whr/2002/en/whr02_en.pdf. [Accessed May, 2012].
2. Merkler M, Reiner Z. The burden of hyperlipidaemia and diabetes in cardiovascular diseases. Fundament Clin Pharmacol. 2007;21:1-3.
3. Mayor S. NICE calls for wider use of statins. BMJ. 2006;332:256. doi:10.1136/bmj.332.7536.256-d.
4. Woloshin S, Schwartz LM, Kerin K, et al. Estimating the impact of adding C-reactive protein as a criterion for lipid lowering treatment in the United
States. J Gen Intern Med. 2007;22:197-204. doi:10.1007/s11606-006-0033-z.
5. Stossel TP. The discovery of statins. Cell. 2008;134:903-5. doi:10.1016/j.cell.2008.09.008
6. Endo A. The discovery and development of HMG Co-A reductase inhibitors. J Lipid Res. 1992;33:1569-82.
7. Endo A. A gift from nature: the birth of the statins. Nat Med. 2008;14:1050-2. doi:10.1038/nm1008-50.
8. Endo A. Monacolin K. A new hypercholesterolemic agent produced by Monascus species. J Antibiot (Tokyo). 1979;32:852-4.
9. Tobert JA. Lovastatin and beyond: the history of HMG Co-A reductase inhibitors. Nat Rev Drug Discov. 2003;2:517-26. doi:10.1038/nrd1112.
10. Endo A, Tsujita Y, Kuroda M, et al. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of
3-hydroxy-3-methylglutaryl-coenzyme A reductase. Eur J Biochem. 1977;77:31-6.
11. Ginsberg HN, Le NA, Short MP, et al. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovas-
tatin: implications for regulation of apolipoprotein B synthesis. J Clin Invest. 1987;80:1692-7.
12. Marais AD, Naoumova RP, Firth JC, et al. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial
hypercholesterolemia. J Lipid Res. 1997;38:2071-8.
13. Anonymous. Choice of lipid-lowering drugs. Med Lett Drugs Ther. 1998;40:117-22.
14. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors: similarities and differences. Clin Phar-
macokinet. 1997;32:403-25.
15. Wiklund O, Angelin B, Bergman M, et al. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J
Med. 1993;94:13-20.
16. Stein E, Davidson MH, Dujovne CA, et al. Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with
combined hyperlipidemia: a prospective trial. J Cardiovasc Pharmacol Ther. 1996;1:107-16.
17. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292:1160-4.
18. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-9.
19. Bradford RH, Shear CL, Chremos AN, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results, I: efficacy in modifying plasma lipo-
proteins and adverse event profile in 8,245 patients with moderate hypercholesterolemia. Arch Intern Med. 1991;151:43-9.
20. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med.
1995;333:1301-7.
21. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA.
1990;264:71-5.
22. US Food and Drug Administration. FDA alert for healthcare professionals regarding Crestor (Rosuvastatin Calcium). [online] FDA website. Avail-
able from http://www.fda.gov/cder/drug/infosheets/HCP/RosuvastatinHCP. Htm. [Accessed May, 2012).
23. Jane A. The safety of statins in clinical practice. Lancet. 2007;370:1781-90.
24. Gruer PJK, Vega JM, Mercuri MF, et al. Concomitant use of cytochrome p450 3A4 inhibitors and simvastatin. Am J Cardiol. 1999;84:811-5.
25. McKenney JM, Davidson MH, Jacobson TA, et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assess-
ment Task Force. Am J Cardiol. 2006;97:89-94.
26. Naveed S, David P, Heather M. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735-
42.
27. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med.
2004;350:1495-504.
28. Wiviott SD, de Lemos JA, Cannon CP, et al. A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and
PROVE IT-TIMI 22. Circulation. 2006;113:1406-14.
29. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syn-
dromes: phase Z of the A to Z trial. JAMA. 2004;292:1307-16.
30. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med.
2005;352:1425-35.
31. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy.
J Am Coll Cardiol. 2006;48:438-45.
32. Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial in-
farction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-45.
33. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient
ischemic attack. N Engl J Med. 2006;355:549-59.
34. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol
levels: results of AFCAPS/TexCAPS. JAMA. 1998;279:1615-22.
35. Server PS, Daholf B, Poulter NR, et.al Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or
lower than average cholesterol concentrations in Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTLLA): a multi centric
randomized controlled trial. Lancet. 2003;361:1149-58.
36. ALLHAT Officers and Coodinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients rand-
omized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA.
2000;283:1967-75.
37. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Col-
laborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-96.
38. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial.
Lancet. 2002;360:1623-30.
39. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J
Med. 2008;359:2195-207.
40. Collins R, Armitage J, Parish S, et al. for the Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering
with simvastatin in 5,963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-16.
41. Scandinavian Simvastatin Survival Study study group. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-9.
42. Sacks FM, Pfeffer MA, Moye LA, et al. for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events
after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-9.
43. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravas-
tatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-57.
44. Schwartz GG, Olsson AG, Ezekowitz MD, et al. for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study
Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled
trial. JAMA. 2001;285:1711-8.
45. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-48.
46. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248-61.
47. Tikkanen MJ. Statins: Within-group comparisons, statin escape and combination therapy. Curr Opin Lipidol. 1996;7:385-8.
48. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280-7.
49. The ACCORD Study Group: Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med. 2010.
50. Deedwania Prakash C. Comparison of Rosuvastatin Versus Atorvastatin in South-Asian Patients at Risk of Coronary Heart Disease (from the IRIS
Trial). Am J Cardiol. 2007;99:1538-43.
51. Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: was it the molecule or the mechanism ? Arterioscler Thromb Vasc Biol. 2007;27(2):257-
60.
7 History of Angiotensin
Receptor Blockers
Pancholia AK, Jain V, Tewari S
INTRODUCTION AND SCIENTIFIC latt conducted the experiments where he constricted the renal blood
flow in dogs and he found that the ischemic kidneys did in fact se-
BACKGROUND
crete a chemical that caused vasoconstriction.1 In 1939, it was dis-
The cardiovascular (CV) system is complex, which comprises of the covered that renin itself did not cause the rise in blood pressure, but
heart and blood vessels. Diseases, such as hypertension, congestive was an enzyme, which catalyzed the formation of the substances that
heart failure, angina pectoris, atherosclerosis, rheumatic heart, ar- were responsible for vasoconstriction, namely, angiotensin (Ang) I
rhythmias and vascular inflammation may afflict the CV system. The and II. Compounds that block the action of Ang II by preventing Ang
CV drugs attempts to treat this variety of diseases are in fact targeting II from binding to Ang II receptors on blood vessels and thus respon-
the heart and blood vessels in multiple ways. sible for reducing the blood pressure are named “angiotensin recep-
Hypertension has many, complex and not entirely known caus- tor blockers” (ARBs).
es. They also differ across the individuals. In some, the source is in
the kidney related to excess hormones of various kinds and to nar- THE ANGIOTENSIN II RECEPTOR
rowing of the aorta, but there are very likely many more causes. There
are also known contributing factors to the disease, such as family The actions of Ang II are mediated by angiotensin receptors (AR),
history, obesity, high salt consumption, smoking, and emotional and AT I and AT II. These receptors are members of the G protein-cou-
physical stress. The complexity of causes and incomplete under- pled receptors family, which are seven transmembrane helices, con-
standing of hypertension leaves room for multiple possible means of nected by interchanging extracellular and intracellular loops.2,3 Each
addressing the disease through drugs. G protein-coupled receptor couples to a specific G-protein, which
In 1898, physiologists Tigerstedt (Fig. 7.1) and Bergmann exper- leads to activation of a special effector system. AT I receptors are for
imented with rabbits by injecting them with kidney extracts. Their instance primarily coupled through the Gq/11 group of G-proteins.3
results suggested that the kidneys produced a protein, which they Two more ARs have been described, AT III and AT IV, but their role is
named renin, that caused a rise in blood pressure. In 1930s, Goldb- still unknown (Fig. 7.2).4
Figure 7.1: Robert Tigerstedt, the Finnish physiologist. Figure 7.2: Renin angiotensin pathway
The first discoverer of renin
Distribution of Angiotensin II stroke or MI than those with low plasma renin activity.16,17 Thereaf-
Receptors in the Body ter, the development of pharmacological probes that block the renin-
angiotensin system helped to define the contribution of this system
Angiotensin receptors (AT I) are mainly found in the heart, adrenal to blood pressure control and to the pathogenesis of diseases, such
glands, brain, liver and kidneys.5,6 Their main role is to regulate blood as hypertension, congestive heart failure and chronic renal failure.
pressure, as well as fluid and electrolyte balance. AT II receptors are Thus, the concept of treating hypertension and congestive heart fail-
highly expressed in the developing fetus, but they decline rapidly af- ure by a specific blockade of the renin-angiotensin system was first
ter birth.4 In the adult, AT II receptors are present only at low levels established with the use of saralasin, a nonselective peptidic antag-
and are mostly found in the heart, adrenal glands, uterus, ovaries, onist of Ang II receptors.18-24 With saralasin, it became possible to
kidneys and brain (Table 7.1).5 demonstrate that Ang II receptor blockade, alone or in combination
with salt depletion, lowers blood pressure in hypertensive patients
Functions of AT I and AT II Receptors and improves systemic hemodynamics in patients with congestive
heart failure.18-25 However, saralasin had many drawbacks. Because
As shown in Table 7.1, all the known clinical effects of Ang II are me- it is a peptide, it had to be administered intravenously. This charac-
diated by the AT I receptor. The physiological role of AT I receptors teristic limited its use to hours or a few days at maximum. In addi-
is very well documented experimentally and clinically. AT I receptor tion, at higher doses, saralasin had some partial agonist, Ang II-like
knockout mice are characterized by a low blood pressure and high effects.
circulating renin levels.7 These mice were also recently shown to dis- The next major breakthrough in the understanding of the renin-
play less left ventricular remodeling and an improved survival after angiotensin system was triggered by the development of orally ac-
myocardial infarction (MI).8 The physiological role of the AT II recep- tive angiotensin-converting enzyme (ACE) inhibitors.25-30 Studies
tor is only partially understood. In recent years, several new func- performed with these agents rapidly confirmed and reinforced the
tions have been attributed to AT II receptors, including inhibition of seminal clinical observations made with saralasin. ACE inhibitors
cell growth, promotion of cell differentiation and apoptosis.9-12 Thus, are now recognized as an important therapeutic step to control
AT II receptors could have an important role in counterbalancing blood pressure in hypertensive patients and to reduce morbidity and
some of the effects of Ang II mediated by AT I receptors. However, mortality in patients with congestive heart failure.
this topic remains a matter of debate because controversial results In addition, because of their ability to lower proteinuria, ACE
have been published.13,14 More recent data also suggest that AT II re- inhibitors have become an essential component of the treatment of
ceptors could mediate the production of bradykinin, nitric oxide and chronic renal diseases to delay the progression of renal failure.31 ACE
perhaps prostaglandins in the kidney.15 Additional studies are now inhibitors are also very effective in reducing CV morbidity and mor-
needed to confirm these multiple roles of AT II receptors in humans. tality in patients with a high CV risk profile, including those with dia-
betes.32 ACE is an enzyme with multiple effects, not all of which are
FUNCTIONS BEYOND mediated through ARs. Thus, the hope has been that Ang II receptor
blockers would produce more specific actions and fewer side effects
HYPERTENSION CONTROL
than ACE inhibitors.
In the 1970s, a series of observations demonstrated that Ang II has When ACE inhibitors became available, the more specific ap-
deleterious effect on the heart and kidney, and that patients with proach of blocking Ang II receptors were abandoned. Nevertheless,
high levels of plasma renin activity are at a higher risk of developing research continued. This resulted in the most recent therapeutic de-
TABLE 7.1 Angiotensin II receptors and their functions and location

Receptor Actions Location
AT I Vasoconstriction, increase sodium retention, suppress renin secretion, increase endothelin Vessels, brain, heart, kidney, adrenal
secretion, increase vasopressin release, activate sympathetic activity, promote myocyte glands and nerves
hypertrophy, stimulate vascular and cardiac fibrosis, increase myocardial contractility, induce
arrhythmias, stimulate plasminogen activator inhibitor 1 and stimulate superanoxide formation
AT II Antiproliferation/Inhibition of cell growth, cell differentiation, tissue repair, apoptosis, Adrenal glands, heart, brain,
vasodilation (NO mediated?), kidney and urinary tract development, control of pressure/ myometrium, fetus
natriuresis, stimulate renal prostaglandins and stimulate renal bradykinin and NO
AT III Unknown neuroblastoma cells in amphibians
AT IV Renal vasodilator; stimulate plasminogen activator inhibitor 1 Brain, heart, vessels, lungs, prostate,
adrenal gland and kidney
Chapter 7  History of Angiotensin Receptor Blockers 61
velopment of specific, nonpeptide, orally active Ang II receptor an- a group at DuPont had already started the screening of nonpep-
tagonists.33 tide mimics of Ang II by using existing substances from chemical
libraries.37
THE RENIN-ANGIOTENSIN CASCADE AND Research investigators at Takeda in particular David J Carini
discovered in 1982 the weak nonpeptide Ang II antagonists S-8307
ANGIOTENSIN II RECEPTOR SUBTYPES
and S-8308 from a group of 1-benzylimidazole-5-acetic acid deriva-
The renin-angiotensin system is an enzymatic cascade that starts tives.38 S-8307 and S-8308 have moderate potency, short duration of
with the cleavage of angiotensinogen by renin to form the inactive action and limited oral bioavailability; however, they are selective
decapeptide Ang I. Thereafter, Ang I is converted by ACE to form Ang and competitive AT I receptor antagonists without partial agonist ac-
II. Although there are other angiotensin peptides with biological ef- tivity.39 A group at DuPont postulated that both Ang II and the Takeda
fects, Ang II is the major end product of the system. However, Ang I leads were bound at the same receptor site.38 These two substances
and II can be generated by other enzymatic pathways.34,35 Thus, Ang served as lead compounds for further optimization of AT I receptor
I can be formed by nonrenin enzymes, such as tonin or cathepsin, blockers.39
and Ang I can be converted to Ang II by these enzymes along with Using nuclear magnetic resonance studies on the spatial struc-
the heart chymase. Today, the quantitative contribution of these al- ture of Ang II, scientist at DuPont discovered that the Takeda struc-
ternative pathways to the generation of Ang II remains unclear. The tures had to be enlarged at a particular position to resemble more
discovery of specific Ang II receptor antagonists has confirmed the closely to the much larger peptide Ang II.37 Computer modeling was
existence of various subtypes of Ang II receptors (Fig. 7.3). used to compare S-8308 and S-8387 with Ang II and it was seen that
Ang II contains two acidic residues near the NH2 terminus. These
DEVELOPMENT OF SARALASIN groups were not mimicked by the Takeda leads and therefore it was
hypothesized that the acidic functional groups would have to be
Because of saralasin, the first Ang II antagonist and the development added to the compounds. The 4-carboxy-derivative EXP-6155 had a
of the first ACE inhibitor captopril, it was generally acknowledged binding activity which was ten-fold greater than that of S-8308, which
that Ang II receptor antagonists might be promising as effective an- further strengthened this hypothesis.38 By replacing the 4-carboxy-
tihypertensive agents.36 Saralasin was developed in the early 1970s group with a 2-carboxy-benzamido-moiety the compound EXP-6803
and is an octapeptide analogue of Ang II, where the amino acids was synthesized. It had highly increased binding affinity, but was
Asp1, Ile5 and Phe8 have been replaced with Ser1, Val5 and Ala8, re- only active when administered intravenously. Replacing the 2-car-
spectively. boxy-benzamido-group with a 2-carboxy-phenyl-group created the
lipophilic biphenyl-containing EXP-7711, which exhibited good oral
Development from Saralasin to Losartan activity, but slightly less affinity for the AT I receptor.39 To enhance
and Eprosartan the oral bioavailability and duration of action further, the polar car-
boxyl group was replaced with a more lipophilic tetrazole group and
Saralasin was not orally bioavailable, had short duration of action the compound thus formed was named LOSARTAN, which was de-
and showed partial agonist activity and therefore it was not suit- veloped in 1986 and losartan became the first successful Ang II an-
able as a drug.37 Thus the goal was to develop a smaller nonpeptide tagonist drug, approved as such in the United States in 1995 and was
substance with similar inhibition and binding features. At this time, marketed by Merck.38,39
Figure 7.3: Non angiotensin-converting enzyme (ACE) pathway

This development was laborious and expensive work and it is ap-

THE ARB CONTROVERSY—
proximated that the process from the Takeda structures to the final
substance, losartan, took more than fifty person-years in biological
MYOCARDIAL INFARCTION
testing and chemical modifications. Using a different lead optimiza- In 2006, ARBs had come across a serious controversy when a review
tion from S-8308, Eprosartan was developed by SmithKline Beecham article was published in Circulation, examined the results of some
in 1992. Eprosartan does not have a biphenyl-methyl structure, but in randomized trials, which compared an ARB with a different drug
order to mimic the C-terminal end of Ang II the 5-acetic acid group class in a variety of clinical conditions including hypertension, heart
was replaced with a thienylacrylic acid and a 4-carboxy-moiety.38 failure and renal failure. The conclusion of the review was that ARBs
Eprosartan is a selective, potent and competitive AT I antagonist and may increase the risk of MI, and consequently, patients may need
its binding to AT I receptors is rapid, reversible, saturable and of high to be informed about the risk.41 The probable explanation for this
affinity.4,39 effect was that, as a consequence of AT I blockade, ARBs increase
Ang II levels several-fold above baseline by uncoupling a negative-
DEVELOPMENT FROM LOSARTAN feedback loop. Increased levels of circulating Ang II result in unop-
posed stimulation of the AT II receptors, which are, in addition, up-
TO OTHER DRUGS
regulated. Unfortunately, data suggest that AT II receptor stimulation
Losartan, valsartan, candesartan, irbesartan, telmisartan and ol- may be less beneficial than previously proposed and may even be
mesartan all contain a biphenyl-methyl group. Losartan is partly harmful under certain circumstances through mediation of growth
metabolized to its 5-carboxylic acid metabolite EXP 3174, which is promotion, fibrosis and hypertrophy, as well as proatherogenic and
a more potent AT I receptor antagonist than its parent compound40 proinflammatory effects. As expected, the conclusion triggered not
and has been a model for the continuing development of several oth- only a scientific debate, but also an uncontrolled reporting by media
er ARBs.39 Valsartan, candesartan and irbesartan were all developed and even anxious reactions in patients treated with ARBs.
in 1990. However, other studies have found that ARBs do not increase the
“Valsartan”, first marketed by Novartis, is a nonheterocyclic ARB, risk of MI.42 To date, there is no consensus on whether ARBs have a ten-
where the imidazole of losartan has been replaced by an acylated dency to increase the risk of MI and further investigations are underway.
amino acid. Valsartan was initially approved in Europe in 1996 for
the treatment of hypertension in adults, approval in USA was granted CARDIOVASCULAR PROTECTION—
shortly thereafter in 1997.
A BREAKTHROUGH FOR HIGH-RISK
“Irbesartan” was developed by Sanofi Research and is longer
acting than valsartan and losartan and it has an imidazolinone ring
PATIENTS
where a carbonyl group functions as a hydrogen bond acceptor in- Despite the controversy of AMI-ARB paradox, the recent Ongoing
stead of the hydroxymethyl group in losartan. Irbesartan is a non- Telmisartan Alone and in combination with Ramipril Global End-
competitive inhibitor.4 point Trial (ONTARGET) and Telmisartan Randomized Assessment
“Candesartan cilexetil” is a benzimidazole, which was devel- Study in a CE Intolerant subjects with CV Disease (TRANSCEND)
oped at Takeda and is an ester carbonate prodrug. In vivo, it is studies with the ARB telmisartan, the largest outcome trial program
rapidly converted to the much more potent corresponding 7-car- with an ARB, have extended this evidence base in the broadest cross
boxylic acid, candesartan. In the interaction of candesartan with section of CV high-risk patients, and provided important new in-
AT I receptor the carboxyl group of the benzimidazole ring plays sights into the benefits of renin-angiotensin system (RAS) blockade.
an important role. Candesartan and its prodrug have stronger ONTARGET and TRANSCEND recruited patients who were at high
blood pressure lowering effects than EXP 3174 and losartan.39 risk of vascular events. These patients, who did not have established
“Telmisartan”, which was discovered and developed in 1991 by heart failure and had well controlled blood pressure, had not previ-
Boehringer Ingelheim, has carboxylic acid as the biphenyl acidic ously been studied in clinical trials with ARBs.
group. It has the longest elimination half-life of the ARBs of about Telmisartan provided CV protection similar to ramipril, but
24 hours.4 was better tolerated. These studies add to the growing evidence
“Olmesartan medoxomil” was developed by Sankyo in 1995 and that the effects of RAS inhibitors are not solely dependent on blood
is the newest ARB in the market, marketed in 2002. It is an ester prod- pressure reduction. Together with other smaller outcomes studies,
rug like candesartan cilexetil. In vivo, the prodrug is completely and ONTARGET and TRANSCEND provide useful insights into the rela-
rapidly hydrolyzed to the active acid form olmesartan. It has a hy- tive importance of hypertension and other risk factors at different
droxyisopropyl group connected to the imidazole ring in addition to stages of the “cardiovascular continuum”. Based upon the clinical
the carboxyl group (Fig. 7.4).39 trial results of these trials, the US Food and Drug Administration
Contd...
Contd...
Figure 7.4: Discovery and development of angiotensin receptor blockers (ARBs)

(FDA) in October 2009 has approved a new indication for ARB-tel-

ARBs UNDER DEVELOPMENT
misartan for the reduction of the risk of MI (heart attack), stroke or
death from CV causes in patients 55 years of age or older at high risk Several new nonpeptide ARBs are undergoing clinical trials or are
of developing major CV events who are unable to take ACE inhibi- at preclinical stages of development. Among these are embusartan,
tors. fonsartan and pratosartan. Pratosartan, for example, has a novel
Closely following the USFDA approval, European Commission structure: a seven-membered ring that bears an oxo moiety (C = O)
has also approved ARB telmisartan in November 2009 to reduce the fused to the imidazole ring, and its affinity for the AT I receptor is
risk of CV morbidity in high CV risk patients. about seven times higher than losartan. The purpose of the oxo group
is similar to that of the carboxylic acid groups on other ARBs.
THE NEW CHALLENGE—ARBs AS A Other attributes of ARBs are also under investigation, such
as the positive effects of telmisartan on lipid and glucose metabo-
CANCER RISK FACTOR
lism and losartan’s effects of lowering uric acid levels. Such effects
Recently in 2010, ARBs have faced a new challenge based on a study might lead to new indications for these drugs, but further research is
published in Lancet Oncology.43 A meta-analysis of randomized needed.
controlled trials suggests that ARBs are associated with a modestly
increased risk of new cancer diagnosis where researchers have iden- SELECTED ABBREVIATIONS AND
tified what they call is a modest, but significant link between ARB
ACRONYMS
therapy and the development of new cases of cancer. The Case West-
ern Reserve University School of Medicine claim that their findings • ACE—angiotensin-converting enzyme
suggest ARB therapy results in a 1.2% absolute risk of any type of can- • AMI— acute myocardial infarction
cer developing in patients receiving at least 1 year of treatment. Lung • Ang—angiotensin
cancer was the only solid organ cancer that appeared to be signifi- • ARBs—angiotensin receptor blockers
cantly increased in patients taking ARBs. But given the limited data, • CHARM—Candesartan in Heart failure Assessment in Reduc-
it is not possible to draw conclusions about the exact risk of cancer tion of Mortality
associated with each particular drug. These findings warrant further • CV—Cardiovascular
investigation. Although this paper was faced criticism by several au- • ELITE-1—Evaluation of Losartan in The Elderly study
thors. • FDA—Food and Drug Administration
• IDNT—Irbesartan Diabetic Nephropathy Trial
TIME LINE OF LANDMARK TRIALS • IRMA—Irbesartan in patients with type 2 diabetes and Microal-
buminuriA
WITH ARBs
• LIFE—Losartan Intervention for Endpoint-reduction in Hyper-
During the journey of ARBs from 1997, they were compared with pla- tension Study
cebo and other antihypertensive drugs including ACE-inhibitors in • LVEF—Left Ventricular Ejection Fraction
various clinical conditions like heart failure, hypertension, diabetes • ONTARGET—The Ongoing Telmisartan Alone and in Combina-
and nondiabetes nephropathy and in post-MI state. tion with Ramipril Global Endpoint Trial
There were four trials in patients with heart failure (ELITE II, • OPTIMAAL—Optimal Trial in Myocardial Infarction with Angio-
Val-HEFT, CHARM and I-PRESERVE), two trials in patients with tensin II Antagonist Losartan’s
post-AMI (OPTIMAAL and VALIANT), four trials in high risk patients • PROFESS—The Prevention Regimen for Effectively Avoiding
for cardiovascular outcome (LIFE, SCOPE, VALUE and ONTARGET/ Second Stroke
TRANSCEND), four trials in diabetic patients for the renal outcome • RENAAL—Reduction of End points in Non–insulin-dependent
(IDNT, IRMA-2, RENAAL and MARVAL) and one trial in patients with diabetes mellitus with Angiotensin II Antagonist Losartan
stroke (PRoFESS). Apart from that there are some small trials of tel- • Val-HEFT—Valsartan Heart Failure Trial
misartan published recently in diabetic patients (TRENDI, DETAIL, • VALIANT—VALsartan In Acute myocardial infarction Trial
SMOOTH, AMADEO and VIVALDI) The time line of these landmark • VALUE—The Valsartan Antihypertensive Long-Term Use
ARBs trials is shown in the Table 7.2. Evaluation.
TABLE 7.2 Landmark trials across ARBs
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Elite II
Heart Val-HeFT
failure Charm
Preserve
Post-MI Optimaal
Valiant
Life
CV Scope
Value
Ontarget
Transcend
IDNT
Renaal
IRMA-2
Renal Marval
Innovation
Trendy
Detail
Smooth
Diabetes Amadeo
Vivaldi
Stroke Profess
KEYWORDS: Angiotensin-converting enzyme (ACE) inhibitors; Angiotensin receptor blockers; AT II receptor; Myocardial infarction;
Heart failure; Hypertension
REFERENCES
1. Van Epps HL. “Harry Goldblatt and the discovery of renin”. J Exp Med. 2005;201(9):1351.
2. De Gasparo M, Catt KJ, Inagami T, et al. “International Union of Pharmacology. XIII. The Angiotensin II Receptors”, Pharmacol Rev. 2000;52(3):415-
72.
3. Hunyady L Ji H, Jagadeesh G, et al. “Dependence of AT I angiotensin receptor function on adjacent asparagine residues in the seventh transmem-
brane helix”. Mol Pharmacol. 1998;54(2):427-34.
4. Burnier M, Brunner HR. “Angiotensin II receptor antagonists”, Lancet. 2000;355(9204):637-45.
5. Dihn DT, Frauman AG, Johnston CI, et al. “Angiotensin receptors: distribution, signalling and function”, Clinical Science. 2001;100(5):481-92.
6. Matsubara H. “Pathophysiological role of angiotensin II Type 2 receptor in cardiovascular and renal diseases”, Circ Res. 1998;83(12):1182-91.
7. Sugaya T, Nishimatsu S, Tanimoto K, et al. Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem.
1995;270:18719-22.
8. Harada K, Sugaya T, Murakami K, et al. Angiotensin II type 1a receptor knockout mice display less left ventricular remodeling and improved sur-
vival after myocardial infarction. Circulation. 1999;100:2093-9.
9. Nakajima M, Hutchinson HG, Fujinaga M, et al. The angiotensin II type 2 (AT II) receptor antagonizes the growth effect of the AT I receptor: gain-
of-function study using gene transfer. Proc Natl Acad Sci USA. 1995;92:10663-7.
10. Stoll M, Steckelings M, Paul M, et al. The angiotensin AT II-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin
Invest. 1995;95:651-7.
11. Meffert S, Stoll M, Steckelings UM, et al. The angiotensin II AT II receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol
Cell Endocrinol. 1996;122:59-67.
12. Morrissey JJ, Klahr S. Effect of AT II receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol. 1999;276(1 pt 2):F39-F45.
13. Li JS, Touyz RM, Schiffrin EL. Effects of AT I and AT II angiotensin receptor antagonists in angiotensin II-infused rats. Hypertension. 1998;31:487-
92.
14. Cao Z, Dean R, Wu L, et al. Role of angiotensin receptor subtypes in mesenteric vascular proliferation and hypertrophy. Hypertension. 1999;34:408-
14.
15. Siragy HM, Carey RM. The subtype-2 (AT II) angiotensin receptor regulates renal cyclic guanosine 39, 59-monophosphate and AT I receptor-
mediated prostaglandin E2 production in conscious rats. J Clin Invest. 1996;97:1978-82.
16. Gavras H, Brown JJ, Lever AF, et al. Acute renal failure, tubular necrosis and myocardial infarction induced in the rabbit by intravenous angiotensin
II. Lancet. 1971;2:19-22.
17. Brunner HR, Laragh JR, Baer L, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972;286:441-9.
18. Brunner HR, Kirsman DJ, Sealey JE, et al. Hypertension of renal origin: evidence for two different mechanisms. Science. 1971;174:1344-6.
19. Gavras H, Brunner HR, Vaughan ED, et al. Angiotensin-sodium interaction in blood pressure maintenance of renal hypertensive and normoten-
sive rats. Science. 1973;180:1369-72.
20. Brunner HR, Gavras H, Laragh JH, et al. Angiotensin-II blockade in man by Sar1-Ala8-angiotensin II for understanding and treatment of high
blood pressure. Lancet. 1973;2:1045-8.
21. Brunner HR, Gavras H, Laragh JH, et al. Hypertension in man, exposure of the renin and sodium components using angiotensin II blockade. Circ
Res. 1974;34(suppl 1):35-43.
22. Gavras H, Ribeiro AB, Gavras I, et al. Reciprocal relation between renin dependency and sodium dependency in essential hypertension. N Engl J
Med. 1976;295:1278-83.
23. Gavras H, Flessas A, Ryan TJ, et al. Angiotensin II inhibition: treatment of congestive cardiac failure in a high-renin hypertension. JAMA.
1977;238:880-92.
24. Turini GA, Brunner HR, Ferguson RK, et al. Congestive heart failure in normotensive man: hemodynamics, renin and angiotensin II blockade. Br
Heart J. 1978;40:1134-42.
25. Ferguson RK, Turini GA, Brunner HR, et al. A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet. 1977;1:775-8.
26. Gavras H, Brunner HR, Turini GA, et al. Antihypertensive effect of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J
Med. 1978;298:991-5.
27. Brunner HR, Waeber B, Wauters JP, et al. Inappropriate renin secretion in hypertension of chronic renal failure unmasked by captopril (SQ 14,225).
Lancet. 1978;2:704-7.
28. Brunner HR, Gavras H, Waeber B, et al. Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Int
Med. 1979;90:19-23.
29. Turini GA, Brunner HR, Gribic M, et al. Improvement of chronic congestive heart failure by oral captopril. Lancet. 1979;1:1213-5.
30. Faxon DP, Creager MA, Halperin JL, et al. Central and peripheral hemodynamic effects of angiotensin inhibition in patients with refractory con-
gestive heart failure. Circulation. 1980;61:925-31.
31. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med.
1993;329:1456-62.
32. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandi-
navian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-35.
33. Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993;45:205-51.
34. Dzau VJ, Sasamura H, Hein L. Heterogeneity of angiotensin synthetic pathways and receptor subtypes: physiological and pharmacological impli-
cations. J Hypertens. 1993;11(suppl 3): S13-S22.
35. Urata K, Kinoshita A, Misono K, et al. Identification of a highly specific chymase as the major angiotensin-forming enzyme in the human heart. J
Biol Chem. 1990;265:22348-82. (2)Adam, M. (2005).
36. “Integrating research and development: the emergence of rational drug design in the pharmaceutical industry”, Studies in History and Philosophy
of Biological and Biomedical Sciences 36
37. Adam, M. (2005), “Integrating research and development: the emergence of rational drug design in the pharmaceutical industry”, Studies in His-
tory and Philosophy of Biological and Biomedical Sciences 36
38. Farsang C, Fisher J. Analogue-based drug discovery. Optimizing Antihypertensive Therapy by Angiotensin Receptor Blockers. 2006. pp.157-67.
39. Aulakh GK, Sodhi RK, Singh M. “An update on non-peptide angiotensin receptor antagonists and related RAAS modulators”, Life Sci. 2007;81(8):615-
39.
40. Sachinidis A, Ko Y, Weisser P, et al. “EXP3174, a metabolite of losartan (MK 954, DuP 753) is more potent than losartan in blocking the angiotensin
II-induced responses in vascular smooth muscle cells”, J Hypertens. 1993;11(2):155-62.
41. Strauss MH, Hall AS. “Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox”. Circulation.
2006;114(8):838-54.
42. Tsuyuki RT, McDonald MA. “Angiotensin receptor blockers do not increase risk of myocardial infarction”. Circulation. 2006;114(8):855-60.
43. Sipahi I, Debanne SM, Rowland DY, et al. “Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials.”
Lancet Oncol. 2010;11(7):627-36.
History of Heparin and
8 Cardiovascular Disease
Protection
Banerjee AK, Ray S
INTRODUCTION first water-soluble anticoagulant discovered.3 Neither Howell nor

McLean attempted to take patent of their discovered substances and
Many a great discoveries in the history of mankind came by chance meanwhile the firm Hynson, Westcott and Dunning started produc-
and were just the opposite of what was meant to be discovered as ing heparin commercially with exorbitant pricing without any fur-
epitomized by the discovery of America by Christopher Columbus ther attempt to purify it. As a result, the substance started showing
who intended to find out a sea route to the East and landed up in the toxic effects in the form of headache, fever and nausea. Howell re-
Bahamaon October 12, 1492 to discover America. ported that purer preparations when used intravenously in human
History repeated itself when William Henry Howell, the eminent did not cause side effects, but the issue was not resolved till 1930.
physiologist at the Johns Hopkins Medical School, Baltimore, USA,
assigned his 2nd year medical student, Jay McLean, in 1916 to work RESEARCH ESCALATES
on a procoagulant, named cephalin, and instead, McLean came up
with a new substance which profoundly inhibited blood clotting.1 Primary work started in Toronto under the leadership of Charles H
That was the beginning of Heparin which reigned for more than half Best of insulin fame and in Stockholm by E Jorpes. Best, while work-
a century in the field of anticoagulation and till date is the gold standing in the laboratory of Henry Dale at England felt the need for an
ard against which the newer molecules are tested. anticoagulant to keep blood fluid during in vitro experiments. After
coming back to Toronto, he started working on heparin to make it
EARLY DAYS the suitable anticoagulant for both experimental and clinical uses.
In one of the most dedicated and systematic approach to develop a
Howell started one of the first laboratories in the United States devot- drug in the history of medicine, Best, in 1928, formed a team of inves-
ed to the research of blood coagulation. In 1915, McLean came over tigators to study heparin. He inducted biochemists Arthur Charles
from San Francisco to study medicine at Johns Hopkins but could (son of the cabinet maker of the university) and David Scott of the fa-
not get a chance immediately. Instead he was given an assignment mous Connaught Laboratories of the University of Toronto to purify
at Howell’s laboratory where he was asked to work on the chemical heparin which they did.
purity of cephalin preparations. Once he completed his assignment In 1929, Best became professor and head of the Department
successfully before time, he started extracting phosphatides from tis- of Physiology at the University of Toronto and investigated the an-
sues other than brain in January 1916. He could isolate cuorin from tithrombotic property of this purified heparin at the University’s
heart and heparphosphatide from liver and was surprised to find a Physiology Department and School of Hygiene.
decrease of coagulation with these agents instead of an enhanced At the same time at the university’s Toronto General Hospital,
coagulation. But in his 1916 paper, he did not discuss these antico- Gordon DW Murray and the surgical team of William Gallie started
agulant phosphatides. He later claimed that Howell deliberately re- using heparin in patients.4 Meanwhile, across the Atlantic, Clarence
moved this topic from his paper.2 However, Howell credited McLean Crafoord, a young thoracic surgeon from the Sabbatsberg Hospital in
with the discovery of anticoagulant phosphatides in his Harvey lec- Stockholm approached Erik Jorpes, an associate professor in the De-
ture in 1917. Emmett Holt, started work with Howell to isolate hep- partment of Chemistry at the Karolinska Institute in 1929 to supply
arphosphatides from liver and named it “heparin” (Latin hepar for him with sufficient amount of good quality heparin for his patients.
liver) to identify it as a separate anticoagulant different in chemical Jorpes replied, “nonpossumus”.
composition from McLean’s heparphosphatides. But later that year, Jorpes visited Best in Toronto to find out about
Howell discovered an aqueous extraction protocol of the an- their insulin research. Incidentally, David Scott showed him about
ticoagulant substance from liver and presented his paper at the their work on crystallization of heparin in the Connaught Labo-
American Physiological Society’s annual meet in 1922. This was the ratories. After return to Stockholm, Jorpes himself started work on
Chapter 8  History of Heparin and Cardiovascular Disease Protection 69
purification of heparin in a separate method and within a few years an update of its clinical use so far including embolectomy, splenec-
approached Crafoord to use his heparin for clinical use.5 Some dif- tomy, postoperative cases, phlebitis, pulmonary embolism, venous
ference of opinion ensued in the following years between the Toron- grafts, mesenteric and coronary thromboses and blood transfusion.
to group and the Stockholm group of researchers. Jorpes commented After being established as a prophylactic agent for development of
that Charles and Scott could not get the major anticoagulant compo- venous and arterial thromboses in different clinical situations, hepa-
nent in their crystalline heparin and even the crystals were not ho- rin needed to be tested in the setting of established thromboses.
mogeneous and greatly varied in their anticoagulant potency which In 1938, Holmin, Ploman and Bostrom each reported one case of
made them unsuitable for clinical use. successful treatment of retinal vein thrombosis with heparin. In the
In 1933, Schmitz and Fischer in Copenhagen purified heparin same year, Magnusson treated a case of posterior inferior cerebellar
independently. In 1935, Jorpes published his work on heparin. He artery thrombosis with heparin. Uncontrolled but larger series of pa-
demonstrated that heparin was composed not only of glucuronic tients with thromboembolism successfully treated with heparin were
acid, but also hexosamine in equal proportion. He also identified soon reported by Murray and Best in 1938, by Crafoord in 1939, by
the sulphate in the ash as chondroitin polysulphuric acid which they Magnusson in 1940 and by Bauer in 1941. These were all Canadian
corrected 2 years later as mucoitin sulphuric acid. Hedenius and and Swedish experience.
Wilander injected Jorpes’ purified heparin in human volunteers and The first clinical use of purified heparin in the United States was
there was no ill effect. by famous Irving Wright on a young patient called Arthur Schulte
On this work, the Swedish company Vitrum AB launched the first suffering from malignant recurrent thrombophlebitis.
intravenously usable heparin in 1936. Thus began the clinical era of Best delivered the Harvey Lecture in 1940 on invitation from HS
heparin. On the other hand, Charles started working with Alexander Gasser of Rockefeller Institute. He chose his subject as “Heparin and
R Todd at the University of Manchester in 1939. They proceeded to Thrombosis”.8 It was one of his best lectures (as per his wife, Marga-
establish the crystalline nature of heparin and to fully analyze the ret). Best stressed on the need for further chemical characterization
chemical components of heparin. They experimented with different of heparin. He recognized Stockholm group’s discovery of heparin
ways of extracting heparin from various beef tissues and confirmed secretion from mast cells. Best considered heparin as not only an
the crystalline identity of heparin. anticoagulant, but also an antithrombotic. However, the molecu-
In 1942, in the final paper in this regard, Scott and Charles re- lar mechanism of its antithrombotic activity remained elusive. He
emphasized that crystalline heparin retained all the anticoagulant warned the cardiac surgeons that heparin was a ‘two-edged sword’.
property of the originally extracted substance and the crystals pre-
pared from different tissues and by different method were identical POSTWAR RESURRECTION
and as such could be used clinically.6
After the Second World War, Connaught Laboratories continued
HEPARIN IN CLINICAL DOMAIN production of heparin commercially but could not purify it further.
In 1949, Peter Moloney and Edith Taylor patented a new method
Best next moved onto the clinical application of heparin. William of heparin production with higher yield and lower cost. Soon after,
Edward Gallie, then considered as the most important person in Connaught Laboratories stopped production of heparin marking the
surgery in Canada, was the surgeon-in-chief of the Toronto General end of an era.
Hospital. He mobilized his team to accelerate and facilitate the clini- Randomized clinical trials in medicine became popular in 1950s.
cal uses of purified heparin. The first randomized trial with anticoagulants was done in 1960 by
Donald Walter Gordon Murray was concerned with the recur- Barritt and Jordan.9 They randomized patients with pulmonary
rent thrombus formation in the lacerated vessels after their surgi- embolism to heparin versus no anticoagulation. Of the 16 patients
cal repair. So he was in dire need of an anticoagulant. He lapped up on anticoagulation, there was no fatality or nonfatal recurrences;
the new heparin in 1929 and in 1935 gave a speech titled “Heparin whereas in the placebo group of 19 patients, there were five deaths
and Thrombosis of Veins” at the Junior Interurban Surgical Club of and five nonfatal recurrences.
Canada in Montreal. Meanwhile Louis B Jaques and TS Perrett joined Trials were designed to find out the dose and mode of delivery of
Murray in his clinical research and in 1937, this Toronto heparin heparin, implication of early treatment and role of dual anticoagula-
group along with Best published the first comprehensive review ti- tion compared to oral anticoagulation only.
tled “Heparin and the thrombosis of veins following injury” in Sur- In 1986, Hull et al.10 compared subcutaneous versus intravenous
gery (1937;2:163-87). heparin for proximal deep vein thrombosis (DVT). It was shown that
In 1939, Murray delivered the prestigious Hunterian Lecture en- adequacy of heparin dose in the first 24 hours is more important
titled “Heparin in Thrombosis and Embolism” before England’s Royal (25% recurrence for inadequately treated patients versus 1.6% for
College of Surgeons.7 He emphasized the need for adequate supply adequately treated patients) irrespective of the route of heparin ad-
of nontoxic heparin for clinical and experimental uses. He also gave ministration.
Raschke et al.11 compared two intravenous regime of heparin in their physical and chemical properties and thereby in their biologi-
1993—one fixed dose regime and the other weight-adjusted regime. cal and clinical effects as well. Low-dose subcutaneous heparin pro-
The former group had inadequate anticoagulation rate of 68% at six duced a lasting anticoagulant effect which was analyzed to be due
hours and 23% at 24 hours whereas the figures for the latter group to the subcutaneously absorbable low-molecular-weight chains of
were 14 and 3% respectively. This translated in a five-fold greater rate heparin (heparin being a mix of low, medium and high molecular
of recurrent thromboembolism in the former group. weight chains) and the action here was mostly the anti-Xa activity of
Brandjes et al.12 in 1992 randomized proximal DVT patients into heparin.13
heparin with acenocoumarol (n = 60) versus acencoumorol alone (n After the initial developmental premise on the basis of their
= 60). Former group had no thrombus extension, two pulmonary em- anti-Xa activity, it was found that they possessed variable amount of
bolism and two recurrences whereas the corresponding figures for anti-IIa activity as well. As a matter of fact, the variable anti-Xa:anti-
the latter group were two, two and eight respectively. IIa activity ratios (e.g. 3.3 for enoxaparin, 2.0 for dalteparin, 1.8 for
All the above three trials showed the immense importance of tinzaparin) are one reason for the variable clinical effects of different
early anticoagulation with monitoring of activated partial thrombo- LMWHs. But it was also realized that there were other factors for the
plastin time (APTT) in cases of thromboembolism. Some suggested clinical effects. One important theory was the release of tissue factor
that with high initial dose of heparin of at least 1250 U/hour infusion, pathway inhibitor (TFPI), tissue plasminogen activator (tPA), inhibi-
this might not be necessary. tion of adhesion molecule release, inhibiting von Willebrand factor,
Present day unfractionated heparin (UFH), the term needed to etc.
be coined to differentiate it from the newly developed low-molec- After the initial trial of LMWH for postsurgical DVT prophylaxis
ular-weight heparin (LMWH), is chiefly derived from bovine lung in 1982, commercial use started a few years later in that situation as
and porcine mucosa. Their main roles remain in the treatment and well as in hemodialysis. LMWHs were used initially only in Europe. It
prophylaxis of venous and arterial thromboembolic disorders. How- took almost 10 years for LMWHs to be accepted in the United States.
ever, they also find important place as adjunct to chemotherapeutic
agents and anti-inflammatory drugs; modulatory agent for growth HEPARIN IN CARDIOVASCULAR DISEASE
factors; treatment of hemodynamic disorders and surface coating of
biomedical devices. In the field of cardiovascular medicine real advance was made by the
However, UFH remains heterogenous in nature. The bovine lung LMWH. Chemical, enzymatic or physical depolymerization and/or
preparations are of higher molecular weight than porcine mucosal fractionation of UFH yield LMWH. Almost 30 years ago, they were
derived heparin. Though their charge density and serpin affinity are first introduced for prophylaxis of surgical thrombosis. Then they
same, the side effect profiles vary slightly. The main side effects of leaped into the arena of acute coronary syndrome (ACS) with great
heparin are bleeding and heparin induced thrombocytopenia (HIT). success.
Because of this heterogeneity, dependence on animal tissue for First tested was dalteparin in 1997 in the Fragmin in Coronary
source, side effects and need for dose monitoring by APTT or ACT Artery Disease (FRIC) trial and then nadroparin in 1999 in the frax-
testing, there came the thought of modifying heparin to avoid these iparine in Ischemic Syndromes (FRAXIS) trial against UFH. The
problems. hard endpoints of death, MI and recurrent ischemia did not differ
from UFH with the LMWH. But the real breakthrough came with the
PROCREATION enoxaparin. A systematic overview in 2004 looked into almost 22,000
patients in different trials of enoxaparin versus UFH in ACS.14 The
Controlled depolymerization and fractionation methods of UFH combined endpoint of death and MI were significantly lesser with
yielded LMWH. These are second generation heparin. The third gen- enoxaparin compared to UFH (10% vs 11%). However, when net
erations of heparin include chemically modified heparin, heparin clinical benefit was analyzed with 30-day event rate of death, MI and
derivatives, oral heparin formulations, and synthetic and biotech- major bleeding, there was no significant difference between the two
nologically derived heparinomimetics. But, as can be easily compre- groups.
hended, none of the newer preparation is as versatile as UFH and More recently in 2004, Superior Yield of the New strategy of
they are finding places in clinical medicine in selective indications enoxaparin, revascularization, and glycoprotein inhibitors (SYNER-
based on relevant clinical trials. GY) trial15 was published. Here 10,027 patients with high-risk non-
Roughly 20–30% of LMWH components are common with UFH. ST segment elevation (NSTE) ACS who were to be treated by early
All these agents are derived from chemical and enzymatic digestion intervention were randomized to get subcutaneous enoxaparin or
of porcine mucosal heparin. Bovine source is not utilized because of UFH. Percutaneous coronary intervention (PCI) outcomes were not
chance of viral contamination. Depending on the specific technique different between the groups but TIMI major bleed was significantly
of depolymerization, different products are yielded which vary in higher with enoxaparin, quite in contrast to expectation.
Chapter 8  History of Heparin and Cardiovascular Disease Protection 71
Published in 2006, Safety and Efficacy of Enoxaparin in Percu- In the 2008 American College of Cardiology/American Heart As-
taneous Coronary Intervention (PCI): An International Randomized sociation (ACC/AHA) guideline for STEMI, patients having fibrino-
Evaluation (STEEPLE) Trial analyzed 3,500 elective PCI cases and lytic therapy have class IA recommendation of enoxaparin, class IB
compared intravenous enoxaparin with UFH. Major issue was to find for fondaparinux and class IC for UFH.
the bleeding complications. Here enoxaparin in both lower (0.5 mg/ For unstable angina/nonST-elevation myocardial infarction
hour) and higher (0.75 mg/hour) doses produced significantly lesser (UA/NSTEMI) enoxaparin again has class IA indication.
major and minor bleeding compared to UFH.
In the setting of ST-segment elevation myocardial infarction SIBLING RIVALRY
(STEMI), the Clopidogrel as Adjunctive Reperfusion Therapy—
Thrombolysis in Myocardial Infarction 28 study (CLARITY-TIMI) 28 The anti-IIa and anti-Xa activities are both very important for
study16 in 2005 demonstrated significantly reduced primary compos- the anticoagulant activity. The LMWHs vary greatly in the ratio
ite endpoints of death, recurrent MI and nonpatency of infarct-relat- of anti-IIA and anti-Xa activities depending largely on their vari-
ed artery prior to angiography in LMWH arm (85% of this was enoxa- able chain lengths. Two studies compared one LMWH against
parin) compared to UFH. At 30 days, the cardiovascular death and another.
recurrent MI were also improved significantly. And all these benefits In the Anti-TNF Research Study Program of the Monoclonal An-
were obtained with a similar major bleeding incidence. tibody Adalimumab (ARMADA) Trial, enoxaparin was compared
A meta-analysis of 25,000 patients gave support to these find- with dalteparin and UFH for modulation of biomarkers of blood-cell
ings. activation. They found better efficacy of enoxaparin compared to the
In 2006, the largest trial in this field was published. In the Enoxa- other two agents.
parin and Thrombolysis Reperfusion for Acute myocardial infarction In the Enoxaparin versus Tinzaparin in Non-ST-segment Eleva-
Treatment—Thrombolysis in Myocardial Infarction 25 (ExTRACT- tion Acute Coronary Syndromes: Results of the Enoxaparin versus
TIMI) 25 trial, 20,000 patients of STEMI were randomized to enoxa- Tinzaparin (EVET) Trial, enoxaparin was compared to tinzaparin in
parin or UFH.17 At 30 days, there were significant (p < 0.001) reduc- NSTE ACS. At seven days, 30 days and also at six months, the primary
tion of death or nonfatal recurrent MI in the enoxaparin group. Major endpoint of death, MI and recurrent angina were significantly lower
bleeding was higher with enoxaparin, but when combined with total with enoxaparin compared to tinzaparin.
cardiovascular outcome, the benefit remained unaltered (p < 0.001).
In the Assessment of the Safety and Efficacy of a New Thrombo- EPILOGUE
lytic (ASSENT) PLUS trial, however, dalteparin was barely better than
UFH at seven days and was similar to UFH at 30 days. Thus, while approaching the centenary year of the discovery of hepa-
More or less, these trials have established the superiority of rin, we witness with pleasure and amazement not only the victory
enoxaparin over UFH in the spectrum of ischemic heart disease of a medicine over a whole gamut of diseases and its supreme reign
(IHD) from elective PCI to ACS and STEMI as far as cardiovascular both directly and by proxy through its numerous offsprings, but also
outcomes are concerned. However, bleeding complications can, at the victory of discipline, diligence and perseverance of mankind to
best, be considered as equivalent to UFH. bring forth this drug into medical practice.
REFERENCES
1. Marcum JA. The development of heparin in Toronto. Journal of the History of Medicine and Allied Sciences. 1997;52:310-37.
2. McLean J, Best CH. Best Papers. Toronto, Ontario: Thomas Fisher Rare Book Library; 1940.
3. Howell WH. Heparin: An anticoagulant. Am J Physiol. 1923;63:434-5.
4. Best CH. Heparin in blood clotting and thrombosis. Essays in Surgery, n.79, pp. 3-9.
5. Jorpes JE. Heparin: A mucopolysaccharide and an active antithrombotic drug. Circulation. 1959;19:87-91.
6. Scott DA, Charles AF, Fisher AM. New crystalline compounds of heparin. Trans R Soc Can. 1942;36:49-53.
7. Gordon DW Murray. Heparin in thrombosis and embolism. Br J Surg. 1940;27:567-98.
8. Best CH. Heparin and thrombosis. Harvey Lect. 1940-41;36:66-90.
9. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet. 1960;1:1309-12.
10. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of
proximal-vein thrombosis. N Engl J Med. 1986;315:1109-14.
11. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard-care” nomogram. A randomized
controlled trial. Annals of Int Med. 1993;119:874-81.
12. Brandjes DP, Heijboer H, Büller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-
vein thrombosis. N Engl J of Med. 1992;327:1485-9.
13. Hoppensteadt D, Walenga JM, Fareed J, et al. Heparin, low-molecular-weight heparins, and heparin pentasaccharide: Basic and clinical differen-
tiation. Hematol Oncol Clin N Am. 2003;17:313-41.
14. Petersen JL, Maheffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated
heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview. JAMA. 2004;292:89-96.
15. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coro-
nary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292:45-54.
16. Sabatine MS, Morrow DA, Montalescot G, et al. Angiographic and clinical outcomes in patients receiving low-molecular-weight heparin versus
unfractionated heparin in ST-elevation myocardial infarction treated with fibrinolytics in the CLARITY-TIMI 28 Trial. Circulation. 2005;112:3846-
54.
17. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N
Engl J Med. 2006;354:1477-88.
9 History of ACE-Inhibitors
Sawhney JPS
It is important from the historical and scientific point of view to un- The first step in the development of ACE-inhibitors (ACEI)
derstand that in 1960s, renin-angiotensin system (RAS), of which was the discovery of ACE in plasma by Leonard T Skeggs and his
angiotensin-converting enzyme (ACE) is a part, was poorly under- colleagues in 1956.5 They showed that the dialysate of plasma from
stood and not largely accepted as being vital for blood pressure (BP) patients with malignant HTN contained hypertensin, but only some
control. The first observation linking renal disease to left ventricle hy- patients with essential benign HTN had hypertensin in the plasma.
pertrophy was reported by Richard Bright in 1836.1 He related hyper- They concluded that hypertensin was present in plasma in two
trophy to an increased resistance to blood flow in the small vessels forms, renin liberates a decapeptide angiotensin-I (Ang I), which is
due to the altered condition of the blood. The relationship between converted by a factor in horse plasma, to the active peptide to angio-
development of systemic arterial hypertension (HTN) and patho- tensin-II (Ang II) in presence of Cl–. They named this factor ACE. The
logical changes in the kidney were hypothesized for many years, with first major breakthrough leading to truly specific ACEI came, when
Franz Volhard suggesting existence of a circulating vasopressor sub- Brazilian scientist Sergio Ferreira reported in 1965 of a brady-
stance. The history of the discovery of the RAS began in 1898, from kinin potentiating factor (BPF) present in the venom of “Bothrops
studies by Tigerstedt and Bergman, who reported the pressor effect Jararaca”, a South American pit viper. This discovery also made
of renal extracts on arterial pressure; based on its origin, they named apparent practical importance of bradykinin, as BPF immensely
the renal compound as renin. They subsequently showed that renal increases both the duration and magnitude of its effects on vasodila-
extracts caused a marked pressor effect in nephrectomized animals.2 tation and the consequent fall in BP. The venom also inhibited ACE,
They also detected the potentiation and protraction of the pressor re- though it was not clear at the time whether or not the two activities
sponse to renin in the nephrectomized recipient. They explained that were related.
the association between renal disease and cardiac hypertrophy was The conversion of the inactive Ang I to the potent Ang II was
due to the kidney release of a vasoactive substance that induced con- thought to take place in the plasma (ACE). However, in 1967, Ng
traction of the blood vessels through a direct action. However, other and Vane showed that plasma (ACE) was too slow to account for this
investigators in the field were unable to repeat their observation, conversion, Ang I was transformed to Ang II primarily while pass-
probably because of inappropriate techniques; moreover, further on ing through the pulmonary circulation.6 Bradykinin and Ang I are
little interest was shown in the biological effects of renal extracts, un- rapidly inactivated in the circulating blood and disappear totally in
til Goldblatt et al. in 1934 showed, that in dogs, clipping of renal ar- a single passage through the pulmonary circulation (Ang I due to
tery raised BP with a hemodynamic profile similar to that in human its conversion to Ang II). However, Ang II passes through the lungs
HTN,3 linking ischemic characteristic of the renal disease with HTN. without any loss. The inactivation of bradykinin and the conversion
These results were confirmed by several groups, paving way for the of Ang I to Ang II in the lungs were thought to be caused by the same
search for the mechanisms involved in the BP increase.1 enzyme.7 In 1970, Ng and Vane using BPF, demonstrated inhibition
Two research groups, working independently, simultaneously of conversion of Ang I to Ang II, during its passage through the pul-
in North and South America (Eli Lilly Research Laboratories in In- monary circulation.8 Bradykinin potentiating factor derived from the
dianapolis and University of Buenos Aires, Argentina, respectively), venom of Brazilian pit viper, is a peptide with potentiating action as-
discovered that renin released a novel vasopressor agent. The Argen- sociated with inhibition of bradykinin by ACE. Molecular analysis of
tine group named it hypertensin, and called its plasma protein sub- isolated BPF led to the development of the nonapeptide “Teprotide”
strate hypertensinogen. The group from the United States named it (SQ 20,881) (Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro), which showed
angiotonin. In 1958, Braun Menendez and Irvine Page suggested that the greatest (ACE) inhibition potency and hypotensive effect in vivo
the peptide should be named angiotensin. The combined name RAS and significantly clarified the importance of ACE in HTN, but, its lack
eventually became commonly used to avoid linguistic confusion.4 of oral activity limited its therapeutic utility.9,10 However, SQ 20,881
was instrumental in demonstrating the possibility of the therapeu-

tic use of an ACEI either as a diagnostic tool11 or in the control of
hypertensive patients.12 The discovery of orally active compounds
certainly was the last logical step in the development of the ACEI, to
establish a new class of antihypertensive drugs.
By early 1970s, knowledge of the structure-activity relation-
ship required for inhibition of ACE was growing. Knowledge of the
structure of the nonapeptide “Teprotide”, and in particular of the site
of cleavage of bradykinin potentiating peptides (BPP), by the ACE,
allowed David Cushman9 in the USA, to devise an elegantly rational
approach in the search for synthetic ACEI. David Cushman, Miguel
Ondetti and colleagues used peptide analogues to study the struc-
ture of ACE, using carboxypeptidase-A as a model. It was known
that the carboxy-terminal amino acid of a carboxypeptidase-A sub-
strate would interact with the active site of the enzyme, and that
the carbonyl of the peptide bond interacted with a zinc ion tightly
bound to the enzyme. Based upon this model, inhibitors of carboxy-
peptidase—A, such as D-2 benzylsuccinic acid, were designed.13
Considering that the converting enzyme was a dipeptidase, it was
assumed that the distance between the carboxyl-binding group and
the zinc ion was greater than that in carboxypeptidase-A. Thus, to
the last amino acid of pentapeptide BPP5a (proline) a succinyl radi-
cal was added.9 The resulting molecule was a weak ACEI, but its oral
activity and specificity opened the way to the synthesis of analogous
substances, leading to the invention of α-methyl analogue captopril
(Capoten; Bristol-Myers Squibb), the first orally-active ACEI in 1975
(Fig. 9.1).9
Captopril was taken into full clinical development and after fol-
lowing several blind alleys in the clinical studies, it was eventually
shown that low doses of captopril were safe and efficacious in control-
ling BP in 50–60% of hypertensive patients. Captopril was approved by
the US Food and Drug Administration (USFDA) in 1981 for treatment
of heart failure and by 1985 for treatment of all types of HTN.
Hypotensive effects of teprotide, in man, triggered the interest
of other pharmaceutical companies in USA and Europe, with aim
of identifying a compound with a much longer duration of action
than captopril and without sulfhydryl groups, as it was believed at
Figure 9.1: Research leading to the first ACE-inhibitor. Source:
that time that some of the side effects (rashes, taste alteration) were Fitzgerald. The discovery of the ACE-inhibitors. Dialog Cardiovasc Med.
due to this substituent. In 1981, it was shown that 20–40 mg once 2001;6(1):38-42
daily dose of first non-sulfhydryl-containing ACEI Enalapril maleate
(Vasotec; Merck & Co.) controlled BP. This drug had twice the sys-
temic bioavailability of the analogue lisinopril (Prinivil; Merck & It appears that local tissue conversion of Ang I plays an important
Co.). Enalapril was marketed in 1985 and lisinopril in 1987, and by role. The inhibition of the formation of angiotensin in the vessel walls
1990s, perindopril (Servier) and ramipril (Hoechst now Aventis) had seems to abolish the facilitatory action of Ang II on neurogenic vaso-
been marketed. constriction. Furthermore, in addition to its therapeutic antihyper-
During the overall developmental period of the ACEI, it was tensive actions, ACEI are presently helping us understand the inter-
thought that their antihypertensive action depended upon the re- play between the RAS and the sympathetic system in the control of
duction of circulating Ang II. However, evidence has accumulated BP.14 The development and availability of number of ACEIs is a clear
that its antihypertensive mechanism is not solely due to this effect. indication that the use of this class of drugs is now consolidating.
Chapter 9  History of ACE-Inhibitors 75
covery could be profitable. The discovery of ACEI was the centered on

SUMMARY the physiological and clinical role of the RAS. Skeggs et al.5 in 1956,
The history and development of the ACEIs reflects the efforts of laid out the target options for modulating the RAS, but it was 25 years
basic and drug-orientated research and example of the relationship before captopril was marketed. The clinical studies with ACEI con-
between university and industry research. Clinical research and drug firmed the important role proposed by the advocates of the RAS; the
discovery have always been closely associated, more importantly, chemical, biological and clinical methods used to develop ACEI have
because clinical research often indicates new areas in which drug dis- inspired and aided attempts to develop new antihypertensive drugs.
REFERENCES
1. Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001;38(6):1246-9.
2. Fitzgerald. The discovery of the ACE inhibitors. Dialog Cardiovasc Med. 2001;6(1):38-42.
3. Goldblatt H, Lunch J, Hanzal RF, et al. Studies on experimental hypertension: 1. Production of persistent elevation of systolic blood pressure by
means of renal ischaemia. J Exp Med. 1934;59:347-79.
4. Skrbic R, Igic R. Seven decades of angiotensin (1939-2009). Peptides. 2009;30(10):1945-50.
5. Skeggs LT, Lentz KE, Kahn JR, et al. The amino acid sequence of hypertensin II. J Exp Med. 1956;104:193-7.
6. Ng KK, Vane JR. Conversion of angiotensin I to angiotensin II. Nature. 1967;216(5117):762-6.
7. Ng KK, Vane JR. Fate of angiotensin I in the circulation. Nature. 1968;218(5137):144-50.
8. Ng KK, Vane JR. Some properties of angiotensin converting enzyme in the lung in vivo. Nature. 1970;225(5238):1142-4.
9. Cushman DW, Cheung HS, Sabo EF, et al. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mer-
captoalkanoyl amino acids. Biochemistry. 1977;16(25):5484-91.
10. Crantz FR, Swartz SL, Hollenberg NK, et al. Differences in response to the peptidyldipeptide hydrolase inhibitors SQ 20,881 and SQ 14,225 in
normal-renin essential hypertension. Hypertension. 1980;2(5):604-9.
11. Rosenthal T, Kissin E, Jacob ET, et al. Angiotensin-converting enzyme inhibitor (SQ 20881) in the diagnosis of renovascular hypertension. Angiol-
ogy. 1979;30:123-8.
12. Gavras H, Brunner HR, Laragh J, et al. An angiotensin converting-enzyme inhibitor to identify and treat vasoconstrictor and volume factors in
hypertensive patients. NEJM. 1974;291:817-21.
13. Byers LD, Wolfenden R. A potent reversible inhibitor of carboxypeptidase A. J Biol Chem. 1972;247:606-8.
14. Ferreira SH. History of the development of inhibitors of angiotensin I conversion. Drugs. 1985;30 Suppl 1:1-5.
10 Antibiotics in Cardiology
Sharma KB
Secondary prophylaxis in cases of rheumatic heart disease: Antibiotics

INTRODUCTION appear to be effective in reducing the incidence of acute rheumatic
Antibiotics (the anti-infection agents) are used for: fever following an episode of suspected GAS pharyngitis. This effect
• Therapy of infections may be achieved at relatively low cost if a single intramuscular peni-
• Prophylaxis against known infections. cillin injection is administered.
So, in cardiology, antibiotics are used for infections: Infectious
EMERGING RELATIONSHIPS OF INFECTIONS endocarditis: Therapy as well as prophylactically in procedures car-
ried out in patients with heart disease:
AND THE CARDIOVASCULAR SYSTEM
• Dental procedures
Infectious agents have been recognized to involve the heart and vas- • Device insertion: pacemaker
cular system for well over a century. Traditional concepts and teach- Pharyngeal flora of patients suffering from heart disease may
ings of their involvement in the pathogenesis of disease have been lead to endocarditis.
by a few established mechanisms. Since the last decade of the 20th • Secondary to procedures
century, there has been renewed interest in the medical and public • Procedure in mouth: Dental procedures
media on infectious diseases affecting the cardiovascular and cer- • Cardiac procedures.
ebrovascular systems, through their relationship with the develop-
ment of acceleration of atherosclerosis. ACUTE RHEUMATIC FEVER
CARDIOVASCULAR INFECTIONS Rheumatic and nonrheumatic valvular heart disease—epidemiol-

ogy, management, and prevention: Antibiotics appear to be effec-
General tive in reducing the incidence of acute rheumatic fever following an
episode of suspected GAS pharyngitis. This effect may be achieved
Syphilitic carditis. at relatively low cost if a single intramuscular penicillin injection is
administered.
Localized Infection The global burden of disease caused by rheumatic fever current-
ly falls disproportionately on children living in the developing world.
Throat Infection Rheumatic heart valve disease causes 400,000 deaths annually,
mainly among children and young adults living in developing coun-
Group A Streptococcus: Leading to acute rheumatic fever, which tries. At least 12 million people are estimated to be currently affected
as time passes involves valves, leading to rheumatic heart disease by RHD with two million patients requiring repeated hospitalization
(RHD). Every subsequent throat infection by Group A Streptococcus and one million requiring, often unaffordable, heart surgery in the
(GAS) leads to worsening of heart valves and if not controlled may next 5–20 years. In many developing countries, the incidence of acute
lead to heart failure and/or death. rheumatic fever approaches or exceeds 100 per 100,000, whereas the
incidence is currently estimated at less than 2 per 100,000 in the US.
Rheumatic and nonrheumatic valvular heart disease—epidemiology, This decline of rheumatic fever in the industrialized world has been
management and prevention: Antibiotics are used for the primary partially attributed to the use of antibiotics for the treatment of GAS
prevention of acute rheumatic fever. infections, but it is also believed to be the result of improved living
Chapter 10  Antibiotics in Cardiology 77
conditions. However, the recent resurgence of rheumatic fever in Early recognition and treatment of streptococcal sore throat has
middle-class families in some parts of the economically developed been shown to reduce the incidence of rheumatic fever in closed
world is a reminder that even in industrialized countries, there is no communities and can play an important role, for example in strepto-
room for complacency. coccal epidemics in schools.
However, prevention of sporadic cases in a susceptible
Historical Perspective in India community is extremely difficult. Education about recognition,
complications and treatment of streptococcal pharyngitis is vital.
Early in 20th century, two physicians in Punjab Ors KL Wig and RP Starting education in schools will be a good strategy especially in
Malhotra described clinically rheumatic fever. In 1950s, in a small developing countries. System for taking throat swabs in schools and
hamlet of Himachal Pradesh, one physician Dr Devi Chand encoun- family contacts in cases of acute rheumatic fever are cost-effective.
tered several cases of acute rheumatic fever. Not having laboratory For primary prophylaxis, single injection of benzathine penicillin
set up, he approached Dr Padmawati, a young physician who after should suffice.
studying medicine in Burma and magnetic resonance cholangiopan-
creatography (MRCP) in UK had joined Lady Hardinge Medical Col- Treatment Program
lege, as a professor of medicine. Dr Devi Chand sent her several sera
for antistreptococcal antibodies. Dr Padmawati asked KB Sharma Secondary prophylaxis of patients of RHD is of utmost importance.
who newly joined as demonstrator in microbiology in the same insti- The regimen should be every four weeks. A throat swab should be
tution to try to set up these tests. He took up the challenge and within taken and cultured for GAS, blood taken for streptococcal serology
one year produced test for antistreptolysin O (ASO). Antistreptolysin and antibiotic therapy given as given below:
O testing was started and in 1958, one World Health Organization • Benzathine penicillin
(WHO) consultant from Prague Dr J Rotta came and helped them to – For children under nine years or 27 kg weight—0.9 mega
set up full streptococcal testing, including ASO, antideoxyribonucle- units every four weeks
ase-B (ADNB), C-reactive protein (CRP) testing and group A strepto- – For children over nine years of age or more than 27 kg
coccal antisera. Unfortunately, Dr Devi Chand had died in a car ac- weight—1.2 mega units every four weeks
cident while returning from Shimla after seeing then the PM Pandit • Sulphadiazine (If allergic to penicillin)
Nehru in 1955. However, Dr Padmawati took cudgels for control of – For children under nine years or 27 kg weight—0.5 g per day
rheumatic fever. Since then for five decades, she has been guiding – For children over nine years of age or more than 27 kg
research and rheumatic fever (RF)/rheumatic heart disease (RHD) weight—1.0 g per day
control program. After retiring from government service, she opened • Erythromycin: 250 mg daily for patients allergic to benzathine
National Heart Hospital in East of Kailash in New Delhi where her penicillin or to sulphadiazine
team continues to work for it. KB Sharma proceeded to France for – Without carditis—treatment for five years or to 18 years of
doctorate at Pasteur Institute, Paris. On his return in 1961, he took age
up the laboratory studies in full earnest helping in laboratory backup – With rheumatic carditis—atleast up to age of 45 years.
for primary and secondary prophylaxis. The program is going on in On every visit, blood should be taken to assess antistreptococcal
full swing and has spread to whole of India. In 1987, Indian Council antibodies and/or CRP.
of Medical Research (ICMR) published a survey of RF/RHD in four
cities—Delhi, Mumbai, Varanasi and Alleppey. Similarly, Dr Padma- INFECTIVE ENDOCARDITIS
wati published a report on continuous secondary prophylaxis pro-
gram. Now also under the government of India Jai Vigyan program, a Infective endocarditis (IE) is an infection of the lining of heart cham-
RF/RHD program is going on in several parts of the country. bers or valves with bacteria, fungi, or other organisms that are re-
leased into the bloodstream. Infective endocarditis occurs most
Treatment commonly in people who have abnormal heart valves or had previ-
ous heart surgery; less commonly, it can occur in otherwise healthy
• Rest people who do not have heart disease. Infective endocarditis may
• Anti-inflammatory drugs. develop following a sequence of events:
However, role of antibiotics is important in: • Bacteria circulate in the bloodstream and become lodged in a
• Prevention of acute attack of rheumatic fever (primary prophy- blood clot on the lining or valves of the heart.
laxis) • The bacteria grow, forming an abnormal structure (called a veg-
• Prevention of recurrence of rheumatic fever—RHD (secondary etation) on the heart valves or lining.
prophylaxis). Infective endocarditis can develop in a small percentage of peo-
ple who undergo dental or other procedures. Antibiotics are com-
monly given to people who are at high-risk of developing IE to reduce • Hypertrophic cardiomyopathy
the likelihood of developing the infection. However, studies of antibi- • Mitral valve prolapse with valvular regurgitation and/or valvular
otics to prevent IE have shown mixed results. Some studies show that thickening
antibiotics can help to prevent IE while others show no benefit. • Most other congenital cardiac abnormalities not listed above
Pharyngeal flora of patients suffering from heart disease may • Unrepaired ventricular septal defect, unrepaired patent ductus
lead to endocarditis. arteriosus
Secondary to procedures • Acquired valvular dysfunction (e.g. mitral or aortic regurgitation
Procedure in mouth: Dental procedures or stenosis)
Cardiac procedures • Atrial septal defect, ventricular septal defect, or patent ductus ar-
• Pacemaker infection teriosus that was successfully closed (either surgically or with a
• Implantable cardioverter-defibrillator infection catheter based procedure) within the past six months.
• Cardiac-device infection
• Cardiac-device endocarditis. Low-Risk
The incidence and management of cardiac-device infection: Infection People with the following conditions are thought to have a low-risk of
is a serious, potentially fatal complication of device implantation. IE. Antibiotics have never been recommended for people with these
The numbers of device implants and infections are rising. Optimal conditions:
care of device infection is not well-defined. • Physiologic, functional or innocent heart murmurs
Cardiac-device infection is a rare complication, with significant • Mitral valve prolapse without regurgitation or valvular leaflet
morbidity and mortality. Complete hardware removal with appropri- thickening
ate duration of antimicrobial therapy results in the best outcomes for • Mild tricuspid regurgitation
patients. • Coronary artery disease (including previous coronary artery by-
pass graft surgery)
Highest Risk • Simple atrial septal defect
• Atrial septal defect, ventricular septal defect, or patent ductus
People with the following conditions are considered to be at the arteriosus that was successfully closed (either surgically or
highest risk of developing IE. Preventive antibiotics are generally rec- with a catheter based procedure) more than six months previ-
ommended for people with the following conditions before certain ously
procedures: • Previous rheumatic fever or Kawasaki disease without valvular
• Prosthetic cardiac valve dysfunction
• History of IE • People with pacemakers or defibrillators.
• Congenital heart disease (CHD)
• Unrepaired cyanotic CHD, including palliative shunts and con- Antibiotic Regimens for Prophylaxis
duits
of Endocarditis in Adults with
• Completely repaired congenital heart defect with prosthetic ma-
terial or device, whether placed by surgery or by catheter inter-
High-Risk of Endocarditis
vention, during the first six months after the procedure • Standard oral regimen: Amoxicillin 2.0 g orally, 1 hour before
• Repaired CHD with residual defects at the site or adjacent to the procedure
site of a prosthetic patch or prosthetic device (which inhibits en- • Inability to take oral medication: Ampicillin 2.0 g intravenous
dothelialization) (IV) or intramuscular (IM) within 1 hour before procedure
• Valvulopathy developing after cardiac transplantation. • Penicillin allergy:
– Clarithromycin or azithromycin 500 mg orally 1 hour before
Moderate Risk procedure
– Cephalexin 2.0 g orally 1 hour before procedure
People with the following conditions are considered to be at mod- – Clindamycin 600 mg orally 1 hour before procedure
erate risk of developing IE. Antibiotic prophylaxis is not generally • Penicillin allergy; inability to take oral medication:
recommended for people with moderate risk conditions. This is an – Cefazolin or ceftriaxone 1.0 g IV or IM 30 minutes before
important change from prior recommendations. procedure
• Valve repair without prosthetic material – Clindamycin IV or IM 1 hour before procedure.
Chapter 10  Antibiotics in Cardiology 79
BIBLIOGRAPHY
1. King A. Nature Reviews Cardiology. 2009;6:325.
2. Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 guideline update on valvular heart disease: focused update on infective endocar-
ditis: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: endorsed by the Society
of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation.
2008;118:887.
3. Robertson KA. Antibiotics for the primary prevention of acute rheumatic fever: a metaanalysis. Commerford PJ, Odell JA: Cardiology and cardio-
thoracic surgery; 2005.
Polypill in Cardiovascular
11 Disease: Current Evidence
and Future Promises
Kuppuswamy V, Choo WK, Gupta S
et al. showed that discontinuation of secondary prevention therapy

INTRODUCTION
was independently associated with four times increased in 1-year
In spite of current scientific advances, cardiovascular disease (CVD) mortality.7
remains the leading cause of death worldwide.1 Current strategies in Combination therapy has been practiced for many years albeit
cardiovascular prevention have succeeded in only limited risk modi- targeting individual risk factor separately. Until recently, statins was
fication. Pharmacological treatments both in primary and secondary only prescribed if serum cholesterol is raised. Antihypertensives
prevention have shown to reduce cardiovascular risk and the fixed- were only prescribed in cases of diagnosed hypertension. This ap-
dose combination therapy “polypill”, is hypothesized to synergize proach unfortunately excluded many who may benefit from such
this effort.2 The polypill simply amalgamates multiple medications drugs. Prescribing statins to those with high cardiovascular risk in
into one single pill. Several polypill formulations have been devel- the absence of disease is now part of standard practice. Measuring
oped and recent trials have demonstrated its short-term feasibility, cholesterol is no longer mandatory in initiating treatment. Similarly,
safety and efficacy in individuals with moderate cardiovascular risk.3 a blanket reduction of blood pressure in those above certain age (i.e.
The benefits of the polypill may be apparent, but many challenges greater than 50 years) is increasingly common.
remain in the development of such a molecule. Trials are currently
conducted to study the formulations, tolerability, compliance, regula- THE BIRTH OF POLYPILL
tory requirements, cost and impact on lifestyle habits.
This chapter aims to review the current evidence for polypill in In 2003, prof. Wald and Law from the Wolfson Institute of Preventive
the prevention of CVD. Medicine, London first conceptualized the polypill a single daily pill
comprising a statin, three antihypertensives, folic acid and aspirin.
CURRENT STRATEGIES IN REDUCING The efficacy and adverse effects of the proposed formulation were
extracted from published meta-analyses of randomized trials, cohort
CARDIOVASCULAR RISK
studies, and meta-analyses of 15 trials of low dose (50–125 mg/day)
The INTERHEART study concluded that nine conventional CVD risk aspirin.8 The objective of the meta-analysis was to look at studies
factors account for 90% of cardiovascular risk.4 Four most important
risk factors—hypertension, hypercholesterolemia, smoking and dia-
betes—account for more than 80% of global CVD burden (Fig. 11.1).
The Health Professionals Follow-up Study concluded that 62% of all
coronary events could be avoided had all men adhered to a healthy
lifestyle.5 However, it is apparent that lifestyle and dietary modifica-
tions alone are not sufficient in combating CVD and compliance to
these modifications can be challenging.
Pharmacotherapy for primary and secondary prevention of CVD
is highly effective (Table 11.1). Combination pharmacological thera-
pies are independently and strongly associated with reduction in car-
diovascular mortality. Danchin et al. in a study of n = 2199 patients
demonstrated that after myocardial infarction (MI), 97% of patients
who received aspirin, b-blockers and statins survived the first year
compared with only 88% in those who received none, one or two of Figure 11.1: Global cardiovascular disease burden due to high blood
these medications.6 A separate multivariable survival analysis by Ho pressure, cholesterol, and overweight5
Chapter 11  Polypill in Cardiovascular Disease: Current Evidence and Future Promises 81
TABLE 11.1 Relative risks of clinical events for primary and secondary prevention with selected drugs
Death Ischemic heart disease [95% Stroke
confidence interval (CI)]
Primary prevention
Aspirin -- 0.68 (0.60–0.77) 0.84 (0.75–0.93)
ACE-inhibitors and Calcium-channel blocker -- 0.66 (0.60–0.71) 0.51 (0.45–0.58)
Statin -- 0.64 (0.55–0.74) 0.94 (0.78–1.14)
Secondary prevention
Aspirin 0.85 (0.81–0.89) 0.66 (0.60–0.72) 0.78 (0.72–0.84)
β-blocker 0.77 (0.69–0.85) 0.73 (0.75–0.87) 0.71 (0.68–0.74)
ACEI 0.84 (0.75–0.95) 0.80 (0.70–0.90) 0.68 (0.56–0.84)
Statin 0.78 (0.69–0.87) 0.71 (0.62–0.82) 0.81 (0.66–1.00)
Source: Adapted from Gaziano AT, et al. Lancet. 2006;368:679-86
TABLE 11.2 Effects of the polypill on coronary heart disease and stroke risk after 2 years of treatment at age 55–64 years
% Reduction in risk (95% CI)*
Risk Factor Agent Reduction in Risk Factor IHD Event Stroke
LDL-Cholesterol Statin 1.8 mmol/L (70 mg/dL) 61 (51–71) 17 (9–25)
Blood pressure 3 classes of drugs at ½ dose 11 mm Hg diastolic 46 (39–53) 63 (55–70)
Platelet function Aspirin 75 mg/d 3 mmol/L 32 (23–40) 16 (7–25)
Serum homocysteine Folic acid (0.8 g/d) Not quantified 16 (11–20) 24 (15–33)
Combined effect All 88 (84–91) 80 (71–87)
*95% CIs include imprecision of the estimates of both the agent reducing the risk factor and the risk factor reduction decreasing risk.
Abbreviations: IHD, Ischemic heart disease; LDL, low-density lipoprotein
Source: Table adapted from Law and Wald. BMJ. 2003;326:1419
aimed to reduce our cardiovascular risk factors: that is low-density

lipoprotein (LDL) cholesterol, blood pressure, serum homocysteine, FAILURE OF CURRENT PREVENTIVE
and platelet function; simultaneously regardless of pretreatment STRATEGIES
parameters. The polypill was estimated to reduce coronary heart
disease (CHD) events by 88% (95% CI of 84–91%) and stroke by 80% Current preventive strategies for CVD are suboptimal. The polyphar-
(95% CI of 71–87%) as illustrated in Table 11.2. One-third of those macy regimens give rise to inadequate prescription, poor compli-
taking the pill over the age of 55 years were expected to gain 11 years ance and high costs. The polypill is hoped to address these problems.
of CVD event-free life. The combined adverse effect of all drugs was
less than 15% of the study population. Inadequate Prescription—“The Treatment Gap”
Polypill although was initially designed to treat those with
ischemic heart disease (IHD), the focus is now moving from Undertreatment of patients with acute coronary syndrome (ACS) is
secondary to primary prevention. That is avoiding or delaying the well-documented. The European Action on Secondary and Primary
development of CVD in healthy population with pharmacother- Prevention through Intervention to Reduce Events (EUROASPIRE) II
apy on the basis of age alone. A four-component polypill (three survey observed 20%, 33% and 53.9% prevalence in smoking, obesity
antihypertensives and a statin) is expected to reduce CVD by 75% and uncontrolled blood pressure in patients with CHD respectively.9
in primary prevention. Furthermore, success in primary prevention Only 43% and 57.5% were on angiotensin-converting-enzyme inhibi-
could substantially diminish the need for secondary prevention. tors (ACEI) and statins respectively. Similar trends were observed in
the EUROASPIRE III study, and Global Registry of Acute Coronary

Events (GRACE) registries.10,11
The World Health Organization study on Prevention of Recur-
rences of Myocardial Infarction and Stroke (WHOPREMISE) found
a concerning record in secondary prevention mostly in low and
middle-income countries.12 This study examined the proportion of
patients with CVD receiving recommended pharmacological agents
in 10 low and middle-income countries. Amongst those with CHD,
81.2% received aspirin, but only 48.1%, 39.8% and 29.8% received
b-blockers, ACEI and statins respectively. Amongst those with cer-
ebrovascular disease, 70.6% received aspirin, but only 22.8%, 27.8%
and 14.1% received b-blockers, ACEI and statins respectively.
Government-driven initiatives to improve prescribing practices
Figure 11.2: Effect of fixed-dose combination on treatment adherence
are common to a few European countries. For example, in the UK,
in patients with hypertension. Source: Figure adapted from Bangalore S,
general practitioners receive incentives for preventive efforts—a et al. Am J Med. 2009;120:713-9
strategy shown to be highly effective.
Poor Compliance—“Five Pills polypill for CVD prevention by region. However, the cost of second-
ary prevention especially with multiple drug regimens does not nec-
versus a Single Pill”
essarily ensure affordability in middle and lower income countries.16
Noncompliance is responsible for almost 10% of all hospital admis- Affordability in a developing economy is defined differently: as work-
sions and compliance to treatment in chronic conditions may be as days required by lowest-waged public servicemen to afford a month-
low as 50%.13 Old age, psychiatric disorders and complexity of treat- long supply of generic secondary prevention drugs. Out-of-pocket
ment are main predictors of poor compliance.14 Compliance strongly expenditure on health is also higher in developing than in developed
correlates with the number of pills taken a day. The psychology of nations.
taking only one tablet a day could improve adherence. The effective- A model on cost-effectiveness of a hypothetical polypill in pre-
ness of the polypill has been tested and proven in the treatments of venting CVD in India showed favorable outcomes (Table 11.4).
acquired immune deficiency syndrome (AIDS), tuberculosis and These estimates suggest that despite a higher cost per disability-
hypertension. Bangalore et al. (2007) in a meta-analysis of four adjusted life year (DALY) in treating lower risk patients, the overall
hypertension trials showed that fixed-dose combination therapy incremental cost-effectiveness ratio remains positive. Fixed-dose
could decrease the risk of noncompliance by a quarter compared to combinations of patented drugs have also been used with proven af-
conventional treatments (Fig. 11.2).15 fordability in the treatment of noncardiovascular diseases.
The Cost of Multiple Medications COMPONENTS OF A POLYPILL

Cardiovascular prevention is cost-effective to the economy. Table Various combinations of a polypill have also been suggested (Table
11.3 shows the incremental cost-effectiveness of a hypothetical 11.5). A Spanish group proposed a combination of 100 mg uncoated
TABLE 11.3 Estimates of cost-effectiveness of a polypill for cardiovascular disease, by region

Incremental Cost-Effectiveness
(cost per DALY averted)
Region > 35% Risk > 25% Risk > 15% Risk > 5% Risk
East Asia and the Pacific $830 $1,440 $2,320 $3,820
Europe and Central Asia $940 $1,450 $1,960 $3,620
Latin American and the Caribbean $920 $1,470 $2,420 $3,740
Middle East and North Africa $720 $1,290 $2,190 $4,030
South Asia $670 $1,250 $1,932 $3,020
Sub-Saharan Africa $610 $1,170 $1,920 $2,960
Note: The risk refers to a 10-year risk of cardiovascular disease.
Source: Disease Control Priorities in Developing Countries, 2nd edition; 2006.
TABLE 11.4 Estimates of cost-effectiveness of a polypill for cardiovascular disease in India

Costs and Effects No Polypill > 35% Risk > 25% Risk > 15% Risk > 5% Risk
Total cost (millions) $23.5 $34.5 $51.4 $92.2 $205.2
MI averted n.a. 10,200 14,400 21,300 31,800
CHD deaths averted n.a. 10,500 13,500 19,600 25,900
Stroke deaths averted n.a. 5,900 7,500 10,500 14,200
DALYs averted n.a. 41,000 57,000 86,000 134,000
Incremental cost-effectiveness (cost per DALY averted) n.a. $300 $990 $1,500 $2,430
Note: For a population of one million adults for treatment over 10 years. Each strategy is compared with no polypill.
n.a. = not applicable.
Source: Disease Control Priorities in Developing Countries, 2nd edition; 2006.
TABLE 11.5 Ongoing polypill trials for primary and secondary prevention
Study (n = patient) Primary/Secondary No of Drugs
Prevention
The Indian Polypill Study Primary 5*
(n = 2000)
Red Heart Pill Pilot Study** Primary 4
(n = 700)
IMPACT** (n = 600) Primary 4
INDIAN Study** (n = 250) Secondary 4
SPANISH Study Secondary 3¥
** Auckland University Newzeland and Dr Reddy’s Laboratories Ltd
* Aspirin, statin, ACEI, β-blocker and thiazide
¥ Aspirin, statin and ACEI
Figure 11.3: Reduction in the risk of ischemic heart disease

aspirin with 40 mg simvastatin and ramipril at three different doses events according to low density lipoprotein cholesterol level and
(2.5, 5 and 10 mg). An Indian group evaluated a combination of 100 years in treatment. The columns represent reduction in the risk of
mg of aspirin and simvastatin with three antihypertensives at low ischemic heart disease events according to duration of treatment
and the mean reduction in LDL cholesterol achieved in each trial.
doses—atenolol, ramipril and thiazide.
Source: Table adapted from Law et al. BMJ. 2003;326:1423
Statins
Evidence supporting clinical efficacy of statins is strong. Law et al. ACE-Inhibitors and Antihypertensive Therapies
(2003) suggested that a 1.5 mmol/L reduction in LDL cholesterol will
reduce cardiovascular events by 20–50% (Fig. 11.3).17 Such reduc- Observational studies have suggested a correlation between blood
tion can be achieved by most statins. pressure and risk of CVD. Antihypertensives are known to reduce
The Prospective Studies Collaboration group examined 61 pro- CVD risk in those with or without hypertension. Law et al. in a meta-
spective studies in a meta-analysis.18 Total cholesterol level was analysis of 147 randomized control trial suggested that the propor-
shown to have a positive correlation with mortality related to CHD. tional reduction in CVD events was the same or similar regardless
The study also concluded that statins can reduce both coronary and of pretreatment blood pressure and presence or absence of CVD.
cerebrovascular events. The Justification for the Use of Statins in Therefore, it was suggested that lowering blood pressure in everyone
Primary Prevention: An Intervention Trial Evaluating Rosuvastatin over a certain age would be beneficial, rather than measuring, moni-
trial (JUPITER) study (2009) demonstrated the benefits of statins in toring and only treating those with hypertension.20
people without previous CVD.19 Statins should no doubt be a corner- Current American Heart Association (AHA) and American Col-
stone component in the fixed-dose combination pill. lege of Cardiology (ACC) guidelines recommend ACEI for patients
following MI, even in the absence of left ventricular dysfunction. Two

meta-analysis examined approximately 30,000 patients in the Heart
Outcomes Prevention Evaluation (HOPE), Prevention of Events
with Angiotensin-Converting-Enzyme Inhibition (PEACE), and the
European Trial on Reduction of Cardiac Events with Perindopril in
Stable Coronary Artery Disease (EUROPA). Angiotensin-converting-
enzyme inhibitors were found to reduce mortality by 14% (odds ratio
0.86, 95% CI 0.79–0.94).21,22 Furthermore, ACEI remained effective
even when administered together with antiplatelet, lipid-lowering
agents and b-blockers. This is important in the development of com-
bination therapies (Fig. 11.4).
Antiplatelet Agents
Aspirin is a key component in cardiovascular prevention; therefore
should be included in any fixed dose combination pill. A meta-
analysis by the Antithrombotic Trialists’ Collaboration group showed
the positive benefits of antiplatelet treatment in patients’ postmyo-
cardial infarction (Figs 11.5A and B).
Antiplatelets could reduce the incidence of any new events sig-
nificantly. For every 1,000 antiplatelet recipients, 18 nonfatal rein-
farctions, 5 nonfatal strokes and 14 vascular deaths were prevent-
ed.23 This study also concluded no significant differences in efficacy
between high and low doses of aspirin; the vascular event rates were
14.1 and 14.5% for 500–1500 mg aspirin and 75–325 mg aspirin,
respectively. At present, 75–162 mg of aspirin is recommended for
ACS.
β-blockers
Long-term treatment with b-blockers after ACS reduces mortality by
approximately 20% and sudden death by 34%.24 Trials on atenolol,
metoprolol, propranolol and timolol concluded that b-blockers are A
Figure 11.4: Effect of angiotensin-converting-enzyme inhibitors on Figures 11.5A and B: Aspirin in secondary prevention. Source:
mortality in different subgroups of high-risk patients. Source: Adapted Data and figure obtained and modified from Antithrombotic Trialists’
from Dagenais GR, et al. Lancet. 2006;368:581-8 Collaboration. BMJ. 2002;324:71-86
prognostic up to approximately 2 years after ACS. No differences in Using Combination Therapy) and the Australian GAP trial (Kanyini-
efficacy exist between them. Those with appreciable intrinsic sympa- Guidelines Adherence with Polypill).
thomimetic activity may exhibit greater benefit. Despite its side ef- Participants in the UMPIRE trial who have had a history of MI
fects, discontinuation of b-blockers was not necessary in most cases. are given a tablet containing 75 mg of aspirin, 40 mg of simvastatin,
Adverse effects can often be minimized by changing the type of b- 50 mg of atenolol and 10 mg of lisinopril. The pill for stroke survivors
blocker or altering the dose. A polypill with variable b-blocker doses will include a similar dosage of aspirin, simvastatin and lisinopril,
is possible. but 12.5 mg of hydrochlorothiazide instead of atenolol. The sample
population has a background of either an MI or stroke or at high risk
POLYPILL IN PRIMARY PREVENTION of cardiovascular events as stratified by the Framingham criteria. The
primary end point of UMPIRE is adherence. Its results will be com-
Wald and Law proposed that everyone over 55 years should be treat- bined with those of Kanyini-GAP and IMPACT and trials from Brazil,
ed with the polypill. Stratifying patients on gender and lifestyle would Canada, China, and South Africa to form a sample size of 7000 and to
add little value to outcome but may increase cost and complexity. carry sufficient impact on cardiovascular research.
Age was assumed to be good screening tool since 96% of deaths from The TIPS 2 is rolled out to further examine the optimal strength
CHD or stroke occur in people aged 55 and above. of Polycap. Here, a low-dose Polycap in TIPS1 is tested against a
Several trials on the polypill in primary prevention are ongo- Polycap containing twice the amounts of the constituents. This study
ing worldwide. In India, Dr Reddy’s Laboratories Ltd (Hyderabad) with 500 participants is expected to complete by the end of the year
and Cadila Pharmaceuticals (Ahmedabad) are involved in the de- 2010. The TIPS study is funded by the Wellcome Trust UK to conduct
velopment of fixed-dosed combination pills for CVD prevention. a 5000-subject study on primary prevention in January 2011. It is
Dr Reddy’s Red Heart pill is studied in six countries. Its formulation aimed at assessing the optimal-strength of Polycap based on TIPS 1
comprises of aspirin (75 mg), simvastatin (10 mg), lisinopril (10 mg) and TIPS 2 and comparing its efficacy with placebo in reducing clini-
and hydrochlorothiazide (12.5 mg). The focus of the Red Heart pill cal events.
is on primary prevention in patients with an estimated 10-year total
WHO CVD risk score of more than 20%. The typical patient would be LIMITATIONS OF THE POLYPILL
a 55-year-old overweight male smoker.
The Indian Polycap Study (TIPS) by Cadila Pharmaceuticals There are still unsolved questions about the polypill. We do not know
uses combination pills aspirin, simvastatin and three antihyperten- the full safety profile of the combination pill nor do we know what to
sives in low doses (atenolol, ramipril and thiazide).25 Over a 12-week do in the event of an adverse reaction. It may be difficult to pinpoint
period, 400 participants were given polycap. Eight other groups with specific side effects to specific component drug. Inflexibility in tai-
200 participants each were given either individual components or loring regimens unique to individual patients could undermine the
part of the combination. A 6–7 mm Hg reduction in systolic and polypill’s development.
diastolic blood pressure was seen in the Polycap group. These alone Polypill risks under dosing or overdosing and may expose recipi-
could account for a 62% reduction in CVD risk and a 48% reduc- ents to more side effects. The efficacy of cholesterol or blood pres-
tion in stroke rates. The combination pill was almost as effective as sure lowering in Polycap is inferior to that of standalone simvastation
individual pills without any increase in side effects. The total cost or standalone antihypertensives. Therefore, the effects of a polypill
for the five generic drugs is USD 17 per year. A polypill is expected cannot be assumed to be a cumulative of its individual components.
to cost far less. Other primary prevention trials are as shown in There are also fears of instability of component drugs when stored to-
Table 11.5. gether. Ramipril and aspirin need to be stored at different pH, while
thiazide may hydrolyze other components. It is noteworthy that
POLYPILL IN SECONDARY PREVENTION some concerns still remain of the risk-benefit ratio of aspirin usage
in those with established CVD. Lastly, some may worry that polypill
The Indian Polypill Pilot study by Dr Reddy’s Laboratories Ltd and can risk advocating a sedentary and unhealthy lifestyle.
Auckland University (New Zealand) examines the effects of polypill
in secondary prevention. The National Center for Cardiovascular Re- CONCLUSION
search (CNIC) in Spain aims to launch a polypill comprising aspirin,
statin and an ACEI by 2010 for less than USD 10 a month. The concept of a polypill in CVD is simple and attractive. All compo-
An Australian-based collaborative effort; the Single Pill to Avert nent drugs are available generically, therefore will make it inexpen-
Cardiovascular Events (SPACE); oversees a few current trials on sive. Combining them in one pill can reduce heart disease and stroke
polypill’s role in secondary prevention.26 Amongst them are the mul- by around 80%. Given its potential impact, the polypill approach is
tinational UMPIRE trial (Use of a Multidrug Pill in Reducing Cardio- unsurprisingly appealing. While polypills is familiar to other fields
vascular Events), New Zealand IMPACT trial (Improving Adherence of medicine, one targeting CHD and stroke still remain hypothetical.
Cost and compliance remain paramount to the potential success years to everyone above 55 years remains to be seen. In conjunction
of the polypill. Fewer consultations will be needed to initiate this pill, with lifestyle modification, the polypill could one day substantially
benefiting parts of the world where access to medical treatment is reduce the burden of CVD worldwide.
limited. The polypill may also facilitate treatment of large propor- Ultimately, a large randomized control trial with longer follow-
tions of high-risk patients in a modern healthcare whom might have up will be needed to assess the true feasibility of the polypill although
evaded follow-up and evaluation. Whether the polypill can fulfil its we await with eagerness the summation of results of the ongoing
promise of reducing CHD and stroke mortality and add 11 event-free studies.
REFERENCES
1. World Health Organization. Cardiovascular disease statistics. [Online] Available from http://www.who.int/mediacentre/factsheets/fs317/en/in-
dex.html. [Accessed June, 2012]
2. Ginés Sanz, Valentin Fuster. Fixed-dose combination therapy and secondary cardiovascular prevention: rationale, selection of drugs and target
population. Nat Clin Pract Cardiovasc Med. 2009;6(2):101-10.
3. Kuppuswamy V, Choo W, Gupta S. Polypill in Cardiovascular Disease: Has its time come? Indian Heart J. 2009;61:322-7.
4. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTER-
HEART study): case-control study. Lancet. 2004;364(9438):937-52.
5. Chiuve SE, McCullough ML, Sacks FM, et al. Healthy lifestyle factors in the primary prevention of coronary heart disease among men: benefits
among users and nonusers of lipid lowering and antihypertensive medications. Circulation. 2006;114:160-7.
6. Danchin N, Cambou JP, Hanania G, et al. Impact of combined secondary prevention therapy after myocardial infarction: data from a nationwide
French registry. Am Heart J. 2005;150:1147-53.
7. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med.
2006;166:1842-7.
8. Law MR, Wald NJ. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419.
9. Kotseva K, et al. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. Lancet. 2001;357:995-
1001.
10. Kristensen SD, Baumgartner H, Drexler H, et al. Highlights of the 2007 scientific sessions of the European Society of Cardiology Vienna, Austria. J
Am Coll Cardiol. 2007;50:2421-30.
11. Granger CB, Goldberg RJ, Dabbous O, et al. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med.
2003;163:2345-53.
12. Mendis S, Abegunde D, Yusuf S, et al. WHO study on prevention of recurrences of myocardial infarction and stroke (WHOPREMISE). Bull World
Health Organ. 2005;83:820-9.
13. Haynes RB, McKibbon KA, Kanani R. Systematic review of randomised trials of interventions to assist patients to follow prescriptions for medica-
tions. Lancet. 1996;348:383-6.
14. Bosworth HB. Medication treatment adherence. In: Bosworth, et al (Eds). Patient Treatment Adherence. New York: Routledge; 2006. pp. 147-94.
15. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med.
2007;120:713-9.
16. Graziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a multidrug regimen in the developing world: a cost-effectiveness
analysis. Lancet. 2006;368:679-86.
17. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: system-
atic review and meta-analysis. BMJ. 2003;326(7404):1423.
18. Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual
data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370:1829-39.
19. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J
Med. 2008;359:2195-207.
20. Law MR, Morris JK, Wald NJ, et al. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 ran-
domised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
21. Dagenais GR, Pogue J, Fox K, et al. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunc-
tion or heart failure: a combined analysis of three trials. Lancet. 2006;368:581-8.
22. Danchin N, Cucherat M, Thuillez C, et al. Angiotensin-converting-enzyme inhibitors in patients with coronary artery disease and absence of heart
failure or left ventricular systolic dysfunction: an overview of long-term randomized controlled trials. Arch Intern Med. 2006;166:787-96.
23. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocar-
dial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
24. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis.
1985;27:335-71.
25. Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a
phase II, double-blind, randomised trial. Lancet. 2009;373(9672):1341-51.
26. The George Institute. Major collaboration investigates four-in-one-polypill. [Online] Available from http://www.georgeinstitute.org/major-col-
laboration-investigates-four-one-polypill. [Accessed May, 2010].
12 The History of Acute Coronary
Syndrome
Bansal M, Mehrotra R, Kasliwal RR
large number of anatomical drawings of heart and coronary vessels

INTRODUCTION
(Fig. 12.1). He even described the course of coronary vessels observ-
The human heart has fascinated man since time immemorial. Virtu- ing that they were “embedded in greasy material”. On one of his draw-
ally all cultures and religions have considered heart to be the seat of ings, ‘The Anatomy of the Old Man’, he wrote, “Vessels in the elderly,
divine presence in the body. Besides, heart has been used to char- through the thickenings of the tunics, restrict the transit of blood”.
acterize a person, like—kind-hearted, open-hearted, etc. Heart has This was clearly the first description of obstructive coronary artery
been known as the organ central to existence and man has always disease.1 Benivieni, a Florentine physician, was a contemporary of
known that once the heart stops, life ends. Thus, there has been an Leonardo. He pioneered the practice of autopsy and is considered as
intrigue surrounding heart, its functioning and in trying to under- the father of pathologic anatomy. In his treatise entitled ‘De Abditis
stand why and how it stops. Morborum Causis’ (The Hidden Causes of Disease), he described the
It is only now, in the first half of 20th century, that heart disease, stenotic changes in the coronary arteries as “ossification”.2
especially coronary artery disease, has become the leading killer The precise description of the closed circulation of humans,
in developed countries and is rapidly spreading in developing however, was described by William Harvey (Fig. 12.2) almost a 100
countries. We now know that coronary artery disease occurs due to years later in 1628 (Exercitatio anatomica de motu cordis et sanguinis
development of atherosclerotic plaques in the coronary arteries,
which in turn are attributed to risk factors like tobacco smoking, lack
of exercise, poor eating habits, overweight, etc, which are largely
attributable to modern lifestyle-based on consumption of refined
foods and minimization of physical activity on part of human beings.
Although infections and their descriptions had dominated the scene
of medicine in earlier centuries, heart disease was quite well known
even then. In this review, we track down the path of discoveries and
wade through the pages of history to unravel the evolution of our un-
derstanding of coronary artery disease and acute coronary syndrome.
ANATOMY AND PHYSIOLOGY OF

CIRCULATION
An understanding of the human anatomy was fundamental to
the development of our understanding of physiology and disease
pathology. More than 3000 years ago, the Egyptians were well adept
at dissecting the human body and embalming it for the process of
mummification. Organs like the liver, lungs, intestines and stomach
were taken out for preservation while heart was left in the body since
the Egyptians considered it the seat of intelligence and thought that it
would be needed in the afterlife. They must have had the opportunity
of observing the details of cardiovascular system during this process.
The credit for first description of the cardiovascular system however, Figure 12.1: The very first drawing of the circulatory
goes to the genius of Leonardo da Vinci (1452–1519), who produced system by Leonardo da Vinci
also the first person to describe the association of hyperlipidemia

with coronary artery disease when he described that the serum of a
man who died during an acute attack of severe chest pain was “thick
like cream”, thus suggesting causality. In 1755, Albrecht von Haller,
the great Swiss anatomist, physiologist, naturalist and poet for the
first time used the Greek word “atheroma” (meaning porridge) to
describe the soft fatty intimal lesions in the arteries. John Fothergill,
an eminent physician (1712–1780) called upon surgeons to perform
autopsy in one of his patients, a 58-year-old man who had died sud-
denly. This patient had a history of “a spasm in the breast— chiefly
when he walked up hill”. The surgeons reported “near the apex a
small white spot, as big as a sixpence, resembling a cicatrix”. Led by
the great John Hunter, the surgeons performed another autopsy on
a similar patient and thus described their findings, “many parts of
the left ventricle were become almost white and hard, having just the
appearance of a beginning ossification. The two coronary arteries,
from their origins to many of the ramifications upon the heart, were
become one piece of bone.”
Thus towards the end of 18th century, a link between the clinical
Figure 12.2: William Harvey (1578–1657) was the first person to syndrome described by Heberden and the pathological changes in
describe the closed circulation of man the coronary arteries seen at autopsies was emerging.
John Wall outlined the natural history of angina pectoris and
ascribed the cause to coronary artery disease in a paper published
in animalibus). As is quite often the case, this landmark discovery in 1772. Black, followed it up after a few years by writing, “the pri-
received a little attention at that time. Though Harvey had accurately mary and original cause of the disorder is perhaps in every instance,
described the passage of blood from the right heart through lungs the ossification of the coronaries—the diseased state of the heart
into the left heart and then through aorta to the body, he did not produces an impeded and weakened action of that organ”, a clear
describe the capillaries as they were not visible to the naked eye. The pointer to ischemic ventricular dysfunction. He was also very
discovery of microscope by Leeuwenhoek enabled Malpighi in 1674 accurately described the risk factors and observed that the coronary
to see and describe capillaries. artery disease occurred less commonly in “the poor, the laborious,
those who use strong exercise, the foot soldier and the female sex”.4
UNDERSTANDING THE PATHOPHYSIOLOGY At the beginning of the 19th century, Edward Jenner, of the small
pox vaccination fame, described his observations on obstructive
OF ACUTE CORONARY SYNDROME
coronary artery disease and the anginal chest pain syndrome. He
With the discovery of the details of the circulatory system having was very beautifully described the postmortem appearance of coro-
been described, the physicians of the 17th century focused their naries in a patient who had suffered from angina in his lifetime. He
attention on understanding the pathophysiology of the chest pain wrote to his friend, “My knife struck something as hard and gritty as
disorder. Friedrich Hoffmann (1660–1742), who was a professor of to notch it. I well remember looking up at the ceiling, which was old
Cardiology at Halle University in Germany, wrote, quite accurately and crumbling conceiving that some plaster had fallen down. But on
for his times, “that the origins of coronary heart disease lie in the further scrutiny, the real cause appeared; the coronaries were be-
reduced passage of blood within the coronary arteries”. In the same come bony canals.” In the same period, the concept of effort induced
period, Giovanni Battista Morgagni described several anginal syn- angina was introduced by Allan Burns who stated that anginal pain
dromes and published the ‘Seats and causes of diseases investigated was a result of imbalance between myocardial oxygen demand and
by anatomy’. The first clear description of angina pectoris however, supply as a result of obstruction in the coronary arteries.
came in 1772, when William Heberden, a British physician, docu- In 1866, Alfred Vulpian, a French physician for the first time used
mented a spasmodic breast disorder that caused episodic chest pain. the term “Myocardial Infarction” (MI) while describing the postmor-
He wrote, “They who are afflicted with it are seized while they are tem appearance of the heart of a patient, who had suffered from is-
walking (especially if it be uphill, and soon after eating) with a pain- chemic heart disease. During the same period, William Porter was
ful and most disagreeable sensation in the breast, which seems as working on coronary disease pathology in animals. In 1893, he dem-
if it would extinguish life if it were to increase or continue, but the onstrated that coronary artery occlusion resulted in the death of the
moment they stand still, all this uneasiness vanishes”.3 Heberden was segment of myocardium which was perfused by the affected artery.5
Chapter 12  The History of Acute Coronary Syndrome 89
These experiments corroborated the findings of Vulpian and estab-

lished the connection between the disease of coronary arteries and
pathological changes in the myocardium. The term “Atherosclerosis”
was used for the first time in 1904 by, Marchland, a pathologist from
Leipzig in Germany, the country where maximum interest was being
generated on this topic.
William Osler (1849–1919) was the most prominent cardiologist
of the early 20th century. His famous work was “Lectures on angina
pectoris and allied states”. Osler depicted coronary vessels at great
length along with coronary sclerosis, emboli’s, thrombi and sudden
cardiac death. His famous saying, “it begins where other diseases
end-in death”, reflected his in-depth understanding of the coro-
nary artery disease. Carl Weigert (1845–1904) published a landmark
paper on coronary thrombosis and embolism. This paper is widely
accepted as the first manual of MI histology. His work was incor-
porated by Cohnheim in his textbook of pathology in which he at-
tributed most of “so called cardiac infarcts” or fatty degeneration, to
advanced coronary artery sclerosis and superimposed thrombosis.
The term “heart attack” was coined by the American cardiolo-
gist James B Herrick (1861–1954) who also made several important Figure 12.3: James B Herrick from Chicago, first used the term “heart
contributions to the understanding of MI as we know it today (Fig. attack” and encouraged the use of ECG for diagnosis of acute myocardial
infarction (MI)
12.3). He was the first person to make clinicians aware that patients
suffering from a “coronary thrombosis” had a characteristic clinical
presentation. He was also very clearly stated that gradual occlusion
of the coronary vessels permitted the heart to adapt and thus total
occlusion of a coronary artery did not necessarily result in death. This
was contrary to the belief held in those times that coronary arteries
were end arteries. Six years later, in 1918, when he showed lantern
slides and used electrocardiogram of coronary obstruction to the
physicians in America and Europe did they become convinced of the
entity.6 The term “heart attack” had now become a household name.
By 1950s and 60s coronary thrombosis had become the known
cause of MI. In 1966, Constantinidies of Vancouver was the first to re-
port fissuring of the atherosclerotic plaque underlying the thrombus.
More recently, the works of Peter Libby of Boston, Davies of London
and Falk of Copenhagen described the mechanism of inflammation
in the culprit plaque, with high concentration of macrophages and
metalloproteinase causing the rupture of the plaque and superim-
posed thrombosis.
EVALUATION OF ACUTE CORONARY Figure 12.4: The earliest ECG machine

SYNDROME
In parallel with the developments taking place in the understanding
of pathophysiology of coronary artery disease, a search for solution modified string galvanometer. Several changes however, were made
of angina engaged many physicians in the 18th and 19th centuries. to his original apparatus before it could be widely used during the
The invention of stethoscope by Laennec RTH (1755–1821) was a First World War (Fig. 12.4). In 1917, Oppenheimer and Rothschild
remarkable advancement in the field of cardiology. But the accu- reported the ECG changes associated with coronary artery disease
rate diagnosis of coronary artery disease became possible with the and Herrick used it to demonstrate his concept of coronary thrombo-
advent of electrocardiograph in the beginning of the 20th century. sis as mentioned above. It was in 1920, that Harold Pardee described
William Einthoven developed the Electrocardiograph in 1901 using a the dramatic ST segment changes and other ECG changes that occur
following MI. He wrote, “T-wave does not start from the zero level United States suggested that it reduced mortality, but it is now known
and quickly turns away in a sharp curve”.7 Wilson and colleagues later that these were of faulty design and probably benefited by reducing
recognized the Q-wave as a manifestation of MI. pulmonary embolism, which was common due to immobilization.
The development of blood tests for markers of myocardial injury The patients of heart attack frequently died suddenly and it was
greatly aided the diagnosis of MI, but it came much later, in 1954. La- recognized that it was due to ventricular fibrillation. In 1956, Zoll
Due, Wroblewski, and Karmen, introduced cardiac enzyme estima- introduced external defibrillation in Boston and soon its benefit in
tion in New York following their experiments on dogs. They observed combination with mouth to mouth breathing and sternal compres-
that cardiac muscle was rich in glutamic oxaloacetic transaminase sion was demonstrated in patients with ventricular fibrillation. The
and its level in blood rose after coronary ligation in dogs and in concept of coronary care units was a direct consequence of this need
humans after MI.8 The subsequent use of creatine kinase and now to keep these patients in close supervision with trained manpower.
troponins has greatly increased the sensitivity and specificity of MI Nurses were trained to keep a close watch on warning arrhythmia
detection. and treat them with Lignocaine. Meanwhile, in 1960s, attention
The development of coronary angiography had started long shifted to treatment of cardiogenic shock using adrenaline and non
ago in 1711, when the Reverend Stephen Hales inserted long glass adrenaline and hemodynamic monitoring using Swan-Ganz cath-
tubes into the internal Jugular vein and carotid arteries of horses. The eter. Cardiac pacing and use of atropine also developed during this
work of Werner Forssman and his famous self-experiment in 1929, time.
in which he inserted Charriere 4, a catheter for bladders, in his ante- United States set up the MI research units to conduct animal
cubital vein and demonstrated its presence in right atrium, is consid- experiments using drugs that could reduce the extent of damage.
ered to be the first cardiac catheterization. Subsequent refinements Only b-blockers were shown to be effective in reducing mortality in
and additions to the route, the catheters and dyes by Mason Sones, the human beings in the first International Study of Infarct Survival
Andre Cournand and Melvin Judkins led to the current technique of (ISIS-I).
coronary angiography where the presence and severity of coronary Fibrinolysis as a treatment was being tried since 1958 by Sherry
plaques could be clearly demonstrated. Coronary angiography had and his colleagues using intravenous streptokinase, but it was only in
become a routine practice in America by 1960s. In 1980, DeWood et 1970s and 1980s that as many as 22 clinical trials were undertaken.
al. performed coronary angiography early in course of acute MI and Two landmark trials-Gruppo Italiano perlo Studio Della sopprav-
demonstrated that 87% of those studied within 4 hours of onset of vivenza nell’Infarto miocardico (GISSI), and ISIS-2, in 1888 and 1989
symptoms had total coronary occlusion in the infarct-related artery.9 showed the mortality benefit of aspirin and streptokinase and these
This, along with a report by Rentrop, on his experience with intrac- became incorporated into the management guidelines of MI.12
oronary administration of streptokinase, lead to the desire to develop Although Gruntzig of Zurich had pioneered angioplasty in 1977,
thrombolytic treatment for acute MI.10 he and others did not use this technique in patients with acute MI.
Hartzler in 1983 showed in his study that percutaneous translumi-
MANAGEMENT OF ACUTE nal coronary angioplasty resulted in successful opening of more than
90% infarct related arteries. A number of well conducted clinical tri-
CORONARY SYNDROME
als in 1990s later on confirmed the beneficial role of primary angio-
All along the course of evolution of the understanding of acute cor- plasty and established it as a technique at least as effective, and even
onary syndrome, the physicians had been looking for a solution to superior to, fibrinolysis.
the malady. The keystone of management, from the time MI became Many other drugs have been tried and shown to be effective in
known, had been absolute bed rest. Since pathological studies had reducing the complications and limiting infarct size in acute MI in
shown that it took 6–8 weeks for the myocardial scar to become firm, the last two decades and the search continues to this date with many
strict best rest was considered appropriate for this duration to pre- new approaches and therapies showing promise for the future.
vent cardiac rupture.11 Some authorities being very ardent believ- Our understanding of the acute coronary syndrome has
ers of this forbade even brushing of teeth by the patient to minimize improved tremendously since the time this entity came to be known.
physical activity! This treatment continued up to as late as 1959. The thrust now is on secondary and primary prevention by drugs
Shorter and shorter periods of rest were subsequently advised and and reduction of risk factors. Furthermore, the concept of vulnerable
the concept of early ambulation developed in the 1990s. plaque, its detection and the management of acute coronary syn-
The earliest treatment available was beta agonists for treatment drome by newer antiplatelet, anticoagulant and anti ischemic thera-
of cardiogenic shock. Trials of anticoagulant therapy in the UK and pies is engaging the cardiologist and the researcher.
Chapter 12  The History of Acute Coronary Syndrome 91
REFERENCES
1. Leibowitz JO. The history of coronary heart disease. Berkeley: University of California press; 1970.
2. Benivieni A. De abditis nonnullis ac mirandis norborum et sanationum causes. Florence. 1507.
3. Heberden W. Some account of a disorder of the breast. London: Royal College of Physicians, Medical Transactions. London: Royal College of
Physician. 1772;2:59-67.
4. Proudfit WL. Origin of the concept of ischemic heart disease. Br Heart J. 1983;50:209-12.
5. Porter WT. On the results of ligation of the coronary arteries. J Physiol. 1893;15:121-248.
6. Herrick JB. An intimate account of my early experience with coronary thrombosis. Am heart J. 1944;27:1-18.
7. Pardee HEB. An electrocardiographic sign of coronary artery obstruction. Arch Intern Med. 1920;26:244-57.
8. LaDue JS, Wroblewski F, Karmen A. Serum glutamic oxaloacetic transaminase activity in human acute transmural myocardial infarction. Science.
1954;120:497-9.
Med. 1980;303(16):897-902.
10. Rentrop KP, Blanke H, Karsch KR, et al. Initial experience with transluminal recanalization of the recently occluded infarct-related coronary artery
in acute myocardial infarction. Clin Cardiol. 1979;2:92-105.
11. Lewis T. Diseases of the Heart. 3rd edition. London, UK: Macmillan; 1946. P. 60.
12. ISIS-2 (Second International Study of Infarct Survival) Collaborative group. Randomized trial of intravenous streptokinase, oral aspirin or neither
among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-60.
History of AMI: A Saga of
13 Transition from Tortoise Walks
to Rabbit Run
Chouhan NS, Chandra P
INTRODUCTION British physicians lead to improved understanding of the clinical and

pathologic sequel of coronary occlusion. Richard Quain initiated a
Coronary artery disease is considered as the largest killer in the detailed study of “fatty diseases of the heart”. In 1850 Quain pub-
world, which created lot of enthusiasm and maximum research was lished a comprehensive review on fatty diseases of the heart based
done on this field in last 100 years. If we go back in the history in describing association of coronary artery sclerosis with myocardial
late 18th and 19th century there was lot of inertia and lack of zest scars.2 He differentiated epicardial fat from “the muscle fiber itself
towards this field as the disease was invariably fatal and in those days degenerates into molecular fatty matter,” a condition he denoted
the main focus was on infectious disease. “fatty degeneration.” Austin Flint described the symptoms acute
History of coronary artery disease and myocardial infarction myocardial infarction (AMI) as feebleness, dyspnea on exertion,
(MI) started way back in 1772 when Willium Heberdan (Fig. 13.1) palpitations, and precordial distress “especially if the patient have
described the angina pectoris. passed the middle period of life, if his habits have been luxurious
In his words “Angina Pectoris, as far as I have been able to and indolent, if he have the arcus senilis or if there be a tendency to
investigate, belongs to the class of spasmodic, not inflammatory obesity” and correlated it with fatty degeneration.3
complaints. For, in the first place, the access and the recess of the fit It took more the 100 years to correlate angina pectoris and MI as
are sudden. Secondly, there are long intervals of perfect health. manifestations of coronary artery disease.
Thirdly, wine and spirituous liquors, and opium, afford consid- Theory of coagulation necrosis was coined by Cohnheim, (Fig.
erable relief. Fourthly, it is increased by disturbance of the mind. 13.2) who wrote in 1882, “The occlusion of a coronary artery, in case
Fifthly, it continues many years without any other injury to the health. it does not prove fatal, leads to the destruction of the contractile sub-
Sixthly, in the beginning it is brought on by riding on horseback or in stance of that portion of the heart, which is fed by the affected artery,
a carriage, as is usual in diseases arising from cirrus or inflammation. and afterwards to the formation there of so-called myocarditic indu-
Seventhly, during the fit the pulse is not quickened. Lastly, its attacks rations.”4
are often after the first sleep, which is a circumstance common to
many spasmodic disorders.”1
STETHOSCOPE ERA
It took more than a century to diagnose acute MI in a living human
being after fatty disease of coronary arteries (later known as coronary
artery disease) was diagnosed at autopsy. There were many known
facts which were wrongly interpreted because of varied presentation
of the disease, which lead to this long delay. The most important mis-
conception till early 19th century was that the coronary artery throm-
bosis leading to coronary occlusion was invariably fatal. Those were
the days when cardiologist’s major tool was stethoscope and unfortu-
nately there were no auscultatory abnormality attributed constantly
to MI, similarly the relationship of symptoms to pathological findings
in ischemic heart disease was very much inconstant and coronary
arteries or the myocardium were not routinely examined at autopsy.
Nevertheless, during the second half of the 19th century various
research papers on clinic pathological correlation of this disease by Figure 13.1: Willium Heberdan
Chapter 13  History of AMI: A Saga of Transition from Tortoise Walks to Rabbit Run 93
Figure 13.2: Cohnheim Figure 13.3: William Osler
Cohnheim’s assessment was remarkable in an era before electro-

cardiography and coronary arteriography. Advancements in imaging
technology in later years made it possible to objectively identify nar-
rowing of the coronary arteries and myocardial ischemia and to cor-
relate the symptoms of the various ischemic heart disease syndromes
with the underlying anatomic and physiologic abnormalities.5
Stevens in his review on coronary artery disease and the
appearance of English translations of the pathology texts of Ziegler
and Cohnheim in the late 1880s had provided the basis for the recent
scientific observations on the pathophysiology of ischemic heart
disease.6
William Osler (Fig. 13.3) subjected that the blocking of a termi-
nal branch of a coronary artery leads to local disturbances of nutri-
tion ultimately leading to infarct of the heart and suggested that the
possibility of short-term survival after coronary occlusion in 1889.7
In late 19th century physicians were so much preoccupied with
Figure 13.4: Willem Einthoven (1860–1927) with early ECG’s
bacteriology that the important observations of Weigert, Cohnheim,
Leyden and others in the 1880s went ignored. John MacWilliam, Wil-
liam Porter and others studies on sudden death and experimental
coronary occlusion, which ultimately led to the recognition of the Waller of having founded this new diagnostic modality. Einthoven
spectrum of syndromes associated with coronary artery disease and recorded the first human electrocardiogram in Europe on April 11,
myocardial ischemia.8,9 One of the first antemortem diagnoses of MI 1892 using the Lippmann capillary electrometer. He initially indi-
was reported in 1896 by George Dock. He claimed, “The epoch-mak- cated the four observed deflections with the characters A, B, C, D
ing discovery of mediate auscultation engrossed the attention and but later adopted the middle characters of the alphabets: P, Q, R,
diverted the minds of physicians especially towards the examination S and T and V of chest leads stand for voltage.11 Clinical implica-
of the valves of the heart and away from the muscle itself.”10 tion of Electrocardiogram were not known till the day a 46-year-old
female patient arrived in the clinic of Hugo Von Ziemssen in 1882
ERA OF ELECTROCARDIOGRAPHY (Fig. 13.5). She was an unskilled laborer called Catharina Serafin
from Upper Silesia in Prussia (Fig. 13.6). A chest tumor had been
Electrocardiogram has come as a savoir at this time as an objective excised together with the left anterior part of her thoracic wall thus
tool to assess these patients where stethoscope has failed. It was Wil- exposing her heart, which could be seen through a thin layer of skin.
lem Einthoven (1860–1927) (Fig. 13.4), who shares the honor with Von Ziemssen stimulated her heart using electric current and could
change her heart rate at will. The recordings (Fig. 13.6) clearly show
that ventricular activity was being produced by electrical impulses
applied to the cardiac surface: extremely interesting, but potentially
fatal investigations!12
For the first decade after the electrocardiograph was introduced
into clinical practice it was used almost exclusively to investigate car-
diac arrhythmias.
James Herrick was the first person who raised the issue that phy-
sicians are so much preoccupied with their beliefs that they are un-
able to admit any deviation from its details as consistent with angina
and infarction.13,14 The application of the relatively new technique
of electrocardiography to coronary artery disease provided Herrick
with “more convincing proof” of the clinical event, we called it acute
MI.15
Fred Smith, a Herrick’s assistant, described the ECG changes
of MI in their electrocardiographic study of experimental coronary
Figure 13.5: Hugo Von Ziemssen (1829–1902) ligation in 1918.16 ECG had made it possible that physicians in 1920s
were making the diagnosis of coronary thrombosis with increased
frequency.
Two lessons were to be learned from Herrick’s experiences:
1. The first was that all medicine needs periodic overhauling. We
should avoid the paralyzing influence of the dead hand of tradi-
tion
2. There was still room for sane, careful, bedside observation.16
It started with diagnosis of angina pectoris and took another 100
years for understanding and diagnosing of acute MI in a living man.
Evolution of Management Concepts

for Acute Myocardial Infarction
In early 20th century with improved recognition and possible sur-
vive after an AMI concept of its treatment was also evolving. James
Herrick was the first person who proposed and established the im-
portance of rest in postinfarction recovery. Patients were required to
stay bedridden for up to 6 weeks and were even forbidden to move
or to feed themselves during the first week.17 For next 50 years the
treatment evolved was mainly for symptom of pain in the form of
morphine or for rhythm disturbances. Wearn reported the need for
hydric restriction and digitalis for symptoms of pulmonary conges-
tion, and caffeine and camphor for preventing and treating hypo-
tension, syncope, and cardiac conduction blocks. Parkinson and
Bedford reported the use of morphine to relieve pain in a series of
100 patients with AMI. Nitrates were contraindicated, due to the risk
of hypotension.18
In 1929, Samuel Levine published the first book exclusively dedi-
cated to the topic of treatment of AMI. He was the one who started
the concept of early detection and management of AMI and recom-
mended the use of quinidine for ventricular tachycardias and adren-
Figure 13.6: Catharina Serafin and her cardiac activity aline for cardiac blocks and syncope.19
Over a period of years it was evident that prolonged bed rest

REPERFUSION ERA (FIG. 13.7)
increases the risk of deep venous thrombosis and pulmonary embo-
lism. Bernard Lown was the first person, who developed the concept Although thrombolytic agents were used in medical practice for
of early mobilization and allowed patients to leave their beds, sit in many years21,35 there role in AMI was started with the results of first
a chair, and walk much earlier, the time of recovery was reduced and randomized clinical trial from 1986, known as GISSI,36 with more
a more rapid return to daily activities was recommended. Pharma- than 11,000 patients. This trial evaluated the safety and efficacy of
cological management also evolved, and the need for intense fluid intravenous streptokinase in this subset. There was a 19% reduction
replacement and oxygen use was recommended.20 in relative risk of mortality in just 3 weeks after treatment and repre-
senting 1 life spared for every 43 patients treated. Benefit was most
CONCEPT OF CORONARY CARE UNITS pronounced in patients treated within the first three postinfarction
hours (reduction in relative risk = 26%) and between the 3rd and 6th
Desmond Julian, introduced coronary care units in the second half of hour (reduction in relative risk = 20%). In patients treated after the
the 20th century, which lead to the greatest isolated advances in the 6th hour, no statistically significant difference was occurred. ISIS-237
treatment of infarction, which was reduced the mortality rate from trial with 17,187 patients,25,32 confirmed the effects of streptokinase
30% to 15% in the first hours of evolution. These units proved critical associated with aspirin, showing a 25% reduction in relative risk with
for: an NNT (number needed for treatment) of 19. A 12% reduction in
• Diagnosis and management of arrhythmias relative risk occurred in those patients who treated between the 12th
• Development of continuous cardiac monitoring and external and 24th postinfarction hour.
defibrillators These agents proved the test of time by showing significant
• Concept of cardiopulmonary resuscitation maneuvers reduction in mortality, and protection against cardiogenic shock
• Better training of physicians and nurses and heart failure and a low incidence of severe adverse effects. They
• Hemodynamic monitoring through the Swan-Ganz catheter became first line therapy in initial hours of AMI.38,39
• Intra-aortic balloon counterpulsation, for management of heart The beneficial effect of thrombolytic agents is time dependent.
failure and cardiogenic shock.21 Impact goes down with each passing minute, maximum benefit is in
first 6 hours; evidence exists that they may be used from 6 hours to 12
PHARMACOTHERAPY ERA hours after symptom onset if there is recurrent chest pain or exten-
sive infarction. The LATE study40 and EMERAS Collaborative Group
From 1770s to 1970s two centuries were passed in understanding study41 showed a significant reduction in mortality (8.9% vs 12%) in
and basis management of AMI. Last 25 years were most fruitful in patients treated between the 6th and the 12th hour with alteplase
terms of improving prognosis and mortality in AMI. Preservation of versus placebo. No benefit was proven after 12 hours.
left ventricular muscle with multiple pharmacological interventions
was the major field of research in these years.22 MIAMI23 and the
ISIS-124 trials had proven the role of b-blockers in significant reduc-
tions in mortality, especially in the first 48 hours of the event, justify-
ing the early use of these drugs. They also showed lower number of
ventricular arrhythmias and less reinfarction in the initial phase.25
Nitrates were tested in different studies, but unable to show any
benefit in the routine use and were indicated only in cases of recur-
ring angina and heart failure associated with AMI.26-28
The use of angiotensin-converting enzyme inhibitors in patients
with poor ventricular function, heart failure or previous infarction
without myocardial reperfusion therapy had been thoroughly stud-
ied and their benefits in reducing mortality and events had been very
well documented.29-31
Lipid lowering therapy was also introduced in same era by stud-
ies like 4S,32 CARE33 and LIPID,34 and were associated with an up to
30% reduction in the incidence of death, in new nonfatal infarctions,
and in the need for myocardial revascularization. Very recently role
of high dose (80 mg) atorvastatin in AMI is also proven. Figure 13.7: Dr William Smith Tillett (1882–1974)
To overcome the delay in administration of thrombolytic therapy not show a statistically significant difference, a significant 33% reduc-
prehospital administration was tried. EMIP study42 was the largest tion occurred in the incidence of the combined outcome of death,
among them, which randomized 5,469 patients and showed that pre- reinfarction and cerebral stroke when percutaneous transluminal
hospital administration of a thrombolytic agent is feasible and safe. coronary angioplasty was compared with thrombolytic therapy (9.6%
The prehospital treatment reduced by 55 minutes the start of throm- vs 13.7%). This study showed important relation exists between the
bolytic therapy as compared with the in-hospital treatment. Never- prognosis and the “door-to-balloon” time, with an increased mortal-
theless, few patients underwent the thrombolytic therapy within the ity as time goes by and no procedure was performed.
first hour of symptom onset. Even though no significant difference
occurred in total mortality, cardiac mortality was reduced by 1.5% by THE PLATELET INHIBITORS
the end of 30 days.
The results of studies were not representative of real world After b-blockers next major reduction in mortality and in the inci-
patients with AMI as Patients with a history of previous myocardial dence of nonfatal infarctions in patients with unstable angina was
revascularization, poor ventricular function, and those in cardiogen- obtained with the use of acetylsalicylic acid in doses ranging from
ic shock, were excluded.37 75 mg/day to 1,300 mg/day shown in the ISIS-2 study,48 which con-
Side effects had also limited the use of thrombolytic therapy. cluded that aspirin should be administered as soon as possible at
It had been associated with an increase in the number of cerebral minimum doses of 160 mg in the presence of acute infarction.
strokes, most of which were hemorrhagic, and in patients older than Recent clinical trials have shown the importance of more ag-
75 years of age, causing death or sequel in most of the patients.37,43 gressive antiplatelet therapy with aspirin, ticlopidine or clopidogrel
The efficacy in terms of complete reperfusion was in range from 60% in higher doses. Presugrel is new entrant with an advantage of early
to 80%43 and even after apparently very successful thrombolysis, the onset of action, but is associated with slight increase in bleeding
risk of recurring ischemia and reinfarction was approximately 20%, risk.49-51 Use of platelet glycoprotein IIb/IIIa blockade in high risk
which was associated with higher rate of morbidity and mortality.44 patients with AMI treated with primary angioplasty was evaluated
in the EPIC study52 and EPILOG.53 An evident benefit was observed
PRIMARY ANGIOPLASTY ERA in those receiving abciximab when compared with those receiving
a placebo. The RAPPORT clinical trial54 was first randomized trial
Limited efficacy, impossibility and limitations of the use of thrombo- which revealed an additional 48% reduction in the incidence of the
lytic agents in myocardial reperfusion led to search for a more effec- combined events death, reinfarction, or need for a new revascular-
tive safe and definitive alternative of thrombolysis the percutaneous ization in the first 30 days with use of abciximab. Over a period of
transluminal coronary angioplasty to evolve over a period of next next few years their use was restricted for complex interventions and
10–15 years as a mainstay in management of AMI. unstable angina.55
Percutaneous transluminal coronary angioplasty was used in
humans for the first time by Andreas Gruentzig in 1977, for the treat- STENTING ERA
ment of ischemic heart disease. The concept of primary angioplasty
was given by DeWood et al. in 1980,20 but its use as primary treatment Introduction of stent implantation has been the major isolated
of AMI was given by Hartzler et al. in 1982. In the 1990s, this proce- change in the era of catheter reperfusion in the last few years. With
dure was widely used, and it was accompanied by a lower recurrence a better understanding and development of the combined use of
of ischemia, a lower incidence of reocclusion and a lower incidence aspirin and clopidogrel in the prophylaxis of thrombotic phe-
of restenosis.45 nomena, thrombosis of stents has been significantly reduced and
The PAMI study46 was the path breaking study for primary implantation of stents in the acute phase of infarction has become
angioplasty which randomized 395 patients with 12 hours of infarc- feasible.
tion evolution randomized for alteplase or primary angioplasty. This Recent clinical trials have shown the potential superiority of
study showed a high index of success with percutaneous transluminal stent implantation over conventional angioplasty. The FRESCO
coronary angioplasty (97%) and a lower immediate incidence of the study56 randomized 150 patients for elective stent placement or
combined outcome of death and reinfarction (5.1% vs 12.0%, p=0.02). conventional angioplasty for the treatment of acute infarction. The
This incidence was maintained by the end of 6 months (8.5% vs 16.8%, study showed no difference in the isolated incidence of death or
p=0.02), in addition to the absence of cerebral bleeding in the group reinfarction, but a great reduction in angiographic restenosis (17% vs
undergoing percutaneous transluminal coronary angioplasty. 43%) and in the need for new revascularization of the infarct-related
The GUSTO IIb trial47 is perhaps the largest and most repre- vessel in up to 6 months (7% vs 25%) was observed. These data are
sentative of all clinical trials, because it used the best thrombolytic similar to those reported in the GRAMI,57 ESCOBAR,58 and STENT-
strategy with accelerated alteplase, and it randomized patients at 57 PAMI59 trials and CADILLAC55 clinical trial. The benefit seems to be
different centers in nine countries. Even though total mortality did secondary to a greater stabilization of the infarct-related vessel in the
acute phase, with greater immediate luminal gain and lower long- centuries to the extent that the scientifically proven facts were
term loss, instead of being due to a more potent inactivation of plate- ignored for decades. Once the entity was proven and accepted, it
let activity. Therefore, until new evidence appears, stents certainly was generated enough enthusiasm that lot of research was done
do not reduce mortality, but interfere positively in the reduction of although with minimal outcome in terms of improving mortality
restenosis and of new interventions. due to limited resources. Last three decades are the most fruit-
Last major trial was TAPAS study which proved importance for ful only after better understanding of pathophysiology of disease
embolic protection devices in selected group of AMI.60 we would be able to come up with so many treatment options
in a very short period of time with significant improvement in
SUMMARY morbidity and mortality. Newer targets like gene therapy, stem
cell therapy, hyperbaric oxygen and many other experimental
Last two generations have seen the major revolution in diagno- treatments are evolving and may change the way we treat AMI for
sis and management of AMI. There was lot of inertia in initial generations to come.
REFERENCES
1. Willius, Frederick A, Keys, Thomas E. Cardiac Classics. St Louis: CV Mosby Co; 1941:217-24.
2. Quain R. On fatty diseases of the heart. Med Chirg Trans. 1850;33:121.
3. Flint A. A practical treatise on the diagnosis, pathology, and treatment of diseases of the heart. 2nd edition. Philadelphia. 1870.
4. Cohnheim J. Lectures on general pathology (Translated from the German 2nd edition by McKee AB). London: New Sydenham Society; 1889.
5. Fye WB. Coronary arteriography—it took a long time! Circulation. 1984;70:781.
6. Ziegler E. A text-book of pathological anatomy and pathogenesis (translated and edited by Macalister D). New York: William Wood & Co; 1887.
7. Osler W. Rupture of the heart. (This unsigned editorial is attributed to Osler by his bibliographer Maude Abbott). Med News. 1889;54:129.
8. Bloomfield AL. Coronary occlusion and myocardial infarction. In: Bloomfield AL, (Ed.). A bibliography of internal medicine: selected diseases.
Chicago: University of Chicago Press; 1961. p. 16.
9. Willius FA. The historic development of knowledge relating to the coronary circulation and its disease: the nineteenth century. Mayo Clin Proc.
1946;21:77.
10. Dock G. Notes on the coronary arteries. Ann Arbor. Ihland Press. 1896.
11. Burch GE, DePasquale NP. A history of electrocardiography. Chicago: Year Book Publisheer; 1964.
12. Aquilina O. A brief history of cardiac pacing. Images Paediatr Cardiol. 2006;27:17-81.
13. Herrick JB. Certain popular but erroneous notions concerning angina pectoris. JAMA. 1910;55:1421.
14. Herrick JB. An intimate account of my early experience with coronary thrombosis. Am Heart J. 1944;27:1.
15. Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA. 1912;59:2015.
16. Smith FM. The ligation of coronary arteries with electrocardiographic study. Arch Intern Med. 1918;22:8.
17. Herrick JB. Thrombosis of the coronary arteries. JAMA. 1919;72:387.
18. Wearn JT. Thrombosis of the coronary arteries, with infarction of the heart. Am J Med Sci. 1923;165:250.
19. Levine SA. Coronary thrombosis: its various clinical features. Baltimore: Williams and Wilkins; 1929.
20. Lown B. The lost art of healing: Houghton Mifflin Company, 1st edition. 1996. p. 332.
21. Day H. An intensive coronary care area. Dis Chest. 1963;44:423-7.
22. The MIAMI trial research group. Metoprolol. In: Acute Myocardial Infarction (MIAMI). A randomized placebo-controlled international trial. Eur
Heart J. 1985;6:199-226.
23. ISIS-1 (First International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous atenolol among 1,6027 cases of sus-
pected acute myocardial infarction. Lancet. 1986;2:57-65.
24. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propanolol in patients with acute myocardial infarction: I. Mortality results.
JAMA. 1982;247:1707-14.
25. Yusuf S, Collins R, MacMahon S, et al. Effect on intravenous nitrates on mortality in acute myocardial infarction: an overview of the randomized
trials. Lancet. 1988;1:1088-92.
26. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomized factorial trial assessing early oral captopril, oral
mononitrate, and intravenous magnesium sulphate in 58.050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669-85.
27. Woods KL, Fletcher S, Roffe CH, et al. Intravenous magnesium sulphate in suspected acute myocardial infarction: Results of the second Leicester
Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet. 1992;339:1553-8.
28. The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial
infarction with clinical evidence of heart failure. Lancet. 1993;342:821-8.
29. Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction.
Results of the Cooperative Scandinaviam Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992;327:678-84.
30. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin converting-enzyme inhibitor, ramipril, on car-
diovascular events in high-risk population. N Engl J Med. 2000;342:145-53.
31. Pedersen TR, Kjekshus J, Berg K, et al. Randomized trial of cholesterol lowering in 4,444 patients with coronary heart disease: The Scandinavian
Simvastatin Survival Study (4S). Lancet. 1994;344:1383-9.
32. Sacks FM, Pfeffer MA, Move LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol
levels. The Cholesterol and Recurrent Events Trial (CARE). N Engl J Med. 1996;335:1001-9.
33. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with
pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-57.
34. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collabora-
tive overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet. 1994;343:311-22.
35. Gruppo Italiano per lo Studio Della Streptochinase Nell’ Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolitic therapy in acute
myocardial infarction. Lancet. 1988;1:397-402.
36. ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 1,7187 cases of suspected acute
myocardial infarction: ISIS-2. Lancet. 1988;2:349-60.
37. Anglo-Scandinaviam Study of Early Thrombolysis (ASSET). Trial of tissue plasminogen activator for mortality reduction in acute myocardial in-
farction. Lancet 1988;2:525-30.
38. The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO
trial. N Engl J Med. 1993;329:673-80.
39. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular
function, and survival after acute myocardial infarction. N Engl J Med. 1993;329:1615-22.
40. Late Study Group. Late assessment of thrombolytic efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction.
Lancet. 1993;342:759-66.
41. The European Myocardial Infarction Project Group. Prehospital thrombolytic therapy in patients with suspected acute myocardial infarction. N
Engl J Med. 1993;329:383-9.
42. Ohman EM, Callif RM, Topol EJ, et al. Consequences of reoclusion after successful reperfusion therapy in acute myocardial infarction. TAMI Study
Group. Circulation. 1990;82:781-91.
43. Third International Study of Infarct Survival Collaborative Group. ISIS-3: a randomized trial of streptokinase vs tissue plasminogen activators
anistreplase and aspirin plus heparin vs aspirin alone among 41,299 cases suspected acute myocardial infarction. Lancet. 1992;339:753-70.
44. Barbash GI, Ohman EM, White HD, et al and the GUSTO Investigators. Rescue thrombolysis for suspected reinfarction following thrombolytic
therapy: experience infarction. Lancet. 1993;342:759-66.
45. Topol EJ, Eha JE, Brin KP, et al. Applicability of percutaneous transluminal coronary angioplasty to patients with recombinant tissue plasminogen
activator mediated thrombolysis. Cathed Cardiovasc Diagn. 1985;11:337-48.
46. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction—The
Primary Angioplasty in myocardial Infarction Study Group. N Engl J Med. 1993;328:673-9.
47. The GUSTO II Investigators: A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial in-
farction. N Engl J Med. 1997;336:1621-8.
48. ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute
myocardial infarction: ISIS-2. Lancet. 1988;2:349-60.
49. CAPRIE Investigators. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;1329-
39.
50. Berger PB, Bell MR, Rihal CS, et al. Clopidogrel versus ticlopidine after intracoronary stent placement. J Am Coll Cardiol. 1999;34:1891-4.
51. Muller C, Buttner HJ, Petersen J, et al. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of
coronary artery stents. Circulation. 2000;101:590-3.
52. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angio-
plasty. N Engl J Med. 1994;330:956-61.
53. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revasculariza-
tion. N Engl J Med. 1997;336:1689-96.
54. Brener SJ, Barr LA, Burcheral JEB, et al. On behalf of the ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators.
Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circula-
tion. 1998;98:734-41.
55. James E Tcheng, David E Kandzari, Cindy L Grines, et al. For the CADILLAC Investigators Benefits and Risks of Abciximab Use in Primary Angio-
plasty for Acute Myocardial Infarction.The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC)
Trial Circulation. 2003;108:1316-23.
56. Antoniucci DA, Santoro GM, Bolognese L, et al. A clinical trial comparing primary stenting of the infarct-related artery with optimal primary an-
gioplasty for acute myocardial infarction. J Am Coll Cardiol. 1998;31:1234-9.
57. Rodriguez A, Bernardi V, Fernandez M, et al. In-hospital and late results of coronary stent versus conventional balloon angioplasty in acute myo-
cardial infarction (GRAMI trial). Am J Cardiol. 1998;81:1286-91.
58. Suryapranata H, Van’t Hof AWJ, Hoorntje JCA, et al. Randomized comparison of coronary stenting with balloon angioplasty in selected patients
with acute myocardial infarction. Circulation. 1998;97:2502-5.
59. Urban P, Stauffer JC, Bleed D. A randomized evaluation of early revascularization to treat shock complicating acute myocardial infarction. The
(Swiss Multicenter Trial of Angioplasty for Shock) SMASH. Eur Heart J. 1999;20:1030-8.
60. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary
intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008;371:1915-20.
14 History of Nitrates
Gupta R, Mangla S, Bhatnagar A, Chopra HK, Parashar SK
ble and difficult to transport, as shown in numerous catastrophes.

INTRODUCTION
The buildings of the Krümmel factory itself were destroyed on two
It is surprising to know that the most commonly used medicine occasions.
“Sorbitrate” in cardiovascular illnesses has its origin first in the form In April 1866, three crates of NG were shipped to California
of explosives, which was used extensively in various constructive and for the Central Pacific Railroad, who wished to experiment with its
destructive industry, especially during Second World War. In fact a blasting capability to speed the construction of the 1,659-foot (506
bitter war was fought for its control over a long period of time. m) Summit Tunnel through the Sierra Nevada. One of the crates ex-
Nitroglycerin (NG), (United States spelling) also known as nitro- ploded, destroyed a Wells Fargo office in San Francisco and killed 15
glycerine, (UK spelling), trinitroglycerin, 1,2,3-trinitroxypropane and people, led to a complete ban on the transport of liquid NG in Cali-
glyceryl trinitrate, is a heavy, colorless, oily, explosive liquid obtained fornia. The on-site manufacture of NG was thus required for the re-
by nitrating glycerol. Since the 1860s, it has been used as an active maining hard-rock drilling and blasting required for the completion
ingredient in the manufacture of explosives, specifically dynamite, of America’s First Transcontinental Railroad.
and as such is employed in the construction and demolition of Liquid NG was widely banned elsewhere as well and this
industries. Similarly, since the 1880s, it has been used by the military finally led to Alfred Nobel and Company’s development of dyna-
as an active ingredient, and a gelatinizer for nitrocellulose, in some mite in 1867, made by mixing the NG with the diatomaceous earth
solid propellants, such as cordite and ballistite. (kieselguhr) found in the Krümmel hills. Similar mixtures, such as
Nitroglycerin is also used medically as a vasodilator to treat heart dualine (1867), lithofracteur (1869) and gelignite (1875), mixed NG
conditions, such as angina and chronic heart failure. It is one of the with other inert absorbents—many different combinations were
oldest and most useful drugs for treating heart disease by shortening tried in order to get around Nobel’s tightly controlled patents. Dyna-
or even preventing attacks of angina pectoris. Nitroglycerin comes in mites containing nitrocellulose, which increase the viscosity of the
the forms of tablets, sprays or patches. Nitroglycerin can be used to mix, are commonly known as “gelatins.”
help destroy prostate cancer, as well as being used as a heart medi- Following discoveries that amyl nitrite helped to alleviate chest
cine. pain, Doctor William Murrell experimented with the use of NG
to alleviate angina pectoris and reduce blood pressure. He began
HISTORY treating patients with small doses in 1878, and it was soon adopted
into widespread use after he published his results in The Lancet in
Nitroglycerin was the first practical explosive stronger than black 1879. The medical establishment used the name “glyceryl trinitrate”
powder. It was synthesized by chemist Ascanio Sobrero in 1847, or “trinitrin” to avoid alarming patients who associated NG with
working under Pelouze TJ at the University of Turin, Italy. Sobrero explosions.
initially called his discovery “pyroglycerine” and warned vigorously
against its use as an explosive. It was later adopted as a commercially WARTIME PRODUCTION RATES
useful explosive by Alfred Nobel. He experimented with safer ways
to handle the dangerous substance; his younger brother Emil and Large quantities of NG were manufactured in both World Wars for
several workers were killed in 1864 in a NG explosion at the family’s use in military propellants. In World War I HM Factory, Gretna, the
armaments factory in Heleneborg, in Sweden. largest propellant factory in the United Kingdom was producing 800
A year later, Nobel founded Alfred Nobel and Company in Ger- tons (812 tons) of Cordite RDB per week. This required 336 tons of
many, building an isolated factory in the Krümmel hills of Geesthacht NG per week (assuming no losses in production). The Royal Navy
near Hamburg. This business exported a liquid combination of NG had its own factory at Royal Navy Cordite Factory, Holton Heath. A
and gunpowder known as “Blasting Oil”, but it was extremely unsta- large cordite factory was also built in Canada in World War I. The
Canadian Explosives Limited cordite factory at Nobel, Ontario was This can be produced by mixing white fuming nitric acid (quite costly
designed to produce 1,500,000 lb (680 tons) of cordite per month. It pure nitric acid in which oxides of nitrogen have been removed, as
required 286 tons of NG per month. opposed to red fuming nitric acid) and concentrated sulfuric acid.
More often, this mixture is attained by the cheaper method of mixing
INSTABILITY AND DESENSITIZATION fuming sulfuric acid, also known as oleum, (sulfuric acid contain-
ing excess sulfur trioxide) and azeotropic nitric acid (consisting of
In its pure form, it is a primary contact explosive (physical shock can around 70% nitric acid, the rest being water).
cause it to explode) and degrades over time to even more unstable The sulfuric acid produces protonated nitric acid species, which
forms. This makes it highly dangerous to transport or use. In this un- are attacked by glycerin’s nucleophilic oxygen atoms. The nitro group
diluted form, it is one of the more powerful explosives, comparable to is thus added as an ester C-O-NO2 and water is produced. This is
the more recent RDX and PETN, as well as the plastic explosive C-4, different from an aromatic nitration reaction in which nitronium
which contains over 90% RDX as its active ingredient. ions are the active species in an electrophilic attack of the molecules’
Early in the history of this explosive it was discovered that liquid ring system.
NG can be “desensitized” by cooling to 5–10°C (40–50°F), at which tem- The addition of glycerin results in an exothermic reaction (i.e.
perature it freezes and contracting upon solidification. However, later heat is produced), as usual for mixed acid nitration. However,
thawing can be extremely sensitizing, especially if impurities are pre- if the mixture becomes too hot, it results in runaway, a state of
sent or if warming is too rapid. It is possible to chemically “desensitize” accelerated nitration accompanied by the destructive oxidizing of
NG to a point where it can be considered approximately as “safe” as organic materials of nitric acid and the release of very poisonous
modern high explosive formulations, by the addition of approximate- brown nitrogen dioxide gas at high risk of an explosion. Thus, the
ly 10–30% ethanol, acetone or dinitrotoluene (percentage varies with glycerin mixture is added slowly to the reaction vessel contain-
the desensitizing agent used). Desensitization requires extra effort to ing the mixed acid (not acid to glycerin). The nitrator is cooled
reconstitute the “pure” product. Failing this, it must be assumed that with cold water or some other coolant mixture and maintained
desensitized NG is substantially more difficult to detonate, possibly throughout the glycerin addition at about 22°C (72°F), much below
rendering it useless as an explosive for practical application. which the esterification occurs too slowly to be useful. The nitra-
A serious problem in the use of NG results from its high freez- tor vessel, often constructed of iron or lead and generally stirred
ing point 13°C (55°F). Solid NG is much less sensitive to shock than with compressed air, has an emergency trap door at its base, which
the liquid, a feature common in explosives; in the past it was often hangs over a large pool of very cold water and into which the whole
shipped in the frozen state, but this resulted in a high number of reaction mixture (called the charge) can be dumped to prevent an
accidents during the thawing process by the end user just prior to explosion, a process referred to as drowning. If the temperature
use. This disadvantage is overcome by using mixtures of NG with of the charge exceeds about 30°C (86°F) (actual value varying by
other polynitrates, for example, a mixture of NG and ethylene glycol country) or brown fumes are seen in the nitrator’s vent, then it is
dinitrate freezes at -29°C (-20°F). immediately drowned.
DETONATION USE AS AN EXPLOSIVE AND A PROPELLANT

Nitroglycerin and any diluents can certainly deflagrate, i.e. burn. Alfred Nobel’s patent application from 1864.
However, the explosive power of NG is derived from detonation, en- The main use of NG, by tonnage, is in explosives such as dyna-
ergy from the initial decomposition causes a pressure wave or gradi- mite and in propellants.
ent that detonates the surrounding fuel. This is a self-sustained shock Nitroglycerin is oil that may explode with heat, pressure or when
wave that propagates through the explosive medium at some 30 it burns. It is extremely unstable, therefore dropping or bumping a
times the speed of sound as a near-instantaneous pressure-induced container can also make it explode.
decomposition of the fuel into a white hot gas. Detonation of NG Alfred Nobel developed the use of NG as a blasting explosive
generates gases that would occupy more than 1,200 times the origi- by mixing the NG with inert absorbents particularly diatomaceous
nal volume at ordinary room temperature and pressure; moreover, earth. He named this explosive dynamite and patented it in 1867. It
the heat liberated raises the temperature to about 5,000°C (9,030°F). was supplied ready for use in the form of sticks, individually wrapped
This is totally different from deflagration, which depends solely upon in greased water-proof paper. Dynamite and similar explosives were
available fuel regardless of pressure or shock. widely adopted for civil engineering tasks, such as building railway
tunnels and cuttings, and for quarrying.
MANUFACTURING Nitroglycerin was also adapted as a military propellant, for use in
guns and rifles. Poudre B, invented in France in 1886, was one of the
The industrial manufacturing process often uses a nearly 50:50 first military propellants to replace gunpowder; but it was based on
mixture of concentrated sulfuric acid and concentrated nitric acid. nitrocellulose, not NG. It was later found to be unstable.
Chapter 14  History of Nitrates 101
Nitroglycerin is a high explosive which is so unstable that the nous use, transdermal patches (trinipatch, transderm nitro, nitro-
slightest jolt, friction or impact can cause it to detonate. The mol- dur) or sprays administered sublingually (nitrolingual pump spray,
ecule contains oxygen, nitrogen and carbon in weak bonds; when natispray). Patients who experience angina when doing certain
it explodes great energy is released as the atoms rearrange to form physical activities, can often prevent symptoms by taking NG 5–10
new molecules with strong, stable bonds like N2 and CO. It is the minutes before the activity also allowing more freedom to enjoy.
speed of the decomposition reaction which makes it such a violent Some forms of NG last much longer in the body than others. These
explosive. A supersonic wave passing through the material causes may come in the form of a pill taken one, two, or three times per
it to decompose almost instantly. This instantaneous destruction day or even as a patch. Proved by research, it is shown that round-
of all molecules is called a detonation and the destructive blast the-clock exposure to nitrates can cause the body to stop respond-
results from the rapid expansion of hot gases. Nitroglycerin has an ing normally to this medicine. Experts recommend that the patches
advantage over some other high explosives, that no visible smoke is be removed at night, allowing the body a few hours to restore its
produced, therefore acting as a “smokeless powder”. responsiveness to nitrates. Shorter-acting preparations can be used
Alfred Nobel then developed ballistite, by combining NG and several times a day with less risk of the body getting used to this
guncotton. He patented it in 1887. Ballistite was adopted by a num- drug. Nitroglycerin was synthesized in 1846 and was first used to
ber of European governments, as a military propellant. Italy was the treat anginal attacks in 1879.
first to adopt it. However, it was not adopted by the British Govern- Angina pectoris is due to an inadequate flow of blood and oxy-
ment. They, together with the British Commonwealth countries, gen to the heart, which is essential for the production of energy. The
adopted cordite, which had been developed by Sir Frederick Abel heart muscle must produce and use the energy in order to be able
and Sir James Dewar, in 1889. The original Cordite Mk I consisted of to pump blood through the lungs and into the arteries. It is believed
58% NG, 37% guncotton and 5% petroleum jelly. Ballistite and cord- that NG corrects the imbalance between the flow of oxygen and
ite were both manufactured in the forms of cords. blood to the heart. The principal action of NG is vasodilation—wid-
Smokeless powders were originally developed using nitrocellu- ening of the blood vessels. Nitroglycerin will dilate veins more than
lose as the sole explosive ingredient; and were therefore known as arteries because dilation of the veins help so that the heart does less
single base propellants. A range of smokeless powders that contain work and requires less oxygen and blood. It also lowers the pressure
both nitrocellulose and NG, known as double base propellants, were in the arteries against which the heart must pump. Dilating the veins,
also developed. Smokeless powders were originally supplied only decreases cardiac preload and leads to the following therapeutic
for military use; however they were also soon developed for civilian effects during episodes of angina pectoris:
use and were quickly adopted for sport. Some are known as sporting • Subsiding of chest pain
powders. • Decrease of blood pressure
“Blasting gelatin”, also known as gelignite, was invented by • Increase of heart rate
Nobel in 1875, using NG, wood pulp, and sodium or potassium • Orthostatic hypotension.
nitrates. This was an early low-cost, flexible explosive. These effects arise because NG is converted to nitric oxide in the
body by mitochondrial aldehyde dehydrogenase, and nitric oxide
NITROGLYCERIN AND DYNAMITE is a natural vasodilator. Recently, it has also become popular in an
off-label use at reduced (0.2%) concentration in ointment form as an
Alfred Nobel discovered that mixing NG with silica would turn the effective treatment for anal fissure.
liquid into a paste, called dynamite. An advantage of dynamite was
that it could be cylinder-shaped for insertion into the drilling holes Side Effects
used for mining. Nobel received US patent number 78,317 for his
dynamite in 1867. The side effects of NG include lack of sexual desire, headache, painful
urination and increased bowel movements. Patients are often told to
Medical Implications sit or lie down during and immediately after taking NG to reduce the
risk of low blood pressure. A drop in blood pressure can be accompa-
Medical Use nied by weakness or dizziness.
Shortly after the invention of NG, this substance was noticed to
Nitroglycerin belongs to a group of drugs called nitrates, which be capable of inducing a violent headache. Headaches are the most
includes many other nitrates like isosorbide dinitrate (Isordil) and prominent side effect of nitrate therapy. This was due to the release
isosorbide mononitrate (Imdur, Ismo, Monoket). In medicine, of nitric oxide (NO) by NG. Such studies have led to propose that NO
where it is generally called glyceryl trinitrate, NG is used as a heart may be the causative molecule in migraine pain. The importance of
medication (under the trade names Nitrospan, Nitrostat and Tri- NO as a potential initiator of the migraine attack opens new direc-
dil, amongst others). It is used as a medicine for angina pectoris tions for other vascular headaches and pharmacological treatment
(ischemic heart disease) in tablets, ointment, solution for intrave- of migraines.
Nitroglycerin Tablets taken at the very inception of chest discomfort. After taking the NG
pill, relief often follows within 1–2 minutes, but not all types of chest
A common form of medical NG is a small white tablet that patients pain respond to NG.
slip under the tongue. Another form is NG sprays that are a conveni-
ent alternative for someone awakened by angina attacks at night. INDUSTRIAL EXPOSURE
These two forms are not for routine use, only to be used at the onset
of chest pain. A patch is another form of NG. The medication con- Infrequent exposure to high doses of NG can cause severe head-
tained in the patch is slowly released and absorbed through the skin aches known as “NG head”. These headaches can be severe enough
and into the bloodstream; however, it will not relieve an attack that to incapacitate some people; however, humans develop a tolerance
has already started. to and dependence on NG after long-term exposure. Withdrawal
Since 1879, NG pills have been a standard treatment for angi- can (rarely) be fatal; withdrawal symptoms include headaches and
na and heart attacks, but it wasn’t until the 1970s that researchers heart problems; with re-exposure to NG, these symptoms may dis-
understood that the body converts NG into nitric oxide, a messenger appear.
molecule that tells the smooth muscles surrounding blood vessels to For workers in NG manufacturing facilities, this can result in a
relax. “Monday morning headache” phenomenon for those who experi-
When a pill is needed the person places it under the tongue ence regular NG exposure in the workplace leading to the develop-
and allows it to dissolve, which usually takes about 20–30 seconds. ment of NG tolerance for the vasodilation effects. Over the weekend
Nitroglycerin can also be chewed, but is less effective when it is the workers lose the tolerance to NG and when they are re-exposed
swallowed without being dissolved. Its actions make a gentle tingling on Monday the prominent vasodilation produces tachycardia, dizzi-
sensation under the tongue. Nitroglycerin is more effective when ness and a headache.
15 History of Calcium Channel
Blockers
Guha S, Mukherjee S, Karmakar RN
The calcium channel blocker (CCB) is a well established class of not traditionally considered excitable, such as cells of the immune
drugs for the treatment of cardiovascular diseases (CVD) includ- system, although their function here remains unclear4 Harald Reuter
ing hypertension, angina, peripheral vascular disorders and some was one of the pioneers in establishing the essential role of calcium
arrhythmic conditions. There are at least two types of calcium channels in cardiac function.5
channels, L and T. The conventional long-lasting opening calci- Over the following years, the possibility of existence of difference
um channel is termed the L-type channel and is blocked by CCB. in structural as well as functional properties of various calcium chan-
T-type channels open transiently at more negative potentials than nels was recognized (Fig. 15.1). The work of Hagiwara, using starfish
the L-type. However, currently there are no specific T-type channel eggs produced the first evidence that there might be more than one
blockers clinically available. type of calcium channel.6 Subsequently, classification of two current
Voltage-sensitive Ca2+ channels (L-type or slow channels) me- components in mammalian sensory neurons was done according
diate the entry of extracellular Ca2+ into smooth muscles, cardiac to their biophysical properties.7,8 The terms low- and high-voltage-
myocytes, sinoatrial (SA) and atrioventricular (AV) nodal cells in re- activated (LVA and HVA, respectively) channels were introduced to
sponse to electrical depolarization. Ca2+ is a trigger for contraction describe these components based on their difference in conduct-
in both smooth muscles and cardiac myocytes, although by different
mechanisms. Ca2+ channel antagonists, also called Ca2+ entry block-
ers, inhibit Ca2+ channel function. This leads to relaxation in vascu-
lar smooth muscle, especially in arterial beds. In the heart, these
drugs may also produce negative inotropic and chronotropic effects
through their action on nodal cells.
Voltage-gated calcium channels are involved in the normal
functioning of various types of cells like neuronal, neurosecretory
and muscle cells. These also play major role in various pathological
processes that occur in these cells. Paul Fatt and Bernard Katz first
discovered it in crustacean muscle, when they left the Na+ out of their
bathing medium and found that the muscle still generated action
potentials.1 Subsequently this observation was followed by detailed
investigation by Fatt and Ginsborg.2 Susumu Hagiwara then contin-
ued more precise characterization of the calcium conductances in
various invertebrate tissues. Hagiwara and Byerly3 comprehensively
reviewed the early work in invertebrates in an article entitled “Calci-
um channel”. At that time it was hypothesized that all calcium chan-
nels were very similar. Thereafter work on mammalian tissues began
and got advanced over years in parallel with studies in invertebrates.
As a result of many extensive works from different parts of the world
the characters of mammalian calcium channels and ions got refined.
Calcium action potentials and subsequently calcium currents were
discovered in various areas including mammalian skeletal and car-
diac muscle, and subsequently in all excitable cells. Calcium chan- Figure 15.1: Calcium channel heteromeric complex
nels are now also known to be present at low levels in many cells Source: Redrawn from Walker and De Waard, 1998
ance. Various molecules were also being investigated to alter the cium removal, and that this uncoupling could be overcome by in-
function of different varieties of calcium channels. The introduc- creasing extracellular calcium concentrations.11 Indeed, Verapamil
tion of pharmacological tools led to the classification of certain HVA was the first organic molecule to be described as a “calcium antago-
channels as “long lasting” or L-type channels which were sensitive to nist”. Fleckenstein was the person to coin the term “calcium antag-
the dihydropyridines (DHP), and present in skeletal muscle, heart, onist” for any drug that blocked excitation-contraction coupling,
smooth muscle and neurons.9 Kurt Beam conclusively identified which is quite in the same way as removal of external calcium ion.
voltage-gated calcium channels as the voltage sensors in skeletal Later, he also found nifedipine as a calcium antagonist, the first mol-
muscle by expressing them in myotubules from dysgenic mice that ecule of many in the therapeutically important class of DHP. Hass
lacked these channels.10 Researches on non L-type calcium chan- and Hartfelder reported that verapamil possessed negative inotropic
nel and their clinical relevance has been an ongoing process (Table and chronotropic effects that were not seen with other vasodilatory
15.1). agents, such as nitroglycerin. Fleckenstein suggested that the nega-
Furthermore, renoprotective and neuroprotective effects, as well tive inotropic effect resulted from inhibition of excitation-contrac-
as cardioprotective action of cilnidipine have been demonstrated in tion coupling and that the mechanism involved reduced movement
clinical practice or animal examinations. After the introduction of of Ca2+ into cardiac myocytes. Reports of similar works conducted in
nifedipine as an antihypertensive drug, many Ca2+ channel blockers different parts of the world enriched our knowledge about calcium
with long-lasting action for blood pressure have been developed to channel blockers. Godfraind and Polster in Belgium noted the effects
minimize sympathetic reflex during antihypertensive therapy, which of cinnarizine and flunarizine on excitation-contraction coupling in
have been divided into three groups; namely, first, second and third vascular smooth muscle. They showed that the effect of the diphenyl-
generation based on their pharmacokinetic profiles. piperazine analogs cinnarizine and lidoflazine in preventing agonist-
Cilnidipine is a new type of calcium antagonist accompanied induced vascular smooth muscle contraction could be overcome by
with L-type and N-type calcium channel blocking function. It was raising the concentration of Ca2+ in the extracellular medium; they
jointly developed by Fuji Viscera Pharmaceutical Company, Japan used the term calcium antagonist to describe these agents.12
and Ajinomoto, Japan and approved to come into market for the first Development of newer molecules has been an ongoing process
time and used for high blood pressure treatment in 1995. Compared and enriching the armamentarium of practitioners. A derivative of
with other calcium antagonists, clinidipine can act on the N-type cal- verapamil, gallopamil, and other compounds, such as nifedipine,
cium channel existing in sympathetic nerve end besides acting on also were found to block Ca2+ movement through the cardiac myo-
L-type calcium channel, similar to most of the calcium antagonists. cyte Ca2+ channel and thereby alter the plateau phase of the cardiac
Since cilnidipine directly inhibits the sympathetic neurotransmitter action potential. Subsequently, drugs in several chemical classes
release by N-type Ca2+ channel-blocking property, the drug can be have been shown to alter cardiac and smooth muscle contraction by
expected as fourth generation, providing an effective strategy for the blocking or “antagonizing” the entry of Ca2+ through channels in the
treatment of CVD. myocyte membrane.13 Extensive work on second-generation drugs
The endeavor to introduce laboratory discoveries into clinical led to the selective introduction of a number of agents of the 1,4-di-
practice progressed over decades. Evolution of pharmacological hydropyridine class including amlodipine, benidipine, cilnidipine,
agents continued in parallel with the discoveries of various proper- felodipine, isradipine, lacidipine, lercanidipine, manidipine, nica-
ties of calcium channels (Table 15.2). It was in the year 1960 when rdipine, nivadipine, nimodipine, nisoldipine and nitrendipine.14,15
Albrecht Fleckenstein at the University of Freiburg demonstrated In spite of structural similarity to nifedipine, these agents do differ
that verapamil and prenylamine produced effective electromechani- in a number of important pharmacodynamic and pharmacokinetic
cal uncoupling in the heart, that these effects mimicked those of cal- properties, some of which are therapeutically significant.
TABLE 15.1 Properties of several recognized voltage-activated calcium channels

Type Channel Name Where Found Properties of the Calcium Blocked By
Current
L Cav1.1–Cav1.3 Cardiac, skeletal, smooth muscle, neurons Long, large, high threshold Verapamil, DHPs, Cd2+, aga-IIIA
(Cav1.4 is found in retina), endocrine cells,
bone
T Cav3.1–Cav3.3 Heart, neurons Short, small, low threshold sFTX, flunarizine, Ni2+, mibefradil
N Cav2.2 Neurons, sperm Short, high threshold Ziconotide, gabapentin, CTX-GVIA,
aga-IIIA, Cd2+
P/Q Cav2.1 Neurons Long, high threshold CTX-MVIIC, aga-IVA
R Cav2.3 Neurons, sperm Pacemaking SNX-482, aga-IIIA
Chapter 15  History of Calcium Channel Blockers 105
TABLE 15.2 Clinical pharmacology of some calcium channel-blocking drugs

Drug Half-life (hours) Indication Dosage
Dihydropyridines (DHP)
Amlodipine 30–50 Angina, hypertension 5–10 mg orally once daily
Felodipine 11–16 Hypertension, Raynaud’s phenomenon 5–10 mg orally once daily
Isradipine 8 Hypertension 2.5–10 mg orally twice daily
Nicardipine 2–4 Angina, hypertension 20–40 mg orally every 8 hours
Nifedipine 4 Angina, hypertension, Raynaud’s 3–10 mcg/kg IV; 20–40 mg orally every 8 hours
phenomenon
Nimodipine 1–2 Subarachnoid hemorrhage 40 mg orally every 4 hours
Nisoldipine 6–12 Hypertension 20–40 mg orally once daily
Nitrendipine 5–12 Investigational 20 mg orally once or twice daily
Non-DHP
Diltiazem 3–4 Angina, hypertension, Raynaud’s 75–150 mcg/kg IV; 30–80 mg orally every 6 hours
phenomenon
Verapamil 6 Angina, hypertension, arrhythmias, migraine 75–150 mcg/kg IV; 80–160 mg orally every 8 hours
Safety profile of calcium channel blockers were questioned in with links to the industry were more knowledgeable or had greater
last few decades. These concerns included excess CV mortality,16 basic and clinical experience.13
and increased risk of gastrointestinal bleeding and cancer.17,18 A Currently the calcium channel antagonists are one of seven prin-
meta-analysis of trials of first-line antihypertensive agents indi- cipal classes of antihypertensive agents. There is age old debate on
cated that hypertensive patients who had received calcium channel the appropriate choice of agent for the treatment of hypertension.
antagonists had a significantly increased risk of myocardial infarc- Various clinical trials including ALLHAT (The Antihypertensive and
tion relative to patients who had received b-blockers. Similarly, a Lipid Lowering Treatment to Prevent Heart Attack), ANBP2 (Sec-
cohort of elderly patients taking calcium channel antagonists for ond Australian National Blood Pressure Study) and ASCOT (Anglo-
hypertension had an increased risk of cancer development and the Scandinavian Cardiac Outcome Trials) all have differences in study
same authors proposed that these agents also increased the risk of designs, risk profiles and baseline blood pressures, making it difficult
gastrointestinal hemorrhage in hypertensive patients and, most sur- to formulate any universal guideline. JNCVII (the Seventh Report of
prisingly, that this risk was greater than for patients taking aspirin. the Joint National Committee for the prevention, detection, evaluation
These studies, essentially observational in character, have been dis- and treatment of high blood pressure) continues to support the use of
cussed and criticized extensively and the appropriateness of selec- thiazide diuretics as a first step drug combined with drugs from other
tion of control population has been questioned and issues of con- classes according to risk conditions.22 Thiazide diuretics remain the best
founding error have been raised.19,20 However, despite significant evaluated agents and they convincingly reduce incidences of hyperten-
and well-founded criticism of these studies important issues have sion-linked morbidity and mortality. Evidence supports the use of calci-
come out. Rapid-acting formulations of nifedipine can significantly um channel antagonists for hypertension with coronary artery disease
increase cardiac rate through sympathetic reflex activation and may or diabetes. ALLHAT concluded that for those patients with diabetes
generate “coronary steal”, a phenomenon not associated with long amlodipine was as effective as chlorthalidone in all end points except
acting formulations or with second-generation intrinsically long-act- heart failure.23 However, nisoldipine was inferior to lisinopril in reduc-
ing agents such as amlodipine. A second issue was raised regarding ing ischemic events in the Appropriate Blood Pressure Control in Diabe-
financial conflicts of interest. A survey of the literature for articles dis- tes trial (ABCD).24 It was hypothesized that pharmacological property
cussing the safety controversy between March 1995 and September differences between nisoldipine and amlodipine may account for this
1996 revealed that authors supporting the safety of calcium channel difference. In contrast, ASCOT observed that amlodipine (with added
antagonists were significantly more likely than neutral or critical au- perindopril as required) was superior to atenolol (with added thiazide
thors to have financial relationships with the manufacturers of these as required).25 Another comparative study, Comparison of Amlodipine
agents (96%, versus 60 and 37% respectively P < 0.001).21 This finding versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) com-
may, reflect a genuine conflict or may simply represent that authors pared amlodipine or enalapril with placebo in patients with coronary
artery disease and normal blood pressure and observed a reduction Introduction of CCB into the armamentarium of physicians
in clinical events with amlodipine, but not with enalapril.26 In non was a landmark in the history of medical sciences. It does continue
CV fields nimodipine has been shown to be effective in reducing the to have a significant clinical role in the treatment of hypertension,
occurrence of neurological deficit due to vasospasm.27 They also particularly hypertension associated with complicating disorders
show moderate efficacy in a variety of other conditions, including of diabetes, coronary artery disease and where other agents are
hypertrophic cardiomyopathy, migraine and Raynaud’s phenomenon contraindicated in addition to its uses in other CV and non CV
and preterm labor. conditions.
REFERENCES
1. Fatt P, Katz B. The effect of inhibitory nerve impulses on a crustacean muscle fibre. J Physiol. 1953;121(2):374-89.
2. Fatt P, Ginsborg BL. The ionic requirements for the production of action potentials in crustacean muscle fibres. J Physiol. 1958;142(3):516-43.
3. Hagiwara S, Byerly L. Calcium channel. Annu Rev Neurosci. 1981;4:69-125.
4. Cahalan MD, Wulff H, Chandy KG. Molecular properties and physiological roles of ion channels in the immune system. J Clin Immunol.
2001;21(4):235-52.
5. Reuter H. The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration. J Physiol. 1967;192(2):479-92.
6. Hagiwara S, Ozawa S, Sand O. Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J Gen Physiol.
1975;65(5):617-44.
7. Carbone E, Lux HD. A low voltage-activated calcium conductance in embryonic chick sensory neurons. Biophys J. 1984;46(3):413-8.
8. Fedulova SA, Kostyuk PG, Veselovsky NS. Two types of calcium channels in the somatic membrane of new-born rat dorsal root ganglion neurons.
J Physiol. 1985;359:431-46.
9. Hess P, Tsien RW. Mechanism of ion permeation through calcium channels. Nature. 1984;309(5967):453-6.
10. Mynlieff M, Beam KG. Developmental expression of voltage-dependent calcium currents in identified mouse motoneurons. Dev Biol.
1992;152(2):407-10.
11. Fleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Ann Rev Pharmacol Toxicol.
1977;17:149-66.
12. Godfraind T, Polster P. Etude comparative de medicaments inhibitant la response contractile de vaisseaux isole’s d’origine humaine au animale.
Therapie. 1968;33:1209-17.
13. Triggle DJ. Calcium channel antagonists: clinical uses—past, present and future. Biochem Pharmacol. 2007;74(1):1-9.
14. Epstein M. In: Epstein M, (Ed.). Calcium antagonists in clinical medicine. 3rd edition, Philadelphia, PA: Hanley and Belfus; 2002.
15. McDonough SI (Ed.). Calcium channel pharmacology. New York: Kluwer Academic/Plenum Publishers; 2004.
16. Pahor M, Psaty B, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive
agents: a meta-analysis of randomized controlled trials. Lancet. 2000;356:1949-54.
17. Pahor M, Carbonin P, Guralnick JM, et al. Risk of gastrointestinal hemorrhage with calcium antagonists in hypertensive patients over 67 years old.
Lancet. 1996;347:1061-5.
18. Pahor M, Guralnik JM, Ferruci L, et al. Calcium channel blockade and incidence of cancer in aged populations. Lancet. 1996;348:493-7.
19. Opie LH. Calcium channel blockers (CCBs) in hypertension; reappraisal after new trials and major meta-analyses. Am J Hypertens. 2001;14:
1074-81.
20. Angell M. Science on trial. New York: Norton; 1996.
21. Stelfox HT, Chua G, O’Rourke K, et al. Conflict of interest in the debate over calcium channel antagonists. N Eng J Med. 1998;338:101-6.
22. Seventh Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. NIH Publication;
August 2004. 04-5230.
23. ALLHAT officers and coordinators for the ALLHAT collaborative research group. Major outcomes in high-risk hypertensive patients randomized
to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Pre-
vent Heart Attack Trial. J Am Med Assoc. 2002;288:2981-97.
24. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with noninsu-
lin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645-52.
25. Dahlof B, Sever PS, Poulter N, et al. Prevention of cardiovascular events with and antihypertensive regimen of amlodipine adding perindopril as
required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering
Arm (ASCOT-BPLA): a multicentre randomized clinical trial. Lancet. 2005;366:895-906.
26. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary artery disease and normal
blood pressure. The CAMELOT study: a randomized clinical trial. J Am Med Assoc. 2004;292:2217-26.
27. Philippon J, Grob R, Dagreou F, et al. Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine Acta Neurochir
(Wien). 1986;82(3-4):110-4.
Antiplatelet Therapy—History
16 and Future Trends, with Special
Reference to Prasugrel
Singh M, Sharma V, Singh A
INTRODUCTION decisions. This review will discuss existing evidence address-

ing these issues. It also will assess evidence for how these newer
Atherosclerosis often starts in late adolescence or early adulthood. antiplatelet drugs compare with each other in particular popula-
Clinical manifestations including coronary artery disease, stroke, tions. The role of these newer antiplatelet drugs is evolving, and it
and peripheral vascular disease occur years later. Ischemic coronary is not always clear how best to utilize them. This review evaluates
artery disease has a variety of presentations, including stable angina, clopidogrel, ticlopidine, dipyridamole, the combination aspirin
unstable angina, non-ST-segment-elevation myocardial infarction 25 mg/extended-release dipyridamole ER 200 mg (aggrenox) and the
(NSTEMI) and STEMI. Any of these presentations except stable an- novel drug prasugrel.
gina are considered an acute coronary syndrome. Atherosclerotic
cerebrovascular disease also has a variety of presentations, from HISTORIC MILESTONES IN ANTIPLATELET
asymptomatic carotid stenosis to transient ischemic attack (TIA) to
THERAPY
thromboembolic stroke. Likewise, peripheral vascular disease may
be asymptomatic or may manifest in a variety of ways, such as inter- Antiplatelet therapy as on today has evolved over a century. Prior to
mittent claudication of the lower extremity, symptomatic aortic an- 1882, platelets were just thought of as dust particles. Important land-
eurysm or renovascular disease. The pathogenesis of atherosclerosis mark discoveries are given in the Table 16.1.
is complex. Dyslipidemia, endothelial dysfunction, immunologic
factors, inflammatory factors, and other contributors, such as plate- CLASSIFICATION OF ANTIPLATELET DRUGS
let aggregation play a role. Antiplatelet medications are a pharmaco-
logic component of secondary prevention of vascular disease caused Antiplatelet therapy as on today is not confined to just age old aspi-
by atherosclerosis.1 For many years, aspirin has been considered the rin. Today various targets or legends on platelets are attacked by dif-
standard agent. Studies have shown aspirin to reduce the occurrence ferent drugs paving way for double or even triple antilplatelet therapy
of major cardiovascular events, such as death, recurrent myocardi- in relevant clinical conditions (Fig. 16.1). A pharmacological classifi-
al infarction (MI), recurrent angina, nonfatal stroke or progression cation of antiplatelet drugs is given in Table 16.2.
to severe angina. In a meta-analysis,2 aspirin was found to prevent
vascular death by approximately 15% and nonfatal vascular events PATHOPHYSIOLOGY OF
by about 30%. Many clinical practice guidelines for the use of anti-
ATHEROTHROMBOSIS—ROLE OF
platelet agents include aspirin as the primary oral antiplatelet agent
for acute vascular events.3,4 Newer antiplatelet agents have begun
PLATELETS
to come to the forefront as adjuncts to or substitutes for aspirin in Atherosclerosis as a process starts very early in the lifetime of an
certain clinical situations. The mechanisms of action of thienopyri- individual. Endothelial dysfunction is a process which involves
dines clopidogrel, ticlopidine and of dipyridamole differ from that of imbalance of pro- and antiocclusive forces in the vascular lumen.
aspirin. Consequently, these different chemical agents would be ex- This atherosclerotically-activated endothelium results in the activa-
pected to differ from aspirin and possibly from one another in effica- tion of platelets in numerous single steps, which is transient initially,
cy, effectiveness or safety as antiplatelet medications. Some of these but becomes permanent once plaque rupture occurs. It results in
characteristics may even depend on patient population. Because of catastrophic events depending upon the location, i.e. acute myo-
their mechanisms of action, the effects of the newer antiplatelet drugs cardial infarction (AMI) in coronary circulation and acute ischemic
would be expected to be at least additive to aspirin’s effect. Know- stroke in carotid circulation.5 These different players (endothelium,
ing what evidence exists on the efficacy, effectiveness and safety receptors and platelets) are the potential targets of current and future
of these newer antiplatelet medications is fundamental to clinical antiplatelet therapy.
TABLE 16.1 Historic milestones of antiplatelet therapy

1882 Giulio Bizzozero describes platelets
1953 Lawrence Craven reports that aspirin prevents heart attacks
1960 Harvey and co-workers explain antiplatelet action of aspirin
1970 Alan and others describe molecular basis of platelet aggregation
1970–80 Sulfinpyrazone and dipyridamole used as an alternate to aspirin
Late 1980 Ticlopidine introduced
1980 B Coller discovers monoclonal antibody to glycoprotein (GP) IIb/IIIa
1980 RGD mimetics discovered
1990 Clopidrogrel discovered
1994 GP IIb/IIIa inhibitors approved for clinical use
1998 Adenosine diphosphate (ADP) receptor antagonists used for preventing coronary stent thrombosis
2005 Prasugrel tested in Joint Utilization of Medications to Block Platelets Optimally—Thrombolysis in Myocardial Infarction (JUMBO-TIMI) 26
Figure 16.1: Targets of antiplatelet drugs
TABLE 16.2 Classification of antiplatelet drugs

Under normal conditions of arterial blood flow initial contact
Established Drugs Novel Drugs
of a circulating platelet with the intact endothelium is mediated by
Cyclooxygenase inhibitor: aspirin ADP-blockers (thienopyradines): vWF or the endothelial surface molecule P-selecting.6 Next occurs
prasugrel firm binding and adhesion through the interaction of von Willebrand
ADP-blockers (thienopyridines): ADP-blockers (nonthienopyridines): Factor (vWF) and platelet GP Ib receptor.7 This is followed by release
ticlopidine clopidrogrel cangrelor ticagrelor of platelet activation products like ADP, Thromboxane A2 (TXA2),
Phosphodiesterase inhibitor: Others: collagen receptor GPVI epinephrine, serotonin and CD40 legand, etc. Finally, at the site of
dipyridamole blocker von Willebrand factor plaque rupture subendothelial matrix comes in contact with plate-
(vWF) receptor GP Ib blocker lets producing conformational change and release of platelet gran-
thromboxane receptor blocker ules which contain various vasoactive substances.8
(picotanide)
Platelets possess various collagen receptors, most importantly
GP IIb\IIIa inhibitors: abciximab GP Ia\IIa integrin meant for firm adhesion or GPVI receptor which
eptifibatide tirofiban mediate strong platelet activation.9 Once activated, the release of
Chapter 16  Antiplatelet Therapy—History and Future Trends 109
ADP and TXA2 sustain the cascade which produce further recruit- reduced absorption after meals, extra platelet TXA2 formation and
ment of fresh platelets into activation. Platelet receptors ADP are genetic variability of cyclooxygenase enzyme.20 These factors may be
P2Y1 and P2Y12, each mediating a specific signaling pathway. While responsible for the so called aspirin resistance.
P2Y1 produces shape changes in platelets and transient aggregation,
it is the P2Y12 which maintains sustained aggregation. Hence, it is Sulfinpyrazone and Dipyridamole
the target of thienopyridine drugs.10
Thromboxane A2 on the other hand activates platelets through These drugs were extensively evaluated in the 1970s and 1980s for
the thromboxane prostanoid (TP) receptor resulting in cyclic adeno- their antiplatelet activity. While sulfinpyrazone is a weak reversible
sine monophosphate (cAMP) dependent cascade. inhibitor of cyclooxygenase, dipyridamole increases cAMP thereby
Now, binding of two platelets with each other (aggregation) is blunting the response of platelets to aggregation stimuli. These drugs
dependent on the numerous platelet receptors: GP IIb\IIIa integrin have not been particularly effective antiplatelet therapies. There is a
receptors. They function as fibrinogen receptors and one molecule revival of interest in a fixed dose combination of extended-release
of fibrinogen bind with two platelets. Thrombin then finally converts dipyridamole 200 mg + 25 mg aspirin. This combination aggrenox
fibrinogen to fibrin and makes this aggregation irreversible.11 is used in BID dosage for TIA and acute ischemic stroke. The risk
All this knowledge about platelet activation opens various tar- reduction of 22% when compared to aspirin alone is noted [(Euro-
gets of therapeutics in antiplatelet therapy. It also tells us about the pean/Australasian Stroke Prevention in Reversible Ischemia Trial
role of platelets in inflammation and angiogenesis.12 (ESPRIT)]. However, because of dipyridamole’s vasodilatory effects,
it should not be used in patients with co-existing coronary artery dis-
ANTIPLATELET THERAPY ease.21-23
Antiplatelet therapy is required against atherothrombotic process ADP RECEPTOR BLOCKERS—

in various conditions. Acute events like acute ischemic stroke, acute
THIENOPYRIDINES
STEMI, acute NSTEMI and unstable angina necessitate different
approach in contrast to stable angina or intermittent claudications. Adenosine diphosphate is one of the most potent stimulant for plate-
As noted in the classification table, few drugs have firmly established let activation and subsequent aggregation. Adenosine diphosphate
place while some are evolving novel molecules.13 binds to the purinergic receptors P2Y1 and P2Y12. Stimulation of
P2Y1 receptors mobilizes calcium, shape changes and transient
Aspirin platelet aggregation where as P2Y12 stimulation produces perma-
nent platelet aggregation. Thienopyridine group of drugs (clopidog-
This drug available for over half a century now, remains the cor- rel and ticlopidine) are antagonistic at P2Y12 receptor. Both these
nerstone of the antiplatelet therapy. It acts by inhibiting enzyme drugs are prodrugs and undergo hepatic metabolism by cytochrome
cyclooxygenase and thus blocks the production of TXA2. Since plate- P450 34Y. This unknown metabolite then binds to P2Y12 receptor.
lets are anucleate cells, this inhibition lasts till the specific platelet Because of this, when given in usual doses, their action is delayed
circulates.14 Aspirin has the advantage of rapid absorption and rapid for several days. So, acute response needs loading doses. Ticlopidine
onset of action (within 1 hour of intake). Repeated delivery increases proved to have outcomes similar to aspirin in unstable angina.24
antiplatelet effect; maximum effect is seen in 5–6 days.15 Later on when combined with aspirin, it proved additional benefit in
The various indications of aspirin include both acute and stable preventing stent thrombosis. But this drug had one major side effect:
events. Aspirin dosage has been an evolving chapter, but now low- thrombocytopenia. So when another thienopyridine clopidogrel was
dose aspirin regimen has been established. For most indications, a tested in Clopidogrel Aspirin Stent International Cooperative Study
dose of 75–100 mg daily is recommended. Aspirin when used for sec- (CLASSICS) and it showed comparable efficacy with lack of danger-
ondary prevention of cardiovascular events undoubtedly produces ous thrombocytopenia, it replaced ticlopidine.25 Clopidogrel versus
25% reduction of events. The same is not the case with primary pre- Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study on
vention. Conflicting results have been obtained. It was shown to be clopidogrel proved its capacity as secondary preventor versus aspi-
helpful in primary prevention of cardiovascular events in males while rin.26 Clopidogrel is used in acute coronary syndromes and following
not so in females. Females obtained better protection against stroke coronary angioplasty as a “dual therapy” along with aspirin. Clopi-
when aspirin was used as primary prevention in this indication.16-19 dogrel in Unstable Angina to Prevent Recurrent Ischemic Events
The so called “resistance” to aspirin in certain patient populations (CURE), percutaneous coronary intervention (PCI)-CURE, Clopi-
seem to be a misnomer. While aspirin inhibits generation of TXA2 dogrel for the Reduction of Events During Observation (CREDO),
only, there are many other pathways for platelet aggregation. Aspirin Clopidogrel and Metoprolol in Myocardial Infarction Trial (COM-
is less effective in patients with diabetes, those taking nonsteroidal MIT) or Clopidogrel as Adjunctive Reperfusion Therapy—Thrombol-
anti-inflammatory drugs (NASAIDs) concomitantly; there may be ysis in Myocardial Infarction (CLARITY-TIMI) 28 studies have proved
the benefits of this dual therapy.27 Interestingly, Clopidogrel for High Inhibition and Patient Outcomes (PLATO) study. It is orally given at
Atherothrombotic Risk and Ischemic Stabilization, Management and 90 mg twice daily.
Avoidance (CHARISMA) study showed that this dual therapy is no
better than aspirin alone for primary prevention.28 Management of PRASUGREL
Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH)
study showed that this dual therapy is not superior to clopidogrel Mechanism of Action (Fig. 16.2)
alone in secondary prevention of ischemic cerebrovascular events.29
Optimal dose of clopidogrel: The initial loading dose has in- Prasugrel is a rapid, potent, selective, consistent and irreversible
creased from 300 to 600 mg and maintenance dose (MD) from 75 to inhibitor of ADP. It is a thienopyridine P2Y12 antagonist just like
150 mg daily. This is expected to enhance the antiplatelet properties ticlopidine and clopidogrel. Like these two, it is also a prodrug
of clopidogrel [Clopidogrel Optimal Loading Dose Usage to Reduce which needs hepatic metabolism to a thiolactone which is fur-
Recurrent Events (CURRENT) and Optimizing Antiplatelet Therapy ther metabolized to an active metabolite. This active metabolite is
in Diabetes Mellitus (OPTIMUS) studies].30 detected in human plasma within 15 minutes of dosing and reach-
Resistance to clopidogrel is reported in certain patients. It may es a maximum concentration at about 30 minutes.33 Prasugrel is
be related to increased platelet activity in smokers, diabetics or expected to overcome few limitations of clopidogrel namely slow
hypertriglyceridemia. Genetic alteration in CYP34Y metabolism onset of action and variability in antiplatelet effect. In experimen-
enzyme may be responsible in some. tal trials, prasugrel has shown 10–100 folds more potency com-
pared to clopidogrel.34
GLYCOPROTEIN IIA/IIIB RECEPTOR
BLOCKERS Indications
This receptor is the most abundant receptor on the platelets (80,000 To reduce the thrombotic events in patients with acute coronary syn-
copies per platelet). These receptors by binding to vWF and fibrino- drome (ACS) (unstable angina, NSTEMI, STEMI) who are to be man-
gen act as the final common pathways for platelet aggregation acti- aged with PCI.
vated by any other stimulus. So, GP IIb/IIIa blockers have become an
indispensable part of interventions in acute coronary syndromes.31 Dosage
Currently, three agents are available: abciximab (which is a monoclo-
nal antibody) eptifibatide (KGD sequence containing heptapeptide) Loading dose is 60 mg. Maintenance dose is 10 mg daily. For patients
and tirofiban (nonpeptide RGD sequence mimetic). While abcixi- who are more than 75 years old or who weigh less than 60 kg MD is to
mab has longer half-life, the latter two have short half-life. Throm- be reduced to 5 mg daily.
bocytopenia is the main side effect (incidence is 5% with abciximab
while it is 1% with the other two agents). Abciximab is used for PCI
only, while the other two are used in high-risk unstable angina also.
NOVEL DRUGS—SPECIAL REFERENCE

TO PRASUGREL
There are many new antiplatelet drugs, targeting different path-
ways of platelet aggregation, in advanced stages of clinical testing.
Amongst them different new P2Y12 antagonists are most likely to be
introduced in clinical routine. Three such drugs are a thienopyridine,
orally available prasugrel and two nonthienopyridines: cangrelor
(for IV use) and ticagrelor (oral formulation). The latter groups of
nonthienopyridine drugs are direct competitive inhibitors of P2Y12
platelet receptors. They have a more rapid onset and loss of action.32
Cangrelor is being investigated in cangrelor versus standard therapy
to achieve optimal management of Platelet Inhibition-percutaneous
coronary intervention (CHAMPION-PCI) and CHAMPION–PLAT-
FORM studies as an alternative to GP IIb/IIIa inhibitors. Dose is
300 µg/kg bolus and 4 µg/kg/min infusion. Ticagrelor is being tested
against clopidogrel in the setting of STEMI and NSTEMI in Platelet Figure 16.2: Mechanism of action of prasugrel
Chapter 16  Antiplatelet Therapy—History and Future Trends 111
Assess Improvement in Therapeutic Outcomes by Optimizing Plate-

let Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction
(TRITON-TIMI), 38 study used a prasugrel regimen of 60 mg loading
and MD of 10 mg daily compared to standard clopidogrel regimen
(300 mg loading and 75 mg daily). The reduction in primary end-
points was a significant 24% reduction in Ml, a 34% and 52% reduc-
tion in urgent target vessel revascularization and stent thrombosis
(regardless of stent type) was also shown. There was, however, an
increase in rates of major bleeding.36 This increased risk of bleeding
has been found to be more in high-risk subgroups (age > 75 years and
wt < 60 kg) and that too related to maintenance period. Hence, it is
recommended that low MD (5 mg) should be used in such patients.
Another trial Prasugrel in Comparison to Clopidogrel for Inhibition
Figure 16.3: Precautions and contraindications of Platelet Activation and Aggregation—Thrombolysis in Myocardial
Infarction (PRINCIPLE-TIMI) 44 comparing prasugrel (60 mg load-
ing and 10 mg daily) with increased dose clopidogrel (600 mg loading
and 150 mg daily) has shown that amongst patients undergoing PCI,
Contraindications and Precautions (Fig. 16.3) prasugrel resulted in greater platelet inhibition.
• Active pathological bleeding. FUTURE TRENDS

• Prior TIA or stroke. Do not start in patients likely to undergo
coronary artery bypass graft (CABG). Cautious use is recom- Apart from above discussed drugs (established one and novel thera-
mended in end-stage renal disease (ESRD), severe hepatic pies) molecules targeting those aspects of platelet physiology are
impairment, lean body mass (< 60 kg) and age more than being tested which have not been tested so far. Antibodies against
75 years. collagen receptor GPVI or the vWF receptor GP1b37 thromboxane
The safety and efficacy of prasugrel in comparison to clopidogrel receptor antagonist S18886 seems to have excellent antithrombotic
was shown in JUMBO-TIMI 26 study.35 A recently published Trial to activity in animal models of stent thrombosis.38
REFERENCES
dial infarction, and stroke in high-risk patients. BMJ. 2002;324(7329):71-86.
2. Albers GW, Amarenco P. Combination therapy with clopidogrel and aspirin: can the CURE results be extrapolated to cerebrovascular patients?
Stroke. 2001;32(12):2948-9.
3. Albiero R, Hall P, Itoh A, et al. Results of a consecutive series of patients receiving only antiplatelet therapy after optimized stent implantation.
Comparison of aspirin alone versus combined ticlopidine and aspirin therapy. Circulation. 1997;95(5):1145-56.
4. Algra A, van GJ. Is clopidogrel superior to aspirin in secondary prevention of vascular disease? CCTCM. 2000;1(3):143-5.
5. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med.
1992;326:310-8.
6. Jackson SP, Nesbitt WS, Kulkarni S. Signaling events underlying thrombus formation. J Thromb Haemost. 2003:1:1602-12.
7. Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost. 2003;1:1335-42.
8. Siess W. Molecular mechanisms of platelet activation. Physiol Rev. 1989;69:58-178.
9. Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor. Blood. 2003:102:449-61.
10. Daniel JL, Dangelmaier C, Jin J, et al. Molecular basis for ADP-induced platelet activation I. Evidence for three distinct ADP receptors on human
platelets. J Biol Chem. 1998:273:2024-9.
11. Shattil SJ. Function and regulation of the beta 3 integrins in hemostasis and vascular biology. Thromb Haemost. 1995;74:149-55.
12. Pinedo HM, Verheul HM, D’Amato RJ, et al. Involvement of platelets in tumour Angiogenesis. Lancet. 1998;352(9142):1775-7.
13. Cattaneo M. Platelet P2 receptors: old and new targets fbrantithrombotic drugs. Expert Rev Cardiovasc Ther. 2007;5:45-55.
14. Evangelista V, Manarini S, Di Santo A, et al. De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosyn-
thesis by aspirin. Circ Res. 2006:98:593-5.
15. Cipollone F, Patrignani P, Greco A, et al. Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable
angina. Circulation. 1997:96:1109-16.
16. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ (Clin Res Ed). 1988;296(6618):313-6.
17. Physician’s Health Study Group. Physician’s health study: aspirin and primary prevention of coronary heart disease. N Engl J Med. 1989:321:
1825-8.
18. Manson JE, Stampfer MJ, Colditz GA, et al. A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA.
1991;266:521-7.
dial infarction, and stroke in high-risk patients. BMJ. 2002;324(7329):71-86.
20. Patrono C, Rocca B. Drug insight: aspirin resistance—feet or fashion? Nat Clin Pract Cardiovasc Med. 2007;4:42-50.
21. Schaper W. Dipyridamole, an underestimated vascular protective drug. Cardiovasc Drugs Ther. 2005;19:357-63.
22. Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): ran-
domised controlled trial. Lancet. 2006;367(9523):1665-73.
23. De Schryver EL, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane
Database Syst Rev. 2007;3:CD001820.
24. Balsano F, Violi F, Cimminiello C. Ticlopidine in unstable angina. Circulation. 1990;82:2282-3.
25. Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with
aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative
study (CLASSICS). Circulation. 2000;102:624-9.
26. CAPRIE Steering Committee. A randomised blinded, trial of ciopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE
Steering Committee. Lancet. 1996;348(9038):1329-39.
27. Eshaghian S, Kaul S, Amin S, et al. Role of ciopidogrel in managing atherothrombotic cardiovascular disease. Ann Intern Med. 2007:146:434-41.
28. Bhatt DL, Fox KA, Hacke W, et al. Ciopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med.
2006:354:1706-17.
29. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and ciopidogrel compared with ciopidogrel alone after recent ischaemic stroke or transient
ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-7.
30. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus
and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007;115:708-16.
31. Kong DF, Califf RM, Miller DP, et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein llb/llla integrin in ischemic heart
disease. Circulation. 1998:98:2829-35.
32. Greenbaum AB, Grines CL, Bitt JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing per-
cutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J.
2006;151:689.
33. Brandt JT, Close SL, Iturria CD, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic re-
sponse to clopidogrel but not prasugrel. J Thromb Haemost doi: 10.1111/j. 1 538-7836.2007.02775.x, published online September 27, 2007.
34. Niitsu Y, Jakubowski JA, Sugidachi A. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor
antagonist activity. Semin Thromb Hemost. 2005;31:184-94.
35. Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a nous! thienopyridine P2Y12 antagonist,
with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI
26 trial. Circulation. 2005;111:3366-73.
36. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-
15.
37. Kleinschnitz C, Pozgajova M, Pham M, et al. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and llb/llla blockade
on infarct size, functional outcome, and intracranial bleeding. Circulation. 2007;115:2323-30.
38. Vilahur G, Casani L, Badimon L. A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an
experimental model of stent-induced thrombosis. Thromb Haemost. 2007;98:662-9.
17 History of Antiarrhythmic Drugs
Wander GS, Kaushal S
Based on his professional experience, Wenckebach described

INTRODUCTION
the effect of quinine on AF.4 He reported on the patient’s account,
Cardiac arrhythmias are considered as one of the most common who could cure himself of attacks of AF. Based on the patient’s
causes of sudden cardiac death worldwide.1 There has been a steady personal experiences subsequently, he concluded that quinine
progress in the development of treatment modalities for arrhythmias can cure underlying AF of recent onset (acute AF) but not of many
and a greater progress has been possible with the electronic devices years duration (chronic AF). Impressed by the case report of Wenck-
rather than the drugs.2 The slow development has been due to the ebach, Walter Frey, a Swiss physician, conducted systematic tests on
involvement of multiple factors in the genesis of arrhythmias. various quinquina alkaloids (like quinine, cinchonine and quinidine)
The history of ventricular fibrillation dates far back to 3500 BC. in 1918.4,6 He documented that quinidine was the most effective
Nearly 3000 years later, Vesalius described “worm-like” movements alkaloid against atrial flutter and fibrillation being capable of con-
of heart in animals before death.3 Edmé Félix Alfred Vulpian, in 1874, verting arrhythmias into sinus rhythm. Quinine, on the other hand,
coined the term “mouvement fibrillaire” to probably describe both was found to have a moderate and irregular action.4 Quinidine is
atrial and ventricular fibrillation. John A MacWilliam, a physiologist considered to be the prototype of antiarrhythmic drugs and has been
at the University of Aberdeen, gave an accurate description of the used widely in the 20th century for the management of supraven-
arrhythmia in 1887, years before electrocardiography was used. The tricular and ventricular arrhythmias.7
paper on electrocardiogram recording of ventricular fibrillation was
first published by August Hoffman in 1912. PROCAINAMIDE
QUINIDINE A few years after the introduction of quinidine, procaine (local an-
esthetic) was reported to have similar cardiac effects as quinidine.
The history of use of antiarrhythmics dates back to more than 100
years back and was hallmarked by the discovery of cardiac actions
of cinchona derivatives.2,4 Although Quinidine was introduced as
an antiarrhythmic in 1918, its history predates to as early as the 17th
century. Even before quinidine was used as an antiarrhythmic drug,
digitalis was being used for slowing the ventricular response and for
cardiovascular function improvement in patients with atrial fibrilla-
tion (AF).5 Quinidine is an optical isomer of quinine and is derived
from the cinchona plant (Fig. 17.1) which was named after the coun-
tess of Cinchon, who used its powder for the treatment of malaria.
Its cardiac properties were first reported by Georg Ernst Stahl (pub-
lished in 1744) who observed that an excessive intake of cinchona
bark can cause edema due to a decrease in the cardiac performance.4
Probably, the first use of quinidine was reported by French
Physician, Jean-Baptiste de Senac, who used it for AF described as
“Rebellious palpitations” in 1749.6 The cinchona bark was used for
treating cardiac rhythm disorders by William Saunders and Johann
Oppolzer during the 18th and 19th centuries. Van Heyningen first
described quinidine in 1848. It was later prepared and given its
present name by Pasteur in 1853.6 Figure 17.1: Cinchona succirubra
One of the major contributors to the introduction of procainamide nytoin in treating ventricular tachycardia induced by experimentally
was the World War II and loss of Indonesia as a source for cinchona provoked MI in animal models, dogs.4,8 It was also found to be use-
alkaloids.2 Mautz, in 1936, demonstrated that procaine if applied di- ful in managing tachycardia in human beings, especially occurring
rectly on the myocardium could elevate the ventricular threshold for as a result of digitalis toxicity.4,6 The popularity of phenytoin peaked
electrical stimulation. This effect was interpreted as the mechanism during the 1960s but a decade later, the US Food and Drug Adminis-
responsible for antiarrhythmic effect of procaine. The major draw- tration (FDA) announced that the data available was insufficient for
back to its widespread use in therapeutics was its short duration of its formal approval leading a major blow to its use as an antiarrhyth-
action due to rapid enzymatic hydrolysis.6 Additionally, procaine mic.9
caused central nervous system effects like tremors and respiratory Another antiarrhythmic drug synthesized in the same time
depression.4,6 These adverse features led to a series of systematic period as phenytoin was disopyramide. Despite its synthesis in
studies on various congeners and metabolites of procaine culmi- 1954, it was not commercially available until 1978.4,6 Its pharmaco-
nating in the discovery of procainamide by Mark et al. in 1951.4 It is logical actions and toxicity profile were found to be similar to that of
effective for ventricular arrhythmias. quinidine and procainamide.2 The therapeutic efficacy was first
Although, procainamide emerged as a safer alternative to quini- demonstrated in animal models in 1962 by Marken and van
dine, their toxicity profiles were found to be similar.2 In addition, the Armon.10 The major drawbacks were significant antimuscarinic and
search for substances with chemical structure similar to procaina- negative inotropic actions.8
mide was discouraged for a long time due to its tendency to cause
systemic lupus erythematosus like syndrome.4 SPARTEINE
A common animal model used to screen for antiarrhythmic
activity was the “Harris dos” that demonstrates extremely high-fre- Sparteine, an alkaloid derived from Scotch broom known as
quency ventricular ectopic activity after two-stage coronary artery Sarothamnus scoparius (Fig. 17.2), was another antiarrhythmic
ligation. This arrhythmia is especially sensitive to sodium channel drug with sodium channel blocking properties that was found to be
blockers and so the first wave of new antiarrhythmics were drugs slightly effective.4 It was used for the treatment of sinus tachycardia;
derived from existing structures and demonstrating activity in this prevention of AF after electroreduction, atrial tachycardia and extra-
and other models (i.e. primarily sodium channel blockers). systoles; ventricular arrhythmias. It was later reported that 10% of
the patients are unable to metabolize sparteine and, therefore, are
LIDOCAINE at risk of developing intoxication. Due to these adverse effects and
availability of better agents, sparteine never got FDA approval for use
Following procaine, another local anesthetic that found a place in in patients with arrhythmias.11,12
the management of arrhythmias was lidocaine. It is a derivative of
gramine, an alkaloid isolated from a reed plant indigenous to Central
Asia. Isogramine was first synthesized in 1935 by two Swedish chem-
ists, Euler and Erdtman. But the clinical application was halted by
local irritation and other adverse effects with isogramine. The work
by Löfgren led to the discovery of lidocaine (also known as xylocaine)
in 1943 followed by its approval for use in Sweden and United States
in 1948.4 The first clinical application of lidocaine was in the preven-
tion of ventricular tachycardia in 1950 followed in 1962 by success in
treating arrhythmias during cardiac surgery, postoperatively or those
resulting from myocardial infarction (MI).4,6 As lidocaine could be
used only by intravenous route, its orally active analogues, mexile-
tine (1986) and tocainide (1984) were developed later.8
PHENYTOIN
The unfolding of understanding of electrophysiological actions of
antiarrhythmic drugs and cardiac sodium channels shifted the focus
towards the search for more potent antiarrhythmics which blocked
these channels.2 Phenytoin which was chemically different from the
preceding antiarrhythmics, was first isolated by Blitz in 1908.4 Harris
and Kokernot, in 1950, discovered the therapeutic efficacy of phe- Figure 17.2: Sarothamnus scoparius
Chapter 17  History of Antiarrhythmic Drugs 115
in USA led to its approval by the US-FDA in June 1990 for treating
AJMALINE
documented ventricular tachycardias.15
An alkaloid with quinidine like membrane stabilizing activity was
isolated from Rauwolfia serpentina (Fig. 17.3) in 1931 by a Pakistani BRETYLIUM
scientist, Siddiqui. This substance was subsequently named ajma-
line after the name of an Indian physician Hakim Ajmal Khan. Years Bretylium was initially introduced as an antihypertensive agent in
after its isolation, Kleinsorge and Zipf in 1958 introduced ajmaline 1959. It soon became obsolete for this indication due to its erratic
as a class Ia antiarrhythmic drug.4 It was made available in European absorption and rapid development of tolerance.16 Several years later,
countries and has been used as a first-line agent for treatment of ven- it received approval for emergency treatment of drug-resistant ven-
tricular arrhythmias in Europe and Japan.13 But its high antiarrhyth- tricular fibrillation or sustained ventricular fibrillation in 1978.8
mic efficacy was found to be fraught with risk of induction of arrhyth-
mias (QT prolongation) and neutropenia.14 AMIODARONE
MORICIZINE The discovery of amiodarone was based on an accidental observation

by G V Anrep in 1946 who found that one of his assistants suffering
The principle that high potency block of a single pharmacologic tar- from angina pectoris dramatically improved by using khella (herbal
get is desirable because it minimizes the side effects that come with remedy).4 Later, amiodarone was developed as an antianginal drug
nonspecific drugs is now well-established near dogma in drug devel- by a Belgian company in 1961 with the use of benzofuran moiety
opment circles of all types. present in khellin.17,18 Its antiarrhythmic property was noted a few
Soviet Union developed moricizine in 1964 at the Institute of years later by a physician in Argentina, Dr Mauricio Rosenbaum.
Pharmacology of the Academy of Medical Sciences of USSR.8,15 The The impressive results published by Dr Rosenbaum led to the use of
compound was originally called ethmozin, ethmosin or etmozin.15 amiodarone by clinicians world over, except in USA, with the notion
The clinical development of moricizine as an antiarrhythmic drug that it was a unique antiarrhythmic drug that was useful in almost all
spans over a period of 21 years with the initial trials conducted in cases and was virtually free of adverse effects.18 In the late 1970s, the
USSR from 1966 to 1971, followed by United States. The observations US FDA sanctioned the procurement of amiodarone from Canada
during preclinical trials resulted in interruption in its development and Europe for use in patients with life-threatening arrhythmias on
on two occasions. The first interruption took place in 1978 when a a compassionate basis.17 With the widespread use of amiodarone,
monkey died due to unexplained reasons which was later reported to its adverse effects began to be published in medical publications.
be dosing error. The other interruption in 1982 was due to prolifera- Despite the reluctance shown by FDA, amiodarone was approved in
tive liver disease in rat model. However, the further trials conducted 1986 for treatment of drug-resistant recurrent or sustained ventricu-
lar fibrillation.8 This approval was in sharp contrast to the approval
process of any other modern drug as amiodarone’s approval was not
based on rigorous randomized clinical trials, though, the US-FDA
did issue black box warning on the label regarding its toxicity profile.
Despite the realization that amiodarone was useful in AF, its use for
this condition remained off label in lieu of lack of controlled clinical
trials.17
Landmark clinical trials that have moved the arrhythmia field
forward include demonstrations of modest benefit with amiodarone
in patients convalescing from MI [Canadian Myocardial Infarction
Amiodarone Trial (CAMIAT) and European Myocardial Infarction
Amiodarone Trial (EMIAT)].19,20
FLECAINIDE AND OTHERS

In 1966, Riker Laboratories, USA investigated the effects of substitut-
ing fluorine atoms for hydrogen atoms in various organic pharma-
ceuticals. Procainamide was one of the base molecules used dur-
ing this study to create new molecules which demonstrated local
anesthetic effects. A few of these molecules were tested for their
Figure 17.3: Rauwolfia serpentina antiarrhythmic effects in animal models resulting in the synthesis of
flecainide in 1972. The testing of flecainide’s actions in healthy hu- Studies of b-blockers, including some of the first cardiology meg-
man beings started in late 1970s and by 1978, flecainide was proven atrials, suggested antiarrhythmic efficacy in some settings.25,26
to be an antiarrhythmic agent.4 A series of parallel studies were con-
ducted in Germany and United States that led to its commercial re- CALCIUM BLOCKERS
lease in Germany in 1982 and in 1985 in USA.
The other antiarrhythmic drugs with similar properties as fle- The role of calcium in the contraction of cardiac muscles was known
cainide were also developed during 1970s. These included encainide since 1883.4 The principle of “calcium antagonism” was first defined
and lorcainide.4 The development of encainide was a result of study and described by Albrecht Fleckenstein, who along with his col-
by Dykstra et al. who described the synthesis of lysergic acid deriva- leagues, studied the properties two vasodilators verapamil and pre-
tives with antiarrhythmic activity. One of these agents, MJ 9067 or nylamine. It was found that these agents had a negative inotropic
encainide, which is a benzanilide compound, was shown to possess effect on the heart and purely by chance, calcium was reported to
5–10 times the antiarrhythmic potency of procainamide without antagonize this effect.4
adverse effects on other cardiac parameters. The efficacy of single
intravenous doses in ventricular extrasystoles and supraventricu- ATROPINE AND OTHERS
lar arrhythmias was described in 1979. While in 1980, Roden et al.
demonstrated that oral encainide therapy was capable of totally sup- Atropine, derived from the leaves and berries of deadly nightshade
pressing ventricular ectopy in 10 out of 11 patients with stable, high plant (Fig. 17.4), was originally used as a poison. Although it was first
frequency, nonsustained ventricular arrhythmias. Over the next few isolated in 1831, it was not until 1867 when von Bezold demonstrated
years, encainide emerged as one of the most potent antiarrhythmic that atropine could block the cardiac effects of vagal stimulation. Sir
drugs.21 James Mackenzie studied its effects on digitalized patients with AF
The search for coronary dilators in the 1970s led to the discov- and also found that it could revert partial heart block.4
ery of etafenone followed by propafenone which also demonstrated Magnesium gained importance in cardiology, after years of ne-
antiarrhythmic properties.4 Propafenone came up in the German glect, following the controversies created by Cardiac Arrhythmias
market in 1978 and in USA in 1990.4,22 The electrophysiological Suppression Trial (CAST). The history of use of magnesium dates
effects shown by propafenone led to its placement under Class Ic back to 1935 when Zwillinger reported the role of magnesium in the
antiarrhythmic drugs.4 treatment of digitalis-induced arrhythmias. Thereafter, the concept
of low serum magnesium and serum potassium levels being associ-
β-BLOCKERS ated with cardiac arrhythmias, led to magnesium being a subject of
numerous clinical trials.4
Almost a decade after Ahlquist’s report on adrenotropic receptors, Adenosine was initially introduced for managing broad complex
Powell and Slater in 1958 serendipitously discovered that dichlo- tachycardia. Within a span of 5 years, its therapeutic uses expanded
roisoprenaline (DCI) was a selective beta adrenoceptor blocker in
a variety of smooth muscle preparations.4,23 Dichloroisoprenaline
was later studied by Riddel et al. who reported that it could control
tachycardia and arrhythmias after the removal of pheochromocy-
toma.4 During the same time period, Sir James Black, working at the
Glasgow University, was searching for drugs with antianginal effects.
He studied DCI for its coronary dilator properties but did not find
it suitable for decreasing myocardial oxygen consumption. Later,
along with Stephenson, a chemist at the Imperial Chemical Industry
(ICI), Sir James Black synthesized pronethalol (alderin) in February
1960.4,23 This drug proved to be an effective antianginal drug and also
successful in the treatment of cardiac rhythm disorders.4 Though the
trials on pronethalol began in 1962, its further assessment was dis-
continued due to production of tumor of thymus gland in mice.4,23
Propranolol, another product of ICI, soon replaced pronethalol
in 1964. Propranolol and other b-blockers that were subsequently
developed retained the antianginal, antiarrhythmic and antihyper-
tensive properties of pronethalol, but lacked the carcinogenic poten-
tial.23 Sotalol, a cardioselective b-blocker and class III antiarrhythmic
agent, was first described in 1964 by Dungan and Lish.4 Its additional
effects on cardiac action potential were demonstrated in 1970.24 Figure 17.4: Atropa belladonna
and it became the first line therapy for narrow as well as broad com- proposed in 1991 by the Task Force of the Working Group on Ar-
plex tachycardia. Its widespread use began in 1990.27 rhythmias of the European Society of Cardiology.33 This scheme was
considered to be more comprehensive and physiologically based.
CLASSIFICATION
RECENT STUDIES
In order to have a better understanding of the various antiarrhyth-
mic drugs, Vaughan Williams in 1972 classified these drugs into four The cardiac arrhythmia suppression trial was initiated by the Nation-
classes on the basis of their predominant antiarrhythmic actions.28,29 al Heart, Lung and Blood Institute (NHLBI) in 1986.34 It followed the
This classification was later modified in 1974 by the subdivision of Cardiac Arrhythmia Pilot Study (CAPS), sponsored by National Insti-
Class I into Ia and Ib by Singh and Hauswith and again in 1981 by tutes of Health, which reported that flecainide, moricizine and en-
addition of Class Ic by Harrison.30 Another classification system was cainide could suppress premature ventricular depolarizations with
introduced by Hoffman and Bigger in 1971 who proposed two groups an acceptable incidence of adverse effects.28 Although this study did
of drugs based on the studies on novel antiarrhythmics available at not possess power to evaluate the effects on mortality, yet it provided
that time.30 The first group consisted of drugs that prolonged action sufficient data for planning CAST. The initial results of CAST I were
potential duration (APD) and decreased Vmax by inhibiting sodium published in 1989 and those of CAST II in 1992.34 Cardiac Arrhythmi-
currents. The second group of drugs had no effect on the sodium cur- as Suppression Trial I was interrupted in March 1989 when flecainide
rents but reduced APD. The current classification scheme used is a and encainide caused a 2–3 fold increase in mortality compared to
hybrid of the two schemes. the placebo group.28 In both these trials, the antiarrhythmic drugs
Vaughan Williams classification was considered imperfect, but were effective in suppressing the asymptomatic ventricular arrhyth-
provided a simple way of grouping the antiarrhythmic drugs (Table mias, but also resulted in an increase in mortality. As a consequence,
17.1).31,32 After the publishing of CAST results, a report was pre- labeling of all the antiarrhythmic drugs was modified along with
pared known as Sicilian Gambit which argued against the Vaughan more stringent regulatory guidelines by the US-FDA.34 The Survival
Williams classification.29 This Sicilian Gambit classification was With Oral D-Sotalol (SWORD) Trial that followed CAST also met with
the same fate dampening the enthusiasm for new drug development
for arrhythmias.35
TABLE 17.1 Vaughan Williams antiarrhythmic classification
Despite the discouraging results of CAST and SWORD Trials,
Class Drugs some useful antiarrhythmic drugs, such as dofetilide, ibutilide and
I Prolongs sodium channel inactivation azimilide evolved.35 Dofetilide and ibutilide have been approved by
Ia Procainamide FDA while azimilide is still an investigational drug. Dronedarone, a
Disopyramide newer benzofuran derivative and a multichannel blocker, was devel-
Quinidine oped as a structural analogue of amiodarone but lacking the iodine
Ib Lidocaine moiety. It was approved in 2009 by the US-FDA for the management
Mexiletine of AF.36 Budiodarone, celivarone and vernakalant are some of the
Phenytoin other agents with structural similarity to amiodarone which are in
Ic Flecainide clinical trials.37 Pilsicainide is a pure class Ic agent which has not
Propafenone been FDA approved, but was both developed and marketed only in
II Blocks b-adrenergic receptor Japan for the treatment of supraventricular and ventricular tachy-
Esmolol cardia. In 2001, pilsicainide became one of the best selling drugs for
Propranolol its manufacturers.38 Drugs that are currently in relatively late phase
Atenolol development are listed in Table 17.2.39-41
III Blocks potassium efflux The recent years have witnessed an upsurge in the field of cath-
Amiodarone eter ablation techniques and device-based therapies for cardiac
Sotalol arrhythmias. This is because of the fact that antiarrhythmic drug
Bretylium therapy is limited by the low efficacy as well as the potential for both
IV Blocks slow calcium channels cardiac and extracardiac adverse effects. Despite this, the role of an-
Verapamil tiarrhythmic drugs in comprehensive therapeutic strategy cannot be
Diltiazem undermined. The long history of antiarrhythmic drug development
V Miscellaneous reflects the persistent need for an ideal antiarrhythmic agent result-
Adenosine ing in an ongoing process for discovering additional approaches and
Digoxin targets for treating arrhythmias.
TABLE 17.2 New antiarrhythmic drugs currently in clinical trials

Drug Indication Mechanism of Action
Amio-aqueous As for IV amiodarone As for amiodarone
Azimilide Maintenance of sinus rhythm in AF Blockade of multiple K+ currents
DTI-0009 Rate control in AF Adenosine receptor blocker
Piboserod Maintenance of sinus rhythm in AF Blockade of atrial serotonin on 5HT4 receptors
RSD1235 Maintenance of sinus rhythm in AF Atrial selective action potential prolongation
Tecadenoson (CVT-510) Rate control in AF Adenosine receptor blocker
Tedisamil Maintenance of sinus rhythm in AF Blockade of multiple K+ currents
ACKNOWLEDGMENT
We are thankful to Dr Shivani Tandon MD (student) Pharmacology for helping us in literature search and in writing the article.
REFERENCES
1. Liberthson RR. Sudden death from cardiac causes in children and young adults. N Engl J Med. 1996;334:1039-44.
2. MJA Walker. Antiarrhythmic drug research. Br J Pharmacol. 2006;147:S222-31.
3. Ventricular fibrillation. [online] Available from http://www.reference.com browse/inexcitable. [Accessed July 2010].
4. Historical development of antiarrhythmic drug therapy. In: Liideritz B (Ed). History of disorders of cardiac rhythm, 3rd edition. New York: Wiley-
Blackwell; 2002. pp. 87-114.
5. Rosen MR. Concept of the vulnerable parameter: Sicilian Gambit classification revisited. J Cradiovasc Pharmacol. 2010;55:428-37.
6. Moe GK, Abildskov JA. Antiarrhythmic drugs. In: Goodman LS, Gilman A (Eds). Goodman and Gilman’s The Pharmacological Basis of Therapeu-
tics, 3rd edition. New York: Macmillan; 1966. pp. 699-715.
7. Nappi JM, Mason JW. Quinidine. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder publication; 1996. pp.
1362-7.
8. Bigger JT, Hoffman BF. Antiarrhythmic drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P (Eds). Goodman and Gilman’s The Pharmacological Basis
of Therapeutics, 8th edition. New York: Pergamon Press; 1991. pp. 840-73.
9. Richard NF. Phenytoin. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder publication; 1996. pp. 1338-41.
10. Wharton JM, Hill JN, Freedberg NA, et al. Disopyramide. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder
publication; 1996. pp. 1273-95.
11. Sparteine. [online] Available from http://en.wikipedia.org/ wiki/Sparteine. [Accessed June 2010].
12. Wink M. Production of Quinolizidine Alkaloids in in vitro cultures of legumes. In: Nagata T, Ebizuka Y (Eds). Biotechnology in Agriculture and
Forestery 51: Medicinal and aromatic plants. New York: Springer; 2002. pp. 118-23.
13. Keisecker C, Zitron E, Luck S, et al. Class Ia antiarrhythmic drug ajmaline blocks HERG potassium channels: mode of action. Naunyn Schmiede-
bergs Arch Pharmacol. 2004;370(6):423-35.
14. Antidysrhythmic drugs. In: Aronson JK (Ed). Meyler’s side effects of cardiovascular drugs. London: Elsevier; 2009. pp. 263-430.
15. Marganroth J, Abi-Samra F. Moricizine. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder publication; 1996.
pp. 1331-8.
16. Anderson JL. Bretylium tosylate. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder publication; 1996. pp.
1264-73.
17. Richard N Fogoros. Free Heart Disease Newsletter. The Strange History of Amiodarone. [online] Available from http://heartdisease.about.com/od
/drugsforheartdisease/a/amiodarone_hx.ht. [Accessed June 2010].
18. Kerr CR, Rosenbaum MB. Amiodarone. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder publication; 1996.
pp. 1247-64.
19. Cairns JA, Connolly SJ, Roberts R, et al. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular
premature depolarisations: CAMIAT. Lancet. 1997;349:675-82.
20. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left ventricular failure dysfunction
after recent myocardial infarction: EMIAT. Lancet. 1997;349:667-74.
21. Woosley RL, Wood AJJ, Roden DM. Encainide. N Engl J Med. 1988;318:1107-15.
22. Reiffel JA, Murray KT, Prystowsky EN. Propafenone. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadelphia: Saunder pub-
lication; 1996. pp. 1349-62.
23. Hormone analogues. In: Walter Sneader (Ed). Drug discovery: A history. USA: Wiley publications; 2005. pp. 188-225.
24. Singh BN. Sotalol. In: Messerli FH (Ed). Cardiovascular Drug Therapy. Philadelphia: Saunder publication, 2nd edition; 1996. pp. 1369-77.
25. Beta-Blocker heart attack trial research group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results.
JAMA. 1982;247:1707-14.
26. The Norwegian multicenter study group. Timolol induced reduction in mortality and reinfarction in patients surviving acute myocardial infarc-
tion. N Engl J Med. 1981;304:801-7.
27. Clifford J, Cam JJ. Intravenous adenosine as an antiarrhythmic agent. In: Messerli FH (Ed). Cardiovascular Drug Therapy, 2nd edition. Philadel-
phia: Saunder publication; 1996. pp. 1239-47.
28. Woosley RL. Antiarrhythmic drugs. Annu Rev Pharmacol Toxicol. 1991;31:427-55.
29. Rosen MR. Principles of electropharmacology. In: Saksena S, Dorian P (Eds). Electrophysiological disorders of the heart. USA: Elsevier; 2005. pp.
129-40.
30. Pugsley MK. The cardiovascular and antiarrhythmic actions of a series of kappa opioid agonists and related compounds. University of British
Columbia: PhD thesis; 1995.
31. Vaughan Williams EM. Classifying antiarrhythmic actions: by facts or speculation. J Clin Pharmacol. 1992;32(11):964-77.
32. Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol. 1984;24(4):129-47.
33. Principles of Pharmacotherapy and antiarrhythmic drugs. In: Sung RJ, Lauer MR (Eds). Fundamental approaches to the management of cardiac
arrhythmias. USA: Kluwer Academic Publishers; 2000. pp. 91-130.
34. Pratt CM, Moye LA. The Cardiac Arrhythmia Suppression Trial. Circulation. 1995;91:245-7.
35. Rosen MR. The evolution of antiarrhythmic targets. Circulation. 2002;106:1180-2.
36. Patel PD, Bhuriya R, Patel DD, et al. Dronaderone for atrial fibrillation: A new therapeutic agent. Vasc Health Risk Manag. 2009;5:635-42.
37. Mason PK, DiMarco JP. New pharmacological agents for arrhythmias. Circulation: Arrhythmia and Electrophysiology. 2009;2:588-97.
38. Amoeba innovation: The alternative to ventures. In: Kneller R (Ed). Bridging Islands: Venture companies and the future of Japanese and American
Industry. New York: Oxford University Press; 2007. pp. 192-231.
39. Camm AJ. Clinical differences between the newer antiarrhythmic agents. Europace. 2000;1(Suppl.C):C16-22.
40. Sager PT. New advances in class III antiarrhythmic drug therapy. Curr Opin Cardiol. 2000;15:41-53.
41. Dorian P. Antiarrhythmic drug therapy of atrial fibrillation: focus on new agents. J Cardiovasc Pharmacol Ther. 2003;8(Suppl.1):S27-31.
Enhanced External
18 Counterpulsation and
Its Clinical Applications
Chopra HK, Krishna CK, Sambi RS, Aggarwal KK, Parashar SK, Manjuran RJ, Gupta R,
Bansal M, Kasliwal RR, Mittal S, Srivastava S, Nanda NC
by the need to explore and demonstrate success in its clinical ap-

INTRODUCTION
plications. The concept of increasing the aortic diastolic pressure to
The treatment of ischemic heart disease (IHD) has moved on gradu- increase coronary perfusion pressure and blood flow was first intro-
ally from the use of simple vasodilator nitrates to complex multi- duced in USA by Kantrowitz in 1953. He showed in an animal study
ple medications and interventional procedures including coronary that, if coronary arteries were perfused at elevated pressure during
artery bypass graft (CABG) and percutaneous coronary intervention diastole the coronary blood flow can be increased by 20–40%.5
(PCI). Current treatments for IHD are able to decrease the incidence The state-of-the-art angina treatment has evolved from a prin-
of morbidity and mortality in many patients. In clinical practice phy- ciple described in 1953 by the Kantrowitz brothers at Harvard.
sicians routinely see patients who have recurrent symptoms in spite The phase-shift, diastolic augmentation principle, led to a better
of maximal medical therapy and who are not a candidate of conven- understanding of the myocardial oxygen consumption differences
tional revascularization procedures like PCI and CABG and still have between “flow work” and “pressure work”. This new understanding
objective evidence of myocardial ischemia. This group of refractory on improving blood flow to the ischemic myocardium by increasing
angina poses a challenge to cardiologist and they are frequent visi- coronary perfusion became the research objective. Many attempts
tors to outpatient clinics. In the United States, there are about 25,000– were made to develop effective means of providing mechanical car-
75,000 new cases of refractory angina patients are diagnosed annu- diac assistance for patients with low, cardiac output syndromes.5
ally. The overall new cases of symptomatic coronary artery disease Early research, done by Harken and associates at Harvard in
(CAD) diagnosed each year are 400,000.1 It’s reported that 10–15% of the late 1950s, used direct counterpulsation techniques. Through a
the patients with angina meet the criteria set for refractory angina.2 femoral cut-down procedure and external pulse actuation, this tech-
In India there are 40.9 million diabetic patients and more than 29.8 nique withdrew and then returned the blood to the arterial system.
million people are with CAD the incidence of refractory angina is In a number of studies this direct technique was used to document
increasing at a very high rate due to increase in life expectancy and increased coronary flow, decreased coronary AVO2 difference and
increase number of severe CAD patients now survive.3 reduced LV pressure.5
The current nonpharmacological treatment strategy available In the early 1960s laboratory studies with animals demonstrated
for refractory angina patients is enhanced external counterpulsation the potential efficacy of counterpulsation as a treatment following
(EECP), neurostimulation (NS), percutaneous transmyocardial laser coronary occlusion. This finding provided the first evidence that
revascularization (TMR), percutaneous in situ coronary venous arteri- counterpulsation could quickly enhance the development of coro-
alizations and gene therapy. Of these treatment modalities EECP ther- nary collateral circulation, suggesting the possible clinical applica-
apy is the only evidenced based therapy which is able to address both tion of counterpulsation to the treatment of patients with coronary
the myocardial supply and demand in the management of angina pec- insufficiency and angina. While promising, it was also evident that
toris. EECP is offered as an effective noninvasive mechanical treatment the requirement for femoral cut down and hemolysis caused by this
through which we can increase the myocardial blood flow (MBF) to the technique severely limited the clinical usefulness of this invasive ap-
ischemic region and simultaneously decreasing the myocardial oxygen proach.5
demand by reducing the left ventricular (LV) systolic work load.4 This concept of counterpulsation leads to development of inva-
sive intra-aortic balloon pump (IABP) counterpulsation and nonin-
HISTORICAL BACKGROUND vasive EECP. Also at Harvard, during this same time period, Birtwell
and Clauss, produced counterpulsation by introducing a catheter
AND DEVELOPMENT
with a long slender inflatable balloon catheter into the ascending
The evolution of counterpulsation techniques has been driven by the aorta via the femoral artery (IABP). Saline was pumped in and out
very need to improve the technical performance of equipment and of this balloon by means of the counterpulsing actuator. There have
Chapter 18  Enhanced External Counterpulsation and Its Clinical Applications 121
been continuing developments in the design of the IABP and its in- at the National Institutes of Health suggested that results could be
flation/deflation techniques, and, although surgical insertion is still improved if blood was expressed from the extremities in a sequen-
required, this approach has found clinical application in support tial manner. Development and testing of these “sequenced” systems
of circulation during and after coronary surgery and in cardiogenic determined that they achieved greater cardiac output and increased
shock. Intra-aortic balloon pump offers advantages over direct coun- the ratio of diastolic to systolic pressures than did nonsequenced sys-
terpulsation in that its effects are created close to the aorta and the tems.5
hemolysis associated with direct counterpulsation is avoided. Modi- During the 1970s, Zheng and colleagues at Sun Yat Sen University
fied and refined over the last 40 years, this device remains a primary in China, reported on their studies with a newly designed sequenced
therapy for assisting the heart function of patients in cardiogenic pulsation system that used four sets of compression bladders on the
shock.5 patient’s legs, buttocks and arms. They devised a system in which the
In the mid-1960s, several scientists were involved in the evolu- pneumatic cuffs inflated sequentially, not simultaneously as they
tion of counterpulsation to a noninvasive technique using externally had before. In these trials, effects of the sequenced system were stud-
applied pressure generated by hydraulic systems. These systems ied in patients with angina pectoris and AMI. In more than 90% of
used various devices to encase the patient’s lower limbs and com- the 200 patients with angina pectoris, this device provided long-term
press the vascular bed displacing arterial and venous blood centrally. symptomatic relief with minimal relapse.5 Several studies on MI and
Although these early external counterpulsation devices were some- cardiogenic shock were reported during the 1970s. In 1975 air driven
what primitive, studies with them demonstrated the potential of this pneumatic EECP system was developed. In 1992 the first clinical
approach to increase survival in patients with myocardium infarc- study was published with an enhanced version of external counter-
tion, cryogenic shock and in relief of angina pectoris.5 pulsation, hence EECP using three sets of cuffs wrapped around the
Initial equipment for noninvasive counterpulsation was hydrau- lower extremities with sequential inflation from the distal calf cuff to
lic driven with a single water filled bladder applied in the lower limb.6 the lower and finally the upper thigh cuffs. The hemodynamic effects
As the evolution of noninvasive external counterpulsation devices of EECP were confirmed to achieve similar hemodynamic benefits as
progressed, hydraulic systems were replaced with pneumatics, and the invasive IABP.7
redesign of compression elements sought to improve results and These same investigators also compared the hemodynamic
patient comfort. Clinical applications of this modality, beyond car- effects of sequenced and nonsequenced compressions and
diac or circulatory assistance in acute conditions, were also explored various configurations of compression devices in healthy volun-
with varying degrees of success. In a 1986 review of the progress of teers and patients with coronary heart disease. Results confirmed
external counterpulsation, Soroff and associates reported that mixed that sequenced systems were far more effective in raising diastolic
results of clinical trials with these systems were owing to technical pressures.5
difficulties with the equipment.5 Favorable results reported by Chinese investigators, led scien-
In the mid-60s, Soroff, Birtwell and others at Harvard developed tists in United States, to reassess the efficacy of this modality in the
a device for external counterpulsation. It was a hydraulic system that treatment of patients with chronic angina pectoris. These studies,
pumped water in and out of cuffs applied to the lower extremities. which included patients with subacute pectoris refractory to other
It was clear that Soroff and Birtwell’s device had advantages over medical intervention and with evidence of myocardial ischemia,
the IABP. It was noninvasive and also increased venous return as it were performed using a newly developed and “enhanced” counter-
boosted coronary perfusion pressure. Though cumbersome, this pulsation system. Designated EECP, the system employs a three-cuff
early hydraulic device increased survival rates of patients with acute compression configuration and sophisticated computerized control
myocardial infarction (AMI) and cardiogenic shock and relieved an- of the inflation/deflation sequence. It has been studied for its abil-
gina. However, in the United States, external counterpulsation was ity to provide both short-term and sustained relief of symptoms of
eclipsed by the emergence of coronary bypass surgery and angio- angina pectoris and to provide sustained improvements in perfusion
plasty.5 of ischemic areas of the myocardium.5
While physicians in the United States turned their attention to
these dramatic new developments in invasive treatments, physi- RESEARCHERS IN THE 1970s
cians in China adopted the concept of external counterpulsation and
AND LATE 1980s
refined the technology. Treatment was made easier to administer
and more comfortable for patients by using pneumatic cuffs instead The Chinese researchers in collaboration with researchers at the
of hydraulic cuffs.5 State University of New York at Stony Brook continued to refine
All of the external counterpulsation systems used in studies be- the technique of external counterpulsation. In 1989, researchers at
fore the 1970s employed “nonsequenced” pulsation, that is, com- Stony Brook began clinical studies of EECP treatment. These stud-
pression of the vessels was performed simultaneously along the full ies demonstrated that the treatment produces a number of positive
length of the compression element. During the late 1960s, scientists effects that are maintained for at least three years after a full course
of treatment. Multi-center clinical trials were later done to confirm (LVDD), left ventricular hypertrophy (LVH), left atrial volume index
the results. The trials also showed the extent of treatment benefit (LAVi) assessed by 3D echo; before and after external counterpulsa-
with greater accuracy, determined the patients who gained the most tion. Sixty adult patients over the age of 20 years attending medicine
from treatment and measured the effect of treatment on medication outdoor patient department (OPD) or admitted in medical wards—
requirements, exercise capability and quality of life.5 indoor patient department (IPD) were taken for this study. The study
Enhanced external counterpulsation treatment has evolved and population consisted of a total of 60 subjects with 37 males and 23
is being used with no reported complications as an outpatient treat- females.
ment of chronic angina patients. EECP treatment does not require Patients with HF [New York Heart Association (NYHA) Class II
the adoption of new medical practices; it is an improvement of exist- or III]17,18 despite conventional therapy, LV systolic dysfunction with
ing medical practices made possible by the advanced technology of a a LVEF of less than 35%. Patients were classified as having idiopathic
new delivery system.5 cardiomyopathy if they had no hemodynamically significant CAD or
other known causes of HF. Patients with HF and documented history
EECP and CVD Protection: 3D Echo Validation: of IHD and/or diagnostic coronary arteriography were assumed to
have ischemic cardiomyopathy. Patients with diastolic HF—HF with
A Promising Approach8
normal ejection fraction (HFNEF). Diagnosis of HFNEF was made
Cardiovascular disease (CVD) has become a major public health on the basis of all the three following criterias:19,20 (1) definitive evi-
problem in many developing countries. The prevalence of CAD in dence of clinical signs and symptoms of congestive HF, (2) normal
Indian adults was estimated to be 3–4% in rural areas and 8–20% in LVEF more than 50% within 72 hours of the event and (3) evidence
urban areas.9-13 World Health Organization (WHO) estimates that by of LVDD on echocardiography. Patients who underwent prior PCI or
the year 2015, CVD could be the most important cause of mortality CABG more than 3 months prior to enrollment. Patients with syn-
in India. Reducing the morbidity and mortality associated with CVD drome X who were diagnosed if there is angina or angina-like chest
is becoming as much a public health challenge as it is a research pain with exertion and ST segment depression on treadmill exercise
challenge. Conventional treatment options typically include life- testing with normal coronary angiography.21
style modification, prescription drugs and surgery. These treatment The following patients were excluded from this study:
modalities are often effective at relieving symptoms, but they have • Acute coronary syndrome less than 6 weeks prior to enrollment
several drawbacks; are frequently ineffective at extending life, are • Non-bypassed left main coronary with a luminal stenosis greater
associated with numerous side effects and complications, and are than 50%
expensive. Percutaneous coronary intervention and CABG carries a • Coronary artery bypass grafting less than 3 months, PCI less than
significant risk of death and often leads to other morbid events. In ad- 6 months prior to enrollment
dition, a significant number of successfully treated patients become • Cardiac catheterization has done less than 2 weeks prior to
“treatment failures” over time. Following CABG, it is estimated that enrollment
only 75% of patients remain free of cardiac ischemia for five years, a • Presence of an implantable cardioverter-defibrillator or pace-
figure that drops to 50% by 10 years.14 Most new medical advances maker
for CVD are being enhanced in the line of the existing therapies: • Arrhythmias that would significantly interfere with the triggering
prescription drugs and invasive surgical procedures. But a recent ad- of the EECP device
vancement in anti-aging therapeutics, i.e. external counterpulsation • Clinically significant valvular heart disease (aortic stenosis, mi-
is a new paradigm for treating heart disease.15 Enhanced external tral stenosis or aortic regurgitation). Acute myocarditis, history
counterpulsation is an established, noninvasive therapy for patients of sudden death, history of severe peripheral vascular disease,
with stable angina secondary to CAD16 congestive heart failure (HF) deep vein thrombosis, phlebitis, stasis ulcer and/or pulmonary
with normal or near-normal LV function. The hemodynamic effects embolism, aortic aneurysm
of EECP are similar to those of intra-aortic balloon counterpulsation, • Chronic obstructive pulmonary disease with a forced expiratory
with similar diastolic augmentation and afterload reduction. Evi- volume at 1 second (FEV1) less than 1.5 L. Coagulation abnor-
dence has shown that through improvement of vascular endothelial malities resulting in an international normalized ratio greater
function and recruitment of collateral vessels, EECP provides many than 2.5
clinical benefits. This study was designed to investigate the effect • Uncontrolled hypertension [systolic blood pressure (SBP) below
of external counterpulsation on CVD and HF protection through 180 mm Hg, diastolic blood pressure (DBP) above 110 mm Hg]
various echocardiographic variables. This prospective, pilot, obser- A detailed history and physical examination and medical history
vational study was conducted to evaluate the efficacy of EECP on was conducted to rule out any exclusion criteria and the measured
CVD protection by influence on various echo variables, such as left data of each patient was recorded on a prepared performa sheet.
ventricular myocardial performance index (LVMPI), left ventricu- Informed consent was taken from all subjects participating in this
lar ejection fraction (LVEF), left ventricular diastolic dysfunction study. After providing written informed consent, eligible patients
were subjected to echocardiographic evaluation. The various echo automatically integrated 2D echocardiographic images and their
variables included were LVMPI, left ventricular mass index (LVMi), positions in real time and calculated LVM directly from traced endo-
LVDD, LVEF and LAVi. Once randomized, patients underwent 35 cardial contours without geometric assumptions. The components
hours of EECP treatment sessions, each lasting 1 hour, could be giv- of LV mass including LV internal dimension (LVID), interventricu-
en once or twice per day. External counterpulsation equipment was larseptal thickness (IVST), and posterior wall thickness (PWT) were
supplied by the manufacturer, Scottcare (Nicore Model) from USA. all also measured at end-diastole LVMi was calculated by dividing
The equipment consisted of an air compressor, a console, a treatment LVM by BSA. BSA was calculated using the formula of Dubois and
table and two sets of three cuffs. Before the treatment session, three Dubois, (BSA = 0.007184 × W0.425 × H0.725, Where W is weight in Kg
pneumatic cuffs were wrapped around the patient’s calves, lower and H is height in cm). LVH was defined in absolute terms as LVMI
thighs, and upper thighs and cuffs were inflated and deflated in a more than 131 g/m2 in men and more than 100 g/m2 in women.26
sequence synchronized with the events in the cardiac cycle through RWT was assessed to characterize LVH into concentric remodeling,
computer-interpreted ECG signals. During diastole, the cuffs inflate concentric and eccentric hypertrophy,26,27 RWT of the LV was ex-
sequentially from the calves proximally, resulting in augmented di- pressed as the ratio of twice the posterior wall thickness to the end-
astolic central aortic pressure and increased coronary perfusion diastolic cavity dimension,28 i.e. [(2 × PWd ) / LVIDd]. Concentric
pressure. Compression of the vascular bed of the legs also increases remodeling was defined as RWT greater than 0.45 in the absence of
venous return and cardiac output. Rapid and simultaneous decom- LVH; concentric hypertrophy as defined as RWT greater than 0.45 in
pression of the cuffs at the onset of systole permits systolic unloading the presence of LVH; eccentric hypertrophy as defined as RWT less
and decreased cardiac workload. At the start of treatment, external than 0.45 in the presence of LVH. Left ventricular ejection fraction
compression was progressively increased, as needed, to raise dias- was taken as the measure of Left Ventricular Systolic function. LVEF
tolic pressures gradually. In our study the protocol-specified applied was calculated from the 3D data sets by use of Simpson’s method.29
pressure was 300 mm Hg and was reached within 5 minutes of the A 3D system was developed that automatically integrated 2D echo-
initiation of treatment. Finger plethysmography was used to monitor cardiographic images and their positions in real time and calculated
correct timings. At each treatment session, vital signs were recorded, LVEF directly from traced endocardial contours without geometric
pulse oximetry was monitored continuously during the treatment assumptions. The mean LVEF in normal population is taken as 59.2 ±
session and the subject’s clinical status was reevaluated if the oxygen 6%.30 Systolic dysfunction was defined as EF less than 50%. Diastolic
saturation dropped by greater than 5%. Patients were advised to uri- function is determined by pulsed-wave Doppler (PWD) examina-
nate immediately prior to treatment. Lower extremities were exam- tion of mitral (before and with Valsalva maneuver) and pulmonary
ined for areas of redness or ecchymosis, adverse experiences were venous inflow, as well as Doppler tissue imaging of the mitral annu-
reported. An adverse reaction was defined as the development of lus. Pulsed-wave Doppler derived transmitral inflow velocities were
any new symptom or complaint from the time of randomization. All obtained in the apical four-chamber view with the sample volume
medications (except on demand NTG) remained unchanged for the placed at the mitral valve leaflet tips.31 Measurements included the
duration of the study. Each patient was instructed to record each an- transmitral early diastolic (E-wave) and atrial (A-wave) velocities to
gina attack, its time of occurrence, duration, severity, its relationship calculate E/A ratio, mitral ‘E’ wave deceleration time (MEDT), the
to precipitating factors and the number of nitroglycerin tablets used isovolumic relaxation time (IVRT) and duration of the mitral flow
to ease the attack. Within one week after completion of 35 treatment with atrial contraction (A-dur).31 In pulmonary veins (PV) Doppler
sessions, echocardiogram was repeated. All patients underwent 3D recordings32 three distinct velocity components were measured: a
echocardiogram performed on Philips iE33, in left lateral decubitus systolic velocity (PVs), a diastolic velocity (PVd) and atrial flow re-
position using 5–10 MHz transducer, by a consultant cardiologist ex- versal (PVa) along with the duration of pulmonary vein atrial flow
perienced in echocardiography. reversal (a-dur). Tissue Doppler imaging (TDI) was used to obtain
Left ventricular myocardial performance index was calculated LV myocardial velocities with a sample volume placed at the mitral
as summation of isovolumetric contraction time (IVCT) and iso- annulus,33 i.e. to assess early diastolic peak velocity within the septal
volumetric relaxation time (IVRT) divided by ejection time (ET). The mitral annulus (E’) to calculate E/E’ ratio. The grading for diastolic
IVCT, IVRT and ET were calculated at the mitral annulus. LVMPI = dysfunction was performed using the Galderisi Cardiovascular Ultra-
(ICT+IRT)/ET, was obtained by subtracting ET from the interval sound 2005 recommendations.34 The mitral inflow early filling veloc-
between cessation and onset of the mitral inflow velocity to give the ity (E) to atrial filling velocity (A) ratio was used for initial categoriza-
sum of ICT and IRT. The normal value for LVMPI in the adult population. If the E/A was less than 1, Grade I DD (impaired relaxation) was
tion is between 0.34 and 0.40, with some age dependency.22-24 Left present. If the E/A ratio was in the normal range (1–2) and the decel-
ventricular hypertrophy was calculated by determining left ventricu- eration time was greater than 150 ms, then the other Doppler indexes
lar mass (LVM), body surface area (BSA), left ventricular mass index were used to determine if filling was normal (normal diastolic func-
(LVMi) and relative wall thickness (RWT). LVM was estimated by 3D tion) or “pseudonormal” (Grade II DD). If there were two other Dop-
data sets using Simpson’s method.25 A 3D system was developed that pler indexes suggestive of elevated filling pressures (change in E/A
with Valsalva of greater than 0.50; pulmonary venous systolic (S) ve- syndrome X. Pre EECP the mean LVMPI was found to be abnormally
locity less than diastolic (D) velocity; pulmonary venousatrial rever- prolonged in all the group of patients with HF (0.64 ± 0.1), patients
sal duration greater than mitral A duration greater than 35 ms or ratio with HFNEF (0.58 ± 0.12), post PTCA patients (0.52 ± 0.11) and post
of E to the velocity of early mitral annular ascent[(E’) of >10)], then CABG patients (0.56 ± 0.14); except in the group of patients with syn-
Grade II DD was considered to be present. If the E/A ratio was greater drome X the mean LVMPI was within normal range (0.39 ± 0.11). Post
than 2 and the deceleration time was less than 150 ms, and at least ECP treatment the mean LVMPI was reduced to 0.46 ± 0.15, 0.45 ±
one other Doppler index suggestive of elevated filling pressures was 0.24, 0.42 ± 0.23, 0.44 ± 0.21 in patients with HF, HFNEF, patients who
present, the subject was considered to have restrictive pattern Grade had prior PTCA, post PTCA patients and post CABG patients respec-
III DD (if the change in E/A with Valsalva was > 0.50) or grade IV DD tively. There was a significant difference in the overall mean LVMPI
(if the change in E/A with Valsalva was < 0.50). These groups (Grades from baseline (0.54 ± 0.2) to post-treatment (0.43 ± 0.1) in the total
III and IV) were combined for the purposes of analysis end-systolic study population (p < 0.001) (Figs 18.1 to 18.5).
left atrial volumes were measured using realtime 3D echocardiogra- Of the total study population; six patients with syndrome X had
phy images (RT3DE). Reference ranges for ratio of LAV to BSA with no LVDD; 8 (40%) patients of HFNEF, 11 (64.7%) patients with syn-
LAVi greater than 95th percentile was used to define LA enlargement drome X, 4 (25%) patients with HF, 2 (50%) patients with CAD with
(> 30 ml/m2 for women and > 33 ml/m2 for men).35 The data were prior PTCA, were found to have Grade I LVDD with mean E/E’ ratio
analyzed using software computer statistical package ‘SPSS 10’. For
each variable, the average values and standard deviation were esti-
mated. Using multivariate analysis of ‘SPSS 10’, correlations between
each variable was defined. Methods for statistical analysis mean and
standard deviation (SD) of the numerical variables with unpaired
student t-test and chi-square test were used for group comparisons.
The Pearson correlation was used for correlation analysis. A prob-
ability value of less than 0.05 was considered as significant. The de-
mographics and characteristics of the study population are given in
Table 18.1. Of the total 60 patients, 20(33%) patients had HFNEF, 16
(26.7%) had HF, 4 (6.7%) had CAD with prior PTCA, 3(5%) patients
had CAD with prior CABG and 17 (28.3%) patients were diagnosed as
TABLE 18.1 Baseline patients characteristics

Variables
Figure 18.1: Pre ECP and post ECP mean LVMPI
No. of patients 60
in the subset of patients
Age (yrs) 61.8 ± 13.8
Male gender 37 (61.7%)
Female gender 23 (38.3%)
Hypertension 37 (66.7%)
Diabetes mellitus 29 (48.3%)
CAD 14 (23.3%)
Metabolic syndrome 54 (91.3%)
HFNEF 20 (33.3%)
HF 16 (26.7%)
– Ischemic cardiomyopathy 9 (15%)
– Idiopathic cardiomyopathy 7 (11.7%)
CAD with prior PTCA 4 (6.7%)
CAD with prior CABG 3 (5.0%)
Syndrome X 17 (28.3%)
Abbreviations: CABG, Coronary artery bypass graft; CAD, Coronary artery Figure 18.2: Pre ECP and post ECP mean LVEF (%) in the subset of
disease; HF, Heart failure; HFNEF, HF with normal ejection fraction. patients with heart failure
Figure 18.3: Pre ECP and post ECP mean E/E’ in the subset of patients with HF, HFNEF, post PCI, post CABG and syndrome X
found that; as all their patients with E/E’ ratio greater than 12 were
significantly benefitted by ECP treatment (p < 0.05), but not the pa-
tients with E/E’ less than 12. In summary, ECP treatment significantly
reduced baseline Grade II or Grade III diastolic dysfunction and E/E’
ratio greater than 12, but not in patients with baseline E/E’ < 12, base-
line normal diastolic function or Grade I diastolic dysfunction. The
mean LVEF in the subset of patients with HF treatment was 30.7 ± 3.1;
post ECP the mean LVEF was increased to 36.9 ± 3.2 which was sta-
tistically significant (p < 0.001). In the remaining patients, who had
mean LVEF within normal range, there was no significant difference
pre and post ECP (p value-NS). Before EECP treatment the mean
Figure 18.4: Pre ECP and Post ECP mean LAVi in the total population LVMI adjusted for BSA in all the subsets of patients was 101.9 ± 10.3.
with HF, HFNEF, Post PCI, Post CABG and Syndrome X After ECP treatment the LVMI was 95.7 ± 9.5. There was no significant
difference observed in the baseline and post-treatment levels. Out of
total study group, 18 (30%) had no LVH, 23 (38.3%) had concentric
remodeling, 13 (21.7%) had concentric LVH, 6 (10%) had eccentric
of 11.2 ± 0.8. Post EECP treatment; there was statistically no signifi- LVH. There was no much significant difference after treatment with
cant change in grades of LVDD and E/E’ ratio. But of the nine patients EECP in the patterns of LVH. Pre EECP the mean LAVi in the total
with HF, three patients with CAD with prior CABG, 2(50%) patients population was increased to 33.4 ± 5.6 ml/m2. Post EECP the mean
with CAD with prior PTCA and one patient with syndrome X, who LAVi reduced to 24.8 ± 4.2 ml/m2, which was statistically significant
had Grade II LVDD with mean E/E’ ratio of 15.5 ± 0.9; and of the three (p < 0.001). Of the total 24 patients, i.e. 17 patients with syndrome
patients with HF, two patients with HFNEF, who had Grade III LVDD X, four patients with CAD with prior PTCA, three patients with CAD
with mean E/E’ ratio of 19.5 ± 0.5; there was significant reduction in with prior CABG, angina counts (angina episodes per week) were
baseline Grade II and Grade III LVDD and E/E’ ratio to 9.4 ± 0.8 in 6.9 ± 2.1 at baseline and 2.5 ± 0.4 post-treatment. The difference in
patients with Grade II LVDD and 11.05 ± 0.5 in patients with Grade change in angina counts from baseline to post-treatment showed a
III LVDD, which was statistically significant (p < 0.05). Authors also trend to statistical significance (p < 0.001). NTG usage at baseline
Figure 18.5: Pre ECP and post ECP mean LVMi in the subset of patients with HF, HFNEF, post PCI, post CABG and Syndrome X
was 6.1 ± 2.1 and 3.5 ± 2.2 post-treatment which was statistically not pathy have lower perfusion pressure resulting in decreased coronary
significant. But in patients with HF; NHYA class was 2.6 ± 0.1 at base- flow and insufficient oxygen supply at the cellular level secondary
line which was significantly reduced to 1.7 ± 0.1 post EECP treatment, to ventricular hypertrophy; so by increasing perfusion pressure and
with a trend to statistical significance (p < 0.001) The present study decreasing cardiac work, EECP might improve oxygen supply and
showed that the application of 35 session of 1 hour daily of EECP over promote the recovery of nonfunctional areas of the myocardium.
approximately 7 weeks was safe and well-tolerated in patients with Other possible mechanisms of benefit from EECP in HF include
stable HF, patients with syndrome X, patients with prior CABG and the effects of EECP on endothelial function, an increase in nitric
prior PTCA. In authors’ study they found that the Doppler-derived oxide,37,38 with subsequent coronary and systemic vasodilation.
myocardial performance index (LVMPI); a nongeometric and nonin- Alternatively, EECP treatment has been shown also to decrease levels
vasive assessment of global cardiac function including components of endothelin-1, a potent endothelium-derived vasoconstrictor that
from both systole and diastole;23 which was prolonged at baseline; is felt to contribute to the pathogenesis of HF.38,39 In patients with
was significantly reduced after 35 cycles of ECP treatment especially HFNEF, the authors found EECP reduced baseline Grade II or III
in the subset of patients with HF and HFNEF (p < 0.001), which in diastolic dysfunction, baseline E/E’ ratio of greater 12 with raised LV
turn shows that EECP treatment improves the global cardiac func- filling pressures, but not in patients with baseline E/E’ less than 12,
tion. Similarly in the group of patients with HF with systolic dys- baseline normal diastolic function or Grade I diastolic dysfunction
function; there was significant improvement in the ejection fraction (impaired relaxation). Authors’ results were consistent with a study
(p < 0.001) post-treatment with EECP as compared to baseline LVEF by Estahbanaty et al.40 who also demonstrated similar results. These
less than 50%. There was no benefit seen in the patients who had results show that EECP improves diastolic function in selected patients
LVEF greater than 50%. It appears that the study subjects benefited and provides new insight into potential clinical applications of EECP
from EECP, regardless of the ischemic or nonischemic etiology of especially in patients with HFNEF with Grade II or III diastolic dysfunc-
their HF. While a decrease in the ischemic burden in patients with tion and baseline E/E’ ratio of greater than 12. Left atrial (LA) size is an
ischemic HF and development and recruitment of the new collat- independent marker of adverse clinical outcomes in conditions,
eral vessels with enhancement of coronary artery dilatation;36 may such as atrial fibrillation, MI and HF.41-46 Many studies have shown
explain the beneficial effects in patients with CAD, but the mecha- that measurement of LA volume indexed to BSA is a more sensitive
nism of the beneficial effects of EECP in patients with idiopathic indicator of LA size.1 Authors’ study has shown that there was a 25.7%
cardiomyopathy are still unknown. Patients with dilated cardiomyo- reduction in LAVi levels from baseline after EECP treatment, which
was highly encouraging. So EECP treatment significantly reduces As a result of these diastolic augmentation activities, the patient’s
atrial remodeling measured by echo as left atrial volume index, peak diastolic pressure is significantly increased, benefiting circula-
which in turn reduces the adverse clinical events in HF and MI. Re- tion in the heart muscle and in other organs as well. At the same time,
ductions in LVMi are considered to be a surrogate marker of improve- the patient’s systolic pressure is reduced, to the general benefit of the
ment in the cardiovascular health of hypertensive and HF patients.47 vascular system.
However; in authors’ study they found that there were no significant
changes seen in mean LVMi (pre EECPP and post EECP), as well as in ENHANCED EXTERNAL
the patterns of LVH compared to baseline. May be it requires a long-
COUNTERPULSATION
term follow-up to determine the changes in LVH by EECP. EECP has
also shown a significant beneficial impact on the functional status of
Technique
patients with syndrome X, who had prior CABG or prior PCI, patients
with HF as measured by significant decrease in angina episodes Inflation Sequentially, Deflation Simultaneously
(p < 0.001) and NHYA class (p < 0.001). These beneficial effects of (Figs 18.6A and B)
EECP may be explained by increasing coronary collateral vessel
development and coronary endothelial function, decreasing oxi- Clinical studies suggest that the increase in myocardial perfusion
dative stress, promoting favorable remodeling and concomitant pressure stimulates the use of collateral vessels that are already
improvement in central or peripheral arterial function.48 The present
study has certain limitations. This study was an open-label study and
did not have a parallel control or placebo group and this was a short
term study that only examined immediate effects of EECP; long-term
effects were not determined. There was no interobserver and intrao-
bserver variability in their study. Since this study is a hospital based
study, most of the patients were already on medications.
WHAT IS THE PRINCIPLE OF MECHANISM?

This action also provides therapeutic advantages by reducing the
heart’s after-load. Since the vascular beds in the lower extremi-
ties are essentially empty, the resistance to blood flow is markedly
reduced, thereby decreasing the amount of work that the heart must
do to pump blood to these areas (reducing oxygen demand within
the myocardium). Figure 18.6A
Figure 18.6B
Figures 18.6A and B: Technique of enhanced external counterpulsation
present, but unused, thereby allowing oxygenated blood to bypass improves microcirculation in the whole body, reduces hardening the
ischemic (starved) areas in the heart. Other cardiologists believe that blood vessels, and is an integral part of heart and vascular wellness
the myocardium may actually develop new vasculature. program.
WHAT ARE THE EFFECTS OF EECP? WHAT ARE THE INDICATIONS?

It enhances intercoronary and intracoronary collaterals (natu- Patient with angina, after heart attack, after angioplasty, after bypass,
ral blood channels), it enhances blood flow in the heart and brain enlarged heart, HF, micro vascular diseases (syndrome X), erectile
arteries, it improves heart output, it prevents and improves the HF, dysfunction, evolving stroke/brain attack, diffuse cortical atrophy
improve the pumping action of the heart, it improve ejection frac- (diminished circulation in the small vessels of brain), alzheimer’s
tion, reduces LV filling pressures, improves microcirculation of the diseases, parkinsonism, peripheral vascular diseases, abdominal
heart/brain/kidney/retina, improves effort tolerance, reduces an- angina, restless leg syndrome (cramps), etc.
gina, reduces chamber size in enlarged heart, reduces oxidative
stress, increases nitric oxide levels, increases vascular growth factor, WHAT ARE THE CONTRAINDICATIONS?
hepatocyte growth factor, fibroblast growth factor, reduces HSCRP,
BNP, improves circulation in the brain, kidney, eye, abdomen, sexual DVT, uncontrolled HT, arrhythmia, aortic aneurysm, pregnancy,
organs and extremities, improves perfusion in the heart and brain, aortic diseases, AR, PVD.
REFERENCES
1. American Heart Association. Heart disease and stroke statistics. Dallas, TX: American Heart association; 2005.
2. Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina: report from the ECS Joint Study Group on the Treatment of
Refractory Angina. Eur Heart J. 2002;23:355-70.
3. Gupta R. Burden of coronary heart disease in India. Indian Heart J. 2005;57:632-8.
4. Prasad GN, Ramasamy S, Joy M Thomas, et al. Enhanced external counterpulsation (EECP) therapy: current evidence for clinical practice and who
will benefit? Indian Heart J. 2010;62:296-302.
5. http://www.medlinkseecp.com/history.php/2009
6. Lawson WE, Hui JC, Soroff HS, et al. Efficacy of enhanced external counterpulsation in the treatment of angina pectoris. Am J Cardiol. 1992;70:859-
62.
7. Food and Drug Administration (FDA). Medical Devices. [online] Available from www.fda.gov/heart/treatment/medicaldevices/medicaldevices.
html. [Accessed July 2012]
8. Chopra HK, Krishna CK, Ravinder S, et al. Enhanced external counterpulsation and CVD protection: 3D echo validation : A Promising Approach,
Indian Heart J. 2011;63:438-45.
9. Reddy KS, Shah B, Varghese C, et al. A Responding to threat of chronic diseases in India. Lancet. 2005;366:1746-51.
10. Goyal A, Yusuf S. Burden of CVD in Indian subcontinent. Indian J Med Res. 2006;124:235-44.
11. Gupta R. Burden of coronary heart disease in India. Indian Heart J. 2005;57:632-8.
12. Ghaffar A, Reddy KS, Singhi M, et al. Burden of non-communicable diseases in south Asia. BMJ. 2004;328:807-10.
13. Gupta R. Coronary Heart Disease in India: Absolute numbers and economic burden. Rapid response to Ghaffar A, Reddy KS, Singhi M Burden of
non-communicable diseases in South Asia. BMJ. 2004;328:807-10.
14. Foster ED. Reoperation for coronary artery disease. Circulation. 1985;72(Suppl V):V59-V64.
15. Amsterdam EA. Enhanced external counterpulsation: Chronicle of a new approach to the therapy of angina pectoris. CR and R.18:15-19.
16. Soran O, Crawford LE, Schneider VM, et al. Enhanced external counterpulsation in the management of patients with cardiovascular disease. Clin
Cardiol. 1999;22:173-8.
17. Soran O, Fleishman B, Demarco T, et al. Enhanced External Counterpulsation in Patients with Heart Failure: A Multicenter Feasibility Study. Con-
gest Heart Fail. 2002;8(4):204-8, 227.
18. Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th edi-
tion. Boston: Little, Brown; 1994.
19. Paulus WJ, European Study Group. How to diagnose diastolic heart failure. Eur Heart J. 1998;19:990-1003.
20. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation. 2000;101:2118 -21.
21. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic reso-
nance imaging. N Engl J Med. 2002;346(25):1948-53.
22. Eidem BW, Tei C, O’Leary PW, et al. Nongeometric quantitative assessment of right and left ventricular function: myocardial performance index
in normal children and patients with Ebstein anomaly. J Am Soc Echocardiogr. 1998;11:849-56.
23. Harjai KJ, Scott L, Vivekananthan K, et al. The Tei index: a new prognostic index for patients with symptomatic heart failure. J Am Soc Echocardi-
ogr. 2002;15:864-8.
24. Bruch C, Schmermund A, Dagres N, et al. Severe aortic valve stenosis with preserved and reduced systolic left ventricular function: diagnostic
usefulness of the Tei index. J Am Soc Echocardiogr. 2002;15:869-76.
25. Agabiti-Rosei E, Muiesan ML, Salvetti M. Review: New approaches to the assessment of left ventricular hypertrophy. The Adv in Cardiovasc Dis.
2007;1(2):119-28.
26. Savage DD, Garrison RJ, Kannel WB. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham study. Circula-
tion. 1987;75(suppl I):I26- 33.
27. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for interven-
tion. Am J Kidney Dis. 1996;27:347-54.
28. Ganau A, Devereux RB, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll
Cardiol. 1992;19:1550-8.
29. Siu SC, Rivera JM, Guerrero JL, et al. Three-dimensional echocardiography. In vivo validation for left ventricular volume and function. Circulation.
1993;88:1715-23.
30. Erbel R, Schweizer P, Herrn G, et al. Apical two dimensional echocardiography:normal value for single and biplane determination of left ventricu-
lar volume and ejection fraction. Dtsch Med Wochenshr. 1982;107:1872.
31. Quinones MA, Otto CM, Stoddard M, et al. Recommendations for quantification of Doppler echocardiography: A report from the Doppler
quantification task force of the nomenclature and standards committee of the American Society of Echocardiography. J Am Soc Echocardiogr.
2002;15:167-84.
32. Rossvoll O, Hatle LK. Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pres-
sures. J. Am Coll Cardiol. 1993;21:1687-96.
33. Dumesnil JG, Paulin C, Pibarot P, et al. Mitral annulus velocities by Doppler tissue imaging: Practical implications with regard to preload altera-
tions, sample position, and normal values. J Am Soc Echocardiogr. 2002;15:1226-31.
34. Galderisi M. Diastolic dysfunction and diastolic heart failure: diagnostic, prognostic and therapeutic aspects. Cardiovasc Ultrasound. 2005;3:9.
35. Pritchett AM, Jacobsen SJ, Mahoney DW, et al. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol.
2003;41:1036-43.
36. Masuda1 D, Nohara1 R, Hirai T, et al. Enhanced external counterpulsation improved myocardial perfusion and coronary flow reserve in patients
with chronic stable angina. Eur Heart J. 2001;22;1451-8.
37. Qian XX, Wu WK, Zheng ZS, et al. Effect of EECP on nitric oxide production in coronary disease. J Heart Dis. 1999;1(1):193. Abstract 769.
38. Wu GF, Zheng QS, Zheng ZS, et al. A neurohormonal mechanism for the effectiveness of EECP. Circulation. 1999;100(18):I-832. Abstract 4390.
39. Garlichs CD, Zhang H, Werner D, et al. Reduction of serum endothelin-1 levels by pneumatic external counterpulsation. Can J Cardiol.
1998;14(suppl F):87F. Abstract 25.
40. Estahbanaty G, Samiei N, Maleki M, et al. Echocardiographic characteristics including tissue Doppler imaging after enhanced external counter-
pulsation therapy. Am Heart Hosp J. 2007;5(4):241-6.
41. Pritchett AM, Jacobsen SJ, Mahoney DW, et al. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol.
2003;41:1036-43.
42. Moller JE, Hillis GS, Oh JK, et al. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation. 2003;107:2207-
12.
43. Tsang TS, Barnes ME, Gersh BJ, et al. Prediction of risk for first age-related cardiovascular events in an elderly population: the incremental value
of echocardiography. J Am Coll Cardiol. 2003;42:1199-205.
44. Osranek M, Fatema K, Qaddoura F, et al. Left atrial volume predicts the risk of atrial fibrillation after cardiac surgery: a prospective study. J Am Coll
Cardiol. 2006;48:779-86.
45. Modena MG, Muia N, Sgura FA, et al. Left atrial size is the major predictor of cardiac death and overall clinical outcome in patients with dilated
cardiomyopathy: a longterm follow-up study. Clin Cardiol. 1997;20:553-60.
46. Tsang TS, Barnes ME, Gersh BJ, et al. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to
cardiovascular risk burden. Am J Cardiol. 2002;90:1284-9.
47. Maisel AS. Cardiovascular and renal surrogate markers in the clinical management of hypertension. Cardiovasc Drugs Ther. 2009;23(4):317-26.
48. Wilmer W Nichols, Juan C, et al. Enhanced external counterpulsation treatment improves arterial wall properties and wave reflection characteris-
tics in patients with refractory angina. JACC. 2006;6:1208-14.
Lycopene and Related Tomato
19 Carotenoids in Coronary
Heart Disease
Henkin Y
mato products appears to be more bioavailable than that from raw

INTRODUCTION
tomatoes. The release of lycopene from the food matrix due to pro-
Carotenoids are natural pigments synthesized by plants and micro- cessing, the presence of dietary fat and heat-induced isomerization
organisms. They consist of over 600 fat-soluble pigments, many of from an all-trans to a cis conformation enhance its bioavailability. In
which have been isolated in foods and are responsible for the natu- synthetic nutritional supplements, lycopene is usually dispersed in
ral yellow, orange and red colors of fruits and vegetables. Although vegetable oil with the help of surface active compounds.
some dietary carotenoids serve as sources of vitamin A, the majority Mean serum concentrations of lycopene in different popula-
are devoid of provitamin A activity.1 tions range from 0.22 nmol/ml to 1.06 nmol/ml, although interindi-
Lycopene is a lipophilic highly unsaturated natural acyclic iso- vidual variation is typically very large. Its level is affected by several
mer of b-carotene containing 11 conjugated and 2 unconjugated biological and lifestyle factors, such as aging and body mass, but not
double bonds (Fig. 19.1).2,3 It is synthesized by plants and micro- gender. The European Community Multicenter Study on Antioxi-
organisms but not by animals, and is found in relatively few foods dants, Myocardial Infarction and Breast Cancer (EURAMIC) study
(Table 19.1). The majority of lycopene consumed in the western found significant geographical variations in tissue lycopene levels,
world is derived from tomato products, although apricots, guava, with Moscow and Edinburgh having the highest median concentra-
watermelon, papaya, pink grapefruit and some seafood also contrib- tions of lycopene at 0.36 mg/g of fatty acid, and Helsinki and Malaga
ute to dietary intake. More than 80% of the US dietary intake of lyco- having the lowest mean concentrations (0.21–0.23 mg/g).
pene is estimated to come from tomato sources, including ketchup,
tomato juice, spaghetti sauce and pizza sauce.2
The lycopene content of tomatoes can vary significantly with rip- TABLE 19.1 Lycopene content of various foods
ening and the environmental conditions in which the fruit matures, Lycopene Content (mg/100 g wet basis)
ranging from 50 mg/kg to 150 mg/kg. While its blood concentrations Fresh tomato 5.0–15.0
roughly equal to those of b-carotene, certain organs (such as adi- Tomato juice/sauce 5.0–15.0
pose tissue) selectively concentrate lycopene so that its tissue levels
Spaghetti sauce 9.3–18.2
greatly exceed those of b-carotene. Owing to its lipophylicity, the
Ketchup 9.9–17.0
majority of lycopene in the blood is attached to low-density lipopro-
tein (LDL) and high-density lipoprotein (HDL). Watermelon 2.3–7.2
Papaya 0.1–5.3
BIOAVAILABILITY AND ABSORPTION Pink guava
OF LYCOPENE Carrot 0.7–0.8

Pumpkin 0.4–0.5
In tomatoes which are the main source of lycopene in our diet, it
Apricot 0.01–0.05
is locked in chromoplasts which greatly reduce its bioavailability.
Thus, lycopene levels in serum or tissues do not correlate well with Pink grapefruit 0.4–3.4
overall intake of fruits and vegetables. Lycopene from processed to- Sweet potato 0.02–0.1
Source: Adapted from Omoni AO, Aluko RE. The anticarcinogenic and
anti-atherogenic effects of lycopene: a review. Trends Food Sci Tech.
2005;16:344-50. Shi J, Xue SJ. Stability of lycopene during food processing
and storage. In: Preedy VE, Watson RR (Eds). Lycopene—nutritional,
medicinal and therapeutic properties. Enfield, New Hampshire: Science
Figure 19.1: Molecular structure of all-trans lycopene publishers; 2008.
Chapter 19  Lycopene and Related Tomato Carotenoids in Coronary Heart Disease 131
ROLE OF OXIDATION IN THE PATHOGENESIS ANTIOXIDANT PROPERTIES OF LYCOPENE

OF CORONARY HEART DISEASE
Antioxidants are protective agents that inactivate ROS and inhibit
Coronary artery disease is a chronic process that begins during ado- LDL oxidation. In addition to several endogenous antioxidants, a
lescence and slowly progresses throughout life.4 In a healthy coro- number of antioxidants, such as vitamin E, vitamin C, polyphenols
nary artery, the endothelial cells lining the inner surface of the artery and carotenoids are available from foods. Epidemiological studies
produce a host of chemicals that prevent penetration of lipoproteins suggest that diets rich in fruits and vegetables are associated with
and inhibit thrombin activation and platelet adhesion. According to a reduced risk of cardiovascular disease (CVD).5 However, rand-
the response-to-vascular injury theory, injury to the endothelium by omized controlled studies using antioxidants, such as vitamin C,
local disturbances of blood flow at angulated or branch points, along vitamin E and b-carotene have mostly yielded disappointing and
with a group of systemic risk factors, such as elevated blood pressure, even deleterious results.6,7 Although these results cast some doubt
hyperglycemia, hypercholesterolemia and cigarette smoking damage about the benefits of antioxidants in the prevention of coronary heart
these endothelial cells and cause “endothelial dysfunction” resulting disease (CHD), it is generally believed that the reasons for these
in increased lipoprotein permeability and white blood cell adhesion. disappointing results may be related to the low antioxidant potency
Diffusion of lipoproteins and inflammatory into the endothelial and of the agents used in the studies.
subendothelial spaces, accompanied by secretion of cytokines and Although it lacks provitamin A activity, the many conjugated
growth factors, promotes the formation of the atherosclerotic plaque. double bonds of lycopene make it a potentially powerful antioxidant.
The most atherogenic lipoprotein is the LDL that can penetrate The antioxidant activity of lycopene is highlighted by its singlet oxy-
dysfunctional endothelial cells and accumulate in the subendothe- gen-quenching property and its ability to trap peroxyl radicals, mak-
lial space. Unmodified LDL particles appear to be relatively inert ing it is the strongest antioxidant of all carotenoids.
and produce little reaction in the blood vessel. However, LDL par- A number of in vitro studies have shown that lycopene can pro-
ticles can be modified in the subendothelial space by reactive oxy- tect native LDL from oxidation.8-11 Conversely, when healthy hu-
gen species (ROS), representing highly reactive oxidant molecules man subjects consumed a lycopene free diet for a period of 2 weeks,
generated endogenously through regular metabolic reactions. They their serum lycopene levels decreased by 50% by the end of week
react with cellular components causing oxidative damage to lipids, 2, and at the same an increase of 25% in the in vivo lipid oxidation
proteins and deoxyribonucleic acid (DNA). Oxidation of the LDL is was observed. Karppi et al. found that plasma lycopene, lutein and
known to take place in several stages starting with the native LDL b-carotene were the most powerful antioxidants for explaining the
and progressing to seeded LDL, minimally modified LDL, and finally content of in vivo oxidatively modified LDL in serum in 349 men and
the fully oxidized LDL particle. Oxidative modifications facilitate the women.12
recognition of modified LDL by the macrophage’s scavenger recep- However, not all studies have demonstrated an effect of lycopene
tors, facilitating its accumulation by macrophages as well enhanc- on LDL oxidation and one study has even shown increased oxidation
ing other proatherogenic effects, such as chemotaxis of monocytes; of LDL (as measured by the ferrous oxidation—xylenol orange assay)
cytotoxicity to a variety of cells causing endothelial injury; increased on enrichment with lycopene and lutein, indicating that the relation
expression of adhesion molecules at the endothelial cell surface; between lycopene and LDL oxidation may be complex.8
inhibition of the endothelium-dependent relaxation, etc.
Atherosclerotic plaques can increase in volume and encroach on ADDITIONAL POTENTIAL MECHANISMS FOR
the vascular lumen. However, although a gradual increase in plaque
INHIBITION OF ATHEROSCLEROSIS
volume can cause angina pectoris by reducing coronary lumen
diameter, this does not usually result in myocardial necrosis. The
BY LYCOPENE
latter is usually caused by plaque rupture, occurring as a result of Martin et al. examined in vitro the effect of b-carotene, β-carotene,
disruption of the fibrous cap which allows contact between the lutein, zeaxanthin and lycopene on the expression of key adhesion
highly thrombogenic lipid core and blood. In recent years, the role molecules involved in the atherosclerosis process and determined
of inflammatory cells in the rupture of atheromatous plaques has the subsequent binding of U937 monocyte cells when carotenoids
become appreciated. Inflammation characterizes all phases of were incubated with human aortic endothelial cells.13 While other
atherothrombosis and provides a critical pathophysiological link carotenoids were ineffective, lycopene attenuated interleukin-1b-
between plaque formation and acute rupture by generating potent stimulated and spontaneous cell adhesion to these monocyte cells
proinflammatory cytokines that induce hepatic production of acute by 20 and 25%, respectively.
phase reactants, such as C-reactive protein (CRP) and serum amy- Fuhrman et al.9 showed that the addition of lycopene to mac-
loid A. Inflammatory cells accumulate in the fibrous cap, weaken it rophage cell lines decreased cholesterol synthesis and increased
and increase its tendency to rupture. LDL receptors via the inhibition of cellular 3-hydroxy-3-methylglu-
taryl-coenzyme A (HMGCoA) reductase, the rate-limiting enzyme Noninvasive Imaging Studies of

in cholesterol synthesis. Incubation with lycopene in vitro resulted Atherosclerosis
in a 73% decrease in cholesterol synthesis, which was greater than
that achieved with β-carotene. Lycopene also resulted in an increase Correlates of atherosclerosis can be determined in several vascular
in LDL degradation in the cells themselves and an increase in the beds using noninvasive techniques, such as ultrasound. Perhaps
removal of LDL from the circulation. To test their finding in hu- the most commonly used technique in clinical studies is the intima-
mans, the investigators fed 6 men 60 mg lycopene for 3 months. They media thickness (IMT) of the carotid arteries, which has shown good
found a 14% reduction in plasma LDL cholesterol with no significant correlations with clinical coronary and cerebrovascular events.
change in HDL cholesterol. Data from the Kuopio Ischaemic Heart Disease Risk Factor
Kim et al. have shown inverse correlations between serum lyco- (KIHD) study suggests that the thickness of the inner wall of blood
pene concentrations and arterial stiffness in healthy women14 and in vessels and the risk of myocardial infarction were reduced in 725
patients with the metabolic syndrome.15 men aged 46–64 years with higher serum concentrations of lyco-
Other suggested mechanisms by which lycopene could inhibit pene.19
atherosclerosis include intracellular gap junction communication The Atherosclerosis Risk in Communities study examined the
and hormonal and immune system modulation, as well as diminish- cross sectional association of serum vitamin levels, the susceptibil-
ing the apoptosis of injured cells. ity of LDL to oxidation with carotid IMT in 231 asymptomatic age-,
sex-, race-, and field center-matched case-control pairs. Increase in
EPIDEMIOLOGICAL STUDIES a-carotene and lycopene were associated with nonsignificantly low-
er odds of having increased IMT scores, whereas b-carotene, retinol,
A number of epidemiological studies have suggested that a diet rich and α-tocopherol were unrelated to IMT.20
in a variety of fruits and vegetables results in lower risk of CHD.16 The Gianetti et al. studied 11 healthy control subjects, 11 patients
evidence in support of the role of lycopene in the prevention of CHD with uncomplicated hypertension, and 11 patients with essential hy-
stems primarily from the epidemiological observations on normal pertension plus peripheral vascular disease who were matched for
and at-risk populations. The present knowledge largely relies on the age, sex, smoking habit and body mass index. A statistically signifi-
data obtained from dietary estimates, plasma levels or tissue concen- cant correlation was found between lycopene and IMT max. Plasma
trations of lycopene in relation to the risk of CHD. lycopene did not significantly correlate with any of the soluble adhe-
sion molecules tested.21
Relationship between Dietary Intake of In the Asymptomatic Carotid Atherosclerotic Disease In Man-
fredonia Study (ACADIM), the serum concentrations of vitamin A,
Lycopene and Coronary Heart Disease
vitamin E, lycopene and b-carotene were all significantly lower in
In the prospective Massachusetts Health Care Panel Study, high di- 640 participants with increased carotid IMT when compared with
etary intake of total carotenoids was associated with reduced risk of participants normal IMT values.22
fatal myocardial infarction and CVD death.5 In the prospective Rotterdam Study on serum carotenoids and
Results from the Women’s Health Study (WHS) showed that atherosclerosis, there was a modest inverse association between
women with the highest intake of tomato-based foods rich in lyco- levels of serum lycopene and atherosclerosis, assessed by the pres-
pene had a somewhat reduced risk for CVD compared to women ence of calcified plaques in the abdominal aorta in 108 cases of aor-
with a low intake of those foods.17 Although the correlation was not tic atherosclerosis and 109 controls. The association between serum
strong in the overall study population, women who consumed seven lycopene levels and atherosclerosis was most pronounced among
servings or more of tomato-based foods like tomato sauce and pizza subjects who were current and former smokers. No association with
each week had a nearly 30% risk reduction in total CVD compared risk of aortic calcification for the serum carotenoids b-carotene,
to the group with intakes of less than one serving per week. The lutein and zeaxanthin was observed.23
researchers also found out that women who ate more than 10
servings per week had an even more pronounced reduction in risk Relationship between Serum Levels of
(65%) for specific CVD outcomes such as heart attack or stroke.
Lycopene and Cardiovascular Disease
In the a-Tocopherol, b-Carotene Cancer Prevention (ATBC)
study, the dietary intake of lycopene was inversely associated with Street et al. conducted a nested case-control study examining serum
risks of cerebral infarction [relative risk (RR) 0.74, 95% confidence carotenoid concentrations that were measured 7–14 years before
interval (CI) 0.59–0.92] and intracerebral hemorrhage (RR 0.45, 95% the onset of myocardial infarction.24 Although there appeared to be
CI 0.24–0.86), but the association was attenuated after adjustment for an increased risk of myocardial infarction in the lowest quintile of
other dietary antioxidants in the multivariate model.18 serum lycopene concentration, there was not a dose-response rela-
Chapter 19  Lycopene and Related Tomato Carotenoids in Coronary Heart Disease 133
tion and the trend was not statistically significant. Serum b-carotene from 10 European countries to maximize the variance in exposure
concentrations, however, were significantly and inversely associat- within the study. Adipose tissue needle aspiration biopsies were tak-
ed with risk of myocardial infarction. After stratifying the results by en shortly after the infarction and analyzed for levels of carotenoids
smoking, the authors found that this relation was limited to smokers and tocopherols. Adipose lycopene levels expressed as milligrams
only. per gram of fatty acids varied from the lowest at 0.21 to the highest at
Data from the Physician’s Health study was used to evaluate the 0.36. When examined singularly, each of the carotenoids appeared to
relationship between lycopene and CHD in a prospective, nested, be protective. Upon simultaneous analyses of the carotenoids, how-
case-control design. While Hak et al. found inverse associations ever, using conditional logistic regression models that controlled for
between serum lycopene levels and the risk of stroke,25 but not age, body mass index, socioeconomic status, smoking, hypertension,
myocardial infarction.26 Using baseline blood samples from 1982, and maternal and paternal history of disease, lycopene remained in-
Sesso et al. did not find such associations in a database using base- dependently protective, with an odds ratio of 0.52 for the contrast of
line blood samples from 1996 in the same study.27 the 10th and 90th percentiles (95% CI 0.33–0.82, p = 0.005). Results
The Kuopio Ischemic Heart Disease Risk Factor study evaluated also showed a dose response relationship between each quintile of
the relationship between serum antioxidant levels and CVD in 725 adipose tissue lycopene and the risk of myocardial infarction. The
middle-aged men free of CHD and stroke at baseline. In a Cox’s pro- protective potential of lycopene was maximal among individuals
portional hazards’ model adjusting for covariates, men in the lowest with the highest polyunsaturated fat stores. The associations for a-
quartile of serum levels of lycopene had a 3.3-fold risk of the acute and b-carotene were largely eliminated.
coronary event or stroke as compared with others.28 A component of this larger EURAMIC study representing the
Lower blood lycopene levels were also found to be associated Malaga region was analyzed further. In this case-control study con-
with increased risk for and death from coronary artery disease in a sisting of 100 cases and 102 controls, adipose tissue lycopene levels
population study comparing Lithuanian and Swedish cohorts with showed an odds ratio of 0.39 with 95% CI of 0.13 and 1.19.
different rates of death from coronary artery disease.29 In the Aus-
trian stroke prevention study, lower levels of serum lycopene and a- CONCLUSION
tocopherol were reported in individuals from an elderly population
at high risk for microangiopathy-related cerebral damage, which is Lycopene is a strong antioxidant found naturally in various food
considered as a risk factor for cerebrovascular disease.30 products and also available in concentrated form as food supple-
ment. In vitro as well as in vivo studies demonstrate its ability to in-
Relationship between Lycopene Tissue Levels hibit the oxidation of LDL in the blood. Many, though not all, epi-
demiological studies have shown inverse associations between the
and Coronary Heart Disease
concentrations of lycopene in food, blood and tissues and the risk of
While serum levels may give some indication of the dietary intake of atherosclerosis and CVD. However, the ultimate proof that lycopene
lycopene, the major determinant of the substance’s biologic effects supplementation can be used to prevent CVD should rely on long-
is its tissue concentrations. An attempt to investigate such a relation- term, prospective randomized studies. Until such evidence accrues,
ship was made in the multicenter, case-control EURAMIC study.31 the potential benefits of lycopene in preventing atherosclerosis will
Incidence cases and frequency-matched controls were recruited remain speculative.
REFERENCES
1. Britton G. Structure and properties of carotenoids in relation to function. FASEB J. 1995;9:1551-8.
2. Clinton SK. Lycopene: Chemistry, Biology, and Implications for Human Health and Disease. Nutr Rev. 1998;56:35-50.
3. Agarwal S, Rao AV. Tomato lycopene and its role in human health and chronic diseases. CMAJ. 2000;163(6):739-44.
4. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I:
pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114;2850-70.
5. Gaziano JM, Manson JE, Branch LG, et al. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascu-
lar mortality in the elderly. Ann Epidemiol. 1995;5:255-60.
6. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: sys-
tematic review and meta-analysis. JAMA. 2007;297:842-57.
7. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events
in men with previous myocardial infarction. Lancet. 1997;349:1715-20.
8. Dugas TR, Morel DW, Harrison EH. Impact of LDL carotenoid and alpha-tocopherol content on LDL oxidation by endothelial cells in culture. J
Lipid Res. 1998;39:999-1007.
9. Fuhrman B, Elis A, Aviram M. Hypercholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and
augmentation of LDL receptor activity in macrophage. Biochem Biophys Res Commun. 1997;233:658-62.
10. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids. 1988;33:981-4.
11. Steinberg FM, Chait A. Antioxidant vitamin supplementation and lipid peroxidation in smokers. Am J Clin Nutr. 1998;68:319-27.
12. Karppia J, Nurmia T, Kurla S, et al. Lycopene, lutein and b-carotene as determinants of LDL conjugated dienes in serum. Atherosclerosis.
2010;209:565-72.
13. Martin KR, Wu D, Meydani M. The effect of carotenoids on the expression of cell surface adhesion molecules and binding of monocytes to human
aortic endothelial cells. Atherosclerosis. 2000;150:265-74.
14. Kim OY, Yoe HY, Kim HJ, et al. Independent inverse relationship between serum lycopene concentration and arterial stiffness. Atherosclerosis.
2010;208:581-6.
15. Hyun YY, Oh YK, Hyo HL, et al. Association of serum lycopene and brachial-ankle pulse wave velocity with metabolic syndrome. Metab Clin Exp.
2010. pp. 1-7.
16. Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr. 2000;71(suppl):1691S-5S.
17. Sesso HD, Liu S, Gaziano JM, et al. Dietary lycopene, tomato-based food products and cardiovascular disease in women. J Nutr. 2003;133:2336-41.
18. Hirvonen T, Virtamo J, Korhonen P, et al. Intake of flavonoids, carotenoids, vitamins C and E, and risk of stroke in male smokers. Stroke.
2000;31;2301-6.
19. Rissanen TH, Voutilainen S, Nyyssönen K, et al. Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease
Risk Factor Study. Am J Clin Nutr. 2003;77:133-8.
20. Iribarren C, Folsom AR, Jacobs DR, et al. Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-
LDL with carotid atherosclerosis: a case-control study. The ARIC Study Investigators. Arterioscler Thromb Vasc Biol. 1997;17:1171-7.
21. Gianetti J, Pedrinelli R, Petrucci R, et al. Inverse association between carotid intima-media thickness and the antioxidant lycopene in atheroscle-
rosis. Am Heart J. 2002;143:467-74.
22. Riccioni G, D’orazio N, Palumbo N, et al. Relationship between plasma antioxidant concentrations and carotid intima-media thickness: the
Asymptomatic Carotid Atherosclerotic Disease in Manfredonia Study. Eur J Cardiovasc Prev Rehabil. 2009;16(3):351-7.
23. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, et al. Serum carotenoids and atherosclerosis: the Rotterdam Study. Atherosclerosis. 2000;148:
49-56.
24. Street DA, Comstock GW, Salkeld RM, et al. Serum antioxidants and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk
factors for myocardial infarction? Circulation. 1994; 90:1154-61.
25. Hak AE, Ma J, Powell CB, et al. Prospective study of plasma carotenoids and tocopherols in relation to risk of ischemic stroke. Stroke. 2004;35:
1584-8.
26. Hak AE, Stampfer MJ, Campos H, et al. Plasma carotenoids and tocopherols and risk of myocardial infarction in a low-risk population of US male
physicians. Circulation. 2003;108:802-7.
27. Sesso HD, Buring JE, Norkus EP, et al. Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men. Am J Clin
Nutr. 2005;81:990-7.
28. Rissanen TH, Voutilainen S, Nyyssönen K, et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary
events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr. 2001;85:749-54.
29. Kristenson M, Zieden B, Kucinskiene Z, et al. Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: con-
comitant cross sectional study of men aged 50. BMJ. 1997;314:629-33.
30. Schmidt R, Fazekas F, Hayn M, et al. Risk factors for microangiopathy-related cerebral damage in Aistrian stroke prevention study. J Neurol Sci.
1997;152:15-21.
31. Kohlmeier L, Kark JD, Gomez-Gracia E, et al. Lycopene and myocardial infarction risk in the EURAMIC Study. Am J Epidemiol. 1997;146:618-26.
20 History of Oils, Fats and
Coronary Heart Disease
Jain P
INTRODUCTION et al. (1933) later demonstrated that inhibiting thyroid function

in dogs and then feeding them cholesterol does increase blood
While now there is no doubt about the veracity of the “lipid hypoth- cholesterol and induce lesions.4 Another argument for not taking
esis”, it remained controversial for better part of the last century. Anitschkow’s findings seriously was that the blood cholesterol lev-
Most clinicians in the middle of the 20th century considered athero- els achieved in rabbits were 500–1,000 mg/dL or higher; the human
sclerosis to be an inevitable consequence of aging—the senescence levels were almost never that high. But as a counter to this argument,
hypothesis—about which nothing could be done. Over the next four Anitschkow later showed that more modest increases of blood cho-
decades, the case against cholesterol became stronger, based on sev- lesterol levels in rabbits could also induce lesions, though it required
eral lines of evidence. But only after the statins, the potent inhibitors more prolonged feeding. Later, demonstration that lesions could also
of cholesterol biosynthesis became available; the treatment of hyper- readily be produced in guinea pigs,5 goats,6 hens and parrots,7 and,
cholesterolemia became good medical practice in early 90s. ultimately, in almost every animal species, including nonhuman
primates,8 went a long way towards confirming Anitschow’s observa-
THE BEGINNINGS tions. Nevertheless, extrapolation from animals to humans could not
be accepted in the absence of supporting evidence.
In 1913, Anitschkow, a young experimental pathologist working at
the Military Medical Academy in St Petersburg, found that feeding PROTEIN TOXICITY VERSUS
purified cholesterol dissolved in sunflower oil to rabbits induced
LIPID HYPOTHESIS
arterial lesions closely resembling those of human atherosclerosis.1,2
Over the next few years, Anitschkow and his group established that The rationale for Anitschkow’s studies came from a paper by Igna-
in fatty streaks, most of the lipid was present in cytoplasm of the so towski (1909),9 who was pursuing a hypothesis put forward by the
called “foam cells”.3 Over long periods of cholesterol feeding, there Nobel Prize-winning microbiologist Metschnikow that an excess of
was deposition of connective tissue, converting the fatty streak to fi- protein in the diet accelerated the aging process. Ignatowski found
brous plaque, covered by a fibrous cap. The severity of lesions was that feeding rabbits large amounts of meat, eggs and milk was indeed
proportional to the degree of increase in blood cholesterol and the toxic in young rabbits, affecting liver and adrenals, but in adult rab-
duration of cholesterol feeding. Anitschkow also speculated that bits, the major effect was development of arterial lesions resembling
cholesterol was entering the arterial wall from the blood and the human atherosclerosis. Because atherosclerosis was thought to be
cholesterol-loaded cells were probably white blood cells that had in- a hallmark of aging, Ignatowski concluded that this finding con-
filtrated the arterial wall. firmed Metschnikow’s “protein toxicity” hypothesis. It remained for
Anitschkow’s findings were by and large rejected. Some inves- Anitschkow to show that the arterial damage could be induced by
tigators tried to confirm his findings, but most of them used rats or feeding cholesterol purified from egg yolks without the protein. The
dogs as animal models. Cholesterol feeding in these species failed new findings generated the “lipid hypothesis” of atherogenesis,
to induce atherosclerotic lesions. Therefore, they concluded that refuting the “protein toxicity” hypothesis.
Anitschkow’s results must reflect some peculiarity of the rabbit,
a strict herbivore, that has zero cholesterol intake and a very low OBSERVATIONS IN FAMILIAL
fat intake. The rabbit model was dismissed as irrelevant to human
HYPERCHOLESTEROLEMIA
disease. What was not appreciated was that the rats and dogs, un-
like rabbits, are very efficient in converting cholesterol to bile The first indication that coronary heart disease (CHD) might be
acids. Consequently, even on very high cholesterol intakes, the blood linked to cholesterol came from case reports of children with fa-
cholesterol in these species did not increase appreciably. Steiner milial hypercholesterolemia (FH) who had developed CHD at an
early age. It was however thought that the blood cholesterol levels in than 260 mg/dL, whereas that in Japan was ~160 mg/dl; the number
patients with FH are very high, so these case reports cannot support a of fatal heart attacks over 10 years was ~70/1000 men in Finland and
link between CHD and more modest elevations of blood cholesterol. less than 5/1000 men in Japan. The coronary death rates plotted on
The reason for this argument is related to how “high cholesterol” was a graph against blood cholesterol level fell roughly in a same straight
defined at that time. line for all seven countries, strongly suggesting that the population
Like other laboratory parameters, the traditional way of defining risk was roughly proportional to the blood cholesterol level.
high blood cholesterol has been a value above the 95th percentile; In the same study, Keys also showed that the blood cholesterol
anything below that was considered as “normal”. When the 95th per- levels were proportional to the saturated fat intake. The contribution
centile criterion was applied to blood cholesterol levels in the US in of saturated fats to the total daily calorie intake in Finnish men was
the 40s, 95% of the population had values below 280 mg/dL, so any over 20%, whereas that in Japanese men was only about 2.5%. Again,
value below 280 mg/dL was considered as “normal”. Yet, most heart the values for the other countries fell roughly along a single line. To
attacks occurred in people with cholesterol levels between 200–280 summarize, the data showed that the population risk of fatal heart
mg/dL. Therefore, if abnormal cholesterol is defined as greater than attacks correlated with the blood cholesterol level, which was in turn
or equal to 280 mg/dL, most heart attacks will be occurring in in- correlated with dietary intake of saturated fat. Little or no correlation
dividuals with so called “normal” blood cholesterol levels (200–280 was found between total fat intake and the risk, highlighting the cen-
mg/dL). Thus, most clinicians of that time concluded that high blood tral role of saturated fat intake.
cholesterol level was irrelevant to atherosclerosis and heart attacks.
Honolulu Heart Study
DIET AND THE HEART
The findings in the Seven Countries Study did not establish dietary
As early as 1916, a Dutch physician, CD de Langen, posted to the saturated fat or high blood cholesterol as causal but strongly sup-
Dutch East Indies as a public health officer, suspected that diet ported the lipid hypothesis, though genetic differences or differences
played an important role in blood cholesterol level. He observed that in lifestyles might explain the correlation. To decide that the differ-
blood cholesterol levels of the natives in Indonesia were consider- ences in cholesterol levels and heart attack rates in different popula-
ably lower than those of the Dutch colonists and speculated that tions are due to the differences in diet or other lifestyle-related fac-
this might be due to the rich diet of the Dutch, compared with the tors and not due to differences in genetic makeup, investigators in
frugal diet of the natives.10 In 1922, he performed the first reported Hawaii compared the blood cholesterol levels and the heart attack
controlled study of dietary effects on blood cholesterol.11 He put five rates in the Hawaiian, San Francisco and native Japanese popula-
Indonesian natives on a cholesterol-rich diet consisting of eggs and tions on the island of Honshu.14 The Japanese who had moved to
meat and found that after 3 months, their blood cholesterol levels Hawaii had higher blood cholesterol levels and higher heart attack
had increased by ~27%. He also reported that Indonesians who had rates than the Japanese on Honshu. The difference was even more
migrated to Amsterdam had cholesterol levels just as high as those of striking in those who had settled in San Francisco. Because the mi-
their Dutch counterparts, presumably because they had adopted the grants studied had moved into their new environments only for a few
dietary habits of Holland. generations, their gene pools could not have changed significantly.
The rise in blood cholesterol levels and the accompanying increase
Seven Countries Study in heart attack rates following migration must have been due to en-
vironmental factors like changes in dietary habits. The saturated fat
By 1955, Ancel Keys, a pioneer in nutrition research in the US, was intake was indeed found to be higher in Hawaii and San Francisco
convinced that blood cholesterol level was determined significantly than on the island of Honshu.
by the amount and the nature of the fat in the diet. Pursuing this line
of thought, if blood cholesterol was a major determinant of CHD, Saturated versus Polyunsaturated Fats
then populations with fat-rich diets should have higher blood cho-
lesterol levels and higher heart attack rates than other populations. By early 50s, Kinsell15 and Ahrens16 had independently established
To demonstrate this, Keys and his colleagues launched the Seven that saturated fats raise and polyunsaturated fats lower blood cho-
Countries Study, selecting countries that spanned the full range of lesterol in humans. Their metabolic ward studies in hospitalized sub-
blood cholesterol levels—lowest in Japan to highest in Finland.12,13 jects were single-variable studies, keeping all the elements in the diet
In several different communities in each country, blood samples constant, except that a saturated fat was substituted for a polyunsatu-
were drawn for cholesterol measurement. The nature of the diet was rated fat or vice versa. The total fat content of diet was kept same and
determined by a questionnaire and in a subset of the population by there was no change in body weight. Both utilized a liquid formula
chemical analysis and the CHD death rate correlated with these two diet in the form of a milk shake of known composition. Each subject
variables. The mean blood cholesterol in East Finland was greater served as his or her own control and the results were highly repro-
Chapter 20  History of Oils, Fats and Coronary Heart Disease 137
ducible though the magnitude of the effect varied from individual 40% of total calories. About 800 men, most of them elderly, were ran-
to individual. Similar results were obtained by others using different domly assigned to one or the other dining room and followed for up
methods but all arriving at the same basic conclusion.17-19 to 8 years. Most of the subjects were free of CHD at the beginning.
Later studies showed that the effect of cholesterol content of The blood cholesterol level in the men eating in dining room B fell
the diet on blood cholesterol is usually less pronounced than the promptly after the change in diets and continued to be lower than
effect of the saturated fat content. In order to lower blood cho- that for the men eating in dining room A. The mean difference was
lesterol levels significantly, it is usually necessary to reduce the 29.5 mg/dL (12.7%). Neither group showed any significant change in
cholesterol content of the diet to 300 mg per day or less.20 Also, if body weight. The number of combined events (definite MI, fatal or
a subject has been taking greater than or equal to 600 mg of choles- nonfatal; stroke; or peripheral atherosclerosis requiring amputation)
terol per day, increasing cholesterol intake further will not increase was reduced by 31% in the experimental group (48 vs 70; p < 0.05).
blood cholesterol level much further. On the other hand, reducing Another study using the same approach was conducted in Fin-
the cholesterol intake to ~100 mg per day is likely to reduce blood land.24,25 Instead of separate dining halls in a single institution, two
cholesterol considerably. Also, the impact of adding cholesterol to separate psychiatric hospitals were selected, leaving the diet at one
the diet is greater when the ratio of polyunsaturated to saturated hospital (Hospital N) unchanged but introducing a polyunsaturated
fatty acids is low.21 fat-rich diet at the other (Hospital K). The major diet changes were
replacement of milk fat by soybean oil and substitution of polyun-
Clinical Outcomes of Dietary saturated fat-rich margarine for butter. After 6 years, the diets at Hos-
pitals N and K were switched for the next 6 years. This cross over de-
Fat Intervention Trials
sign greatly enhanced the value of this study that recruited over 2,000
By the end of 60s, major epidemiological and metabolic ward stud- subjects with almost 30,000 person-years of follow-up. Furthermore,
ies had documented the role of diet in determining blood cholesterol the study was blinded in the sense that the causes of death were
levels. The next logical step in establishing the lipid (and diet-heart reviewed by physicians who did not know from which hospital the
hypothesis) hypothesis was to conduct dietary intervention trials subjects came from. On the experimental diet, blood cholesterol
with clinical outcomes as the end points. levels were 12–18% lower than on the standard Finnish diet with a
In 1957, Dr Paul Leren started a pilot study at Oslo, Norway, to death rate from CHD one-half or less (p < 0.001). The results in wom-
check how much of a decrease in blood cholesterol level could be en were in the same direction but reached statistical significance
obtained by diet and whether it could be sustained.22 The key only among the women in Hospital N (p < 0.001).
element of his diet was a marked reduction in saturated fat and These three studies, all statistically significant, followed greater
cholesterol intake and an increase in polyunsaturated fat intake. Each than 3,600 subjects for 5–12 years. All three involved the reduction of
of the 412 male survivors of myocardial infarction (MI) who served as serum cholesterol by substituting polyunsaturated vegetable fats for
his subjects had to consume a pint of soybean oil every week for a saturated animal fats. These were not low-fat diet trials. In all three
period of 5 years. Sixty percent of the subjects were “excellent” adher- studies, the drop in serum cholesterol was substantial with poly-
ers and their blood cholesterol levels fell from a mean of 296 mg/dL unsaturated rich diet and decrease in adverse cardiovascular end
at baseline to 232 mg/dL (−21.6%) during the course of the study. The points. Results of these studies could have ushered the beginning of
mean drop in cholesterol level for the group as a whole was 17.6%. an era of the popularity of polyunsaturated fatty acid (PUFA) rich oils
Fifty-four (26%) of the patients in the control group had recurrence in early 70s had the results been accepted universally. But there was
of MI during the 5 years of follow-up, compared with only 34 (16%) in still an influential group on both sides of the Atlantic that was not
the usual diet group (p < 0.03). There was no difference in all-cause convinced that high blood cholesterol was a causative factor for ath-
mortality, but the study was not statistically powered to address to erosclerosis. Only after the National Institute of Health (NIH) spon-
this outcome. A follow-up of the same subjects at 11 years showed a sored the landmark Coronary Primary Prevention Trial and showed
strikingly lower MI mortality in the treated group (p < 0.004).23 that cholestyramine (a drug) could reduce CHD risk by lowering
Around the same time, another landmark dietary intervention blood cholesterol levels,26,27 that reduction of high blood cholesterol
study was conducted in the Wadsworth VA Hospital in Los Angeles become a serious therapeutic goal. The Coronary Primary Preven-
that includes a domiciliary facility where healthy but needy veterans tion Trial, showed that treatment with a bile acid binding resin re-
could reside at no cost. They take almost all their meals in one of the duced major coronary events in hypercholesterolemic men by 19%
two dining halls on the premises. In the late 1950s, Dayton and col- (P = 0.05). The NIH followed this up with a National Consensus De-
leagues perceived this as suitable setting to test the effects of unsatu- velopment Conference on Lowering Blood Cholesterol to Prevent
rated fat on atherosclerosis.24 All the men in the study were assigned Heart Disease. For the first time, the NIH went on record advocating
to dining hall A or dining hall B. Dining hall A continued to serve the screening for hypercholesterolemia and urging aggressive treatment
usual diet, but dining hall B started serving a modified diet rich in for those at high risk. Thus, the institute initiated the National Cho-
vegetable oil, rich in polyunsaturated fat, instead of the animal fat. lesterol Education Program, making prevention of CHD a national
The total fat content of the two diets was kept the same, providing public health goal.
also proposed reducing saturated fats in food to decrease the risk of

A NOTE ON THE SAGA OF TRANS FATS28
heart attack. In response to increasing public awareness, many fast-
In 1902, Wilhelm Normann, a German scientist patented the process food companies began using partially-hydrogenated oils containing
of partial hydrogenation of liquid oils, forming trans fatty acids. By trans fats instead of beef tallow and tropical oils high in saturated fats.
1907, Crosfield and Sons brought their hydrogenation technology Yet, use of hydrogenated oils in foods had never been completely sat-
to the US. Partially-hydrogenated oils increased the shelf life of the isfactory. Because the center arm of the triglyceride is shielded some-
food, without compromising on texture and taste, and were cheaper what by the end triglycerides, most of the hydrogenation occurs on
than butter. In 1911, Procter and Gamble of the US introduced the the end triglycerides. This makes the resulting fat more brittle. A mar-
Crisco vegetable shortening, manufactured by hydrogenation of cot- garine made from naturally more saturated tropical oils will be more
tonseed oil, in grocery stores of America. This was the first food prod- spreadable than a margarine made from hydrogenated soy oil.
uct containing man-made fat to join our food chain. Housewives of More serious downsides of trans fats began to emerge in 1990s.
that era cooked with lard and butter. An object of a massive promo- Prior to 1990, few researchers suspected that partially-hydrogenated
tion, Crisco was advertised as a healthier alternative to animal fats. oils were bad for health. Research studies conducted during the
In addition, a cookbook containing 615 Crisco recipes was distrib- 90s started revealing a correlation between trans fatty acids and
uted free of charge to American housewives. Advertisements in the increased low-density lipoprotein (LDL) cholesterol levels and in-
Ladies’ Home Journal touted Crisco as better than butter for cook- creased risk of CHD. Following publication of numerous scientific
ing, as well as giving lighter and flakier fried foods. Crisco became studies that showed the same results, health advocacy groups started
popular almost immediately. Sales in 1912 amounted to 2,600,000 lb calling for a stop to use of partially-hydrogenated oils in deep frying
(1,180,000 kg) and had reached 60,000,000 lb by 1916. By September operations. Around the same time, nutrition labels on food packages
1914, Berlin Mills had begun marketing another shortening product became a hotly debated topic. In 1999, the US government proposed
trademarked as “Kream-Krisp”. Initial production began at about a law requiring food manufacturers to list trans fat contents on food
2,000 lb/d, but later had reached 30,000 lb/d. Kream Krisp was mar- labels, but it could not be passed as a law. However by 2002, the US
keted as a wonderful new vegetable shortening. “Not only is Kream government agreed that there is no safe level of trans fats and that
Krisp a pure food, wholesome, appetizing, better than butter for all people should consume as little of hydrogenated fats as possible. In
good cooking, but is also a great money saver. It will cut your lard 2003, Denmark became the first country to regulate trans fats on a na-
and butter bill squarely in two.” A loaf cake (all ingredients) baked tional basis, putting a very small cap on the amount that foods might
with Kream Krisp cost about 15¢ in 1915 compared with about 24¢ contain. Later in 2003, the US Food and Drug Administration (FDA)
using butter. The cost of Kream Krisp alone was 16¢/lb compared passed a law requiring that trans fat be listed on the Nutrition Facts
with 44¢/lb for best dairy butter. Kream Krisp had the appearance of labels, giving food manufacturers 3 years to comply. In response,
a high-grade unsalted butter. A newspaper clipping of June 1915 de- many food manufacturers reformulated their products to limit trans
scribed foods including doughnuts, cake, muffins and pretzels made fat. In 2006, the American Heart Association specified a daily limit of
with Kream Krisp as delightful and the secret was attributed to the less than 1% of calories from trans fats. Later in the same year, New
shortening. York became the first US city to pass a regulation limiting trans fats
Trans fats gained widespread popularity during World War II, in restaurants. Multiple cities and states have since proposed similar
when many people began using margarine and shortening as alterna- regulations. The consumption of trans fats in India remains unregu-
tives to rationed butter. From late 50s, the American Heart Association lated and uninhibited to date.
REFERENCES
1. Anitschkow N, Chalatov S. Ueber experimentelle Choleserinsteatose und ihre Bedeutung fur die Entstehung einiger pathologischer Prozesse.
Zentralbl Allg Pathol. 1913; 24:1-9.
2. Anitschkow N. Ueber die Veranderungen der Kaninchenaorta bei experimenteller Cholesterinsteatose. Beitr Pathol Anat. 1913;56:379-404.
3. Anitschkow N. Experimental atherosclerosis in animals. In: Cowdry EV (Ed). Arteriosclerosis: A Survey of the Problem. New York: Macmillan;
1933. pp. 271-322.
4. Steiner A, Kendall FE. Atherosclerosis and arteriosclerosis in dogs following ingestion of cholesterol and thiouracil. Arch Pathol. 1946;42:433-44.
5. Bailey CH. Observations on cholesterol-fed guinea pigs. Proc Soc Exper Biol. 1915;13:60-2.
6. Chalatow S. Bemerkungen an den Arbeiten uber Cholesterinsteatose. Virchows Arch A Pathol Anat Histol. 1929;272:691-708.
7. Anitschkow N. Einige Ergebnisse der experimentellen Atherosklerosforschung. Verhandlungen den Deutschen Pathologischen Gesellschaft.
1925;20:149-54.
8. Clarkson TB. Animal models of atherosclerosis. Adv Vet Sci Comp Med. 1972;16:151-73.
9. Ignatowski A. Uber die Wirkung des Tierischen Eiweisses auf die Aorta und die paerenchymatosen Organe der Kaninchen. Virchows Arch Pathol
Anat. 1909;198:248-70.
10. DeLangen CD. Cholesterol-metabolism and racial pathology. [Dutch] Geneeskundig tijdschrift voor Nederlandisch-Indie. 1916;56:1-34.
11. DeLangen CD. Cholesterol contents of blood in the Dutch Indies. [Dutch] Geneeskundig tijdschroft voor Nederlandisch-Indie. 1922;62:1-4.
Chapter 20  History of Oils, Fats and Coronary Heart Disease 139
12. Keys AJT, Anderson F, Fidanza MH, et al. Effects of diet on blood lipids in man, particularly cholesterol and lipoproteins. Clin Chem. 1955;1:34-52.
13. Keys AC, Aravanis HW, Blackburn FS, et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven
countries. Acta Med Scand Suppl. 1966;460:1-392.
14. Robertson TL, Kato H, Rhoads GG, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and
California. Incidence of MI and death from coronary heart disease. Am J Cardiol. 1977;39:239-43.
15. Kinsell LW, Partridge J, Boling L, et al. Dietary modification of serum cholesterol and phospholipid levels. J Clin Endocrinol Metab. 1952;12:909-
13.
16. Ahrens EH, Blankenhorn DH, Tsaltas TT. Effect on human serum lipids of substituting plant for animal fat in diet. Proc Soc Exp Biol Med.
1954;86:872-8.
17. Bronte-Stewart B, Antonis A, Eales L, et al. Effects of feeding different fats on serum-cholesterol level. Lancet. 1956;270:521-7.
18. Beveridge JM, Connell WJ, Mayer GA. Dietary factors affecting the level of plasma cholesterol in humans: the role of fat. Can J Med Sci. 1956;34:441-
55.
19. Keys A, Anderson JT, Grande F. Prediction of serum-cholesterol responses of man to changes in fats in the diet. Lancet. 1957;273:959-66.
20. Connor WE, Connor SL. Dietary cholesterol and coronary heart disease. Curr Atheroscler Rep. 2002;4:425-32.
21. Schonfeld GW, Patsch L, Rudel L, et al. Effects of dietary cholesterol and fatty acids on plasma lipoproteins. J Clin Invest. 1982;69:1072-80.
22. Leren P. The effect of plasma cholesterol lowering diet in male survivors of MI. A controlled clinical trial. Acta Med Scand Suppl. 1966;466:1-92.
23. Leren P. The Oslo diet-heart study. Eleven-year report. Circulation. 1970;42:935-42.
24. Dayton SML, Pearce H, Goldman A, et al. Controlled trial of a diet high in unsaturated fat for prevention of atherosclerotic complications. Lancet.
1968;2:1060-2.
25. Turpeinen O. Diet and coronary events. J Am Diet Assoc. 1968;52:209-13.
26. Miettinen M, Turpeinen O, Karvonen MJ, et al. Effect of cholesterol-lowering diet on mortality from coronary heart disease and other causes. A
twelve-year clinical trial in men and women. Lancet. 1972;2:835-8.
27. Lipid Research Clinics Coronary Primary Prevention Trial. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relation-
ship of reduction in incidence of coronary heart disease to cholesterol lowering. J Am Med Assoc. 1984;251:365-74.
28. http://www.heart.org/HEARTORG/GettingHealthy/FatsAndOils/Fats101/A-History-of-Trans-Fat_UCM_301463_Article.jsp
21 History of Cardiac Fitness
Somasundaram M, Raghothaman S
INTRODUCTION a 6-month exercise program consisting of 30 minutes of daily saw-

ing activity for one of his male patients who had a diagnosed chest
Cardiac fitness is a medically supervised program to help heart disorder. Parry, in 1799, independently noted the beneficial effects
patients recover quickly and improve their overall physical, mental of physical activity in his patients who suffered from chest pain.
and social functioning. The goal is to stabilize, slow or even reverse Although these reports were written long before any formal recogni-
the progression of cardiovascular disease, thereby reducing the risk tion or definition of coronary artery disease, undoubtedly some of
of heart disease, another cardiac event or death. Cardiac rehabilita- these patients had experienced anginal disease or myocardial infarc-
tion programs include: tions (MIs). This initial, apparently positive attitude towards physi-
• Counseling so the patient can understand and manage the dis- cal activity was all but forgotten by the time Herrich, in 1912, gave
ease process his original clinical description of an acute MI. Expressed concern
• Beginning an exercise program regarding physical exertion and the increased risk of ventricular
• Counseling on nutrition aneurysm rupture or heightened arterial hypoxemia precipitated
• Helping the patient modify risk factors, such as high blood the adoption of a conservative treatment approach in which patients
pressure, smoking, high blood cholesterol, physical inactivity, were kept at bed rest for 6–8 weeks post-MI. Pharmacological man-
obesity and diabetes agement of cardiac patients was limited. The agents most commonly
• Providing vocational guidance to enable the patient to return to used were digitalis and nitroglycerin. The traditional medical man-
work agement of physical inactivity for coronary patients was reinforced
• Supplying information on physical limitations in the 1930s by two physicians, Mallory and White. These men found
• Lending emotional support that the necrotic myocardial region transformed into scar tissue after
• Counseling on appropriate use of prescribed medications. about 6 weeks. Therefore, they advised a minimum of 3 weeks in bed
According to the US Public Health Service (USPHS), a car- for patients with even the smallest MI. Continued limited physical
diac rehabilitation program is defined as a program that involves activity was prescribed after patient hospital discharge. Stair climb-
the following: ing often was prohibited in some cases for up to a year. During this
• Medical evaluation so-called convalescent period, the patient’s tendency to become
• Prescribed exercise an invalid was enhanced. Follow-up medical management gave
• Education little advice to patients regarding functional cardiac capacity, stress
• Counseling of patients with cardiac disease. management, or education about the disability and its limitations.
This chapter shall discuss the history of cardiac fitness under Frequently, patients did not return to work and soon were consi
the following purviews: dered as nonproductive members of society. Research during the
• History of cardiac fitness programs first 3 decades of the 20th century focused mainly on better methods
• History of cardiac rehabilitation after a coronary event of diagnosing and classifying cardiac disorders and simple testing
• History of aerobics as a way of maintaining cardiac fitness for “circulatory efficiency”. Little emphasis was placed on the actual
• History of the other uses of cardiac fitness. development or evaluation of the rehabilitation program.
Chair therapy was introduced in the 1940s, and by the early
HISTORY OF CARDIAC FITNESS PROGRAMS 1950s, 3–5 minutes of daily walking was advocated, beginning at
4 weeks. Clinicians gradually began to recognize that early ambula-
The relative importance of physical activity for patients with so- tion avoided many of the complications of bed rest, including pulmo-
called “disorders of the chest” was noted some 200 years ago. In nary embolism (PE), and that it did not increase the risk. However,
1772, a physician named Heberden published a report describing concerns about the safety of unsupervised exercise remained strong;
Chapter 21  History of Cardiac Fitness 141
this led to the development of structured, physician-supervised had attempted either to retrain for another job or seek a different
rehabilitation programs, which included clinical supervision, as well position in their company. In 1940, the New York State Employment
as electrocardiographic monitoring. Service asked the New York Heart Association to assist in evaluating
cardiac workers to determine the level of activity, the cardiac patient
Rehabilitation Starts Soon after could perform safely. This request eventually led to the establish-
ment of the work classification unit or work evaluation unit. Cardiac
an Acute Coronary Syndrome
work evaluation units were located in teaching hospitals, rehabilita-
By the 1960s, numerous studies demonstrated that early activity after tion centers and community hospitals. Patients were referred by pri-
an MI safely negates the adverse effects associated with prolonged vate physicians and employers and from institutions and vocational
bed rest. Saltin et al. reported that the functional capacity of normal agencies. At the unit, patients were evaluated for their physical and
subjects confined to bed for 3 weeks decreased approximately 33%. psychological capacity for work. Cardiologists performed laboratory
Equally important was his finding that an appropriate equal time of tests, resting electrocardiograms (ECGs), and a master’s step test.
training was necessary to restore the subjects to their pre bed-rest A variety of health care professionals interviewed the patients. Most
condition. After 3 months of twice-daily rigorous exercise programs, evaluations took 3 weeks to complete and, after a team conference,
all patients exceeded their control states. recommendations were made to the referring party. No formal exer-
Inpatient cardiac rehabilitation became more formalized cise program was included or prescribed for the patients. The pur-
in the 60s primarily through the efforts of Wenger, Zohman and pose of these units was three-fold:
Tobis, and Bruce in the 50s. The adopted programs instituted early 1. To provide a clinical service by using a team evaluation of the
supervised reconditioning during the acute post-MI phase while work capacity of the cardiac patient and offering an opportunity
the patient was still in the coronary care unit (CCU) and during the for appropriate job placement;
postacute phase while the patient was in the step-down unit. The 2. To serve as an educational instrument for training physicians
protocol of Wenger et al. consisted of a 14-step program of progres- and for informing the general public; and
sively increasing physical activity levels with emphasis in three areas: 3. To serve as a research organization for studying cardiac patients
graded physical exercises, activities of daily living and educational by looking at the relationship of the cause of cardiac disease to
activities. The program usually was initiated in the CCU after the pa- the ability to work.
tient’s clinical condition was stable. Physical activities at this stage Thus, the cardiac work evaluation unit was an early approach to
required low-level oxygen demand. They included self-care and what we know today as cardiac rehabilitation. Criticism grew, how-
supervised active and passive range of motion exercises; progressive ever, in the 1950s over the small numbers of patients being referred
ambulation was added shortly thereafter. Patient and family educa- and the methods used to classify coronary disability. This situation
tion programs paralleled the graded physical activities. This struc- caused fragmentation of evaluation and care of these patients. Grad-
tured plan greatly assisted the patient towards discharge and an early ually, the effectiveness and success of the units dwindled. In 1952,
return to normal living. Levine and Lown openly questioned the need for enforced bed rest
Zohman’s program provided exercise using an equicaloric tech- and prolonged inactivity after an MI. Based on work performed in
nique that matched the level of energy expenditure with exercise of a Boston hospital during the 1940s and spurred by the manpow-
equal caloric value. The exercises were monitored by radiotelemetry, er needs during World War II (WWII), they helped liberalize the
and energy costs were measured as a check on the rehabilitation attitudes among physicians regarding the need for rigid restrictions
activities. The favorable outcome of these structured programs en- of activity. From their work, they concluded that long-continued
couraged the development of similar programs around the country. bed rest “decreases functional capacity, saps morale, and provokes
Soon, other hospitals also were experiencing the positive economic complications”. Their highly published report caught the attention
implications of early intervention. These included a hastened recov- of many and raised numerous clinical questions about the manage-
ery time and decreased hospital stay; improved functional status at ment of cardiovascular disease.
the time of discharge and in turn, an earlier return to work. Exercise-based cardiac rehabilitation programs were initiated
in the 1950s to reverse the physical deconditioning and reduced
Need for Early Return to Work and Exercise exercise capacity produced by such hospitalizations and attendant,
restricted physical activity. Exercise training was central to revers-
By the late 1930s, many members of the labor force were retired ing this deconditioning process. Exercise training was also central
on disability because of cardiac problems. The New York State Em- to cardiac rehabilitation efforts because exercise was one of the few
ployment Service, concerned about the growing numbers of men interventions documented to delay the onset of classic angina pec-
on disability, decided to investigate the situation. A survey identi- toris before the availability of b-blockers, calcium blockers, coronary
fied that 80% of the individuals receiving disability were coronary artery bypass graft (CABG) and percutaneous transluminal coronary
patients, who had not returned to their jobs. Furthermore, only 10% angioplasty (PTCA).
these reports have also given rise to a number of heated controver-

REHABILITATION / MAINTAINING
sies in the realm of medical research in recent years. For example,
FITNESS AFTER DISCHARGE
many researchers have accepted that a correlation exists between
By the end of the 1960s, Hellerstein, a well-known Cleveland cardi- physical activity and reduction of risk of heart disease; however,
ologist encouraged by the results of his inpatient program, boldly they question whether exercise actually reduces the risk or if it is
chose to incorporate physical exercise into a follow-up program after “just that healthy people exercise more than unhealthy ones” (Lavie
hospital discharge. A formalized study was conducted involving 200 et al., 1987, p. 67).
post-MI patients at the Cleveland YMCA and later at the local Jewish
Community Center. Hellerstein was criticized severely by his peers Stress on Importance of Physical Activity
for his innovative but risky approach. The study clearly demonstrated
that cardiac patients could benefit physiologically from regular pro- At the 13th Scientific Session of the American Heart Association
gressive exercise and enjoy improved psychological confidence with- (AHA) in Chicago in 1953, the noted physician Louis Katz told the
out a negative effect on either mortality or morbidity. The success of medical community that “physicians must be ready to discard old
his medically supervised program offered a new dimension, the out- dogma when they are proven false and accept new knowledge.” The
patient program, to cardiac rehabilitation. As a result of the work of need to continue research on physical activity and to assimilate this
Hellerstein, Wenger, Zohman and others, the concept of progressive new information into the practice scheme for the cardiac patient
supervised activity for the post-MI patient and the postsurgical pa- was emphasized. Turelland Hellerstein urged physicians to provide
tient has taken its rightful role in the practice of medical therapeutics. a more positive philosophy and a more comprehensive approach in
Despite multiple advances, Hellerstein’s original ideas have not treating cardiac patients. The application of work physiology princi-
been improved upon significantly. However, due to changing patient ples was stressed. Turell and Hellerstein recommended a graded step
demographics, many more patients now have the opportunity to program (a prototype to contemporary cardiac rehabilitation) based
receive the benefits offered by cardiac rehabilitation. Multifactorial on established energy requirements of physical activity and patient
intervention, including aggressive risk factor modification, has be- exercise tolerance with continual evaluation of cardiovascular func-
come an integral part of present day cardiac rehabilitation. tion. Thus, the prevailing theme of this period was clinical research
These educational components are deemed important enough on physical activity and its relationship to coronary artery disease.
to be required for accreditation by the American Association of Car- The strength of the new research provided visible evidence to a
diovascular and Pulmonary Rehabilitation. doubting medical society. Dwight Eisenhower, the then President of
Then there started a growing consensus that exercise contributes the United States, suffered a heart attack in office. His physician was
positively towards the prevention of cardiovascular disease. Several the noted Paul Dudley White, a man strongly committed to the posi-
longitudinal studies have been conducted in recent years which tend tive effects of exercise. He prescribed graded levels of exercise, in-
to support this viewpoint. One of the first such studies was conduct- cluding swimming, walking, and golf, for his celebrated patient. This
ed in Framingham, Massachusetts, in the late 1960s. In an attempt regimen was viewed by many physicians as reckless and inappropri-
to determine the causes of coronary heart disease, the researchers ate, especially given the patient’s eminence. The result turned out
questioned over 1,600 persons who had a history of the disease. This to be so positive for President Eisenhower that he created the Presi-
data enabled the Framingham study researchers to establish a risk dent’s Youth Fitness Council, later to be renamed the President’s Fit-
indicator known as “Type A behaviour” (Stamler, 1983, p. 82). In this ness Council by President Kennedy.
way, it became possible to isolate which members of the population
will stand a greater chance of contracting cardiovascular disease. For Cardiac Rehabilitation in the
example, although men in general stand a greater risk of this than
Present Day Scenario
women do, elaborations of the Framingham Study have determined
that women who experience early menopause run a seven times A comprehensive cardiac rehabilitation program today consists of
greater risk of heart disease than women for whom menopause oc- several phases: Phase I—inpatient hospital phase beginning in the
curs later in life (Notelovitz, 1987, p. 121). CCU; Phase II—outpatient hospital-based phase for 2–4 months;
The Framingham Study also isolated numerous other factors and Phase III—maintenance phase for 4–6 months or even up to 12
contributing to the risk of cardiovascular disease, including a seden- months. Each phase has its own objective for patient care and pro-
tary lifestyle. On this basis, it can be seen that physical exercise and gression. Each phase has an educational component commensurate
fitness provide possible approaches to counter this risk. This view with the patient’s level of knowledge of the disability and level of
was supported in a study conducted by Paffenbarger and Asion of activity. Most programs today include a graded exercise test not
Type A behavior is possibly in large numbers of Type A people and only as a screening procedure but also as a functional evaluation for
whether it results in primary and/or secondary prevention of coro- prescription and progression.
nary heart disease” (Stamler, 1983, p. 77). The findings published in
Increasing Role of a Physiotherapist Mar 14, 2002: Physical fitness levels turned out to be the greatest pre-
dictor of how long someone might live—more important than smok-
The role of a physical therapist in cardiac rehabilitation has also ing habits, having high blood pressure or a personal history of heart
expanded over the last 25 years. Initially, the physical therapist did attacks—in a new study of more than 6,000 California men.
not see patients in the CCU. Physical therapy involvement came after
the patient was stabilized and out of the CCU. Progression of activ- Jan 24, 2005: The American Heart Association says doctors should be
ity was outlined by the physician on a day-to-day basis. Treatment more aggressive in encouraging heart attack patients to exercise and
consisted of simple range-of-motion activities and ambulation. Most follow cardiac rehabilitation recommendations to avoid a second
monitoring and telemetry were performed by the nurse. Currently, heart attack.
physical therapists are responsible for directing cardiac rehabilita-
tion programs in a variety of facilities: private community hospitals, Aug 7, 2007: World-renowned cardiac surgeon Dr Mehmet Oz and
health maintenance organizations, private physical therapy offices, celebrity fitness trainer Bob Greene announce first-of-its-kind heart
sports and athletic conditioning centers, and community centers. health program.
Their involvement includes evaluation and treatment in all three
major phases. In addition, some physical therapists have acquired Summary of Cardiac Rehabilitation
the necessary skills to conduct exercise tests without direct physician
supervision. Cardiac rehabilitation has increased dramatically in recent years.
Physical therapists also have demonstrated competency in Inpatient and outpatient programs in the hospital and at community
responding to life-threatening and emergency situations as docu- sites are being implemented all over the country. Better equipment
mented by their (1) certification in the AHA basic life support course and greater experience with exercise and patient education have
and (2) certification in the AHA advanced life support course, which made cardiac rehabilitation safe and beneficial for the majority of
includes extensive testing of ability to identify rapidly complex patients with MIs and coronary artery bypass surgery. Equally sig-
arrhythmias. This new role brings with it a change in professional nificant, research over the last 10 years has provided empirical data
relations and an enormous responsibility and challenge in educa- suggesting that cardiac rehabilitation programs are safe and effective
tion, research and patient care. method of improving physical, physiological and psychological well-
being and greatly enhance the quality of life for cardiac patients.
Evolution of Cardiac Fitness/Rehabilitation
Programs in the United States AEROBICS FOR CARDIAC
FITNESS—ITS HISTORY
1979: Established in 1979, the cardiac rehabilitation program was
among the first in the US to take a comprehensive disease manage- Aerobics is a fairly new form of exercise. It was Dr Kenneth H Cooper,
ment approach to secondary heart attack prevention by focusing an exercise physiologist for the San Antonio Air Force Hospital, Tex-
treatment not only on exercise but also on lifestyle changes. as, who coined the term ‘aerobics’ to describe the system of exercise
that he devised to help prevent coronary artery disease. Dr Cooper
Aug. 8, 1981: The first known heart fitness center in the US built at the originally formulated aerobic exercises specifically for astronauts,
cost of millions near Lake Arrowhead. but soon realized that the same set of exercises are useful for the gen-
eral public as well, especially those suffering from obesity, who are
Aug. 1988: Cardiac rehabilitation services were initiated in August of more likely to develop various heart diseases. Dr Cooper, an avowed
1988 at Greater Regional Medical Center. exercise enthusiast, was personally and professionally puzzled about
why some people with excellent muscular strength were still prone
1989: Established a cardiac rehabilitation service in 1989, which was to poor performance at tasks, such as long-distance running, swim-
initially funded only through research funds, but which has now ming and bicycling. He began measuring systematic human perfor-
become fully integrated in the comprehensive cardiac treatment mance using a bicycle ergometer and began measuring sustained
program offered through the University College London Hospitals performance in terms of a person’s ability to use oxygen. His ground-
(UCLH) Foundation Trust. breaking book, “Aerobics”, was published in 1968, and included sci-
entific exercise programs using running, walking, swimming and
Sep. 2001: As well, a paper was published in September 2001 in The bicycling. The book came at a fortuitous historical moment, when
New England Journal of Medicine acknowledging the importance of increasing weakness and inactivity in the general population was
cardiac rehabilitation in modifying risks for heart disease and reduc- causing a perceived need for increased exercise. It became a best-
ing mortality due to heart attack. seller. Cooper’s data provided the scientific baseline for almost all
modern aerobics programs, most of which are based on oxygen-con- to raise any creative debate on the topic further, the last bits of criti-
sumption equivalency. cism on aerobics soon died down, never to stick its neck out again.
In a matter of months, the book became a big hit amongst the
fitness-minded American public, and its sales quickly crossed the Advent of Sport Aerobics
million dollar mark, a feat that nonfiction or non-novel publica-
tions rarely achieved at that time. Expert analysts attributed the huge Howard and Karen Schwartz are the two persons who developed a
popularity that Aerobics received in sales, to the growing realization very new and competitive sport known as sport aerobics in the year
amongst the American public regarding the importance of being fit. 1983. Their group organization called the sport fitness international
The percentage of fit Americans had been in a downslide as the aver- holds the credit of organizing the first national aerobic champion-
age man and woman had begun to live a sedentary lifestyle, seek- ship in the year 1984. Sport aerobics at the beginning, started fea-
ing solace in the many comforts that advancements in technology turing competition in four categories namely individual male and
offered in the post-World War II years. Many were desperate to shed female, mixed pairs and trio which have the facility to include any of
their idling lifestyles and the timing of aerobics to hit bookstands the three athletes. In the year 2002, the competition was upgraded to
could not have been any better. The new book, explaining a number a group of six athletes. The judgment of the competitors is done on a
of scientific exercise programs that use walking, jogging, bicycling one minute, forty-five seconds routine done to music. Judges choose
and swimming in a constructive way, was not only easy for the public two criteria namely the artistic merit and the technical merit with an
to follow, but was also found to be very effective in boosting overall overall 10 points each. In 1996, sport aerobics was formally adopted
fitness levels, and there began the revolution—an exercise form that as a gymnastique discipline.
was to take the fitness world by storm.
Shortly after the publishing of Cooper’s book about the exer- Evolution of Aerobics for Cardiac
cise system, Aerobics in 1968, a person known as Jackie Sorenson
Fitness in the United States
developed a series of dance routines known as the aerobic dance to
considerably improve the cardiovascular fitness. In this way, aerobic 1967: Local physicians, the Physical Education Department of
dance and other form of exercises gained existence and made its way McMaster University and the YMCA started the Burlington Family
cautiously among the masses all over United States and many other YMCA’s Post Cardiac program in 1967. Today, the program is one of
counties and that too in a very short span of around 2 decades. The the largest and best-known cardiac exercise programs in Canada.
number of aerobics participant in the US alone raises from an esti-
mated 6 million in 1978 to 19 million in 1987. Thus, from the above 1968: Dr Cooper wrote a book about aerobic exercise. While he did
lines, one can easily see the tremendous popularity of aerobics not coin the term step aerobics, and in most cases talked about
among the people around the world. aerobic exercise like running, Cooper’s book did move us closer to
Aerobic exercises evolved continuously during the next 2 or 3 starting step aerobics as a form of exercise on its own.
decades. Dance aerobics, water aerobics, step aerobics, all were the
products of that period. Even Dr Cooper himself would not have 1977: Polar invented the first electrocardiograph (ECG) accurate
thought at that time that his brain child would one day achieve such wireless heart rate monitor. Polar FT7 men’s heart rate monitor
diversity and unparalleled levels of popularity in the world. Now, watch (black/silver) for those who want to know if they are improv-
it is believed that there are more than one billion aerobic followers ing their fitness or burning fat.
around the globe, more than half of whom reside in the North Ameri-
can continent alone. Sep. 18, 2007: Combining aerobic exercise and weight training may
Aerobics, like many other exercise and diet forms, has not had improve blood sugar control in people with Type 2 diabetes, a Cana-
a smooth transition into the fitness schedules of people without dian study shows.
its share of complaints and criticisms. The foremost amongst the
negative arguments raised against aerobics was that it is not a com- Nov. 12, 2004: The Michigan study confirms the findings of small-
plete exercise form, and hence not suitable for athletes and combat er studies showing that people who have suffered heart attacks
services, as Dr Cooper claimed when he formulated aerobics in its rebound faster and live longer when they do cardiac rehabilitation that
original form. Certain critics complained about how aerobics could involves exercise.
injure a person in the long run, and how aerobics is ineffective in
reducing obesity. But, when juxtaposed with a sedentary lifestyle, OTHER ADVANTAGES OF A FIT LIFESTYLE—
the positives of aerobics far outweigh the negatives and soon fitness
HISTORY OF ITS DISCOVERY
experts started to promote aerobic exercise as a major item in their
workout schedules. Also, its effectiveness when combined with other Not only is cardiovascular health good for children physically, it
workouts drew more people into trying out the new workout. Unable turns out that it may also promote intelligence. In a study published
in Proceedings of the National Academy of Sciences of the United cognition and cardiovascular fitness but not muscle strength and
States of America (PNAS), researchers say they have demonstrated a the longitudinal prediction by cardiovascular fitness on subsequent
clear positive association between adolescent fitness and adult cog- academic achievement, speak in favor of a cardiovascular effect on
nitive performance. brain function,” University of Southern California (USC) research-
The results of the study also show the importance of getting er Nancy Pedersen said, in their sample that the researchers also
healthier between the ages of 15 years and 18 years while the brain looked at 260,000 full-sibling pairs, 3,000 sets of twins and more than
is still changing. The research team looked at data for all 1.2 million 1,400 sets of identical twins. Having relatives enabled the research
Swedish men born between 1950 and 1976 who enlisted for manda- team to evaluate whether the results might reflect shared family en-
tory military service at the age of 18. In every measure of cognitive vironments or genetic influences. Even among identical twin pairs,
functioning they analyzed—from verbal ability to logical perfor- the link between cardiovascular health and intelligence remained
mance to geometric perception to mechanical skills—average test strong, according to the study. Thus, the results are not a reflection of
scores increased according to aerobic fitness. Boys who improved genetic influences on cardiovascular health and intelligence. Rather,
their cardiovascular health between ages 15 and 18 exhibited sig- the twin results give further support to the likelihood that there is
nificantly greater intelligence scores than those who became less indeed a causal relationship. “The results provide scientific support
healthy over the same time period. Over a longer term, boys who for educational policies to maintain or increase physical education
were most fit at the age of 18 were more likely to go to college than in school curricula,” Pedersen said, “Physical exercise should be an
their less fit counterparts. Although they could not establish directly important instrument for public health initiatives to optimize cogni-
causality, the fact that they “demonstrated associations between tive performance, as well as disease prevention at the society level.”
BIBLIOGRAPHY
1. American Association of Cardiovascular and Pulmonary Rehabilitation. [Online] Available from http://www.aacvpr.org/certification/.
2. Blair SN, Kampert JB, Kohl HW, et al. Influences of cardio-respiratory fitness and other precursors on cardiovascular disease and all-cause mortal-
ity in men and women. JAMA. 1996;276:205.
3. Bruce RA. Evaluation of functional capacity in patients with cardiovascular disease. Geriatrics. 1957;12:317.
4. Cohen BS, Grant A. Acute myocardial infarction: effect of a rehabilitation program on length of hospitalization and functional status at discharge.
Arch Phys Med Rehabil. 1973;54:201-6.
5. Cohen BS. A program for rehabilitation after acute myocardial infarction. South Med J. 1975;68:145-8.
6. Detrich H. Effects of immobilization upon various metabolic and physiologic functions of normal men. Am J Med. 1948;4:3.
7. Detry JM, Rousseau M, Vandenbroucke G, et al. Increased arteriovenous oxygen difference after physical training in coronary heart disease. Cir-
culation. 1971;44:109.
8. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circula-
tion. 2002;106:1883.
9. Heberden W. Some accounts of a disorder of the chest. Med Trans Coll Physician. 1772;2:59.
10. Hellerstein H. Exercise therapy in coronary disease. Bull NY Acad Med. 1968;44:1028-47.
11. Katz LN. Symposium: Unsettled clinical questions in the management of cardiovascular disease. Circulation. 1953;18: 430-50.
12. LaMonte MJ, Barlow CE, Jurca R, et al. Cardiorespiratory fitness is inversely associated with the incidence of metabolic syndrome: a prospective
study of men and women. Circulation. 2005;112:505.
13. Laukkanen JA, Lakka TA, Rauramaa R, et al. Cardiovascular fitness as a predictor of mortality in men. Arch Intern Med. 2001;161:825.
14. Lee IM, Sesso HD, Oguma Y, et al. Relative intensity of physical activity and risk of coronary heart disease. Circulation. 2003;107:1110.
15. Lemaitre RN, Siscovick DS, Raghunathan TE, et al. Leisure-time physical activity and the risk of primary cardiac arrest. Arch Intern Med.
1999;159:686.
16. Levine SA, Lown B. Armchair treatment of acute coronary thrombosis. JAMA. 1952;148:1365.
17. Mallory GK, White PD, Salcedo-Salger J. The speed of healing of myocardial infarction: a study of the pathological anatomy of seventy two cases.
Am Heart J. 1939;18:647-71.
18. Manson JE, Hu FB, Rich-Edwards JW, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart
disease in women. N Engl J Med. 1999;341:650.
19. Masters AM, Oppenheimer ET. A simple exercise tolerance test for circulatory efficiency with standard tables for normal individuals. Am J Med
Sci. 1929;177:223.
20. Moss AJ, DeCamilla J, Davis H. Cardiac death in the first six months after a myocardial infarction: potential for mortality reduction in the early
posthospital period. Am J Cardiol. 1977;39:816.
21. Parry CH. An Inquiry into the Symptoms and Causes of Syncope Anginosa Commonly Called Angina Pectoris. London, England: Caldwell and
Davis; 1799.
22. Redwood DR, Rosing DR. Circulatory and symptomatic effects of physical training in patients with CAD and angina pectoris. N Engl J Med.
1972;286:959.
23. Saltin B, Bloomquist G, Mitchell JH, et al. Response to exercise after bedrest and after training. Circulation. 1968;38 (Suppl VII):1-78.
24. Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation. 1999;99:963.
25. Turell D, Hellerstein H. Evaluation of cardiac function in relation to specific physical activities following recovery from acute myocardial infarc-
tion. Prog Cardiovasc Dis. 1958;1(2):237.
26. Wagner A, Simon C, Evans A, et al. Physical activity and coronary event incidence in Northern Ireland and France: the Prospective Epidemiologi-
cal Study of Myocardial Infarction (PRIME). Circulation. 2002;105:2247.
27. Wenger N. The use of exercise in the rehabilitation of patients after myocardial infarction. JSC Med Assoc. 1969;65(Suppl 1):66-8.
28. Wenger NK, Gilbert CA, Siegel W. Symposium: The use of physical activity in the rehabilitation of patients after myocardial infarction. South Med
J. 1970;63:891-7.
29. Wenger NK. Coronary Care—Rehabilitation After Myocardial Infarction. Dallas, TX: American Heart Association; 1973.
30. Zohman L, Tobis JS. A rehabilitation program for inpatients with recent myocardial infarction. Arch Phys Med Rehabil. 1968;49:443.
31. Zohman L. Early ambulation of post-myocardial infarction patients: montefiore hospital. In: Naughton J, Hellerstein HK (Eds). Exercise Testing
and Exercise Training in Coronary Heart Disease. Orlando, FL: Academic Press Inc; 1973. pp. 329-35.
32. Zohman LR, Tobis JS. Cardiac Rehabilitation. Orlando, FL: Grune and Stratton Inc; 1970.
22 History of Blood Pressure
and Its Measurement
Hegde BM
“If you want to understand today, you have to search yesterday.”

—Pearl Buck
INTRODUCTION the mercury manometer, but still we needed to puncture an artery

to measure the pressure. Ludwig’s kymograph and Vierordt’s coun-
Measurement of arterial pressures started with the study of radial ter pressure sphygmograph were the further innovations. In the year
pulse by Charaka around 400 BC, which was copied by Hippocrates 1860, Etienne Jules Marey brought in lots of newer innovations on the
around 100 BC in Greece where by then the Samhitas had reached; sphygmograph, which was further, refined in London a Homeopath,
brought along by the returning army of Alexander, the Great. The RE Dudgeon. Pioneering its popular usage was achieved by Bour-
Egyptians, the Arabs and the Chinese had also developed their own don Sanderson who later went on to become the Regius Professor of
methods of the crude appreciation of the arterial pulse pressure. The Medicine at Oxford. It was Potain that suggested that all is not in or-
three finger study of the pulse, originally described by Charaka, was der in this area and he brought in arterial resistance into the picture,
endorsed by Hippocrates in his thesis. In the intervening 2500 years but was ignored by the majority of his peers.
plenty of water has flowed down the Ganges River. None of those dis- Surgeon Faivre, in 1856, was the first to use intra-arterial blood
coveries and innovations are yet to unravel the greatest mystery of pressure measurement during surgery through a cannula. The story
how blood flows inside the blood vessels and how the heart, a small of noninvasive measurements started with Samuel Siegfried Karl Rit-
muscular pump weighing 300 g could pump blood into this huge sea ter von Basch in Vienna who in 1870 introduced an inflatable bal-
of capillaries where even a small red blood cell (RBC) has to squeeze loon, but it was very complicated. Zadek, following on his predeces-
itself through those very tiny tubes, requiring enormous energy! This sor, measured the intra-arterial pressures simultaneously to compare
process, if it is true, requires enormous energy for blood movement the two methods with success.
inside the closed system where the blood gets collected from the Gradual improvements have brought us to the present era which
capillary swimming pool to be sent back to the same pool. The heart started in Turin, Italy in 1896 by Scipione Riva Rocci. Lewis WH made
could be compared to a swimming pool pump! Many of us think some improvements, but the present wider cuff was the invention of
that our generation is responsible for all the newer developments in von Recklinghausen in 1911. All these could only measure the so
this area. Reminds me of what an African Proverb once said: “Until called systolic pressure recorded when the arterial lumen gets to-
lions have their historians, tales of the hunt shall always glorify the tally occluded. All these methods have only been able to record the
hunters.” so called systolic blood pressure. There was then a craze for record-
ing the diastolic blood pressure, which was given a boost by Hill and
THE BEGINNING Bernard in London in 1897 and Underwood in 1962. But more than
them all, it was the Russian surgeon from St Petersburg, NC Korot-
Reverend Stephen Hales (1677–1761), who began the first enquiry koff who for the first time noted that the auscultation of the brachial
into blood flow, in 1733 inserted a long glass tube into his mare’s artery beyond the obstruction starts to emit loud sounds at the level
crural artery and saw blood running up the tube to a height of 8’4”! at which the systolic pressure and further lowering gave different
He continued to do many other physiological studies to be elected sounds which at one stage completely disappeared. He called that as
Fellowship of the Royal Society (FRS) in 1718 only to be followed the diastolic pressure at the disappearance of the Korotkoff’s sounds.
by the French Royal Society in 1753. Thus began the present era of The spin off of this discovery was the use of binaural stethoscope
blood pressure measurement directly. Johannes Müller, a historian, in place of Laennec’s tube or the so called uniaural stethoscope. Dr
once wrote that this discovery overshadowed even the discovery of Seagull provides a nice translation of Korotkoff’s article in the Rus-
blood itself in its impact on science. Poiseuille, in 1828, introduced sian Journal of Clinical Medicine 1956; volume 4 and number 11.
LATER DEVELOPMENTS WHAT IS THE FUTURE?

These days sensors on the thumb, strain gauges, photocells and even With the advent of progress in physics and fluid flow dynamics, our
semiconductors seem to have joined the bandwagon for recording ideas of blood pressure and its measurement need refining, to say the
blood pressure more accurately; even for continuous monitoring. least. The blood circulation happens in a closed tube system, which is
That said, “I must hasten to add that there are a lot more new data not linear and follows the laws of nonlinear dynamics. The heart that
in this area which are still shrouded in mystery as it was before Rev”. we think is the kingpin in the game never existed in our fetal life for
Stephen Hales started his monumental work. For the beginning, it has nearly 20 weeks and the blood circulated on its own around the body
been now discovered that the diastolic pressure cannot be easily re- with the help of two dorsal tubes, which later became part of the
corded correctly as the Korotkoff’s sounds cannot be easily discerned heart. Blood flow does not, therefore, totally depend on the heart’s
by all doctors and nurses. There are now more sounds described. contractions! Where does the enormous energy that we talked about
Then comes, the bombshell from the largest study, the MRFIT study earlier in the chapter come from for blood circulation? Recent data
where 500,000 people were screened to select 100,000 subjects for the do show that the flowing blood generates its own energy as it flows in
study. The data, in retrospect, did reveal very clearly that the future whirls and not in the way we have been taught in the medical school.
events and complications, even death, depended only on the systolic Angioscopic studies have shown the whirling very clearly in animals
pressure and that the diastolic pressure has very little predictability. as also in man.
The ascendency of the systolic over the diastolic pressure for prog- How then are we keeping the definition of blood pressure as the
nosis is now an accepted fact. Progress in any area of science is change “lateral pressure exerted on the vessel wall by the flowing blood”?
for the better. That is what is happening in this field as well. Our pre- Does flowing blood exert lateral pressure? Is it a simple laminar
sent status could be gauged by the frustration of one of the greatest flow as happens in a straight tube? We need to audit our manage-
researchers in this area, Professor Sir George Pickering, who studied ment strategies. Uffe Ravnskov had audited 17 studies of blood pres-
this all his life. “More people make a living off blood pressure than sure management in the world literature recently and has come up
dying of it.” The abuse and misuse of the sphygmomanometer and the with startling data that the absolute risk reduction (ARR) of blood
multiple attempts at lowering the “normal” range has caused untold pressure lowering using chemical molecules was negligible! There
misery to the common man. These attempts have kept pace with the are more questions in this area than answers. Lot more needs to be
exponential growth of the number of blood pressure lowering drugs done. Here comes the usefulness of the history of blood pressure
from the industry! The history of this saga is very well documented in measurement through the last 2500 years-understand today by
the beautiful book by Professor Jerg Blech, titled “Disease Inventors”. studying yesterday!
BIBLIOGRAPHY
1. Blech Joerg. “Die Krankheitserfinder” (translated) “The Disease Inventors”, ISBN 3-10-004410-X, can be ordered website: www.s-fischer.de
2. Booth J. A short history of blood pressure measurement. Proc. Royal Society of Medicine. 1997;70:793-9.
3. Hegde BM. Is the heart a simple muscular pump? J Ind Acad Clin Med. 2008;9:172-4.
4. Pickering Sr. G. High Blood Pressure. New York: Grune and Stratton, Inc.; 1955. P. 16.
5. Ravnskov U. Chance of survival with or without treatment. BMJ. 2002;324:1353a.
History of Blood Pressure
23 Amplification between the Heart
and Peripheral Arteries
Rourke MO’, Adji A, Namasivayam M
It has been known for almost a century, since adequate manome- ficult to explain. All challenged the existing view that systolic and
try was available, that the pressure wave is amplified in height and diastolic pressure remained the same throughout the arterial tree so
changed in shape as it travels from the aorta to peripheral arteries.1,2 that left ventricular load could be accurately measured from brachial
Figures showing such change have graced the front cover of a stand- artery cuff pressure. Such a view is still assumed in the most recent
ard textbook, McDonald’s Blood Flow in Arteries textbook of Physi- articles in top medical journals.9
ology over many years.3 Changes are not easily explained if one is There were other problems which distracted and deflected
accustomed to thinking of the arterial pulse in terms of peak (sys- researchers and potential researchers in this field of arterial hemo-
tolic) and foot (diastolic) pressures. But the changes are readily ex- dynamics. The patterns of pressure waves were different in different
plained if one appreciates that there is a minute fall (1–2 mm Hg) in animals and were rarely measured in the foreleg by physiologists
mean pressure between aorta and peripheral arteries,4 but (usually) who concentrated on the trunk and more powerfully developed
marked change in pulse pressure, due to wave reflection having its lower limbs.2,3 The patterns of pressure waves in humans under-
greatest effect at the periphery close to reflecting sites.2,3 The phe- going cardiac catheterization or surgery were different to those in
nomenon of wave reflection is readily apparent when one consid- animals, usually showing secondary pressure waves in the systolic
ers the shape of ascending aortic flow and pressure waves. The flow rather than the diastolic part of the wave.2,10 Furthermore, clinicians
ejection wave from the heart is a single spurt, whereas almost always became more interested in images—in angiograms rather than pres-
one can distinguish two (or more) peaks on the pressure wave and in sure waves and pressure gradients, and took less concern on setting
animals with the second wave in diastole.2,3 and maintaining frequency response, and so dynamic accuracy of
The same phenomenon of wave reflection is seen in humans, but catheter manometer systems. The key advance in this area was in-
clinicians almost universally have been taught to interpret the pulse troduction of the pressure tip catheter manometry by Millar and
on the basis of systolic (highest) and diastolic (lowest) pressure in the Murgo,11 which permitted accurate recording of detail in pressure
brachial artery over the course of a single pulse. Mahomed’s study of waves. Unfortunately the cost and complexity of the instruments,
the sphygmogram in the 19th century had shown that the shape of a and rules against reuse have led to declining use in clinical practice.
central (carotid) pressure wave in humans was different to that in the However, the same technology has been introduced into new non-
radial artery,5 but neither he nor others at the time could calibrate invasive tonometers.12,13 This reopened the field of pulse waveform
the pulse and establish amplification in humans. analysis that had been well developed in the early 1900s, prior to
Introduction of cardiac catheterization in the late 1940s for clinical introduction of the cuff manometer.5
diagnostic purposes required better understanding of the pulse, as In animal experimental work, US physiologists, such as Hamil-
did invasive pressure measurement by anesthetists and surgeons ton, Dow and Remington2 pursued their studies of the arterial pulse
for monitoring in complex prolonged surgery, and in intensive waveform in the time domain, trying to keep track of individual un-
care. Studies in humans were undertaken by pioneers in the field, dulations or pressure pulses to explain the effects of wave reflection
with hitherto unexpected results. Those of Earl Wood at Mayo Clinic on the amplitude and shape of the waves in different arteries. In Brit-
showed marked amplification of the pulse wave between aorta and ain, physiologists McDonald and Taylor,14 working with mathemati-
radial artery with the greatest amplification proximally (to the el- cians, devised approaches for studying pressure (and flow) waves in
bow) and the least distally (to the wrist from elbow). Wood and col- the frequency domain by breaking up waveforms into harmonics and
leagues6,7 showed changes in amplification with change in heart rate, comparing the relationship of harmonics to explain relationships of
with posture, and with physiological procedures, such as Valsalva waves in different arteries. This was very rewarding, and permitted
maneuver. Rowell et al.8 showed that exercise could increase radial relationships to be described numerically, with quantification of
artery pressure two-fold with minimal change in the aortic pulse. wave reflection and so explanation of magnitude and origin.15-17
These changes were obviously due to wave reflection, but were dif- Figures 23.1A and B shows how pressure waves recorded along
and at different frequencies explaining contour of the pressure. This

approach was justified by the theoretic calculations of John Wom-
ersley,16 that the artery could be considered to a first approximation
as a linear system with respect to pressure and flow waveforms. All
this work led up to that of Michael Taylor who established Vascular
Impedance as a method for characterizing properties of a complex
vascular bed, and pressure transfer functions as a method for char-
acterizing pressure wave propagation in a vascular bed.17-20 This ap-
proach was taken up by Murgo, Nichols, Gourgon, O’Rourke21-24 and
other clinicians for studying pressure wave amplification in the hu-
man circulation.
Clinical studies of pressure wave transmission in humans was
made possible by the theoretic work of Drzwiecki25 and practical
work of Millar in developing robust and accurate tonometers for
noninvasive measurement of arterial pressure waveforms.12 This was
advanced by the late Ray Kelly and his colleagues in Sydney and Bal-
timore. It was Kelly12,13 who showed that tonometry, properly used,
could measure pressure waveforms from the surface of an artery
or from the overlying skin, which were identical to those recorded
A
within the artery by high fidelity manometer. Kelly also showed the
changes in the pressure waveform that occur with age in the radial
and carotid arteries and explained the reason for such change.26 He
also showed how amplification of the pulse between central aorta
and peripheral arteries varies with age, and is dependent on the
shape of the pressure wave generated in the aorta. His studies with
Yaginuma27 from Japan established how drugs, such as nitroglycerin
alter the properties of large conduit arteries and can thereby mark-
edly reduce wave reflection and lower aortic systolic pressure with-
out any demonstrable effect on peripheral resistance or aortic stiff-
ness, measured as aortic characteristic impedance. This led to a most
important finding, illustrated in Hurst’s textbook “The Heart” from
2005, that aortic and left ventricular (LV) systolic pressure can be
reduced by as much as 20 mm Hg without any reduction in brachial
systolic pressure28 (Fig. 23.2). This finding explained how beneficial
effects of nitroglycerin were not adequately explained by measures of
brachial pressure; these were promptly followed by papers from our
colleagues in Canada29 and Japan.30 These confirmed Kelly’s work
B and began a challenge worldwide on the comfortable acceptance of
brachial cuff systolic pressure as a guide to cardiac risk and the best
Figures 23.1A and B: Pressure waves recorded sequentially at 5 cm guide to initiation and control of arterial pressure by drugs.
intervals between the aortic arch (5 cm from the aortic valve) and the But there was a further benefit to this work in the cardiac cath-
internal iliac artery (50 cm from the aortic valve) in a 16.5 kg wombat, eterization laboratory at St Vincent’s Hospital in Sydney. Kelly and
an Australian marsupial, through (A) A catheter inserted in the femoral colleagues had noted that wave reflection appeared to have a similar
artery, and (B) The amplitude of the first five harmonics of these
pressure waves. Source: Reference 15 effect on the reflected wave in the radial and aortic pressure pulse
and caused this to fall by a like amount.31 We sought a relationship
in the frequency domain, and found this (as a transfer function) to
the aorta of a wombat (an Australian marsupial with relatively long be relatively constant despite differences in age, gender, disease,
trunk and short limbs) could be displayed in the time and frequency drug therapy and body size for adults.32 We found a similar relation-
domain18 with evidence of high reflection amplitude at the end of ship in data previously published, and for aorta-brachial amplifica-
the body and with nodes and antinodes of pressure at different sites tion and aorta-radial amplification.32 Similar results were seen in
Chapter 23  History of Blood Pressure Amplification between the Heart and Peripheral ... 151
expected modulus, such as generated by ourselves, but phase that

was quite unrealistic, with distal pressure appearing to lead proxi-
mal pressure at high frequency.38 The new data were reanalyzed by
reviewers for Journal of Hypertension39 and an error found in calcu-
lation of phase such that synthesized waves were erroneous.
Another method for measuring central pressure from the radial
pressure wave has been tested and shown to conform with the trans-
fer function method in SphygmoCor,40 but this requires the second-
ary pressure wave to be recognizable, which it is not in up to 20% of
persons, usually the young, those with high heart rate, those receiv-
ing vasodilator therapy, those with “systolic” heart failure. This “sec-
ond shoulder method” for measurement of central pressure is based
Figure 23.2: Pressure waves recorded directly in the ascending aorta on the principles that arose from Kelly’s cardiac catheterization work
(top) and brachial artery (bottom) under control condition (left) and with respect to identification of the reflected wave in the pulse. It is
after 0.3 mg nitroglycerin sublingually (right) in a human adult. X = less useful than the transfer function approach and less convenient.
height of pressure pulse if there was no reflection; R = reflected wave.
A further criticism has arisen on the SphygmoCor process and
Source: Reference 28
is based on applanation tonometry applied to the brachial artery.
The careful early studies of Drzewiecki, Millar, Winter, Kelly and oth-
ers established that one must flatten the front wall of the underlying
artery, by compressing this against bone or ligaments behind. The
realistic models of the arterial system in the upper limb.33 Our col- radial and carotid sites are appropriate and at such sites (and espe-
leagues in Baltimore obtained similar results and showed that these cially the radial) an accurate noninvasive pulse waveform can be
applied during interactions such as Valsalva maneuver.34 We sought recorded, which approximates the intra-arterial pressure waveform.
advice from the US Food and Drug Administration (FDA) on which The brachial site is not an appropriate site since there is no bone be-
tests would be necessary for acceptance, then designed a study with hind the artery, and this needs be sensed through the stiff bicipital
Pauca, Kon and colleagues at Wake Forest Medical Center.35 Com- aponeurosis, which extends out from the biceps tendon over the bra-
parisons of generated with simultaneously-recorded aortic pressure chial artery and vein. It has not been possible here to show similarity
waves meet the specified criteria,35 and FDA approval was received of brachial invasive and noninvasive waveforms.
for measurement of aortic pressure with this method as K002742 and This criticism is answered by data of those who apply applana-
K012487. tion tonometry to the brachial artery. The wave appears blunted
The SphygmoCor method36 has been used in hundreds of papers and its form factor approximates that in the carotid artery. Pressure
and has shown benefit for measurement of aortic pressure and indi- amplification can be calculated as [pulse pressure (peripheral) ÷
ces of aortic pressure in clinical trials such as REASON, CAFE, Strong pulse pressure (central)] = [form factor (central) ÷ form factor (pe-
Heart, J-CORE and SubCHIEF. ripheral)]. When the form factors are nearly identical, amplification
This method of measuring central pressure is not without its crit- is trivial and there is no significant difference in pressure between
ics. Slowly, criticism has abated, as it did for use of vascular imped- the central and brachial artery. On the other hand, since radial
ance when first introduced by Taylor and McDonald. The principal tonometry is accurate and form factor is much lower than aortic,
antagonists from Melbourne, Australia, based their argument on use there is substantial difference in systolic pressure between the aorta
of the transfer function, since they could not generate transfer func- and radial arteries, as there is in invasive studies.
tion such as we had recorded. Pressed, they used high fidelity pres- Vlachopoulos et al.41 in a systematic review and meta-analysis
sure transducers and obtained the same modulus of pressure, but have confirmed the value of central pressure and indices over bra-
not phase. The first publication showed modulus inverted, and with chial cuff pressure in prediction of outcome and of anti-hypertensive
negative, as well as positive values.37 The last publication showed the drug effect.
Microvessels in Hypertension:
The Hundred Year Revolution
It is now almost 200 years since Richard Bright1 brought the problem this view in a recorded lecture at Guy’s hospital, “It is always danger-
of hypertension into focus by describing from Guy’s Hospital in Lon- ous to rest in a narrow pathology; and I believe that to be a narrow
don a series of clinical cases of patients with high arterial tension, pathology which is satisfied with what you now see before me on this
whose clinical course was characterized by cardiac failure, suscep- table. In this glass you see a much hypertrophied heart and a much
tibility to stroke, presence of albumin in urine, and at death and au- contracted kidney. This specimen is classical. It was, I believe, put
topsy, showing granular contracted kidneys. Bright noted that dur- up under Dr Bright’s own direction, and with a view of showing that
ing life, these patients’ pulses were “hard” and considerable pressure the wasting of the kidney is the cause of the thickening of the heart.
was required to occlude the radial artery at the wrist. I cannot, but look upon it with veneration, but not with conviction.
Bright’s observations led to recognition of the combination of I think, with all deference to so great an authority, that the systemic
albuminuria, shrunken kidneys, left ventricular (LV) hypertrophy capillaries, and, had it been possible, the entire man, should have
and susceptibility to cerebral and other vascular disease, as Bright’s been included in this vase, together with the heart and the kidneys;
disease. Studies were undertaken at Guy’s (and elsewhere) by clini- then we should have had, I believe, a truer view of the causation of
cians and pathologists, such as Gull and Sutton2 to find a cause and the cardiac hypertrophy and of the disease of the kidney.”
characterize the disease in life. The cause was considered to be con- Sir George Pickering5 and others confirmed the elevation of
striction of small blood vessels in the kidney, but Gull insisted that peripheral resistance in essential hypertension and the presence of
such small vascular disease must be present throughout the whole normal cardiac output in the presence of elevated mean pressure.
body if it caused arterial pressure to rise and the left ventricle to hy- Studies of the microcirculation, however, were nowhere near as
pertrophy, then fail, and the arteries to block or rupture in the brain impressive as those of malignant hypertension, and even in “benign”
and elsewhere. The work of Goldblatt and others confirmed the key hypertension one could not be sure that any arterial hypertrophy
role of the kidney and the issue was settled almost a century later seen may not be due to elevation of pressure itself and not the cause
when Byrom3,4 with support of Sir George Pickering5 described the of hypertension. Study of blood vessels were also difficult to interpret
vicious circle of hypertension whereby the kidney, through release of since all shrunk when removed from the body, and it was difficult to
renin and via angiotensin production, potentiated elevated pressure compare vessels of different size. The changes that one might expect
from any cause and led to its further elevation and eventually to the to see are minute, with a (substantial) increase in mean pressure of
malignant phase. In this phase, damage to, then obstruction and/or 50% caused by just a 10–11% narrowing of a blood vessel. Heagerty,
rupture of small arteries in brain, kidney, retina, led to encephalopa- Mulvany and others studied blood vessels taken from skin biopsy of
thy, renal failure and death of those who did not succumb first to LV normal and hypertensive subjects and showed increased media to
failure. lumen ratio in the latter.6 Heistad and colleagues examined blood
Byrom, with Dodson,3,4 and others characterized the arterial vessels in the brain of normotensive and hypertensive patients and
damage of the malignant phase as being solely due to stretching and animals and showed that these were of greater diameter than in other
tearing of the arterial wall and shedding of endothelium with forma- organs consistent with lesser resistance and lower pressure fall along
tion of thrombi. Byrom found such changes in the brain and kidneys their length.7 Others showed changes in blood vessels of the kidney
of patients with malignant hypertension and showed that he could in hypertensive patients, and for a time, renal biopsy was practiced in
induce such changes in rats by elevation of arterial pressure through the investigation of patients with hypertension and a suspected renal
any mechanisms—even just through momentary elevation of pres- mechanism.
sure from forceful injection of saline into the rat’s carotid artery. The greatest benefit to hypertension in clinical practice has been
Byrom’s experiments combined conventional histology with in vivo introduction of drugs which can break the vicious circle of hyperten-
microscopic evaluation of pial arteries on the surface of the brain sion and which have few side effects. These, and particularly the an-
through Lucite windows fitted into holes previously drilled through giotensin receptor blockers (ARBs) angiotensin-converting enzyme
the skull. The changes seen by Byrom were obviously secondary to inhibitors (ACEIs) and calcium channel blockers (CCBs) of today
elevated arterial pressure and were not the primary cause. They are particularly effective alone or in combination with each other,
could resolve with reduction in arterial pressure. or with diuretics, b-blockers and other agents.8 In clinical practice,
The primary cause of hypertension was sought through studies hypertension is now almost exclusively a disease of the elderly and
of arteries and arterioles in different tissues throughout the body and due not to elevation of peripheral vascular resistance, but to aortic
from the time of Bright in the 1840s. Gull2 insisted that such changes stiffening, and so characterized as isolated systolic hypertension
must be increased peripheral resistance of all organs. He described (ISH).9,9a When mean pressure is elevated as well in the elderly, as a
consequence of increased peripheral resistance, this can usually be pulsations are present in cerebral arteries of patients with this condi-
attributed to rarefaction of the vascular bed consequent on apoptosis tion as well.
of cells and atrophy of tissues.10 The cause of microvascular changes in the brain (and kidney)
Recognition of ISH as a consequence of aortic stiffening, and of of persons with ISH have been investigated by O’Rourke and Safar18
its sinister significance with respect to vascular events, and its re- and described as resulting from impaired capacity of the stiffening
sponse to therapy11-13 has brought back renewed interest in the mi- aorta to cushion the pulsations of flow ejected from the heart, so that
crocirculation, particularly in the brain and kidney. Microvascular those extend down into the small blood vessels and preferentially
disease of the brain and of the kidney in ISH is the most common into those organs with low resistance and very high normal resting
cause of intellectual deterioration and of kidney failure in older per- blood flow. The brain and kidneys are the organs principally at risk,
sons. This manifests in the brain as lacunar infarcts and microbleeds, the heart being protected through compression of its arteries during
and to amyloid deposits as the manifestation of previous micro- systole and the liver protected by mixture of hepatic arterial blood at
bleeds.14,15 Studies of the blood vessels of the brain in such patients high pressure with portal vein blood at low pressure.
show changes similar to but less dramatic than those described in One can be justifiably pessimistic on the possibility of prevent-
malignant hypertension, with a combination of small artery narrowing dementia caused by aortic stiffening, but one can also be as
ing or obstruction, and of tiny aneurysm formation with risk of rup- realistically optimistic about preventing (or delaying) this. As Byrom
ture and cerebral hemorrhage.16,17 stressed and Smirk showed,22 lesions in malignant hypertension
The vascular lesions in the brain of elderly patients with long- can be reversed by appropriate treatment and patients can recover.
standing ISH show similarities not only with those in malignant Patients with high systemic pressure can recover from acute poste-
hypertension, but also with those in children with pulmonary hyper- rior leukoencephalopathy through reduction in blood pressure, as
tension caused by congenital heart disease with left to right shunt can children with pulmonary hypertension by closure of left to right
and with high pulsatile flow entering and passing through the lungs.18 shunt at an early age. Treatment with drugs, which reduces wave
Initially these children have no problems, and their pulmonary mean reflection and high cerebral flow pulsations can prevent or slow
pressure is normal or only slightly elevated, but over the course of down the development of pulse wave encephalopathy and of intel-
several years, pulmonary resistance increases and mean pulmonary lectual deterioration and dementia.18 The outlook is as optimistic
pressure begins to rise.19 In the lung parenchyma one sees the same as Byrom described from malignant hypertension, and Kouwen-
microvascular changes as in malignant hypertension, with a combi- hoven described around the same time for another lethal condition
nation of thrombotic obstruction and wall weakening with formation (ventricular fibrillation).
of small aneurysms and hemorrhage.18,19 Ultimately these changes Frank Byrom was honored by the International Society of Hyper-
cause such permanent damage to the lungs that identification and tension with award of its Franz Volhard Prize in 1974 for his work on
closure of the shunt is futile. malignant hypertension. His other body of work was on the vicious
The mechanism for development of cerebral lesions in elderly circle of hypertension and its reversal by reduction in arterial pres-
patients with ISH, and which cause dementia and stroke, appears sure. He stressed that hypertension and its evil consequences are re-
to be linked to that in malignant hypertension and in pulmonary versible even when advanced to its most lethal phase.
hypertension from left to right hunt.9,9a,18 The mechanism is usually Byrom’s work singled out cerebral and renal vessels as targets of
ascribed to elevated pressure itself, but this cannot be so since in the damage and of treatment when blood pressure elevation causes aor-
children’s lungs, pulmonary mean pressure is initially normal and in tic stiffening, early return of wave reflection and greater damage in
the older persons, the lesions may develop when mean pressure is these highly perfused organs. He did not foresee that his theory also
normal and diastolic pressure low. A common factor is high pulsatile fits the chronic process of aging and aortic stiffening with increase in
flow. This is certainly seen in the lungs of children with left to right pulsatile pressure and increase in pulsatile flow in microvessels.
shunt, but it is also seen in the brain of older persons with ISH and This chapter describes another vicious circle in hypertension.
dementia.18 In such older persons pulsatile flow can extend into the This begins with microvascular disease that may begin with tissue at-
cerebral veins. The lesions in the brain of such persons have been rophy and rarefaction in microvessels. Resulting hypertension caus-
referred to as “pulse wave encephalopathy”.20,21 High cerebral flow es rise in arterial pressure and damage to large blood vessels, espe-
pulsations have not been specifically reported in persons with malig- cially the aorta. Rise in pressure damages these vessels, contributes
nant hypertension, but they have not been sought. In posterior leu- to aortic stiffening and early return of wave reflection, and leads to
koencephalopathy when blood pressure is raised to levels often seen high pulse pressure and high flow pulsations in the small blood ves-
in malignant hypertension, white matter changes are seen which are sels of brain and kidney; these high pulsations cause microinfarcts
similar to those seen in “pulse wave encephalopathy”,20,21 and these and microbleeds, which are the cause of cerebral and renal degen-
usually resolve with appropriate treatment. It is likely that high flow eration in hypertension and with aging.
REFERENCES
History of Blood Pressure Amplification Between the Heart and Peripheral Arteries
1. Wiggers CJ. The pressure pulses in the cardiovascular system. New York: Longmans Green; 1928.
2. Hamilton WF, Dow P. An experimental study of the standing waves in the pulse propagated through aorta. Am J Physiol. 1938;125:48-59.
3. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. London: Hodder Arnold; 2005.
4. Pauca AP, Wallenhaupt SL, Kon ND, et al. Does radial artery pressure accurately reflect aortic pressure? Chest. 1992;102:1193-8.
5. Mahomed FA. The physiology and clinical use of the sphygmograph. Medical Times Gazette. 1872;1:62.
6. Kroeker EJ, Wood EH. Comparison of simultaneously recorded central and peripheral arterial pressure pulses during rest, exercise and tilted posi-
tion in man. Circ Res. 1955;3:623-32.
7. Kroeker EJ, Wood, EH. Beat-to-beat alterations in relationship of simultaneously recorded central and peripheral arterial pressure pulses during
Valsalva maneuver and prolonged expiration in man. J Appl Physiol. 1956;8:483-94.
8. Rowell LB, Brengelmann GL, Blackmon JR, et al. Disparities between aortic and peripheral pulse pressures induced by upright exercise and vaso-
motor change in man. Circulation. 1968;37:954-64.
9. Jamerson KA, Bakris GL, Weber MA. 24-hour ambulatory blood pressure in the ACCOMPLISH trial. N Engl J med. 2010;363:98.
10. O’Rourke MF, Blazek JV, Morreels CL, et al. Pressure wave transmission along the human aorta. Changes with age and in arterial degenerative
disease. Circ Res. 1968;23:567-79.
11. Murgo JP, Millar HD. A new cardiac catheter for high fidelity differential pressure recordings. In 25th Annual Conference on Engineering in Medi-
cine and Biology. Bal Harbour, Florida; 1972. p. 303.
12. Kelly R, Hayward C, Ganis J, et al. Noninvasive registration of the arterial pressure pulse waveform using high-fidelity applanation tonometry. J
Vasc Med Biol. 1989;1:142-9.
13. Kelly R, Karamanoglu M, Gibbs H, et al. Noninvasive carotid pressure wave registration as an indicator of ascending aortic pressure. J Vasc Med
Biol. 1989;1:241-7.
14. McDonald DA, Taylor MG. The hydrodynamics of the arterial circulation. Progress in Biophysics and Chemistry. 1959;9:105-73.
15. O’Rourke MF. Pressure and flow waves in systemic arteries and the anatomical design of the arterial system. J Appl Physiol. 1967;23:139-49.
16. Womersley JR. The mathematical analysis of the arterial circulation in a state of oscillatory motion. Technical Report Wade TR 56-614. Dayton OH,
1957; Wright Air Development Center.
17. Taylor MG. The input impedance of an assembly of randomly branching elastic tubes. Biophysics J. 1966;6:29-51.
18. O’Rourke MF, Taylor MG. Vascular impedance of the femoral bed. Circ Res 1966;18:126-39.
19. O’Rourke MF, Taylor MG. Input impedance of the systemic circulation. Circ Res. 1967;20:365-80.
20. Taylor MG. Wave transmission through an assembly of randomly branching elastic tubes. Biophysics J. 1966;6:697-716.
21. Murgo JP, Westerhof N, Giolma JP, et al. Aortic input impedance in normal man: relationship to pressure wave forms. Circulation. 1980;62:105-16.
22. Nichols WW, Conti CR, Walker WE, et al. Input impedance of the systemic circulation in man. Circ Res. 1977;40:451-58.
23. Merillon JP, Fontenier GJ, Lerallut JF, et al. Aortic input impedance in normal man and arterial hypertension: its modification during changes in
aortic pressure. Cardiovasc Res. 1982;16:646-56.
24. O’Rourke MF. Influence of ventricular ejection on the relationship between central aortic and brachial pressure pulse in man. Cardiovasc Res.
1970;4:291-300.
25. Drzewiecki GM, Melbin J, Noordergraaf A. Arterial tonometry: review and analysis. J Biomech. 1983;16:141-52.
26. Kelly R, Hayward C, Avolio A, et al. Noninvasive determination of age-related changes in the human arterial pulse. Circulation. 1989;80:1652-9.
27. Yaginuma T, Avolio A, O’Rourke M, et al. Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man. Cardiovasc
Res. 1986;20:153-60.
28. Kelly RP, Gibbs HH, O’Rourke MF, et al. Nitroglycerin has more favourable effects on left ventricular afterload than apparent from measurement
of pressure in a peripheral artery. Eur Heart J. 1990;11:138-44.
29. Fitchett DH, Simkus GJ, Beaudry JP, et al. Reflected pressure waves in the ascending aorta: effect of glyceryl trinitrate. Cardiovasc Res. 1988;22:494-
500.
30. Takazawa K, Tanaka N, Takeda K, et al. Underestimation of vasodilator effects of nitroglycerin by upper limb blood pressure. Hypertension.
1995;26:520-23.
31. Kelly R, Daley J, Avolio A, et al. Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension. Hypertension. 1989;14:14-21.
32. Karamanoglu M, O’Rourke MF, Avolio AP, et al. An analysis of the relationship between central aortic and peripheral upper limb pressure waves
in man. Eur Heart J. 1993;14:160-67.
33. Karamanoglu M, Gallagher DE, Avolio AP, et al. Pressure wave propagation in a multibranched model of the human upper limb. Am J Physiol.
1995;269:H1363-9.
34. Chen CH, Nevo E, Fetics B, et al. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure:
Validation of generalized transfer function. Circulation. 1997;95:1827-36.
35. Pauca AL, O’Rourke MF, Kon ND. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure
waveform. Hypertension. 2001;38:932-7.
36. O’Rourke MF, Safar ME, Dzau V. Arterial Vasodilatation. London; Edward Arnold, 1993.
37. Hope SA, Tay DB, Meredith IT, et al. Physiological conditions influence individual arterial transfer function: implications for the reconstruction of
central waveform characteristics. Heart, Lung and Circulation. 2004;13(S2):S67.
38. Hope SA, Meredith IT, Tay D, Cameron JD. ‘Generalizability’ of a radial-aortic transfer function for the derivation of central aortic waveform pa-
rameters. J Hypertens. 2007;25:1812-20.
39. Segers P, Mahieu D, Kips J, et al. The use of a generalized transfer function: different processing, different results! J Hypertens. 2007;25:1783-87.
40. Pauca AL, Kon ND, O’Rourke MF. The second peak of the radial artery pressure wave represents aortic systolic pressure in hypertensive and elderly
patients. Br J Anaesth. 2004;92(5):651-7.
41. Vlachopoulos C, Aznaouridis K, O’Rourke MF, et al. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a
systematic review and meta-analysis. Eur Heart J. 2010;31:1865-71.
Microvessels in Hypertension: The Hundred Year Revolution

1. Bright R. Reports of medical cases selected with a view of illustrating the symptoms and cure of diseases by a reference to morbid anatomy. Lon-
don: Longmans; 1827.
2. Gull WW. Chronic Bright’s disease with contracted kidney (arterio-capillary fibrosis). BMJ. 1872;2:692.
3. Byrom FB, Dodson LF. The causation of acute arterial necrosis in hypertensive disease. J Pathol Bacteriol. 1948;60:357-68.
4. Byrom FB. The hypertensive vascular crisis: an experimental study. London: Heinemann; 1969.
5. Pickering G. High Blood Pressure. 2nd edition. London; J and A Churchill; 1968.
6. Mulvany ML. Vascular remodelling of resistance vessels: can we define this? Cardiovasc Res. 1999;41:9-13.
7. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension. 1989;13:968-72.
8. Miyashita H, Aizawa A, Hashimoto J, et al. Cross-sectional characterization of all classes of antihypertensives in terms of central blood pressure in
Japanese hypertensive patients. Am J Hypertens. 2010;23:260-8.
9. Safar ME, O’Rourke MF, (Eds). Arterial Stiffness in Hypertension. London: Elsevier; 2006.
9a. Birkenhager WH, Reid JL, (Eds). Handbook of Hypertension. No. 23.
10. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. 5th edition. London: Arnold Hodder; 2005.
11. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham study. Am J Car-
diol. 1971;27:335-46.
12. Kannel WB, Wolf PA, McGee DL, et al. Systolic blood pressure, arterial rigidity and risk of stroke, the Framingham study. JAMA. 1981;245:1225-9.
13. Systolic Hypertension in Elderly Program Cooperative Research Group (SHEP). Prevention of stroke by antihypertensive drug treatment in older
persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-64.
14. Henskens LH, van Oostenbrugge RJ, Kroon AA, et al. Brain microbleeds are associated with ambulatory blood pressure levels in a hypertensive
population. Hypertension. 2008;51:62-8.
15. Cullen KM, Kócsi Z, Stone J. Pericapillary haem-rich deposits: evidence for microhaemorrhages in aging human cerebral cortex. J Cereb Blood
Flow Metab. 2005;25:1656-67.
16. Lammie GA, Lindley R, Keir S, et al. Stress-related primary intracerebral hemorrhage: autopsy clues to underlying mechanism. Stroke.
2000;31:1426-8.
17. Vernooij MW, van der Lugt A, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: The Rotterdam Scan Study. Neurology.
2008;70:1208-14.
18. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hyper-
tension. 2005;46:200-4.
19. Edwards JE. Functional pathology of the pulmonary vascular tree in congenital cardiac disease. Circulation. 1957;15:164-96.
20. Bateman GA. Pulse-wave encephalopathy: a comparative study of the hydrodynamics of leukoaraiosis and normal-pressure hydrocephalus. Neu-
roradiology. 2002;44:740-8.
21. Henry-Feugeas MC, De Marco G, Peretti I, et al. Age-related cerebral white matter changes in pulse-wave encephalopathy: observations with
three-dimensional MRI. Magn Reson Imaging. 2005;23:929-37.
22. Smirk FH. High arterial pressure. Oxford: Blackwell; 1957.
The History of Cardiac
24 Rehabilitation: An Evolutionary
Perspective
Sahgal V
sumption of energy required for hunting and gathering. This pattern

INTRODUCTION
lasted for millions of years and thus dictated the genetic patterns of
Human society has undergone three types of transitions which have our biological existence. The ratio of resting metabolic rate to the
greatly impacted health, demographic, nutritional and epidemio- total energy expenditure was low, due to the high total energy needs.
logical.1 Demographic transition was represented by urbanization, The above stated food composition had low glycemic index lead-
as well as technological advancement for work and leisure.2-4 The ing to high sarcoplasmic to adipose ratio—5:1 in males and 3:1 in
nutritional transition was due to mechanization of food production, females. The total energy expenditure and resting metabolic rate
storage, delivery, as well as animal husbandry.5 The epidemiologi- remained relatively constant over this period.9-13
cal transition resulted in the shift from communicable diseases to The genes which regulate the carbohydrate metabolism through
chronic noncommunicable illnesses.6 This chapter explores the ingestion, consequent blood glucose concentration and pancreatic
history of these transitions as it relates to cardiac rehabilitation, i.e. insulin secretion have been selected over millions of years ago.9 This
nutrition and physical activity, pharmacological and interventional resulted in efficient distribution of insulin receptors between the adi-
management. pocyte and myocyte. The insulin efficiency can be defined as the ratio
of the percentage of muscle to fat mass times the oxygen consump-
PREHISTORIC tion (VO2 max). This resulted in competition between adipose tissue
and skeletal muscle for the circulating insulin. This means that physi-
The human evolution scaled the Paleolithic period to the present cal fitness determines body composition, which resulted in pheno-
from 2.5 million to 10,000 years ago.2-8 This represented an ongoing typic expression (lean or obese). In other words body composition
interaction between the human genome and the environment lead- is diet dependent and is determined by physical fitness.10,11 It can
ing either to genetic concordance or discordance.9 A stable environ- also be argued that the human genome is adapted to the Paleolithic
ment over this long period led to genetic concordance, while rapid dietary and physical activity patterns. The Paleolithic diet was high
changes resulted in genetic discordance. This discordance caused in bulk, proteins, fiber; low in carbohydrates (low glycemic load), fat
phenotypic manifestations in the form of morbidity, mortality or dis- intake was quantitatively equivalent but qualitatively different. In
ease.10 this era people lived in small units, the food sources were not limited
The human genome is adapted to the environment of our ances- to the cultivated sites. This was a very mobile society thus famines
tors in which they survived.11 This environment was relatively con- were rare. The individuals were lean with high tissue sarcoplasmic
stant for millions of years with regard to diet and lifestyle, to which to adipose ratio. The fertility rates and life expectancy was low. The
the genetic makeup was conditioned. The last 10,000 years, however Neo and Mesolithic age ushered in 10,000 years ago introduced ag-
ushered in profound changes in human lifestyle and diet due to the riculture, animal husbandry and collective living. Their diet was still
introduction of agriculture and animal husbandry.12 This change was quantitatively similar to the Paleolithic diet, but the source was read-
too abrupt (in evolutionary time scale) to effect genetic adaptation ily accessible in the form of cultivated land and animal husbandry.
leading to discordance. This was manifested as obesity, hyperten- The activity levels, though decreased as compared to the Paleolithic
sion, diabetes, hyperlipidemia, cardiovascular disease (CVD), con- age, were still high in energy consumption as farming was very labor
tributing to increased morbidity and mortality.13 intensive. The human genome was still concordant with this lifestyle.
The dietary composition of humans in the preagricultural age The agricultural revolution resulted in food surpluses, leading to the
was determined by the latitude, season and culture.14 It consisted of need for storage and preservation for easier access. The diet was low
unprocessed plants, hunted marine life and animals from the proxi- fiber content, high in carbohydrates and protein macronutrients. The
mate environment. It was rich in protein, moderate in carbohydrates, fat intake though equivalent, qualitatively differed in that the choles-
high in fibers, vitamins, minerals and low in fat. It fueled large con- terol raising fat was high, total polyunsaturated fats was low and high
Chapter 24  The History of Cardiac Rehabilitation: An Evolutionary Perspective 157
in omega6 fatty acids. The carbohydrates were derived from cereal • Slowing of atherosclerotic process
grains. This indicated a higher glycemic load to which the human ge- • Decrease coronary events through the development of sound
nome was not adapted.2-8 clinical trials, reporting of studies, and meta-analysis thereof.
The industrial revolution ushered in more sophisticated cultiva- The long-term effect and economic liability of this approach was
tion, storage and food preservation techniques. This brought about a also analyzed. This concept resulted in formalizing cardiac rehabili-
radical change in the nature of our food, physical activity and caloric tation and prevention throughout Europe. In Sweden 50–75% of the
utilization (1,240 kcal a day for hunter gatherer to 550 kcal a day), i.e. patients were offered this service, in Germany 70%, in Switzerland
high intake low utilization. The human genome was not adapted for 70%, Italy 25%, Greece 5–10%, Spain less than 5%, Russia 1% respec-
this radical shift, causing insulin inefficiency, which in turn caused tively. In 2007, the European Congress set about to develop qual-
sarcopenia and hyper adiposity leading to obesity, insulin resist- ity indicators, produce systematic changes to close treatment gaps,
ance, hypertension, atherogenicity and Type II diabetes, and CVD. derive evidence based practice guidelines and define components
The above paleoanthropological concepts form the underpinnings of of care that are essential for high quality care, incorporate referral
CVD prevention and rehabilitation.8-14 measures into national cardiovascular data registries for acute coro-
nary syndromes and develop guidelines for programs and program
MODERN TIMES certification.
Europe Britain
Heberden15 first described the effects of exercise on angina in 1771, While aggressive programs were developing in Europe, until the
“I set myself the task of sawing wood for half an hour daily and 6 end of the 1960s UK still was adhering to the old philosophy of 6
months later I was cured”. Professor Oerdel was the first physician weeks of bed rest. The 1970s however, saw analyses of several ran-
to use graded exercise for the management of blood pressure (BP), domized controlled trials which provided type A and B evidence
heart rate, and physical fitness. In the early 1950s the wisdom of pro- resulting in class I and II recommendations for cardiac rehabilitation.
longed bed rest in the treatment of heart disease was questioned by This culminated in adoption of established rehabilitation programs
Levin, Lown Oerdel, (armchair treatment of MI). Dr Peter Beckman throughout Britain and Ireland first on adhoc basis and then the pro-
reintroduced the concept of cardiac rehabilitation first proposed by grams were formalized, registered quality standards developed and
Oerdel in his article entitled. “New treatment of patients after myo- adopted. In the 1970s in UK there were nine cardiac rehabilitation
cardial infarction” emphasizing the role of diet and exercise. He was programs in 1992 it increased to 90, in 1995 there were 199 programs,
subsequently recognized by the Geriatrics Society of Cardiac Reha- and currently there are over 300 registered programs. Cardiac reha-
bilitation and a medal was named after him. This was followed by bilitation was formalized into phase into I–IV. Phase I covered acute
the foundation of the working group on cardiac rehabilitation by hospitalization, phase II 2–6 weeks posthospitalization, phase III 4–6
the European Society of Cardiology (ESC) Congress in Dussesdorf, weeks postcardiac event and phase IV 12 weeks to lifetime. For each
Germany in 1982 and the founding chairmen were Doctors Mather one of these phases specific enrollment criteria were established. In
and Mulecahy. In the late 1980s regular meetings of scientific action summary cardiac rehabilitation was institutionalized this resulted in
group were held under the leadership respectively of Doctors Perk, 20–84% in England and 70% in Ireland being offered formal cardiac
Gohlke, and Sarner in Bad, Krozingen, Valencia, and Bern. In the rehabilitation programs.
early 1990s the ESC Board favored the clustering of working group
and in 1997 a formal merger with the West German Group of Exercise North America
Physiology, Pathology and Electrocardiography was affected at the
congress meeting in Flackhalm, the mission was to improve cardiac The last three decades of the 20th century concentrated on the diag-
rehabilitation services based on basic science in exercise physiology. nosis and management of heart disease.16 The era produced inno-
Under the leadership Bjorn Stadt further organizational improve- vative biochemical, electrical and imaging techniques. The principle
ment occurred resulting in increased scientific presentations within being to prevent myocardial necrosis. The prominent centers in the
the platform of the European Society of Cardiology. The ESC board 20th century were at Baylor University in Texas under the leader-
however was not pleased, and some major West German members ship of Drs DeBakey and Cooley, Cleveland Clinic Foundation led by
threatened to leave. This scenario lead to the birth of the European Drs Ephram, Loop, Lytel and Cosgrove, as well as the centers in Mil-
Association of Cardiopulmonary Rehabilitation in the year 2000, waukee and New York. These successes increased longevity, but the
which flourished and introduced the first rated journal on CV pre- quality of life was significantly compromised. In New York 80% of the
vention and rehabilitation, as well as a textbook on the subject. The individuals receiving disability were suffering from coronary artery
mission of the society was: disease who had not returned to work. Only 10% had even attempted
• Reduce cardiac morbidity and mortality to retrain or find alternative jobs. This led to the New York state em-
• Prevention of cardiac disease ployment services to seek the help of the New York Heart Association
to evaluate the physical activity profile of cardiac patients leading to tory markers, vagal tone electrical stability and endothelial function.
activity classification popularly known as the New York Heart Asso- The financial attractiveness of these programs was shown by many
ciation Activity Classification. By this time simple exercise tests with publications demonstrating significant cost savings between $25,000
tables for normal individuals were available. Levine,17 in 1952, wrote and $50,000 per patient.
about the armchair treatment of acute coronary thrombosis, this was
followed by a critique in 1953 by Katz18 entitled “Unsettled Questions Asia
in the Management of Cardiovascular Disease”. In 1958, Turell and
Hellerstein19 wrote about the evaluation of cardiac function in rela- The history of physical fitness has been connected to diet and physi-
tion to specific physical activities following recovery from acute myo- cal activity in all the Asian cultures since 3000 BC. In India this rela-
cardial infarction (AMI). This was followed by Hellerstein20 with an tionship was verbally transmitted and codified in 600 BC in the Up-
article on exercise therapy in cardiac disease in 1968. In 1957, Bruce21 nishads and refined by Patanjali as Yoga Sutra.
wrote about the functional capacity evaluation in patients with CVD. The modern day India moved rapidly from Neolithic Agrarian
In 1968, Saltin22 et al. described the response to exercise after bed to the modern day industrialized society. This resulted in a radical
rest and training, following up on the 1948 article by Dictrich23 on the change in physical activity and dietary habits. This caused significant
effects of immobilization on metabolic and physiologic function of genomic discordance, i.e. the high glycemic load, poor insulin sen-
normal man. The management of heart disease was revolutionized sitivity, expressed as adiposity sarcropenia, athrogenicity resulting in
by early usage of thrombolytic drugs, coronary artery bypass grafting CVD and diabetes.
and the current procedures of arterial stents of various types. The advances in surgical and medical management of CVD
The 1970s saw some reports on cardiac rehabilitation by Wenger, significantly reduced mortality and increased incidence and preva-
Gilbert and Tobis24 use of physical activity in rehabilitation of car- lence. It is only recently that the principles of cardiac rehabilitation
diac patients. Cohen and Grant25 wrote on the effect of rehabilitation are being institutionalized in the delivery of CV care. The approach
programs on the length of hospitalization and functional status at still is adhoc and only hospital based. It is limited to in non-govern-
discharge, after exercise therapy in coronary disease. These describe mental hospitals catering to the upper segment of society.
the justification of cardiac rehabilitation over traditional rest based The cause of cardiac rehabilitation and prevention was taken
programs. In the United States cardiac rehabilitation is emphasized up by the pioneers in Indian cardiology. In India Padamavati27-32 for
by the American Heart Association (AHA) and the American Asso- the first time demonstrated the relationship between hypertension
ciation of Cardiovascular and Pulmonary Rehabilitation (AACVPR). income groups, age and body weight in India. In the 1950s Devi-
This approach reduces mortality and morbidity and enhances clini- chand,30 and Vaikil,29 commented on the nature of heart disease in
cal, psychological, and functional recovery and improves clinical India. The treatment emphasized medical management and bed rest.
recovery. The next step was to estimate the prevalence of cardiac The 1980s entered the era of surgical intervention in the manage-
rehabilitation amongst survivors of cardiac events in the US. This ment of AMI, pioneered in the North by Naresh Trehan. The decade
was accomplished by the behavioral risk factors assessment study of of 2000 brought to light the role of lifestyle in the etiology of CVD. By
2005, published in 2008 which showed in the 21 states and District this time occasional reports in the literature had described the effects
of Columbia.26 Thirty-four percent of heart attack survivors received of meditation and yoga on high BP and CVD. In 2006 a formal inter-
cardiac rehab. This participation was directly related to education, national conference was organized in Mount Abu by Dr Chopra and
marital status and socioeconomic levels. Somani under the auspices of Brahmkumari. For the first time the
In the United States, aggressive recuperation was introduced, role of lifestyle modifications was emphasized. Enas33,34 in 1996 by
which began with having the patient sit a week or even before that this time had emphasized the unique features of coronary artery dis-
in an armchair as prelude to an introduction of activity. In the 1960s, ease among Indians. The relationship between smoking, obesity, hy-
Kellerman realized that exercising after a heart attack was in fact an pertension, diabetes, hyperlipodemia, insulin resistance and heart
extremely safe activity resulting in speedier recovery and improve- disease was recognized. All these features were lumped together as
ment of quality of life. During this time several randomized con- metabolic syndrome. These are all the features modifiable by lifestyle
trolled trials demonstrated the effect of cardiac rehabilitation on CV changes. Since then an aggressive campaign is being waged in the
mortality, atherosclerotic process, coronary events and rehospitali- professional and lay media. This has resulted in several tertiary care
zation. The mortality reduction from all causes in these studies dem- health centers setting up organized phase based cardiac rehabilita-
onstrated and odds ratio of .80, (95% confidence interval with a range tion programs, starting from the acute event to community integra-
of .68–.93) cardiac mortality reduction had an odds ration of .74 (95% tion. To date cardiac rehabilitation has become the foundation of
confidence interval and a range of .61–.16). The risk reduction result- cardiac care. This cause has been taken up by the medical, religious
ing from prevention programs also was statistically significant. These organizations in India, social and philanthropic organizations. In
programs resulted in change in body composition, lipo protein me- this context the activism of Swami Ramdev stands out in bringing the
tabolism, carbohydrate metabolism, blood viscosity, anti-inflamma- awareness of lifestyle in CV and general health.
Chapter 24  The History of Cardiac Rehabilitation: An Evolutionary Perspective 159
CONCLUSION care has significantly decreased the mortality and increased morbid-
ity. This has increased the socio economic burden of the society. It is
Life style, i.e. physical activity and demography, determines the ge- this context that underpins cardiac rehabilitation and prevention. The
netic competence of the human species to maintain CV health. The 21st century has thus seen cardiac rehabilitation as an integral part of
current interventional and noninterventional approaches to cardiac cardiac management (prevention, treatment and rehabilitation).
REFERENCES
1. Lindberg S. Modern human physiology with respect to evolutionary adaptations that relate to human diet in the past: Integrating approaches to
the study of paleolithic subsistence in press. Elsevier, Richards, MP, Hublen, JJ.
2. Jönsson T, Olsson S, Ahrén B, et al. Agrerarian diet and diseases of affluence—do evolutionary novel dietary lectins cause leptin resistance. BMC
Endocr Dis. 2005;5:10.
3. Cordain L, Eaton SB, Sebastian A, et al. Origin and evaluation of Western diet: health implications for the 21st Century. Am J Clin Nutri. 2005;81:341-
54.
4. Lindberg S, Cordain L, Eaton SB. Biological and clinical potential of paleolithic diet. J Nutri Environ Med. 2003;13:1-12.
5. Eaton SB, Cordain L, Lindberg S. Evolutionary health promotions: a consideration of common counter arguments. Prev Med. 2002;34:119-23.
6. Boaz NT. Evolving Health: The origins of illness, and how the modern world is making us sick. New York: John Wiley and Sons Inc; 2002.
7. O’Keefe JH, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our paleolithic genome, how to become a 21st Cen-
tury hunter and gatherer. Mayo Clin Proc. 2004;79:101-8.
8. Cordain L. The nutritional characteristic of a contemporary diet based upon food groups. J Am Nutri Cent Ass. 2002;5:15.
9. Boyd-Eaton S, Cordain L, Sporting PB. Evolution, body composition, insulin receptor competition and insulin resistance. Prevent Med.
2009;49:283-5.
10. Eaton SB, Eaton SB. An evolutionary perspective on human physical activity and implications for health. Comp Biochem Physiol Part A.
2003;136:153-9.
11. Jenike MR. Nutritional Ecology: diet, physical activity, and body size. In: Panter-Brick C, Layton RH, Rowley, Convey P, (Eds). Hunters and gather-
ers an interdisciplinary perspective. Cambridge UK: Cambridge University Press; 2005. p. 223.
12. Kahn BB, Flier JS. Obesity and Insulin Resistance. J Clin Invest. 1968;106:473-81.
13. Eaton SB, Konner M, Shestak M. Stone ages in the fast lane chronic degenerative diseases in evolutionary perspective. Am J Med. 1988;84:739-49.
14. Ramsden CE, Faurot KR, Carrera-Bastos P, et al. Dietary fat quality and coronary heart disease prevention: a unified theory based on evolutionary,
historical, global, and modern perspectives. Curr Treat Options Cardiovasc Med. 2009;11:289-301.
15. Heberden W. Some accounts of a disorder of the chest. Med Trans Coll Physician. 1772;2-59.
16. Mallory GK, White PD, Sallcedo-Salger J. The speed of healing of myocardial infarction: a study of the pathological anatomy. Am Heart J.
1959;18:647-71.
17. Levine SA, Lown B. Arm chair treatment of acute coronary thrombosis. JAMA. 1952;148-1365.
18. Katz LN. Symposiums: Unsettled clinical questions in the management of cardiovascular disease circulation. 1953;18:430-50.
19. Turell DJ, Hellerstein HK. Evolution of cardiac function in reaction to specific physical activities following recovery from acute myocardial infarc-
tion. Prog Cardiovas Dis. 1958;1(2):237-50.
20. Hellerstein H. Exercise therapy in coronary disease. Bull NY Acad Med. 1968;44:1028-47.
21. Bruce RA. Evaluation of functional capacity in patients with cardiovascular disease. Geriatrics. 1957;12:317-28.
22. Saltin B, Bloomquist G, Mitchell JH. Response to exercise after bed rest and training. Circulation. 1968;38(Suppl VII)1-78.
23. Dietzich H. Effects of immobilization upon various metabolic and physiologic functions of a normal man. Am J Med. 1948;4:3-36.
24. Wenger NK, Gilbert CA, Siege W. Symposium: The use of physical activity in the rehabilitation of patients after myocardial infarction. South Med
J. 1970;63:891-7.
25. Cohen BS, Grant A. Acute myocardial infarction: Effect of a rehabilitation program on length of hospitalization and functional status at discharge.
Arch Phys Med Rehabil. 1973;54:201-6.
26. Ayala C, Xie J, McGruder HF. Receipt of outpatient cardiac rehab among heart attack survivors—United States 2005. CDC Weekly MMWR. [online]
Available from website http://www.cdc.gov/mmwr/preview/mmwrhtml/mm57092.htm. 2008;57 (04):89-94. [Accessed June 2012].
27. Padmavati S, Gupta S, Panlulu GVA. Dietary fat, serum cholesterol levels and incidence of atherosclerosis in Delhi. Circulation. 1959;19:849-55.
28. Mathur KS, Wahipin Malhotra KK, Sharma RD, et al. Dietary fat, serum cholesterol and serum lipid phosphorus in different socio economic
groups in Uttarpradesh. J Indian MA. 1956;33:303.
29. Vakil RJ. Heart disease in India. Am Heart J. 1954;48:439-48.
30. Devichand. Etiology and incidence of heart disease in India. Indian Heart J. 1959;11:117.
31. Padmavati S. Prevention of heart disease in India in the 21st Century need for concentrated effort. Indian Heart J. 2002;54(1):99-102.
32. Padmavati S. Cardiology in the 21st Century and the Indian perspective. Indian J of chest Dis sci. 2002;44(4):243-6.
33. Thomas RJ, King M, Lui K, et al. AACUPR/ACC/AHA 2007 Performance measures on cardiac rehabilitation for referral to and delivery of cardiac
rehabilitation/secondary prevention services. Circulation. 2007;116:1611-42.
34. Enas EA, Garg A, Davidson MA, et al. Coronary heart disease and its risk factors in first-generation immigrant Asian Indians to the United States
of America. Indian Heart J. 1996;48:343-53.
25 A Brief Historical Chronicle
of Hypertension
C Venkata S Ram
Most of the data regarding prevention and treatment are derived

SYSTEMIC HYPERTENSION AS A
from studies conducted in developed countries and predominantly
RISK FACTOR FOR THE GLOBAL
among white populations. However, developing countries must
DISEASE BURDEN critically appraise the vast body of knowledge that has accrued from
Hypertension is an important worldwide public-health challenge, studies in those populations and identify the elements that can be
because of its high frequency and concomitant cardiovascular (CV) applied to their geographical regions. This is of particular interest in
risks and related kidney disease.1,2 Hypertension is ranked third as view of the observed ethnic diversity in the profile of cardiovascular
a cause of disability-adjusted life-years3 and the data indicate that disease (CVD) and varied risk associations in different populations.
untreated hypertension shortens life expectancy by approximately 5 Conventional CVD risk factors, such as smoking, hypertension, and
years.4 Worldwide, the prevalence of hypertension continues to in- elevated blood cholesterol are likely to be relevant and common risk
crease and is expected to affect 1.5 billion people by 2025.5 factors for most populations.11 Thus, increased awareness of the CVD
Overall, 26.4% of the world’s adult population had hypertension burden is needed, as well as appropriate research studies to provide
in 2000. Regions with the highest estimated prevalence of hyperten- direction, and develop preventive strategies for both industrialized
sion had roughly twice the rate of regions with the lowest estimated and developing countries. Otherwise, both medical and socioeco-
prevalence. The highest estimated prevalence for men was in Latin nomic consequences of the increased burden of CVD will be disas-
America and the Caribbean, whereas the highest estimated preva- trous for developing countries since optimal management for the
lence for women was in the former socialist economies (Fig. 25.1). many millions of patients is far beyond the scope of healthcare facili-
Overall, the prevalence of hypertension worldwide was predicted ties.
to increase by 9% in men and 13% in women because of projected
changes in the age distribution of the population, as the global popu- HYPERTENSION AND TARGET
lation is expected to be older by 2025.5 With this continued increase
ORGAN DAMAGE
in the prevalence of hypertension, CV mortality will continue to
increase. The link between hypertension and target organ damage, such as
The effect of blood pressure (BP) on CV risk is progressive and heart failure and renal dysfunction is well appreciated, but this ob-
continuous as BP increases. It is not just systolic BP (SBP) above 140 servation is not new. With regard to renal damage, the Yellow Em-
mm Hg or a diastolic (DBP) above 90 mm Hg. Patients with prehyper- peror’s Classic of Internal Medicine12 pointed out over 4500 years
tension (SPB 130–139 mm Hg and DBP 85–89 mm Hg) are also at risk. ago that “when the pulse is abundant but tense and hard and full like
There is an average doubling of risk for an increase in BP of 20/10 a cord, there are dropsical swellings,” and suggested that “the kid-
mm Hg.6 Patients with prehypertension also have a high prevalence neys pass on the diseases to the heart...”. In the 19th century, it was
of other CV risk factors, including dyslipidemia, diabetes, insulin noted that kidney disease and hypertension often occur together,13
resistance, obesity and the metabolic syndrome,7 as well as present- and in 1871, hypertension was thought to a homeostatic response
ing with earlier evidence of target organ damage compared to nor- to impaired renal excretory function.14 The concept that volume
motensive persons.8 homeostasis and BP regulation are closely linked was further clari-
Reliable information about the prevalence of hypertension in fied by Starling,15 when he emphasized the importance of renal fluid
different world regions, especially in developing countries, is essen- retention in maintaining arterial pressure in circumstances associ-
tial to formulate national and international health policies for pre- ated with circulatory depression (i.e. heart failure).16
vention and control of hypertension.9 However, there is some ques- Prevailing medical opinions as late as the mid-20th century
tion whether the World Health Organization (WHO) cut-off points were that lowering of elevated BP was detrimental because, rather
for hypertension (SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg) are than improve CV outcomes, perfusion of vital organs would be
appropriate in low resource countries, such as India.10 impaired, increasing the risk of CV and renal diseases.17 Now in the
Chapter 25  A Brief Historical Chronicle of Hypertension 161
Figure 25.1: Frequency of hypertension in people aged 20 years and older by world region and sex in 2000 (upper) and 2025 (lower).
Source: With permission from reference 5
21st century, it is clear that CVD, especially hypertension, has be- hypertension. However, a different picture is arising in developing
come a ubiquitous cause of morbidity and a leading contributor to countries.
mortality in most countries around the world. At the World Congress of Cardiology meeting in 2010, it was
The World Health Report from 1999 estimated that 30.9% of reported that there has been a 100% increase in stroke in Southeast
all deaths, as well as 10.3% of the total disease related burden, in and Eastern Asia over the last four decades. This compares to only
terms of disability adjusted life year loss were attributable to CVD a 42% increase in developed countries. INTERSTROKE was a large
during 1998.18 This burden afflicts both men and women, with CV case-control study conducted in 22 countries of predominately low
deaths accounting for 34% of all deaths in women and 28% in men and middle income including Southeast Asia, India and Africa.19
in 1998.11 Results showed that these countries are disproportionately affect-
Cerebrovascular disease has long been linked directly to high BP. ed by the disease accounting for more than 85% of stroke mortality
Stroke is a major global health problem. It is the third leading cause worldwide. Hypertension, it turns out, was the strongest risk factor
of death and the leading cause of adult disability. In the mid-1900s, accounting for over a 2.5-fold increased risk for stroke and was a
a major educational effort was launched in the USA to address the particularly dangerous risk factor for intracerebral hemorrhage.
issue and by the late 1990s stroke rate had dramatically declined Factors leading to this increase were reduced exercise, smoking and
largely through an effort of identification, treatment and control of introduction of a western diet.19
the fore-runner of the modern sphygmomanometer.22 With this

HISTORY OF BLOOD PRESSURE
device, it became possible to measure BP noninvasively and gave
MEASUREMENT individuals the ability to gather data and study the effect of various
In the 2nd century AD, Galen published numerous books on the cir- interventions, both nonpharmacologic and pharmacologic. Al-
culatory system that described at length the variations of the pulse though Riva-Rocci’s instrument was accurate, it could only measure
due to age, sex, season, country, sleep, pregnancy, exercise, bathing, systolic pressure. Then in 1905, Nikolai Korotkoff, a Russian physi-
food and wine.20 Galen’s theory of the physiology of the circulatory cian, suggested using a stethoscope to also measure when the heart
system endured until the 1600s, when the work of William Harvey was at rest, i.e. determining diastolic pressure. Since then, the aus-
established that blood circulates, with the heart acting as a pump. cultatory method using a mercury or aneroid instrument calibrated
In 1726, Stephen Hales’ experimented on a horse and measured the to the nearest 2 mm Hg has been the mainstay of clinical BP meas-
pressure exerted on the walls of blood vessels as blood was flowing urement and considered the most accurate measurement device
through them (Fig. 25.2).21 available. However, these devices can be fragile and easily damaged;
Over the course of the next 150 years, changes in Hales’ experi- thus, users cannot be absolutely certain of their accuracy. Devices
ment perfected his original concept, but each measurement still re- more suited to automated measurements are now being used both
quired invasive monitoring. In 1895, Scipione Riva-Rocci invented in the clinic and by patients who do self-monitoring of their BP in an
outpatient setting. Home monitoring or self-monitoring, improves
the estimate the patient’s true BP.
An advantage of monitoring BP in the office or clinic is that these
measurements are associated with clinical trials. Disadvantages
include patients often have variations in their office pressure (e.g.
white-coat hypertension, masked hypertension) and clinic measure-
ments cannot help in diagnosing white-coat or masked hypertension
and observer error is an issue with conventional BP measurements.23
Advantages of patient self-monitoring include that it is inex-
pensive and convenient, and there are a variety of units available for
home use. In addition, self-monitoring can be an important aspect
for managing hypertension and patients become active participants
in the care of their disease. Blood pressure values obtained with self
measurement are more indicative of BP levels during the day than
are levels obtained in the clinic. Disadvantages of self-monitoring
are that patients must learn how to use varying devices correctly and
results may not be accurate if improper technique is used. Observer
error is a common problem and devices need to be periodically cali-
brated.23
Ambulatory Blood Pressure Monitoring

First described more than 40 years ago,24 ambulatory blood pressure
monitoring (ABPM) allows patients to go about their normal daily
activities while recording BP measurements for 24 hours or longer.
They can be worn on a belt or in a pouch and are connected to a
sphygmomanometer cuff on the upper arm by a plastic tube; most
monitors use the oscillometric technique and are usually programed
to take measurements every 15–30 minutes throughout the day and
night.25 At the end of the recording period, the readings are down-
loaded into a computer and then evaluated.
Ambulatory blood pressure monitoring provides more repre-
sentative values of “real world” BP levels than measurements taken
in the clinic and indicates how BP responds during activity and/or
Figure 25.2: Hales’ Horse, the first documented measurement of sleep periods.26 Target organ damage correlates better with ABPM
intra-arterial pressure. Source: With permission from reference 21 than the clinic BP measurements,27,28 and for any given value of clini-
cal BP, target organ damage is directly related to the mean levels and the recently published Action to Control Cardiovascular Risk in Dia-
variability of ABPM. betes (ACCORD) study have added to the debate.40 Specialists, deci-
The accuracy of the monitors is evaluated by using standard pro- sion makers in health systems and professional advisory bodies have
tocols, and approved devices are usually accurate to within 5 mm Hg been promoting risk stratification, with the intent of focusing atten-
of readings taken with a mercury sphygmomanometer.29 Three lev- tion on persons with high levels of CVD risk.41-43 As a result, conflict-
els of information can be provided using ABPM: an estimate of the ing international treatment thresholds have led to differing levels of
true, or mean, BP level, the diurnal rhythm of BP, and BP variability.29 hypertension treatment and control.
Clinical guidelines currently exist only for estimating true or mean,
levels by ABPM.21,29-31 HISTORY OF ANTI-HYPERTENSIVE DRUGS—
Advantages of ABPM are that it provides the best measure of a
FROM RESERPINE TO ALISKIREN
patient’s BP over 24 hours; more measurements than clinic or self-
monitoring; data regarding the effectiveness of an antihypertensive Hypertension is a silent symptomless condition without overt signs
medication; and data about patients who are non-dippers (those to indicate an individual’s BP is elevated. With the advent of the
whose night-time BP decreases below 10% of the daytime level). mercury manometer, insurance companies required BP should be
Two disadvantages are that ABPM is relatively expensive and may be taken during physical examinations. The resulting data from insur-
inconvenient for patients. ance company actuarial reports linked increased BP to premature
death since the early part of the 20th century.44 However, at the time,
Central Blood Pressure Measurements there were no interventions per se to lower BP. Early interventions
included hyperventilation,45 watermelon extract, calcium diure-
Peripheral BP (brachial measurement), obtained in the clinical set- tin, mistletoe, radiation to the skull46 and pentaquine (Fig. 25.3).47
ting, is an essential parameter for the evaluation and management Orthostatic hypotension was observed with some of these com-
of hypertension. Central BP directly imposes mechanical stress on pounds; however, further evaluation of the BP-lowering effects of
the left ventricle, large arteries and the vital organ vasculature than these interventions showed no long-term reduction. It was not until
peripheral BP, and reflecting ascending aortic BP may be more pre- the late 1940s and early 1950s that the development of antihyperten-
dictive of outcome in specific populations.32,33 Central BP has been sive drugs intensified.17 During this time, various researchers were
evaluated noninvasively by mathematically transforming the radial testing several medications including Rauwolfia serpentina (reser-
artery pulse waveform to the aortic pulse waveform.34-36 pine), veratrum alkaloids, ganglionic blocking drugs and hydralazine
Central BP is thought to indicate how much pressure is being (Figs 25.2 and 25.3).17,48,49
exerted on the heart and brain. As a result, the 2007 European Soci- Since then, remarkable progress was made in the management
ety of Hypertension/European Society of Cardiology guidelines for of hypertension. In the 50 years since the introduction of the thi-
the management of arterial hypertension acknowledged that cen- azide diuretics, many classes of antihypertensive drugs have been
tral BP may be different from BP measured at the arm.37 Although developed and approved for clinical use. These include aldosterone
these guidelines acknowledged that central BP may be important as receptor antagonists, a-receptor blockers, central and periph-
a measure of subclinical organ damage, they also stressed the need eral sympatholytics, b-receptor blockers, angiotensin-converting
for prospective trials to establish its predictive value. enzyme (ACE) inhibitors, calcium-channel blockers (CCBs), and
angiotensin-receptor blockers (ARBs). The latest drug class to show
REDUCING THE BURDEN OF efficacy in lowering BP is the direct renin inhibitors (DRI), which
block the effects of renin on the pro-renin receptor. Aliskiren is the
CARDIOVASCULAR DISEASE
first DRI to be approved to treat hypertension; however, this drug
Interventions to reduce the burden of CVD have been successful has not been evaluated in a large outcome study at this time. These
in decreasing age-adjusted CV mortality.38 Reducing the burden drug classes represent primary treatment options for clinicians in the
of hypertension is dependent on increased awareness, treatment treatment of HTN.17
and control. Strategies should include approaches to prevent the Despite preliminary studies of the BP lowering effects of some of
development of risk factors in the population as a whole by chang- these drug classes, their adverse event profiles turned out to be less
ing social and governmental policy, as well as interventions that can than desirable, which limited their usefulness. Alpha-receptor block-
be applied to high risk individuals.11 Although changes in the life- ers lower BP effectively and were heralded as great compounds for
styles of the general population would result in a lower prevalence of regression of left ventricular hypertrophy (LVH), their lipid-lowering
hypertension,5 patients with specific target organ damage also effects, and being glucose-neutral; however, more subjects rand-
require pharmacologic intervention. omized to a a-blocker (doxazosin) in the Antihypertensive and Lipid
There is still much debate over which thresholds are the most Lowering Heart Attack Trial (ALLHAT)50 experienced an increase
appropriate for initiating treatment of high BP,39 and the results of incidence of heart failure than those randomized to other treat-
Figure 25.3: Therapeutic advances in the treatment of hypertension. Source: Adapted from references 17, 45, and 46.
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker
ments; therefore, the a-blocker arm of the study had to be discontin- Program (SHEP),55 the Systolic Hypertension in Europe (Syst-Eur)
ued early. Now, a-blockers are used in the treatment of hypertension trial56 and the Antihypertensive and Lipid Lowering Heart Attack
in a limited population, i.e. mainly in men experiencing benign pros- Trial (ALLHAT).50
tatic hypertrophy. Although endothelin antagonists were anticipated Selective blockade of b adrenergic receptors was first recog-
with much interest, their development was impeded by tachycardia nized in 1958, with propranolol being the first b-blocker to come
and limited efficacy. into general clinical practice in the early 1960s. Over the years, this
Strategies for the combined use of antihypertensive drugs are es- class of drug has had extensive use as an antihypertensive, antiangi-
sential in achieving targeted BP levels. The goal of combination anti- nal, postmyocardial patients and in heart failure. Beta blockers vary
hypertensive treatment is to improve efficacy and minimize adverse with regard to their selectivity for b1, b2 or a-receptors, as well as for
events. intrinsic sympathomimetic activity and membrane stabilizing activ-
ity. In recent years their utility for hypertension has been questioned
History of Therapeutic Recommendations— because of, concerns regarding safety and tolerability.57 At almost the
same time, new vasodilating b-blockers like carvedilol and nebivolol
Monotherapy to Combination Therapy
have evolved with effective antihypertensive activity and better toler-
Monotherapy treatment with antihypertensive agents will not suffi- ability than the earlier drugs in this class.
ciently impact the majority of patients with hypertension. Although Aldosterone receptor antagonists are effective in lowering
most individual drugs reduce DBP by 4–8 mm Hg and SBP by 7–13 BP and impacting outcomes. Spironolactone has been shown to
mm Hg (on average), the magnitude of this effect is insufficient to reduce BP particularly in combination with the thiazide type diuret-
achieve targeted BP levels in the majority of patients with hyperten- ic. In addition, the Randomized Aldactone Evaluation Study (RALES)
sion. It is estimated that approximately 75% of patients with hyper- showed spironolactone reduced heart failure related events.58 The
tension require multidrug therapy.51 selective aldosterone receptor antagonist, eplerenone, effectively
Of the above classes, several have been shown to reduce CV out- lowered BP and improved outcomes in patients with ventricular
comes. Thiazide diuretics are considered the first effective and oral hypertrophy after a myocardial infarction (MI) in the EPlerenone’s
antihypertensive agents. This class of drugs formed the basis of the neuroHormonal Efficacy and SUrvival Study (EPHESUS).59
first hypertension outcome studies (he Veterans Administration Co- Beta-adrenergic receptor blockers have been a mainstay
operative Study Group52). Subsequent trials over the next 20 years reducing BP and have also been studied extensively with regard to
included the landmark trials: Treatment of Mild Hypertension Study outcomes. For hypertension, the majority of outcome studies men-
Research Group (TOMHS),53 the Swedish Trial of Older Persons with tioned for thiazide type diuretics used b-blockers as a comparator.
Hypertension (STOP-H),54 the Study of Hypertension in the Elderly Outcome studies include b-blocker Heart Attack Trial (B-HAT),60 the
Survival And Ventricular Enlargement (SAVE) trial,61 and the Acute prescribed only when a patient may be intolerant of ACE inhibitor
Infarction Ramipril Efficacy (AIRE) trial,62 which showed b-blockers therapy.
provided additional reduction in CV mortality independent of the
comparator, an ACE inhibitor. Heart failure outcome studies include CONCLUSION
the Metoprolol CR/XL Randomized Intervention Trial in Congestive
Heart Failure (MERIT-HF),63 and the Carvedilol Prospective Rand- The advent of the mercury sphygmomanometer made measurement
omized Cumulative Survival (COPERNICUS) trial.64 of BP an everyday occurrence. Despite data collected by insurance
Based upon JNC-7 recommendations and other outcome stud- companies, patients were not aware the risk of uncontrolled hyper-
ies, inhibitors of the renin-angiotensin-aldosterone system (RAAS) tension. In the 1960s, at least half of the individuals with hyperten-
provide support for treating hypertension, as well as for other com- sion in the United States were unaware of their disease and fewer
pelling indications, such as post MI, diabetic nephropathy, heart than 20% of individuals with elevated BP were controlled to nor-
failure and for high risk CV patients (those at risk of stroke, MI, or motensive levels. A similar picture is now in evidence in developing
death). Within this group of drugs include ACE inhibitors and ARBs.65 countries. Over time, programs that increase awareness of the risk of
Outcome studies have shown the benefit of ACE inhibitor ther- elevated BP can make an impact. In the US today, only a small per-
apy for patients post-MI (SAVE and AIRE);61,62 heart failure [Coop- centage (10–15%) of patients with hypertension are unaware of their
erative New Scandinavian Enalapril Survival Study (CONSENSUS)66 disease and more than 50% are being treated to goal levels.77
and Studies of Left Ventricular Dysfunction (SOLVD);67 diabetic Much of the variation in the success rate in hypertension con-
nephropathy;68 and, patients at high risk of a CV event (Hypertension trol appears to be attributable to the treatment strategy adopted by
Outcomes Prevention Evaluation (HOPE)].69 For these patients, who individual countries. The structure of financial incentives within
were at high risk for CV event, results showed ramipril prevented these systems plays an important role in this health care outcome.
death from a composite of CV causes including MI, stroke, as well as Intervention efforts need to be pursued within individual health
each outcome separately, as well as secondary outcomes including systems, the implications of broader versus more restrictive guide-
death from any cause, the need for revascularization, hospitaliza- lines also need to be examined.78
tion for unstable angina or heart failure, and complications related More effective treatment of hypertension is a key reason for
to diabetes. reductions in stroke, renal failure and heart failure. The discovery
With ARBs, the Losartan Intervention for Endpoint Reduction of more effective agents in the period from the 1960s to the present
in Hypertension (LIFE) study revealed losartan-based therapy was has dramatically improved prognosis. The paradox is that despite
associated with fewer CV events than atenolol-based treatment.70 enormous advances in antihypertensive drug therapy, the number
Reductions were seen in patients post-MI [Valsartan in Acute Myo- of people with uncontrolled hypertension has continued to rise.5
cardial Infarction Trial (VALIANT)],71 diabetic nephropathy (Re- Preventive programs which increase awareness of the risks of uncon-
duction of Endpoints in NIDDM with the Angiotensin II Antagonist trolled hypertension and educate both physicians and patients on
Losartan (RENAAL)72 and Irbesartan Diabetic Nephropathy Trial effective treatment interventions must be implemented in all regions
(IDNT)73 and heart failure (Candesartan on Mortality and Morbid- of the world.
ity in Patients with Chronic Heart Failure (CHARM) Program74 and
Valsartan in Heart Failure (Val-HeFT).75 As well, results of the ON- ACKNOWLEDGMENTS
going Telmisartan Alone and in Combination with Ramipril Global
Endpoint Trial (ONTARGET) Program showed telmisartan was non- The author acknowledges the assistance of Drs Ronald K Miller and
inferior to ramipril for reduction of CV events in high risk patients.76 Robert E Lamb, Practicum Educational Services (USA) in preparing
Thus, ARBs have shown benefit in reducing morbidity and mortal- and styling this paper for publication and for providing the litera-
ity from various CV co-morbid risk factors and many are no longer ture/editorial support.
REFERENCES
1. He J, Whelton PK. Epidemiology and prevention of hypertension. Med Clin North Am. 1997;81:1077-97.
2. Whelton PK. Epidemiology of hypertension. Lancet. 1994;344:101-06.
3. Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360:1347-60.
4. Franco OH, Peeters A, Bonneux L, et al. Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women. Hyper-
tension. 2005;46:280-6.
5. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217-23.
6. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data
for one million adults in 61 prospective studies. Lancet. 2002;360:1903-13.
7. Chobanian AV. Prehypertension revisited. Hypertension. 2006;48:812-4.
8. Toprak A, Wang H, Chen W, et al. Prehypertension and black-white contrasts in cardiovascular risk in young adults: Bogalusa Heart Study. J Hy-
pertens. 2009;27:243-50.
9. Whitworth JA, World Health Organization, International Society Hypertension Writing Group. 2003 World Health Organization (WHO) / Interna-
tional Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:1983-92.
10. Sauvaget C, Ramadas K, Thomas G, et al. Prognosis criteria of casual systolic and diastolic blood pressure values in a prospective study in India. J
Epidemiol Community Health. 2010;64:366-72.
11. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation. 1998;97:596-601.
12. Ruskin A. Classics in Arterial Hypertension. In: CC Thomas (Ed.). Illinois: Springfield; 1956. pp. 164-272.
13. Bright R. Tabular view of the morbid appearances in 100 cases connected with albuminous urine. With observations. Guy’s Hosp Rep. 1836;1:380.
14. Traube L. Uber den Zusammenhang von Herz und Nieren-krankheiten. Gesammelte Beitrage zur Pathologie und Physiologie, vol 2. Berlin:
Hirschwald; 1871. pp. 290-353.
15. Starling EH. The fluids of the body. The Herter lectures. Chicago, Ill: Keever; 1909.
16. Hall JE. The kidney, hypertension, and obesity. Hypertension. 2003;41(3 Pt 2):625-33.
17. Chobanian AV. The hypertension paradox—more uncontrolled disease despite improved therapy. N Engl J Med. 2009;361:878-87.
18. The World Health Report. Making a Difference. Geneva: World Health Organization; 1999.
19. O’Donnell MJ, Xavier D, Liu L, et al. Risk factors for ischemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): A
case-control study. Lancet. 2010;376:112-23.
20. Bedford DE. The ancient art of feeling the pulse. Br Heart J. 1951;13:423-37.
21. Editorial: Stephen Hales-father of hemodynamics. Medical Times. 1944;72:315.
22. Blood Pressure Measuring Devices. [online] Available at http://www.discoveriesinmedicine.com/Bar-Cod/Blood-Pressure-Measuring-Devices.
html. [Accessed June, 2010].
23. O’Brien E, Asmar R, Beilin L, et al. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure
measurement. J Hypertens. 2003;21:821-48.
24. Kain HK, Hinman AT, Sokolow M. Arterial blood pressure measurements with a portable recorder in hypertensive patients. I. Variability and cor-
relation with “casual” pressures. Circulation. 1964;30:882-92.
25. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med. 2006;354:2368-74.
26. White WB. Ambulatory blood-pressure monitoring in clinical practice. N Engl J Med. 2003;348:2377-8.
27. Hoegholm A, Kristensen KS, Bang LE, et al. Left ventricular mass and geometry in patients with established hypertension and white-coat hyper-
tension. Am J Hypertens. 1993;6:282-6.
28. White WB, Schulmen P, McCabe EJ, et al. Average daily blood pressure, not office pressure, determines cardiac function in patients with hyperten-
sion. JAMA. 1989;261:873-7.
29. O’Brien E, Pickering T, Asmar R, et al. Working Group on Blood Pressure Monitoring of the European Society of Hypertension International Pro-
tocol for validation of blood pressure measuring devices in adults. Blood Press Monit. 2002;7:3-17.
30. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals. 1. Blood pressure
measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart As-
sociation Council on High Blood Pressure Research. Circulation. 2005;111:697-716.
31. Myers MG, Tobe SW, McKay DW, et al. New algorithm for the diagnosis of hypertension. Am J Hypertens. 2005;18:1369-74.
32. Miyashita H, Aizawa A, Hashimoto J, et al. Cross-sectional characterization of all classes of antihypertensives in terms of central blood pressure in
Japanese hypertensive patients. Am J Hypertens. 2010;23:260-8.
33. Chirinos JA, Zambrano JP, Chakko S, et al. Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coro-
nary artery disease. Hypertension. 2005;45:980-5.
34. Takazawa K, Kobayashi H, Shindo N, et al. Relationship between radial and central arterial pulse wave and evaluation of central aortic pressure
using the radial arterial pulse wave. Hypertens Res. 2007;30:219-28.
35. Agabiti-Rosei E, Mancia G, O’Rourke MF, et al. Central blood pressure measurements and antihypertensive therapy: a consensus document. Hy-
pertension. 2007;50:154-60.
36. Kohara K, Tabara Y, Tomita H, et al. Clinical usefulness of the second peak of radial systolic blood pressure for estimation of aortic systolic blood
pressure. J Hum Hypertens. 2009;23:538-45.
37. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society
of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the
European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-87.
38. Thom TJ. International mortality from heart disease: rates and trends. Int J Epidemiol. 1989:18:S20–S28.
39. Coca A. Actual blood pressure control: are we doing things right? J Hypertens. 1998;16(suppl 1):45-51.
40. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med.
2010;362:1575-85.
41. Ramsay L, Williams B, Johnston G, et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension
Society. J Hum Hypertens. 1999;13:569-92.
42. Campbell NR. The Canadian Hypertension Recommendations Working Group. The 2001 Canadian Hypertension Recommendations: what is new
and what is old but still important. Can J Cardiol. 2002;18:591-603.
43. Ramsay LE, Wallis EJ, Yeo WW, et al. The rationale for differing national recommendations for the treatment of hypertension. Am J Hypertens.
1998;11:79-88.
44. Hunter ARO. Mortality study of impaired lives. Actuarial Soc. 1923;24:453-6.
45. Vincent S, Cameron AT, Quart. J. Observations upon the Vaso-motor Reflexes. J Exper Physiol. 1915;9:45.
46. Ayman D. An evaluation of therapeutic results in essential hypertension. I. The interpretation of symptomatic relief. JAMA. 1930;95:246-9.
47. Moser M. Historical perspective on the management of hypertension. Am J Med. 1986;80(5 suppl 2):1-11.
48. Wilkins RW. New drug therapies in arterial hypertension. Ann Intern Med. 1952;37:1144-55.
49. Wilkins RW, Judson WE. The use of rauwolfia serpentina in hypertensive patients. N Engl J Med. 1953;248:48-53.
50. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients rand-
omized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-97.
51. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with Hypertension and diabetes: A consensus approach. Am J Kidney
Dis. 2000;36:646-61.
52. VA Cooperative Study Group. Effects of Treatment on Morbidity in Hypertension: Results in Patients With Diastolic Blood Pressures Averaging 115
Through 129 mm Hg. JAMA. 1967;202:1028-34.
53. Treatment of Mild Hypertension Study Research Group (TOMHS). JAMA. 1993;270:713-24.
54. Dahlöf B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).
Lancet. 1991;338:1281-5.
55. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hyper-
tension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991;265:3255-64.
56. Staessen JA, Thijs L, Fagard R, et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in
Europe Trial. J Hypertens. 2004;22:847-57.
57. Mayor S. NICE removes beta blockers as first line treatment for hypertension. BMJ. 2006;333:8.
58. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Al-
dactone Evaluation Study Investigators. N Engl J Med. 1999;341:709-17.
59. Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone,
a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-21.
60. Beta Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality re-
sults. JAMA. 1982;247:1707-14.
61. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocar-
dial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669-77.
62. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarc-
tion Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342:821-8.
63. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
Lancet. 1999;353:2001-7.
64. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol
prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194-9.
65. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. Hypertension. 2003;42:1206-52.
66. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandi-
navian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-35.
67. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-
302.
68. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study
Group. N Engl J Med. 1993;329:1456-62.
69. Yusuf S, Sleight P, Pogue J, et al. The HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. N Engl J Med. 2000;342:145-53.
70. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hyper-
tension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:995-1003.
71. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril or both in myocar-
dial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-906.
72. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with
type 2 diabetes and nephropathy. N Engl J Med. 2001;345: 861-9.
73. Lewis EJ, Hunsicker LG, Clarke WR, et al. Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in
patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-60.
74. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-
Overall programme. Lancet. 2003;362:759-6.
75. Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart
failure. N Engl J Med. 2001;345:1667-75.
76. Yusuf S, Teo KK, Pogue J, et al. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J
Med. 2008;358:1547-59.
77. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008. JAMA. 2010;303:2043-50.
78. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hyper-
tension. 2004;43:10-7.
26 History of Risk Factor
Stratification of Hypertension
Mehta NP, Shah SN
and by about 10 times among the rural residents. Various factors con-
INTRODUCTION
tribute to this rising trend, attributable to several indicators of eco-
Hypertension in adults aged 18 years and above is defined as systolic nomic progress, such as increased life expectancy, urbanization and
blood pressure (SBP) of 140 mm Hg or higher and/or diastolic (DBP) its attendant lifestyle changes including increasing salt intake.5
of 90 mm Hg or higher or any level of BP in patients taking antihyper- The estimated total number of people with hypertension in
tensive medications.1-3 India in 2000 was 60.4 million males and 57.8 million females and
The definition of hypertension has evolved over decades, many projected to increase to 107.3 million and 106.2 million respectively
definitions being issued by various international authorities. In the in 2025.6 With the current rate of hypertension, India will have the
19th century, the concepts of blood vessels and BP started develop- largest number of people with hypertension in the world, with the
ing. The relation was established between high BP and kidney and potential of becoming the “Hypertension capital of world!”
retinal disease. In the 20th century, McLeod described the main fac- Traditionally, only BP levels were used to make decisions about
tors controlling BP. In 1950s, life insurance companies observed that treatment of hypertension. While this approach was suited for
the persons suffering from high BP died earlier than those with lower patients with moderate to severe hypertension (Stage 2–3), it did not
BP levels. Thus, a link was established between high BP and mortality adequately suitable treatment of patients with mild hypertension
rate. (Stage 1). Thus over the years, a risk stratification system was intro-
The Framingham study has made an important contribution to duced based not only on the BP, but also on the individual risk factors
the history of high BP. It has shown that high BP can cause heart fail- of each patient. The main objective was to reduce the BP such that
ure, renal disease, kidney damage, cerebral hemorrhage and organ the absolute risk of premature death or disease due to hypertension
damage. Other Prospective studies have also shown that progressively was reduced.
higher SBP or DBP levels were a harbinger of cardiovascular disease Guidelines regarding stratification of BP and its risk factors have
(CVD), chronic renal disease and cerebrovascular accidents.4 been issued by various organizations and have changed over the last
Recent reports indicate that nearly 1 billion adults (more than few decades. Their main objective is to determine the level at which
a quarter of the world’s population) had hypertension in 2000 and treatment should be initiated and what goals should be achieved to
this is predicted to increase to 1.56 billion by 2025. A meta-analysis reduce the risk maximally.
of hypertension prevalence rate in India demonstrated a significant
increase in the prevalence of hypertension, significantly higher in UNITED STATES GUIDELINES (1977–2003)
urban than in rural populations. However, no nationwide epidemio-
logical studies have been carried out to determine the prevalence of Several organizations have produced guidelines for hypertension,
hypertension. Sporadic studies from different parts of the country but the seven reports of the Joint National Committee on Prevention,
provide data on the epidemiology of hypertension in India. The prev- Detection, Evaluation, and Treatment of High Blood Pressure (JNC
alence of hypertension and prehypertension were higher in males Reports) by a group of US physicians are considered most definitive
when compared to females. The prevalence of hypertension in the and are widely accepted. They are issued by the National High Blood
age group of 30–39 years is 13.7% and increased to a peak of 64% in Pressure Education Program Coordinating Committee who has con-
the age group of 60–69 years. Increasing age, body mass index, waist- ceptualized the hypertension guidelines. Initially risk was stratified
hip ratio and the presence of diabetes or impaired glucose tolerance based only on the level of DBP. However, over the years the SBP levels,
were independent risk factors for both prehypertension and hyper- target-organ damage (TOD), cardiovascular risk factors and associ-
tension.5 ated clinical conditions were recognized to be important as well.
The prevalence of hypertension between 3 decades and 6 dec- “The First JNC Report in 1977” classified BP only based on DBP
ades in India has increased by about 30 times among urban residents (Table 26.1). It did not consider SBP. Therapy was recommended for
Chapter 26  History of Risk Factor Stratification of Hypertension 169
those with DBP above or equal to 105 mm Hg. For patients with DBP ethnic minority groups, elderly and young patients, pregnancy and
between 90 mm Hg and 104 mm Hg, therapy was to be considered.7 surgical patients.9
“The JNC-II Report (1980)” classified hypertension as mild, mod- “The Fourth JNC Report (1988)” did not change the classifica-
erate and severe based only on DBP, with increased risk at all levels of tion of hypertension as described by JNC-III (1984), but made a few
stratification. Target-organ damage or other independent risk factors changes in the management options. It also addressed the same risk
increased the overall risk. Therapy was beneficial to patients with factors and management problems in special groups as in JNC-III.
moderate and severe hypertension; however, in patients with mild The objective of treatment was to maintain BP below 140/90 mm
hypertension, the benefits were to be weighed over the costs, side Hg.10
effects and inconvenience of long-term therapy.8 “The Fifth JNC Report (1993)” reclassified hypertension using a
“The JNC-III Report (1984)” addressed the SBP for the first time, new staging system, which gave equal importance to SBP and DBP
but only as “isolated systolic hypertension” when DBP was less than (Table 26.3). All stages were associated with a progressively increas-
90 mm Hg (Table 26.2). Decision to treat was based on two factors: ing risk of nonfatal and fatal CVD and renal disease. Cardiovascu-
the severity of BP elevation and the presence of other complications lar risks were related to level of BP elevation, dyslipidemia, cigarette
or risk factors like CVD, coronary artery disease, left ventricular smoking, diabetes mellitus, physical inactivity and obesity.
hypertrophy, congestive cardiac failure, peripheral artery disease, JNC-V, for the first time, introduced a list of manifestations of
diabetes mellitus, renal disease, hyperlipidemia, gout, bronchial “TOD” (Table 26.4), which increased the risks of CVD several-fold
asthma and chronic obstructive pulmonary disease. It also includ- at any level of high BP. The objective of treatment was to maintain
ed management problems in special population groups like blacks, SBP below 140 mm Hg and DBP below 90 mm Hg while concurrently
TABLE 26.1 Classification of hypertension according to JNC I (1977) and TABLE 26.3 Classification of hypertension according to JNC-V (1993)*
JNC II (1980) Category Systolic (mm Hg) Diastolic (mm Hg)
Class Diastolic Blood Pressure (mm Hg) Normal† < 130 < 85
Stratum I (Mild) 90–104 High normal 130–139 85–89
Stratum II (Moderate) 105–114 Hypertension‡
Stratum III (Severe) ≥ 115 Stage 1 (Mild) 140–159 90–99
Stage 2 (Moderate) 160–179 100–109
Stage 3 (Severe) 180–210 110–119
Stage 4 (Very severe) ≥ 210 ≥ 120
TABLE 26.2 Classification of hypertension according to JNC-III (1984) and
* Not taking antihypertensive drugs and not acutely ill. When systolic and
JNC-IV (1988)
diastolic pressures fall into different categories, the higher category should
Category* Range (mm Hg) be selected to classify the individual’s BP status. For instance, 160/92 mm
Diastolic Normal BP < 85 Hg should be classified as Stage 2 and 180/120 mm Hg should be classified
as Stage 4. Isolated systolic hypertension is defined as SBP of 140 mm Hg
High normal BP 85–89
or above and a DBP of below than 90 mm Hg and staged appropriately
Mild hypertension 90–104 (e.g. 170/85 mm Hg is defined as Stage 2 isolated systolic hypertension).
Moderate hypertension 105–114 In addition to classifying stages of hypertension on the basis of average
Severe hypertension ≥ 115 BP levels, the clinician should specify presence or absence of target-organ
disease and additional risk factors. For example, a patient with diabetes
Systolic Normal BP < 140
and a BP of 142/94 mm Hg, plus left ventricular hypertrophy should be
(when DBP Borderline isolated systolic hypertension 140–159 classified as having “Stage 1 hypertension with target-organ disease (left
is <90)
Isolated systolic hypertension ≥ 160 ventricular hypertrophy) and with another major risk factor (diabetes).”
* Classification of borderline isolated systolic hypertension (SBP, 140– This specificity is important for risk classification and management.
159 mm Hg) or isolated systolic hypertension (SBP > 160 mm Hg) takes † Optimal BP with respect to cardiovascular risk is less than 120 mm Hg
precedence over a classification of high normal BP (DBP, 85–89 mm Hg) systolic and less than 80 mm Hg diastolic. However, unusually low readings
when both occur in the same person. A classification of high normal BP should be evaluated for clinical significance.
(DBP, 85–89 mm Hg) takes precedence over a classification of normal BP ‡ Based on the average of two or more readings taken at each of two or
(SBP < 140 mm Hg) when both occur in the same person. more visits after an initial screening.
TABLE 26.4 Manifestations of target-organ damage (JNC-V, 1993)

Organ System Manifestation
Cardiac Clinical, electrocardiographic, or radiologic evidence of coronary artery disease; left ventricular hypertrophy or “strain” by
electrocardiography or left ventricular hypertrophy by Echocardiography; left ventricular dysfunction or cardiac failure
Cerebrovascular Transient ischemic attack or stroke
Peripheral vascular Absence of one or more major pulses in extremities (except for dorsalis pedis) with or without intermittent claudication;
aneurysm
Renal Serum creatinine ≥ 130 µmol/l (1.5 mg/dl); proteinuria (1+ or greater); microalbuminuria
Retinopathy Hemorrhages or exudates, with or without papilledema
TABLE 26.5 Classification of hypertension according to JNC-VI (1997)* TABLE 26.6 Cardiovascular risk factors and target-organ damage (JNC-VI,
Category Systolic (mm Hg) Diastolic (mm Hg) 1997)
Optimal† < 120 and < 80 Major Risk Factors Target-Organ Damage / Clinical
Cardiovascular Disease
Normal < 130 and < 85
Smoking Heart diseases
High normal 130–139 or 85–89
Dyslipidemia • Left ventricular hypertrophy
Hypertension‡ Stage 1 140–159 or 90–99
Diabetes mellitus • Angina/prior MI
Stage 2 160–179 or 100–109
Age older than 60 years • Prior coronary revascularization
Stage 3 ≥ 180 or ≥ 110
Sex (men and postmenopausal • Heart failure
*Not taking antihypertensive drugs and not acutely ill. When SBP and DBP
women)
fall into different categories, the higher category should be selected to
classify the individual’s BP status. For example, 160/92 mm Hg should be Family history of CVD Stroke or transient ischemic attack
classified as Stage 2 hypertension and 174/120 mm Hg should be classified Women under age of 65 or Men Nephropathy
as Stage 3 hypertension. Isolated systolic hypertension is defined as SBP of under age of 55
140 mm Hg or greater and DBP below 90 mm Hg and staged appropriately Peripheral arterial disease
(e.g. 170/82 mm Hg is defined as Stage 2 isolated systolic hypertension).
Retinopathy
In addition to classifying stages of hypertension on the basis of average
BP levels, clinicians should specify presence or absence of target-organ Abbreviations: CVD, Cardiovascular disease; MI, Myocardial infarction
disease and additional risk factors. This specificity is important for risk
classification and treatment (Tables 26.6 and 26.7).
† Optimal BP with respect to cardiovascular risk is below 120/80 mm

Hg. However, unusually low readings should be evaluated for clinical Risk Group B includes patients with hypertension who do not have
significance. clinical CVD or TOD, but who do have more than or equal to 1 other
‡ Based on the average of two or more readings taken at each of two or CVD risk factor shown in Table 26.6 excluding diabetes.
more visits after an initial screening.
Risk Group C includes patients with hypertension who have clinical
CVD or TOD as shown in Table 26.6.
controlling other cardiovascular risk factors. Further reduction to a Based on the three categories of hypertension and three risk
level of 130/85 mm Hg may be pursued specially in older patients.11 groups, JNC-VI recommended treatment for patients as shown in
“The Sixth Report of JNC (1997)”, for the first time presented a risk Table 26.7. JNC-VI also established the term “Goal BP”. The goal of
stratification system that was based on the level of BP, and the pres- treatment was set at SBP below 140 mm Hg and DBP below 90 mm
ence or absence of risk factors and TOD. The classification of high BP Hg. For patients with diabetes or chronic kidney disease a lower tar-
was changed to include “optimal blood pressure” and to reduce the get of below or equal to 130/85 mm Hg was established. In case of
stages of hypertension from 4 to 3 (Table 26.5). proteinuria of more than 1 gm per 24 hours a still lower target of be-
JNC-VI introduced a Risk Stratification System, which included low or equal to 125/75 mm Hg was set.12
three risk groups. “The Seventh JNC guidelines (2003)” are the most recent guide-
lines published. They simplified the classification of hypertension by
Risk Group A includes patients with high-normal BP or Stage 1, 2 or reducing the Stages from 3 to 2 (Table 26.8). They also introduced the
3 hypertension who do not have clinical CVD, TOD or other risk fac- term “prehypertension”, which has generated a lot of debate regard-
tors. ing its utility and danger of labeling a large group of normal individu-
TABLE 26.7 Risk stratification and treatment (JNC-VI, 1997)*

Blood Pressure Categories Risk Group A (No risk factors, Risk Group B (At least one risk factor, not Risk Group C (TOD/CCD and/or Diabetes,
(mm Hg) No TOD/CCD)† including diabetes, No TOD/CCD) with or without other risk factors)
High-normal (130–139/85–89) Lifestyle modification Lifestyle modification Drug therapy§
Stage 1 (140–159/90–99) Lifestyle modification (up to 12 Lifestyle modification‡ (up to 6 months) Drug therapy
months)
Stage 2 and 3 (≥ 160/ ≥ 100) Drug therapy Drug therapy Drug therapy
For example, a patient with diabetes and a BP of 142/94 mm Hg plus left ventricular hypertrophy should be classified as having Stage 1 hypertension with
target-organ disease (left ventricular hypertrophy) and with another major risk factor (diabetes). This patient would be categorized as Stage 1, Risk Group
C and recommended for immediate initiation of pharmacologic treatment.
* Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy.
† TOD/CCD indicates target-organ disease/clinical cardiovascular disease (Table 26.6).
‡ For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications.
§ For those with heart failure, renal insufficiency or diabetes.
TABLE 26.8 Classification of hypertension (JNC-VII, 2003)

INDIAN HYPERTENSION GUIDELINES
Category Systolic (mm Hg) Diastolic (mm Hg)
(2001–2007)
Normal < 120 and < 80
Pre-hypertension 120–139 or 80–89 Rather than reinventing guidelines, the Indian Guidelines were pre-
pared based on existing guidelines from JNC VI, World Health Or-
Hypertension
ganization/International Society of Hypertension, European Society
Stage 1 140–159 or 90–99
of Hypertension/ European Society of Cardiology and British Hyper-
Stage 2 ≥ 160 or ≥ 100 tension Society. Relevant data from available Indian literature was
incorporated.
The “First Indian Guidelines for Management of Hypertension”
als, who may never develop high BP in their lifetime, as potentially were released in 2001. These recognized classifications of hyperten-
hypertensive. A discussion in international bodies regarding deletion sion issued by the JNC-VI (1997) and WHO/ISH (1999) (Table 26.5).
of this nomenclature of prehypertension is under consideration for The patients overall risk is assessed based on risk factors, TOD and
future guidelines. Table 26.9 shows the cardiovascular risk factors associated clinical conditions (Table 26.11). Risk stratification is
and TOD.3 based on these factors to determine the prognosis and decision
In addition to describing risk factors and TOD (Table 26.9), the about treatment (Table 26.12).1
guidelines also included some “compelling indications” for treat- Ambulatory blood pressure monitoring (ABPM) was found use-
ment and follow-up of patients with hypertension (Table 26.10). ful to identify white coat hypertension, hypertensive episodes, drug
“Compelling indications” are indications for use of a particular resistant hypertension and hypotensive episodes while on antihy-
treatment based on clinical trial data that demonstrates benefits of pertensive treatment. Hypertension was defined as a 24-hour aver-
such therapy on the natural history of the associated condition. They age above or equal to 135/85 mm Hg, daytime average of above or
involve high-risk conditions that can be direct sequelae of hyperten- equal to 140/90 mm Hg and night-time average of ≥ 125/75 mm Hg.1
sion (heart failure, ischemic heart disease, chronic kidney disease, The “Indian Hypertension Guidelines-II (2007)” maintained the
recurrent stroke) or commonly associated with hypertension (diabe- same definition and classification of hypertension as the first guide-
tes, high coronary disease risk). Therapeutic decisions in such indi- lines (2001) (Table 26.5). The recent terminology of “prehyperten-
viduals should be directed at both “the compelling indication and sion” coined by JNC-VII was not adopted by the Indian Guidelines
controlling blood pressure”.3 since it included a wide range of BP including normal and high nor-
JNC VII specifically recommends that all patients with Stage 2 mal and was considered likely to produce anxiety and increased phy-
hypertension (SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg) should be sician visits in a large subset of the population.
started on two drug combinations, one of which should be a thiazide Among the risk factors for CVD, same factors as in Table 26.11
diuretic. The goal of treatment was to lower and maintain the BP to were maintained with the addition of two risk factors: high sensi-
below 140/90 mm Hg. In patients with hypertension and diabetes or tive C reactive protein (hs-CRP) and homocysteine levels and esti-
chronic renal disease, the goal is modified to below 130/80 mm Hg.3 mated GFR less than 60 ml/min. Target-organ damage was also the
TABLE 26.9 Cardiovascular risk factors and target-organ damage (JNC-VII, 2003)
Major Risk Factors Target-Organ Damage/Clinical Cardiovascular Disease
Hypertension* Heart
Age (older than 55 for men, 65 for women)† • Left ventricular hypertrophy
Diabetes mellitus* • Angina/prior MI
Elevated LDL (or total) cholesterol* • Prior coronary revascularization
Low HDL cholesterol* • Heart failure
Estimated GFR < 60 ml/min Brain
Family history of premature CVD (men aged < 55 or women aged < 65) • Stroke or transient ischemic attack
Microalbuminuria • Dementia
Obesity* (body mass index ≥ 30 kg/m2) Chronic kidney disease
Physical inactivity Peripheral arterial disease
Tobacco usage, particularly cigarettes Retinopathy
*Components of the metabolic syndrome. Reduced HDL and elevated triglycerides are components of the metabolic syndrome. Abdominal obesity is
also a component of metabolic syndrome.
†Increased risk begins at approximately at the age of 55 and 65 for men and women, respectively. Adult Treatment Panel III used earlier age cut points to
suggest the need for earlier action.
Abbreviations: CVD, Cardiovascular disease; GFR, Glomerular filtrate rate; HDL, High-density lipoprotein; LDL, Low-density lipoprotein; MI, Myocardial
infarction
TABLE 26.10 Clinical trial and guideline basis for compelling indications for individual drug classes (JNC-VII, 2003)
Compelling Indication* Recommended Drugs Clinical Trials Data†
DIUR BB ACEI ARB CCB ALD-A
Heart Failure • • • • • ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD,
AIRE, TRACE, Val-HeFT, RALES, CHARM
Post MI • • • ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
High Coronary Disease risk • • • • ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST
Diabetes • • • • • NKF-ADA Guideline, UKPDS, ALLHAT
Chronic Renal Disease • • NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent Stroke Prevention • • PROGRESS
*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is
managed in parallel with the BP.
†Conditions for which clinical trials demonstrate benefit of specific classes of antihypertensive drugs used as part of an antihypertensive regimen to
achieve BP goal to test outcomes.
Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; AIRE, Acute infarction ramipril efficacy; ALLHAT, Antihypertensive
and lipid lowering treatment to prevent heart attack; ANBP2, Second Australian National Blood Pressure; BHAT, Beta-Blocker heart attack trial; CIBIS, Cardiac
insufficiency bisoprolol study II; CONVINCE, Controlled onset verapamil investigation of cardiovascular endpoints; COPERNICUS, Carvedilol prospective
randomized cumulative survival; EPHESUS, Eplerenone Post-AMI heart failure efficacy and survival; HOPE, Heart outcomes prevention evaluation; INVEST,
Investigational vertebroplasty efficacy and safety trial; LIFE, Losartan intervention for endpoint reduction in hypertension study; MERIT-HF, Metoprolol CR/
XL randomized intervention trial in congestive heart failure; MI, Myocardial infarction; PROGRESS, Perindopril protection against recurrent stroke study;
RALES, Randomized aldosterone evaluation study; RENAAL, Reduction of endpoints in NIDDM with the angiotensin II antagonist losartan; SAVE, Survival
and ventricular enlargement; SOLVD, Studies of left ventricular dysfunction; TRACE, Trandolapril cardiac evaluation; Val-HeFT, Valsartan heart failure trial.
DIUR indicates diuretics; BB, β blocker; ACEI, Angiotensin-converting enzyme inhibitor; ARB, Angiotensin receptor blocker; CCB, Calcium channel blocker;
ALD-A, Aldosterone antagonist.
TABLE 26.11 Factors influencing risk (Indian Guidelines–2001)

Risk Factors for CVD Target-Organ Damage (TOD) Associated Clinical Conditions
- Age >60 years - Left ventricular hypertrophy detected • Cerebrovascular disease
by ECG and/or echocardiogram o Ischemic stroke
- Male sex - Ultrasound or radiological evidence o Cerebral hemorrhage
of atherosclerotic plaques in the carotids o Transient ischemic stroke
• Heart disease
- Post-menopausal females - Proteinuria and/or increase in serum creatinine
o MI
(1.2-2.0 mg/dl)
o Angina
- Smoking and tobacco use - Generalized or focal narrowing of retinal o Coronary revascularization
arteries o Congestive heart failure
- Diabetes mellitus • Renal disease
o Diabetic nephropathy
- Family history of premature CVD (Males < 55
o Renal failure (serum creatinine 2 mg/dl)
years, Females < 65 years)
• Vascular disease
-↑Waist-Hip ratio, o Symptomatic arterial disease including
↑LDL cholesterol, nonspecific aortoarteritis
↑Triglycerides, ↓HDL cholesterol o Dissecting aneurism
• Advanced retinopathy
o Hemorrhage or exudate
o Papilledema
Abbreviations: CVD, Cardiovascular disease; ECG, Electrocardiography; HDL, High-density lipoprotein; LDL, Low-density lipoprotein; MI, Myocardial
infarction
TABLE 26.12 Stratifying risk (Indian Guidelines – 2001)

Blood Pressure (mm Hg)
Other Risk Factors and Disease History Stage 1 Stage 2 Stage 3
SBP 140–159 or DBP 90–99 SBP 160–179 or DBP 100–109 SBP ≥ 180 or DBP ≥ 110
I No other risk factors Low risk Medium risk High risk
II 1–2 Risk factorsa Medium risk Medium risk Very high risk
III Three or more risk factors or TODb or Diabetes High risk High risk Very high risk
IV Associated clinical conditionsc Very high risk Very high risk Very high risk
RISK STRATA (Typical 10 years risk of stroke or MI)
Low risk = Less than 15%
Medium risk = 15–20%
High risk = 20–30%
Very high risk = > 30%
a. See Table 26.11
b. TOD = Target-organ damage – see Table 26.11
c. ACC = Associated clinical conditions – see Table 26.11
similar as Table 26.13 with the addition of urine ACR (albumin- WORLD HEALTH ORGANIZATION/
creatinine ratio). Microalbuminuria was added to proteinuria and
INTERNATIONAL SOCIETY OF
elevated creatinine to indicate TOD. Generalized or focal narrow-
HYPERTENSION GUIDELINES (1986–2003)
ing of retinal arteries was replaced by Hypertensive Retinopathy.
The associated clinical conditions remained the same as in Table The World Health Organization/International Society of Hyperten-
26.11. Stratification of risk remained same as in Table 26.12. sion (WHO/ISH) Subcommittee issued guidelines in 1986 and 1989,
TABLE 26.13 Cardiovascular risk factor and target-organ damage (BHS–1999)

Cardiovascular Risk Factors Target-Organ Damage Contributory Factors
–Smoking –Stroke, TIA, dementia –Overweight
–Diabetes –LVH, heart failure –Excess alcohol (>3 units/day)
–Total cholesterol: HDL-cholesterol ratio –Myocardial infarct, angina, CABG or angioplasty –Salt intake
–Family history –Peripheral vascular disease –Lack of exercise
–Age –Fundal hemorrhages or exudates
–Sex –Proteinuria
–Renal impairment
Abbreviations: CABG, Coronary artery bypass graft; HDL, High-density lipoprotein; LVH, Left ventricular hypertrophy; TIA, Transient ischemic attack
which classified hypertension based on DBP similar to the clas- ditions (Table 26.18). The 2003 guidelines had a few minor changes
sification shown in Table 26.1. Classes of hypertension were mild, compared to the 1999 guidelines; microalbuminuria (20–300 mg/
moderate and severe. There was also a subclass of “Borderline” day) was part of TOD in the 2003 guidelines and generalized or fo-
hypertension with DBP in the range of 90–94 mm Hg. Pharmaco- cal narrowing of the retinal arteries was replaced with hypertensive
logical treatment was indicated in moderate or severe hypertension retinopathy grade III or IV. Creatinine of more than 1.4 mg/dl in
(DBP > 105 mm Hg). In patients with mild hypertension, follow-up females and more than 1.5 mg/dl in males was a part of associated
measurements were used to decide the line of treatment. Nonphar- clinical conditions in the newer guidelines as was diabetes.16,17
macological treatment was indicated for borderline hypertension.
Pharmacological treatment was only indicated if DBP was persis-
tently above 100 mm Hg after 3 months or above 95 mm Hg after 6 TABLE 26.14 Classification of hypertension (WHO/ISH–1993)
months.13,14 Categories Systolic (mm Hg) Diastolic (mm Hg)
In 1993, the WHO/ISH guidelines reclassified hypertension Normotension <140 and <90
including systolic as well as DBP (Table 26.14). Hypertension was
Mild hypertension 140–180 and/or 90–105
also classified according to the extent of organ damage (Table
Subgroup-borderline 140–160 and/or 90–95
26.15).15
hypertension
Among the factors influencing treatment, a list of cardiovascular
risk factors was provided (Table 26.16) and other factors like renal Moderate and severe ≥180 and/or ≥105
hypertension
disease, diabetes, smoking, elevated total cholesterol and LDL cho-
lesterol were included as high-risk factors.15 Isolated systolic hypertension ≥140 and <90
WHO/ISH guidelines of 1999 and 2003 changed the classifica- (ISH)
tion (Table 26.17) and introduced risk factor stratification systems Subgroup-borderline ISH 140-160 and <90
that included risk factors for CVD, TOD and associated clinical con-
TABLE 26.15 Classification according to the extent of organ damage (WHO/ISH–1993)

Stage I No objective signs of organic changes
Stage II At least one of the following signs of organ involvement:
— Left ventricular hypertrophy (X-ray, electrocardiography, echocardiography)
— Generalized and focal narrowing of the retinal arteries
— Proteinuria and/or slight elevation of plasma creatinine concentration (1.2–2.0 mg/dl)
— Ultrasound or radiological evidence of atherosclerotic plaque (carotid arteries, aorta, iliac and femoral arteries)
Stage III Both symptoms and signs have appeared as a result of organ damage. These include:
— Heart: Angina pectoris, MI, heart failure
— Brain: Transient ischemic attack, stroke, hypertensive encephalopathy
— Optic fundi: Retinal hemorrhages and exudates with or without papilledema
— Kidney: Plasma creatinine concentration greater than 2.0 mg/dl, renal failure
— Vessels: Dissecting aneurysm, symptomatic arterial occlusive disease
Abbreviation: MI, Myocardial infarction
TABLE 26.16 Cardiovascular risk factors favoring treatment (WHO/ TABLE 26.17 Classification of hypertension (WHO/ISH–1999)
ISH–1993) Category Systolic Diastolic
- Age* - Left ventricular hypertrophy (mm Hg) (mm Hg)
- Gender* - Raised total and LDL cholesterol Optimal <120 <80
- Family history of premature CVD* - Reduced HDL cholesterol Normal <130 <85
- Raised SBP - Diabetes High normal 130–139 85–89
- Raised DBP - Renal disease Grade 1 Hypertension (“mild”) 140–159 90–99
- Smoking - Microalbuminuria Subgroup: Borderline 140–149 90–94
- Previous cardiovascular events* - Obesity Grade 2 Hypertension (“moderate”) 160–179 100–109
- Previous cerebrovascular events* - Sedentary lifestyle Grade 3 Hypertension (“severe”) ≥180 ≥110
* Nonmodifiable Isolated Systolic Hypertension ≥140 <90
Abbreviations: CVD, Cardiovascular disease; DBP, Diastolic blood Subgroup: Borderline 140-159 <90
pressure; HDL, High-density lipoprotein; LDL, Low-density lipoprotein;
SBP, Systolic blood pressure
TABLE 26.18 Factors influencing prognosis (WHO/ISH–1999)

Risk Factors for CVD Target-Organ Damage Associated Clinical Conditions
I. Used for risk stratification Left ventricular hypertrophy (electrocardiogram, Cerebrovascular disease
echocardiogram)
Levels of systolic and diastolic blood pressure Proteinuria and/or slight elevation of plasma creatinine • Ischemic stroke
(Grades 1–3) (1.2 – 2.0 mg/dl)
Men > 55 years Ultrasound or radiological evidence of atherosclerotic plaque • Cerebral hemorrhage
(carotid, iliac and femoral arteries, aorta)
Women > 65 years Generalized or focal narrowing of the retinal arteries • Transient ischemic attack
Smoking Heart disease
Total cholesterol > 6.5 mmol/l (250 mg/dl) • MI
Diabetes • Angina
Family history of premature cardiovascular • Coronary revascularization
disease • Congestive heart failure
II. Other factors adversely influencing prognosis
Reduced HDL cholesterol Renal disease
Raised LDL cholesterol • Diabetic nephropathy
Microalbuminuria in diabetes •R
enal failure (plasma creatinine
concentration > 2.0 mg/dl)
Impaired glucose tolerance Vascular disease
Obesity • Dissecting aneurysm
Sedentary lifestyle • Symptomatic arterial disease
Raised fibrinogen Advanced hypertensive retinopathy
High risk socioeconomic group • Hemorrhages or exudates
High risk ethnic group • Papilledema
High risk geographic region
Abbreviations: CVD, Cardiovascular disease; HDL, High-density lipoprotein; LDL, Low-density lipoprotein; MI, Myocardial infarction
TABLE 26.19 Risk stratification to quantify prognosis (WHO/ISH–2003)

Other Risk Factors and Disease History Stage 1 Stage 2 Stage 3
SBP 140–159 or DBP 90–99 SBP 160–179 or DBP 100–109 SBP ≥180 or DBP ≥110
I No other risk factors Low risk Medium risk High risk
II 1–2 risk factorsa Medium risk Medium risk High risk
III Three or more risk factors or TOD or Associated High risk High risk High risk
Clinical Conditionb
RISK STRATA (Typical 10 years risk of stroke or myocardial infarction)
Medium risk = 15–20%
High risk = More than 20%
a. See Table 26.18
b. Associated clinical conditions (see Table 26.18)
Abbreviations: DBP, Diastolic blood pressure; SBP, Systolic blood pressure; TOD, Target-organ damage (see Table 26.18)
Three major risk categories indicated the likelihood of devel- TABLE 26.20 Classification of hypertension (ESH and ESC–2003)
oping a major cardiovascular event (fatal and non-fatal MI and Category Systolic (mm Hg) Diastolic (mm Hg)
stroke) within the next 10 years—low risk less than 15%, medium risk
Optimal <120 <80
15–20% and high risk more than 20% (Table 26.19). The 1999 guide-
Normal 120–129 80–84
lines also included a group of very high risk which was more than
30% and included patients with associated clinical conditions at any High normal 130–139 85–89
stage of hypertension. This was merged with the high risk group in Grade 1 Hypertension (mild) 140–159 90–99
the 2003 guidelines.16,17 Grade 2 Hypertension 160–179 100–109
(moderate)
EUROPEAN SOCIETY OF HYPERTENSION Grade 3 Hypertension (severe) ≥180 ≥110
(ESH) AND EUROPEAN SOCIETY Isolated systolic hypertension >140 <90
OF CARDIOLOGY (ESC) GUIDELINES— Note: When a patient’s SBP and DBP fall into different categories, the
(2003–2007) higher category should apply. Isolated systolic hypertension can also be
graded (Grades 1, 2, 3) according to the SBP values in the ranges indicated,
Before 2003, ESH and ESC endorsed the WHO/ISH Guidelines. How- provided diastolic values are below 90 mm Hg.
ever the ESH and ESC prepared their own guidelines since the WHO/
ISH guidelines were written for a global audience while Europe is a
more homogenous community where people had a greater life ex-
pectancy and suffered a higher incidence of chronic CVD. “pre-hypertension” suggested by the JNC VII guidelines were not
The 2003 guidelines classified BP as shown in Table 26.20. It also accepted since they imply that a large part of the population is sick
provided risk stratification of hypertension similar to WHO/ISH 1999 and this creates anxiety. It also includes a wide range from normal to
guidelines, but extended risk to include some patients with normal high normal. The 2007 guidelines also stratify cardiovascular risk as
or high normal BP.18 per the 2003 guidelines (Tables 26.21 and 26.22).19
It also included four risk categories—indicating the absolute The guidelines also recommended initiation of treatment
10 years risk of developing a CVD—low risk less than 15%, moder- according to risk factors. It recommends drug therapy in patients
ate risk 15–20%, high risk 20–30% and very high risk more than 30% who have established cardiovascular risk factors or renal disease
(Table 26.21). irrespective of the BP. These patients with normal BP are also
Risk factors, TOD, diabetes and associated clinical conditions advised to start drug treatment. Patients with more than or equal
used to stratify risk are indicated in Table 26.22. The primary goal to 3 risk factors, metabolic syndrome, subclinical organ damage or
of treatment was to reduce the long-term cardiovascular morbidity diabetes with BP in the high normal range are also advised to start
and mortality by addressing the risk factors and the BP levels. Target drug therapy.
levels of BP were < 140/90 and < 130/80 in diabetics.18 This shows that the concepts of BP management are changing
According to the 2007 ESH and ESC guidelines, the classification away from the traditional “normal” versus “abnormal” BP thresholds.
of BP remained as per the 2003 guideline (Table 26.20). The term This views the relationship of BP and risk factors as a continuum,
TABLE 26.21 Risk stratification to quantify prognosis

Other Risk Factors and Disease History Normal High Normal Grade 1 Grade 2 Grade 3
SBP 120–129 or SBP 130–139 or SBP 140–159 or SBP 160–179 or SBP ≥180 or
DBP 80–84 DBP 85–89 DBP 90–99 DBP 100–109 DBP ≥110
I No other risk factors Average risk Average risk Low risk Moderate risk High risk
II 1–2 risk factorsa Low risk Low risk Moderate risk Moderate risk Very high risk
III Three or more risk factors or TODb or Diabetes Moderate risk High risk High risk High risk Very high risk
IV ACCc High risk Very high risk Very high risk Very high risk Very high risk
RISK STRATA (Typical 10 years risk of stroke or myocardial infarction)
Medium risk = 15-20%
High risk = 20-30%
Very high risk = More than 30%
a. See Table 26.21
b. TOD = Target-organ damage – see Table 26.21
c. ACC = Associated clinical conditions – see Table 26.21
TABLE 26.22 Factors influencing prognosis

Risk Factors for CVD used for Stratification Target-Organ Damage
• Levels of systolic and DBP • Left ventricular hypertrophy (ECG Sokolow–Lyons > 38 mm; Cornell
>2440 mm × ms; Echocardiogram; LVMI M ≥ 125, W ≥110 g/m2)
• Men >55 years • Ultrasound evidence of arterial wall thickening (carotid IMT ≥0.9 mm) or
atherosclerotic plaque
• Women >65 years • Slight increase in serum creatinine (M 1.3–1.5, W 1.2–1.4 mg/dl)
• Smoking • Microalbuminuria (30–300 mg/24 hour; albumin-creatinine ratio M ≥ 22,
W ≥ 31 mg/g; M ≥ 2.5, W ≥ 2.5 mg/mmol)
• Dyslipidemia (total cholesterol >250 mg/dl* or LDL-cholesterol >155 mg/
dl*, or HDL-cholesterol M <40, W <48 mg/dl*)
• Family history of premature CVD (M at age <55 years, W <65 years)
• Abdominal obesity (abdominal circumference M ≥102 cm, W ≥88 cm)
• C reactive Protein ≥1 mg/dl
Diabetes Mellitus Associated Clinical Conditions
• Fasting plasma glucose ≥126 mg/dl • Cerebrovascular disease: Ischemic stroke; cerebral hemorrhage; transient
ischemic stroke
• Postprandial plasma glucose ≥198 mg/dl • Heart disease: Myocardial infarction; angina; coronary revascularization;
congestive heart failure
• Renal disease: Diabetic nephropathy; renal impairment (serum creatinine
M > 1.5, W > 1.4 mg/dl)
• Peripheral vascular disease
• Advanced retinopathy: Hemorrhage or exudate, papilledema
* Lower levels of total and LDL cholesterol are known to delineate increased risk but they were not used in this stratification
Abbreviations: CVD, Cardiovascular disease; ECG, Electrocardiography; HDL, High-density lipoprotein; IMT, Intima media thickness; LDL, Low-density
lipoprotein; LVMI, Left ventricular mass index; M, Men; W, Women
with treatment decisions made are based on both risk factors and BP 10-year CVD risk was more than equal to 20% (Table 26.13). Ten-
levels. year cardiovascular risk was to be estimated using a CVD risk chart.
This included age, sex, history of smoking, history of diabetes, ratio
BRITISH HYPERTENSION SOCIETY of total cholesterol to HDL cholesterol and SBP. The target for treat-
ment is below 140/85 mm Hg for most patients, but for patients with
GUIDELINES (1989–2004)
diabetes, renal disease or CVD, the target is lowered to below 130/80
In 1989, the British Hypertension Society (BHS) working party issued mm Hg.22
guidelines for treatment of mild hypertension. Five criteria were used The latest guidelines from the “Fourth working party of the BHS
for identifying patients with mild hypertension at high risk. First, (2004)” included a classification of BP that was the same as that of
patients with a DBP level of 100 mm Hg or more benefitted from treat- the European Society of Hypertension, 2003 (Table 26.20). The treat-
ment. Second, patients with a sustained DBP above 95 mm Hg, but ment indications and targets remained the same as the earlier report
below 100 mm Hg should be monitored regularly and treated only if of BHS III (1999).23
the BP rises above or equal to 100 mm Hg or is influenced by other
risk factors. Third, patient aged more than or equal to 60 years were CONCLUSION
found to have a higher risk of cerebrovascular events and warranted
treatment, but a gradual reduction of BP was required. Patients aged Hypertension, as it is understood today, in terms of its causes, symp-
more than or equal to 80 years were however not recommended for toms and treatment owes a great deal to its evolution as a medical
treatment. Fourth, men showed absolute benefits of treatment great- concept in the history of high BP. The various studies and research
er than women. Fifth included other risk factors like left ventricular undertaken from time to time have helped to shed valuable light in
hypertrophy, hypercholesterolemia, diabetes, smoking and family furthering our understanding of hypertension.
history.20 However, no nationwide studies have been carried out in India
The report of the “Second working party of the BHS (1993)” to determine the prevalence of hypertension. Such epidemiological
established thresholds for initiating treatment in patients. It included studies are urgently needed to determine the baseline against which
SBP and DBP. Patients with an initial measurement of above or equal future trends in risk factor levels can be assessed and preventive
to 110 mm Hg DBP should be treated. Patients with DBP between 100 strategies planned to promote health among all sections of the popu-
mm Hg and 109 mm Hg should have BP rechecked and persistent lations.
DBP above or equal to 100 mm Hg should be started on treatment. With newer recommendations indicating treatment in some pa-
Diastolic blood pressure between 90 mm Hg and 99 mm Hg were tients with “normal” BP, the importance of risk factor stratification
only treated in presence of TOD like left ventricular hypertrophy, re- has come to the forefront. The older thresholds of normal and abnor-
nal disease, diabetes or other risk factors like advancing age, males, mal have been challenged by the concept of a continuum between
family history, dyslipidemia and smoking. In case of ISH, SBP above levels of BP and individual risk factors.
or equal to 160 mm Hg was the threshold to treat.21 The historic importance of “risk factor stratification” as it devel-
The “Third working party of the BHS (1999)” considered SBP oped over the years and evolution of stratification systems has been
and DBP at equal risk and indicated treatment for sustained SBP highlighted in this chapter. This knowledge will only help in improv-
above or equal to 160 mm Hg and sustained DBP above or equal to ing the treatment of this major public health problem, one of the
100 mm Hg. Treatment of patients with BP 140–159/90–99 mm Hg leading contributor to morbidity and mortality in India and world-
was based on TOD and cardiovascular risk factors or if estimated wide.
REFERENCES
1. Indian Guidelines Management of Hypertension. 2001. pp. 1-31.
2. Association of Physicians of India. Indian Hypertension Guidelines-II. Mumbai: API; 2007. pp. 1-26.
3. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension.
2003;42:1206-52.
4. Lorraine G Ogden, Jiang He, Eva Lydick, et al. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to JNC VI
risk stratification. Hypertension. 2000;35:539.
5. Preadeepa R, Mohan V. Hypertension and pre-hypertension in developing countries. Indian J Med Res. 2008;128:688-90.
6. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217-23.
7. Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: A cooperative study. JAMA. 1977;237:
255-61.
8. The 1980 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1980;140:
1280-5.
9. The 1984 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood pressure. Arch Intern Med. 1984;144:
1045-57.
10. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood pressure. Arch Intern Med. 1988;148:
1023-38.
11. The Fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med.
1993;153:154-83.
12. JNC 6. National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-46.
13. Guidelines for treatment of mild hypertension: Memorandum from WHO/ISH meeting. Bull World Health Organ. 1986:64(1):31-5.
15. Guidelines for treatment of mild hypertension: Memorandum from WHO/ISH meeting. Hypertension. 1993;22:392-403.
17. WHO/ISH Statement on management of Hypertension. J Hypertension. 2003;21:1983-92.
18. European Society of Hypertension- European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension- European
Society of Cardiology Guidelines for the management of arterial hypertension. J Hypertension. 2003;21:1011-53.
19. The Task Force of Management of Arterial hypertension of the European Society of hypertension (ESH) and the European Society of Cardiology
(ESC). J Hypertension. 2007;25:1105-87.
20. Treating mild hypertension. Report of British Hypertension Society working party. BMJ 1989;298:694-8.
21. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the second working party of the British Hyperten-
sion Society. BMJ. 1993;306:983-7.
22. Ramsay L, Williams B, Johnston G, et al. Guidelines for management of Hypertension: report of the third working party of the British Hypertension
Society. J Hum Hypertens. 1999;13:569-92.
23. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004—BHS IV. J Hum Hyper-
tens. 2004;18:139-85.
Retracing the Heroic Steps from
27 Lipid Hypothesis to Aggressive

Treatment of Blood Cholesterol—A
Revolution in Preventive Cardiology
Enas EA, Kuruvila AT, Lulla S
Blood cholesterol plays a crucial role in coronary artery disease CARDIOVASCULAR EPIDEMIC
(CAD)—the number one killer of mankind in the 20th century. This
AND CHOLESTEROL WARS
notoriety of CAD is likely to be lost by the middle of the 21st cen-
tury as a result of the tremendous progress made in understanding The cholesterol wars began 100 years ago in Russia when a young
cholesterol and the remarkable progress made in lowering it to previ- pathologist, Nicholai Anitschkow, fed cholesterol to rabbits and pro-
ously unimaginable levels. We review the plethora of evidence sup- duced atherosclerosis of arteries. This experimental study and sub-
porting the lipid hypothesis by tracking its history from Anitschkow’s sequent epidemiological studies triggered a passionate debate as to
1913 classic work on the cholesterol-fed rabbit model to the break- whether cholesterol is the root cause of human ASCVD— the dis-
through 1984 Coronary Primary Prevention Trial (Table 27.1). This ease process that underlies myocardial infarction (MI) and strokes.
first, large, randomized, double-blind primary intervention trial Throughout the 20th century, while the cholesterol wars were raging,
showed that decreasing blood cholesterol significantly reduces CAD more people were dying from ASCVD than those killed in military
events and consequently, blood cholesterol lowering became an offi- combat. Cardiovascular disease (CVD) became the leading cause of
cial national public health goal. Numerous statin trials that followed death in 1949, accounting for 50% of all deaths.
documented the benefits of lowering the low-density lipoprotein France ID and Richard Moore3 in 1969 succinctly summarized
cholesterol (LDL-C) level even in people without high LDL-C levels. the status of the cholesterol wars: “Few controversies are divided in
The National Cholesterol Education Program (NCEP) has standard- the medical community so sharply for such a long time as has the
ized 40 mg/dl as the optimum LDL-C level—roughly equal to total cholesterol hypothesis. The separation between the two points of
cholesterol of 110–120 mg/dl. This article retraces the100 years of an view has become so extreme that, on one hand there are respected
uphill battle and controversy marked by heated debate and some- scientists who believe that the evidence is already so convincing that
times violent disagreement.1 We hope that revealing and sharing this further clinical test is unnecessary, financially wasteful and actually
incredible cholesterol story may help us avoid similar mistakes in the unethical; and, aligned against them are equally respected scientists
future. who believe that the total weight of evidence accumulated over many
years is too slight to justify further work along these lines.”
ATHEROSCLEROTIC CARDIOVASCULAR
DISEASE NICHOLAI N ANITSCHKOW—
THE FATHER OF ATHEROSCLEROSIS
Morphological findings in Egyptian mummies have clearly docu-
mented atherosclerotic lesions in pharaohs who lived more than Elucidation of the role of blood cholesterol in the pathogenesis of
3,500 years ago. Other manifestations of atherosclerosis such as sud- atherosclerosis is often referred to as one of the greatest discoveries
den cardiac death and intermittent claudication were documented of the 20th century. Felix Marchand first introduced the term
approximately 300 BC.2 Atherosclerotic cardiovascular disease (AS- “Atherosclerosis”, in 1904, and he suggested that it was responsi-
CVD) is the most common cause of death in the Western world. ble for almost all obstructive processes in arteries. The first evidence
The pathophysiology of atherogenesis comprises various important that cholesterol causes atherosclerosis had come from Russian phys-
steps, including enhanced endothelial permeability, expression of iologist AI Ignastowsky. In 1908, he showed that rabbits on a diet of
adhesion molecules, monocyte adhesion and immigration, foam cell eggs and meat developed atherosclerosis. However, he thought that
formation, fatty streaks, smooth muscle cell migration and plaque the proteins in the food were responsible. In 1910, Adolph Windaus
formation and, finally plaque rupture and thrombus formation. showed that atheromatous lesions contained six times as much free
Chapter 27  Retracing the Heroic Steps from Lipid Hypothesis to Aggressive Treatment ... 181
TABLE 27.1 Major milestones on the road to acceptance of the lipid hypothesis
1908 Ignatowski produced experimental atherosclerosis by feeding meat, milk and egg yolk to rabbits.
1913 Anitschkow fed cholesterol to rabbits and induced high blood cholesterol levels and arterial lesions similar to human atherosclerosis.
1939 Carl Muller linked familial hypercholesterolemia to xanthomatosis and angina pectoris among Norwegian families with consanguineous
marriages.
1949 Gofman characterized lipoproteins and the strong correlation of blood LDL-C levels with CAD.
1952–54 Kinsell and Ahrens demonstrated significant elevation of blood cholesterol by increasing saturated fat in the diet in healthy subjects.
Substitution of 40% calories in the diet by corn oil decreased the blood cholesterol by 100 mg/dl; substitution by coconut oil increased the
blood cholesterol level by 100 mg/dl.4
1957 Seven Countries Study by Keys demonstrated that the incidence of CAD was directly correlated to blood cholesterol level and saturated fat
intake across populations.
1961 Framingham Heart Study, within a typical American community, demonstrated that the CAD risk is highest in groups with the highest blood
cholesterol levels.
1961 American Heart Association first endorsed the prudent low-fat diet.
1964 Condrad Bloch was awarded Nobel Prize for elucidating the pathway for cholesterol biosynthesis, paving the way for statins a decade later.
1965 The Coronary Drug Project demonstrated reduction in CAD and total mortality with niacin.
1967 Fredrickson and Levy introduced the classification of lipoprotein abnormalities, depending on the pattern of lipoprotein electrophoresis—
the Fredrickson Classification.
1966-69 Leren et al. demonstrated that reducing the blood cholesterol level by reducing saturated fat intake and increasing unsaturated fat intake
(one pint of soybean oil per week) reduces CAD risk in MI survivors.
1974 Goldstein and Brown identified the LDL receptor as the key regulator of cholesterol and lipoprotein metabolism.
1976 Endo discovered the first statin, compactin, a powerful inhibitor of HMG CoA reductase effective in lowering blood cholesterol in animals
and humans.
1980 Alfred W Alberts isolated lovastatin, the first statin to reach the market.
1984 Lipid Research Clinics Coronary Primary Prevention Trial demonstrated significant reduction in CAD in men with high cholesterol treated with
cholestyramine, at a cost $150 million ($40,000 per person)
1984 National Institute of Health (NIH) Consensus Conference declared, for the first time, lowering blood cholesterol to be a National public
health goal.
1984 NIH launched the NCEP.
1985 Goldstein and Brown received Nobel Prize for their groundbreaking work on regulation of cholesterol and lipoprotein metabolism.
1990 The Honolulu Heart Study showed a 3-fold increase in CAD rates among Japanese Americans in California compared to those living in Japan
demonstrating the importance of environmental factors.5
1994 The Scandinavian Simvastatin Survival Study unequivocally demonstrated that statin reduces not only CAD mortality but also total mortality
by 30%.
2004 NCEP designated optimum LDL-C as 40 mg/dl; every 30 mg/dl increase in LDL-C increases the risk by 30%.6
1995– Numerous statin trials demonstrated the safety and benefit of lowering the LDL to <40 mg/dl in > 3,000 people with/without heart disease
2010 or high cholesterol.7
Source: Modified from reference1
Abbreviations: CAD, coronary artery disease; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program.
cholesterol and 20 times as much esterified cholesterol as normal cholesteryl esters, is derived mainly from arterial wall macrophages.
arterial wall. These macrophages originate from circulating monocytes that pene-
Anitschkow, another Russian, first described the role of choles- trate into the subendothelial space. This discovery introduced a new
terol accumulation in the development of atherosclerosis in 1914.2 era in the studies of atherosclerosis. In 1958, editorial in Annals of
He showed that feeding egg yolks and even pure cholesterol promptly Internal Medicine, William Dock compared the significance of the
caused atherosclerosis in rabbits. He also described the foam cell— classic work of Anitschkow to that of the discovery of the tubercle
the hallmark of fatty streak—the first visible lesion of atherosclero- bacillus by Robert Koch, circulation by Harvey and respiratory ex-
sis in cholesterol-fed rabbits. This cell, loaded with droplets rich in change of oxygen and carbon dioxide by Lavoisier.8
But Anitschkow’s experiment fell by the wayside for three dec- the arterial disease and xanthomatosis were secondary to elevated
ades. Since rabbits are normally vegetarians, many scientists ques- blood cholesterol.
tioned the relevance of the development of atherosclerosis in rabbits Nobel laureates, Michel Brown and Joseph Goldstein were fas-
by feeding egg yolks and meat, to atherosclerosis in omnivorous hu- cinated by two young patients a brother and a sister, 6 and 8 years
mans. Furthermore, the blood cholesterol levels in Anitschkow’s rab- old with advanced CAD and a history of myocardial infarction (MI).
bits were very high—500 mg/dl to 1,000 mg/dl—much higher than The children had blood cholesterol levels > 1,000 mg/dl, more than 5
usually seen in humans. In addition, atherosclerosis failed to devel- times the average for adults and most of this was LDL-C. These chil-
op in dogs and rats no matter how much cholesterol these animals dren had a severe form FH (homozygous with both genes defective)
were fed. What the scientists did not realize was that when rats and and their parents had a milder form of the disease (heterozygous
dogs were fed egg yolks, their blood cholesterol level did not go up, with one defective gene).
because these animals rapidly convert cholesterol into bile acids and Brown and Goldstein, who had done pioneering work on
dispose of it through feces. Forest Kendall was, however, able to raise the regulation of cholesterol biosynthesis, later identified genetic
the blood cholesterol and produce atherosclerosis in dogs by remov- absence of LDL-C receptors as the cause for this phenomenon.
ing the thyroid gland. After realizing this, scientists have produced
experimental atherosclerosis in upwards of 20 different animal spe- FAMILIAL HYPERCHOLESTEROLEMIA
cies. They have also demonstrated that atherosclerosis develops
without the astronomic blood levels of Anitschkow’s rabbits. It just Homozygous FH is a rare, but dangerous condition occurring in
takes a little longer at lower blood cholesterol levels. Kendall’s results one per million, whereas, heterozygous FH has a frequency of 1 in
helped revive interest in the so called “lipid hypothesis”. 500 across most ethnic groups. When two heterozygous FH people
marry, which happens in 1 in 250,000 marriages, each child has a
THE LIPID HYPOTHESIS 25% chance (1 in a million overall) of inheriting the defective gene
from both parents. These FH patients lack LDL receptors and hence,
The lipid hypothesis proposes that, a high blood cholesterol level the cells cannot take up LDL-C, which accumulates in the blood. The
is a significant causative factor in atherogenesis and its clinical ex- liver possesses three quarters of body’s LDL receptors.
pression. It does not specify the nature of the hypercholesterolemia At the University of Pittsburg, Dr Thomas Starzl transplanted a
nor how it is brought about. It might be the result of genetic defects, new heart and liver into a six-year-old girl with a severe case of FH
endocrine disorder or diet. It does not propose that hypercholester- and a blood cholesterol level > 1,000 mg/dl. Six months before her
olemia is the only cause. The implied corollary is that reducing blood transplant, she had already had several MIs and had undergone
cholesterol level might reduce atherosclerosis and its complications. two coronary bypass operations and mitral valve replacement.
Direct evidence of regression of coronary atherosclerosis and reduc- Six months after the transplant, her blood cholesterol level came
tion in clinical events has now been documented with large reduc- down to less than 300 mg/dl. The transplanted liver alone had
tion in the blood cholesterol achieved by extremely rigorous dietary enough LDL receptors to remove IDL-C (intermediate density lipo-
intervention, partial ileal bypass surgery and various medications, protein cholesterol) and LDL-C from her blood stream.
validating the lipid hypothesis.1
GOLDSTEIN BROWN AND LDL RECEPTOR
GENETIC EVIDENCE OF HIGH
Cholesterol is needed all over the body because it is a vital compo-
CHOLESTEROL PRODUCING HEART
nent of the membrane that defines every cell. Low-density lipopro-
ATTACKS IN CHILDREN tein cholesterol particles are transported from the blood stream into
As early as 1889, Lehzen reported the case of a child who had xan- the body’s cells by the LDL receptors. This protein (which is produced
thomatosis since age of 3 years and died suddenly at age of 11 years. in the endoplasmic reticulum) cycles between the surface and inte-
Autopsy revealed extensive xanthomatous deposits in coronary and rior of the cell many times, carrying attached LDL particles into the
other arteries. Her sister, age 9, also had cutaneous xanthomas. In cell along with it. Once inside the cell, the LDL is broken down into
retrospect, this was clearly a case of familial hypercholesterolemia its components parts—proteins, phospholipids and cholesterol—by
(FH) that was not known at that time. In 1939, Carl Muller described a roster of specialized enzymes. The freed cholesterol can then be
several cases of familial aggregation of xanthomatosis, hypercho- incorporated into the cell membrane or—depending upon the cell—
lesterolemia and heart disease in Norway where consanguineous be made into other cholesterol-based molecules (steroid hormones
marriages were fairly common at that time. (Such marriages are very and bile acids). It also suppresses the production of 3-hydroxy-
common even today in many regions and communities in South 3-methylglutaryl-coenzyme A (HMG CoA) reductase and the cell in
Asia). His work established FH as a monogenic defect implying that turn makes less of its own cholesterol.
The seminal discovery of LDL receptors by Brown and Gold- second fraction was designated HDL because it deposited at the bot-
stein in 1974 represented a turning point in the history of lipoprotein tom. He was the first to demonstrate that LDL-C is responsible for
research. They were awarded the Nobel Prize for this discovery the rapid progression of atherosclerosis in human beings. Gofman
in 1985. But, equally important, was their discovery of scavenger identified and named intermediate density lipoproteins (IDL), very
receptors on the macrophages. Their research demonstrated that the low density lipoprotein (VLDL) and the two HDL subclasses (HDL2
very high LDL-C levels in FH patients is due to the very low uptake of and HDL3). He also initiated the first multicenter study to prospec-
LDL-C due to absence of receptors in liver; whereas uptake of LDL by tively evaluate the predictive value of various lipoproteins in 5,000
scavenger receptors accounts for LDL loaded cells in xanthomas and healthy men. He developed an atherogenic index and predicted that
atherosclerotic lesions. lipoprotein measurement at a particular age would allow the estima-
The mechanism underlying high blood cholesterol in FH tion of the extent of coronary atherosclerosis and future risk of MI.11
patients and general population is the same. FH patients have high His reports led to an explosion of research on plasma lipoproteins.
blood cholesterol because they lack LDL receptors due to a genetic Gofman is widely considered as “the Father of Clinical Lipidology”.
defect. When a person with normal LDL receptor genes eats a high
fat diet, liver cells accumulate cholesterol and turn down their pro- LDL-C AND LIPOPROTEINS
duction of LDL receptors causing high blood cholesterol levels.
Sixty years ago, scientists knew little more on the subject of fats in
CHOLESTEROL-YEAR SCORE AND blood than that oil and water do not mix. Fatty molecules, such as
cholesterol and triglycerides are, therefore, specially packaged in
CORONARY ATHEROSCLEROSIS
order to travel around the blood stream in the form of lipoproteins
The cholesterol-year score may be useful in defining the risk of ath- (which also transport vitamins and other hydrophobic substances).
erosclerosis in FH patients with severe hypercholesterolemia. The Though lipoproteins vary in size and the proportion of each compo-
concept of cholesterol-year is analogous to pack-years of cigarette nent they contain, they share the same basic structure: an oily core
use and is calculated based on the age and the yearly mean blood of cholesterol and triglycerides surrounded by a coat of cholesterol
cholesterol concentration of the patient. Cholesterol-year score is and phospholipids. The molecules of this outer coat are precisely
highly correlated with tendon xanthomas and calcified coronary ath- arranged to keep the particle soluble in the watery plasma. Finally,
erosclerosis. Most FH patients develop calcific atherosclerosis when one or more proteins become embedded in the outer coat.
cholesterol-year score exceeds 10,000 mg-year/dl. As a corollary, an The liver plays a central role in fat and cholesterol metabolism.
individual with blood cholesterol of 1,000 mg/dl would be expected Intestinal cells absorb fatty acids from the foods and link them
to have significant CAD by 10 years of age, whereas an individual together in groups of three to form triglycerides. These cells pack-
with 500 mg/dl would develop CAD by 20 years, even in the absence age the triglycerides together with the cholesterol absorbed from the
of other significant risk factors.9 intestine and form chylomicrons, the largest type of lipid transport-
ing particles. These chylomicrons are then released into the blood
JOHN GOFMAN—THE FATHER OF stream, giving the plasma its cloudy appearance after a meal. As the
chylomicrons circulate through the body, the enzyme lipoprotein
CLINICAL LIPIDOLOGY
lipase frees the triglyceride and the liberated fat enters the muscle or
In 1949, Dr Edwin J Cohn and Dr John Oncley described two types fat cells. This enzyme was identified and named by Korn in 1955.10
of fat and protein particles which they named alpha-lipoprotein and The plasma turns clear again because the remaining particles
beta-lipoprotein.10 The same year, John Gofman, using ultracentri- are so much smaller than chylomicrons. The chylomicron remnants
fuge, also identified two types of lipoproteins. What Cohn had called so formed are enriched in cholesterol and depleted of triglycerides;
alpha and beta, Gofman renamed high-density lipoprotein(HDL) they are taken up by the liver and repackaged into VLDL—a particle
and low-density lipoprotein (LDL) to reflect their behavior in his ul- smaller than chylomicron, but nearly as rich in triglyceride. VLDL
tracentrifuge.10 At that time, the idea that excess cholesterol in the too enters the blood stream and circulates through the tissues, where
blood ends up in the artery wall was merely a hypothesis and not a lipoprotein lipase again removes triglycerides for delivery to the
particularly popular one. cells. That leaves a smaller, dense particle, the IDL. About half of the
Gofman used an extremely expensive and highly sophisticated IDL particles are taken up by the liver within hours of formation and
analytical ultracentrifuge—one of the two machines available in the their fat and cholesterol molecules are again recycled into VLDL or
world—capable of rotating its tubes 40,000 times per minute to study converted into bile acids. The rest continue to circulate through the
blood cholesterol. The hypercholesterolemic serum samples from blood, where they are eventually converted to LDL-C. After several
their cholesterol-fed rabbits were centrifuged and then sequestered days, LDL-C too is ultimately taken up by the liver. All this packaging
into two different compartments. The first fraction was designated as and repackaging ensures that cells all over the body receive a con-
LDL because it floated towards the surface of the serum sample. The stant supply of just enough fat and cholesterol. The liver acts as a kind
of buffer between the body and the diet removing excess fat and cho- stroke at a very young age—in their 20s and 30s—even in the absence
lesterol from the blood after a meal and doling them out again later. of traditional risk factors. Lp(a) is highly atherogenic, thrombogenic
and antifibrinolytic and also carries virtually all OxLDL in the blood.
OXIDIZED LDL Lp(a) levels vary 1,000-fold among individuals and 7-fold among
populations, and it appears to be particularly common and danger-
Before it can initiate atherosclerosis, LDL has to be modified to oxi- ous among Asian-Indians. When high Lp(a) levels were combined
dized LDL (OxLDL), which has many biological effects that would with other risk factors (such as hypertension, diabetes, smoking,
accelerate atherogenesis. Oxidized LDL impairs the endothelial cell’s hyperhomocysteinemia and/or high total cholesterol to HDL ratio)
ability to produce nitric oxide. Oxidized LDL causes endothelial cells the relative odds of premature CAD ranged from 3- to 122-fold de-
to secrete adhesion molecules and chemoattractants that allow pending upon the number of risk factors present and their severity.14
white blood cells, called monocytes, to penetrate in between the en- Elevated oxidized-Lp(a) levels are associated with presence and
dothelial cells and stick together in the subendothelial space, leading severity of ACS.
to fatty streaks and atherosclerotic plaques. Oxidized LDL turns on More than 34 different Lp(a) isoforms have been identified with
the expression of genes in monocytes, which causes them to convert small isoforms conferring greater risk and larger isoforms carrying
into macrophages and eventually into foam cells. In short, OxLDL minimal or no risk. The small isoforms carry a two-fold risk of prema-
contributes to the entire atherosclerotic process from start to finish. ture vascular disease independent of the Lp(a) concentration. Now
While it is generally agreed upon that LDL undergoes oxidation that Lp(a) is established as a causative factor in atherosclerosis and
and that oxLDL is present in arterial lesions, it is still not known how its measurements standardized, we anticipate an explosive increase
and where LDL gets oxidized in vivo nor which of its many biologi- in research including demonstration of benefits of lowering it in the
cal effects demonstrable in vitro are relevant to atherogenesis in vivo. coming decade.15
Although oxidative modification hypothesis is strongly supported
by several lines of evidence, the antioxidant trials using mostly DONALD FREDRICKSON AND
vitamin E or beta carotene as antioxidants have been uniformly
CLASSIFICATION OF LIPOPROTEINS
negative. Meta-analysis of data from several large studies involving
80,000 subjects shows no beneficial CVD outcome from antioxidant Donald Fredrickson recognized that Gofman’s analytical centrifuge
therapy and some even showing harm.12 method was just too complicated and too expensive to ever be a prac-
tical clinical tool. Preparative ultracentrifugation also suffered from
LOW HDL—THE BODY ARMOR the same drawbacks. Fredrickson, Lees and Levi made extensive use
of paper electrophoresis to identify various lipoprotein disorders
AGAINST ATHEROSCLEROSIS
and assigned them to one of five types (Types I–V). The availability
Unlike LDL-C, the HDL-C transports excess fatty molecules espe- of a relatively inexpensive and simple way of looking at lipoproteins
cially cholesterol out of the tissues and back to the liver to be bro- sparked a wave of enthusiasm among clinicians around the world.
ken down. The importance of HDL-C as a negative risk factor for Fredrickson brought lipoproteins into the vocabulary of the practi-
atherosclerosis was suggested by the pioneering work of Russ, Barr tioner, and this had a profound impact on the clinical management
and Eder and firmly established by Miller and Miller.1 Low HDL-C of lipoprotein abnormalities. His demystification of lipoproteins
is just as good of a predictor of CAD as high LDL-C; low HDL-C is helped practitioners think more clearly about the lipid hypothesis
found in 90% of Asian Indians.13 Regular, sustained physical activ- and the feasibility of preventing atherosclerosis.1
ity and prescription niacin are highly effective in raising the HDL-C. Electrophoresis is a method in which an electric current is
Statin-niacin combination therapy has shown a CAD risk reduction passed through a solution to separate its components by size and
of 60–90%, further underscoring the crucial role of blood cholesterol electrical charge. When strips of paper containing electrophoresed
and its lipoproteins. blood proteins are stained with a fat-soluble dye, 4 lipoprotein bands
appear: Chylomicrons, LDL (β), VLDL (pre β) and HDL(a).
LIPOPROTEIN(A)—A DANGEROUS
GENETIC VARIANT OF LDL HOW HIGH IS HIGH BLOOD CHOLESTEROL?
First described by Berg in 1963, lipoprotein(a) [Lp(a)] is a Since most heart attacks occurred in individuals with so called
genetic variant of LDL containing an additional apoprotein— “normal cholesterol” levels, most doctors considered that blood
apolipoprotein(a)—making it an enigmatic and highly dangerous cholesterol level was irrelevant to atherosclerosis and heart attacks.
lipoprotein. In 1940s, 95% of the US population had blood cholesterol values
Like FH, Lp(a) levels are almost entirely genetically determined, below 280 mg/dl and so any value below 280 mg/dl was considered
and people with very high levels develop premature heart attack and normal. In addition, a blood cholesterol level up to 330 mg/dl was
considered normal by many laboratories. This author was told not not yet developed overt symptoms of CVD or suffered a heart attack
to be concerned when a blood cholesterol level of 320 mg/dl was or stroke. Data gathered in the Framingham Heart Study had more
detected in 1975 during cardiology fellowship. The perception of impact on CAD research than that from any other single epidemio-
“normal cholesterol level” changed when the Seven Countries Study logical study in the 20th century. It served many nations and remains
showed much lower level of blood cholesterol in most of the rest of the bedrock of CAD risk prediction models worldwide. It provided
the world. the first solid and unarguable evidence that individuals with higher
blood cholesterol levels were more likely to experience an MI. For
ANCEL KEYS AND INTERNATIONAL example, compared to Americans with a blood cholesterol level of
175 mg/dl, those who had a blood cholesterol level of 250 mg/dl had
COMPARISON OF CHOLESTEROL LEVELS
double the risk and those with 300 mg/dl had a four-fold risk of heart
The Seven Countries Study (1957) (Ancel keys and international attack.10 In people under 50 years of age each 10 mg/dl increase in
comparison of cholesterol levels) showed marked variation in blood blood cholesterol increased the risk of CVD by 9%.16 In sharp con-
cholesterol levels among countries with Finland having the highest trast, HDL-C is strongly and inversely related to CAD. Although the
(260 mg/dl) and Japan having the lowest (160 mg/dl). The number initial reports showed only LDL-C to be significantly associated with
of fatal heart attacks for 1,000 men over a 10-year period was 70 in CAD, more recent reports showed that both LDL-C and VLDL-C are
Finland and 5 in Japan. The US had the second highest blood cho- strongly and independently correlated with CAD. It showed that this
lesterol of 240 mg/dl and the second highest rate of fatal CAD. When was also true for a number of other risk factors such as high blood
the CAD death rate was plotted against the blood cholesterol levels pressure and smoking. Obesity, diabetes, low HDL-C, lack of exercise
for all seven countries, the data points were roughly on the same and family history of CAD were also later identified as important risk
straight line, strongly suggesting that the population risk was roughly factors from this study.
proportional to the blood cholesterol levels. Another seminal find-
ing in this study was the strong correlation of blood cholesterol levels DIET-HEART DISEASE VERSUS
with saturated fat intake. The contribution of the saturated fat to the
DIET-BLOOD CHOLESTEROL-HEART
total daily caloric intake was over 20% in Finland, but only 2.5% in
Japan. Again, the values for the other countries were roughly along a
DISEASE PARADIGM
single line. Taken together, the data showed that the population risk There was a striking decrease in MI during World War II, which
of fatal heart attacks is proportional to blood cholesterol level which was attributable to the unavailability of animal fats that caused a
is, in turn, proportional to the dietary intake of saturated fat (after decrease in blood cholesterol. Several pathologists have reported
adjusting for obesity, blood pressure, smoking and other dietary fac- that the extent of severity of atherosclerosis at autopsy was much less
tors), underscoring the crucial role of saturated fat intake. More im- during wartime, when food supplies were limited. This was also true
portantly, little or no correlation was found between total fat intake in patients suffering from malnutrition for some time prior to death
and the CAD risk. from chronic debilitating conditions such as cancer, cirrhosis or
When the Japanese with the lowest rate of CAD and blood cho- tuberculosis.1
lesterol level immigrated to Hawaii, the blood cholesterol levels in- In the 1950s and 60s, the only way to lower blood cholesterol was
creased, and the CAD rate doubled. The increase in risk was even to manipulate the diet. This led to the development of the errone-
more striking among Japanese settled in San Francisco, who had ous “Diet-heart disease” paradigm delaying the recognition of the
a 3-fold higher CAD mortality compared to those living in Japan. crucial role of blood cholesterol in CAD. It is often not appreciated
Detailed studies revealed that acculturation to the American way of that there is tremendous variation in the adherence to a healthy diet
life, especially an increase in saturated fat intake from animal sourc- and in the response to such a diet among research participants and
es, was responsible for this phenomenon. These Japanese Americans free living populations. Now we know that it is neither the diet nor
were in the new environment for only a few generations and hence the dietary cholesterol, but the blood cholesterol that determines
not long enough to change their genetic pool. the CAD risk—the “diet-blood cholesterol-heart disease” paradigm.
These causal relationships opened the way to the prevention of CAD
THE FRAMINGHAM HEART STUDY—THE that is supported by intervention studies aimed at reduction of blood
cholesterol levels.2
MOTHER OF ALL EPIDEMIOLOGICAL
STUDIES
IMPACT OF DIETARY CHOLESTEROL
This study was carried out by the National Institute of Health (NIH)
ON BLOOD CHOLESTEROL
in the small town of Framingham, Massachusetts, beginning in 1948
and continuing actively to this day. The Original Cohort consisted Although the patients and public alike are generally advised to follow
of 5,209 men and women between the ages of 30 and 62 who had a low-cholesterol diet, the impact of increasing cholesterol intake
is much less impressive than that of increasing saturated fat in the and a 6% increase in unsaturated fat.20 The population level of blood
diet. Beyond a certain threshold level of cholesterol intake, further cholesterol decreased by 19% (from 225 mg/dl to 182 mg/dl). More
increases have little additional effect on blood cholesterol level.17 importantly, the prevalence of high blood cholesterol decreased by
Adding just 100–200 mg cholesterol per day to a previously cho- 79% (24–5%).21 This change in cooking oil had more beneficial effects
lesterol-free diet can raise blood cholesterol level as much as 20%. on risk factors than all other interventions. The totality of evidence
Once the total daily cholesterol intake has reached about 300 mg/ indicates that replacing saturated and trans fat with unhydrogenated
day, there is a “saturation phenomenon” such that further increase monounsaturated and polyunsaturated fats is more effective in pre-
in cholesterol intake has very little effect on blood cholesterol levels. venting CAD than reducing overall fat intake.19 Reducing the use of
The damage is already done when the total daily cholesterol intake foods containing SAFA and increasing the use of healthy cooking oils
is 300 mg or higher. For most Americans, the daily cholesterol intake high in PUFA (polyunsaturated fatty acids such as corn oil, safflower
is already at or above 500 mg/day on their usual diet. As a corollary, oil and sunflower oil) can reduce the need and use of cholesterol-
an individual who is already on a very high cholesterol diet (500 mg/ lowering medications substantially.
day) can take additional three or more eggs per day without further
raising the blood cholesterol level. On the other hand, in an individ- CHOLESTEROL AGNOSTICS
ual on a very low cholesterol diet (100 mg/day), adding one egg per
day can significantly increase the blood cholesterol level. Egg yolk, The pioneering research of Anitschkow and Gofman suggested a
containing an average of 213 mg of cholesterol, is the single largest causal relationship between blood cholesterol and atherosclerosis,
contributor to dietary cholesterol (36%) in the US. but fell short of proving the case. By the late 1960s, many clinicians
People absorb dietary cholesterol at different rate and also cat- and investigators were already convinced that hypercholesterolemia
abolize it at very different rate. The effect of dietary cholesterol var- should not only be considered a causative factor, but should also be
ies markedly among people due to complex genetic factors; some considered an important and legitimate therapeutic target. But oth-
individuals absorb more than 50% (responders) while others absorb ers including many basic and chemical scientists, particularly in the
less than 5% of dietary cholesterol (nonresponders). For an extreme UK, remained skeptical and critical. By the 1970s, the cholesterol
example, an 88-year-old man who, through much of his life con- skeptics were becoming increasingly vitriolic and even some sug-
sumed 25 eggs each day was surprisingly able to maintain a blood gested that those who believed there was a connection between ath-
cholesterol level between 150 mg/dl and 200 mg/dl. Careful meta- erosclerosis and dietary cholesterol must be in the pay of vegetable
bolic research studies showed that his body was converting dietary oil manufacturers10 (Table 27.2). Despite a wealth of persuasive evi-
cholesterol into bile acids with great efficiency as is done in rats and dence, many cholesterol agnostics continue to argue against testing
some other animals.18 and treatment in both adults and children until after they survive an
MI or stroke.22
Powerful Impact of Dietary Saturated Fats and
Unsaturated Fats on Blood Cholesterol DIETARY INTERVENTION TRIALS
Saturated fatty acid (SAFA) intake increases blood LDL-C concentra- In 1952, Lawrence Kindsell showed that ingestion of plant foods and
tions; therefore, its intake should be reduced to prevent CAD. The avoidance of animal fats significantly decreases the blood cholester-
level of SAFA in the diet has a greater effect on blood cholesterol level ol level in most human beings. The same year, it was shown that the
than does dietary cholesterol itself. Lower habitual intakes of SA- blood cholesterol lowering effects of vegetable fats are due to their
FAs, however, require substitution of other macronutrients to main- unsaturation. During the next few years, millions of people tried to
tain energy balance. Replacement of 5% of energy from SAFA with substitute vegetable for animal fats in their diet.1
energy from unsaturated fats would reduce CAD risk by 42%, while By 1972, the importance of diet in determining blood choles-
the replacement of 2% of energy from trans fat with energy from terol was well established. Three studies in particular—the Leren
unhydrogenated, unsaturated fats would reduce risk by 53%.19 Oslo Study, the Wardsworth Veterans Administration Study, and
The dramatic benefit of such a substitution of SAFA on the popu- the Finnish Mental Hospital Study—showed that diet rich in PUFA
lation level of blood cholesterol was reported from Mauritius—an could significantly reduce blood cholesterol level while a diet rich
island nation with high CAD rates and high blood cholesterol levin SAFA would increase it. These and other studies had collec-
el. The government then instituted a number of population-level tively provided very strong evidence for the lipid hypothesis.1 In
interventions focused on CAD and its risk factors. One interven- the Leren-Oslo Study, 206 MI survivors were advised to drastically
tion included changing the composition of imported oils used for reduce the SAFA intake and were also given one pint of soybean
cooking from predominantly palm oil (49% saturated fat) to almost oil per week to increase the PUFA intake, while an equal number
exclusively soybean oil (14% saturated fat and 81% unsaturated fat). of subjects continued on their usual diet. The PUFA group had an
The change in oil resulted in a 4% decrease in intake of saturated fat 18% reduction in blood cholesterol. During a follow-up of 11 years,
TABLE 27.2 Arguments against dietary and pharmacological control of blood cholesterol levels
George Man23 (1977) “Diet-Heart: End of an Era—the dietary dogma was a money maker for segments of the food industry, a fundraiser for
the heart association and busy work for thousands of fat chemists”
Ahrens EH24 (1979) Commenting on the recommendation to modify the diet of the American public wrote, “such recommendations would
be unwise, impractical and unlikely to lead to reduced incidence of atherosclerotic disease”
Michael Oliver25 (1981) “Reduction of raised serum cholesterol is a card of uncertain quality in the primary prevention of coronary artery
disease” and that “Reduction of raised serum cholesterol could lead to adverse biological changes.” He also advised “It is
probably of little value to reduce serum cholesterol concentrations in patients with overt CAD”
George Mann1 (1984) “They have held repeated press conferences bragging about the cataclysmic breakthrough which the study (CPPT)
directors claim shows that lowering cholesterol lowers the frequency of CAD. They have manipulated the data to reach
the wrong conclusions”
Stephen Hulley, Judith Walsh, “There is an association between low blood cholesterol and noncardiovascular deaths in men and women. There is
Thomas Newman26 (1992) no association between high blood cholesterol and cardiovascular deaths in women. With the exception of those who
already have coronary disease, it no longer seems wise to screen for and treat high blood cholesterol in women. For
primary prevention in patients who do not yet have manifestations of coronary disease it now seems unwise to treat
high blood cholesterol with drugs. These three conclusions indicate the need for a change in direction for cholesterol
policy.”
recurrent MI was observed in 26% of the control group and 16% of (milk, butter, ghee, cream, cheese and ice-cream), coconut meat and
the PUFA group—an impressive 38% risk reduction. Those subjects tropical oils (coconut oil, and palm oil and palm kernel oil) may have
who were fully adherent to this rigorous regimen achieved a 22% greater benefit among Indians, the majority of whom are vegetarians
reduction in blood cholesterol (and probably derived greater and/or consume rather meager quantities of meat.28,29 The American
reduction in MI).1 Heart Association (AHA) went on record as early as 1961 to recom-
The beneficial effect of substitution of SAFA for unsaturated fats mend reducing dietary fat to no more than 25–35% of total calories,
was confirmed in a metabolic ward by Ahrens.4 All the elements in and substituting PUFA for SAFA.
the diet were kept constant, except that SAFA was substituted for
PUFA (or vise versa). The entire diet was given in liquid form as milk DRAMATIC REDUCTION IN BLOOD
shake. After 8 weeks on an ad lib diet, liquid formula was started as
CHOLESTEROL WITH INTESTINAL
the only source of calories—15% coming from proteins, 45% from car-
bohydrate and 40% from fat. On starting the corn oil-rich diet (very
BYPASS SURGERY
high in PUFA), blood cholesterol fell from more than 400 mg/dl to The Program on Surgical Control of Hyperlipidemia (POSCH), a ran-
less than 300 mg/dl and remained there for 8 weeks. On substitution domized clinical trial, was designed to test whether blood cholesterol
of an equicaloric amount of coconut oil (very high in SAFA), blood lowering induced by the partial ileal bypass operation would favora-
cholesterol level rose sharply almost back to the 400 mg/dl level. bly affect all-cause mortality and CAD mortality. The study popula-
Returning to the corn oil formula caused the level to fall again, down tion consisted of 838 MI survivors (417 in the control group and 421
to less than 300 mg/dl.The same results were obtained when but- in the surgery group). When compared with the control group after
ter, lard or coconut oil were substituted for corn oil. The isocaloric 5 years, the surgery group had a 23% decrease in blood cholesterol
substitution of corn oil with butter fat or coconut oil raised the blood level, a 38% decrease in LDL-C level and a 4% increase in HDL-C
cholesterol level by 25–50%. Substitution with palm oil raised it by level. Coronary artery disease and all-cause mortality were reduced.
10–30%. The increase in blood cholesterol observed on equicaloric The extended follow-up of this study showed that surgical treatment
substitution of corn oil with coconut oil was similar or higher than had favorable impact on several outcome measures, stemming from
that with butter. Qualitatively similar results were obtained by Keys marked reduction in LDL-C. There was significant increase in the
and several others.1 disease-free intervals: overall mortality by 2.7 years; CAD mortality
The results of these studies were succinctly summarized in 1957, by 3.8 years; CAD mortality and nonfatal MI by 5.5 years; and coro-
which holds true even today: “It is clear that it is unnecessary to pre- nary intervention procedures by 7 years.30 These results provided
scribe a diet extremely low in total fats to lower the blood cholesterol; strong evidence supporting the beneficial effects of lipid modifica-
exclusion of saturated fats (in butter fat and meat fat) has the great- tion in the reduction of atherosclerosis progression.31 Nonetheless,
est effect, and this effect may be enhanced by substitution of such it is unlikely that most CAD patients would brave to undergo such a
oils as corn oil and cotton seed oil”.27 Reducing the intake of dairy fat draconian measure.
fatal heart attacks (27%) and stroke (26%).1 While there was no
HOW TO LOWER THE BLOOD
decrease in all-cause mortality during the 6-year period of the
CHOLESTEROL?
study itself, the 15-year follow-up (9 years after the study was ter-
Blood cholesterol level can be lowered by dietary modification, intes- minated), showed a highly significant 11% decrease in all-cause
tinal bypass surgery or medications. A change in diet is the first step mortality (p < 0.0004) in the niacin treated groups.32 This was the
in lowering blood cholesterol, but if this does not reduce the blood first trial in which both coronary mortality and all-cause mortality
cholesterol enough, appropriate medications should be started and were significantly reduced. The finding cheered the believers, but
continued indefinitely as intestinal bypass surgery is not a viable did little to move the skeptics.
option as discussed above.
JEREMIAH STAMLER AND AMERICAN
Cholesterol-Lowering Medications HEART ASSOCIATION (AHA)
Although modification of the diet is the preferred method, very few Jeremiah Stamler spent virtually his entire career on researching
Americans have been successful in achieving significant reduction the causation and prevention of CVD, particularly CAD. Dr Stamler
in blood cholesterol through diet. This led to the search for medica- served in leadership capacities in numerous national and interna-
tions. However, the use of medications to lower blood cholesterol tional studies for over 60 years: the Coronary Drug Project, the Na-
was considered quixotic because these would have to be taken life- tional Diet-Heart Study, the DASH Trial, to name just a few. His work
long and there was concern of serious, unexpected side-effects (as in population-based research began in the 1950s and continues to
happened with thalidomide). An extraordinary degree of safety the present. He was the driving force in AHA adopting and advocat-
would have to be demonstrated before widespread use of medicine ing healthy lifestyle for the general public. Author had the honor of
could be accepted. By early 60s, the lipid hypothesis was accepted personally knowing this doyen of preventive cardiology and benefit-
by many specialists in atherosclerosis research community, but not ted from his guidance for author’s own research on heart disease
by the average practitioner. The dietary intervention studies were (Fig. 27.1).33
strongly suggestive, but not totally convincing. In 1961, AHA accepted the causal relationship between blood
cholesterol and atherosclerosis and recommended that people at
Mixed Results from the Coronary Drug Project high-risk of CAD be advised to modify their diets to avoid heart at-
tacks. In 1964, this recommendation was extended to the general
Randomized control trials provide a rigorous evaluation of hypoth- public and in 1965, the American Medical Association made similar
eses generated by results of observational studies. It also provides recommendations. Both AHA and NCEP now recommend limiting
assurance of safety. The answer of the day was provided by the Coro- saturated fat intake to less than 7% of energy and sodium intake to
nary Drug Project. A total of 8,341 male survivors of MI were rand- 1,500 mg along with increasing the intake of fruits and vegetables to
omized in 53 centers. Four different cholesterol-lowering agents more than 4.5 cups per day.34
were selected for the study: dextrothyroxine, estrogen, clofibrate and
nicotinic acid (niacin). Tragically, many of the treatment arms had
to be discontinued due to unfavorable outcome. The d-thyroxine
arm was discontinued first due to serious arrhythmia and increase in
mortality. Men on a high-dose of estrogen (5 mg/d) were discontin-
ued second due to high rate of MI, and the low-dose regimen was dis-
continued third because of a statistically significant increase in all-
cause mortality and an increase in deep vein thrombosis. The other
two arms of the study were continued for the full 5-year follow-up.
Coronary death rates on clofibrate were slightly less than in controls,
but the difference was not statistically significant, and there was no
difference in total mortality. Worst of all, in the clofibrate group there
was a significantly greater incidence of serious side effects includ-
ing angina pectoris, peripheral vascular disease, serious arrhythmias
and venous thrombosis. There was also a two-fold increase in the in-
cidence of gall stones on clofibrate.
Finally, the men on niacin (3 g/d) showed a 10% decrease in
blood cholesterol and a statistically significant decrease in non- Figure 27.1: Dr Enas with Dr Stamler
The AHA’s health promotion and advocacy efforts have to local irritation of the intestinal wall. At that time, it was available
contributed more to the dramatic reduction in CAD deaths in only as a sandy powder that needed to be stirred in water or juice and
the US (69% in the last four decades) than any governmental or- gulped down. To be fully effective, the subjects had to bravely down
ganization. Its goal for the next 10 years (from 2010 to 2020) is to two packets of this gritty stuff three times daily. To make matters
further reduce: death rate due to CAD and stroke by 25%; the preva- worse, the placebo had the same side effects by design and reduced
lence of smoking, high blood pressure, high blood cholesterol and the adherence rate in both groups. Some experts have characterized
physical inactivity by 25%; and eliminate the growth of diabetes the volunteers who put up with the protracted regimen for seven
and obesity.34 years, nothing short of saints who showed exceptional courage for
the advancement of science.
LIPID RESEARCH CLINICS
LRC-CPPT Proves the Lipid Hypothesis
In 1970, the National Heart Lung and Blood Institute (NHLBI) con-
vened an expert panel to disseminate the existing knowledge among The cohort consisted of 3,800 men aged 35–59 years. They had no
other things. This panel recommended the establishment of a net- history of CAD, but were at high-risk of CAD by virtue of blood cho-
work of Lipid Centers of Excellence across the country subsequently lesterol more than 265 mg/dl (>95 percentile). The CPPT came fright-
named as Lipid Research Clinics. These clinics would standardize eningly close to joining the early dietary trials as “case not proved”.
the methods of lipid and lipoprotein analysis and would consult with The reduction in LDL-C was much lower than predicted due to poor
local hospitals, laboratories and doctor’s offices to help them train adherence resulting from GI side effects. At the end of the trial (mean
their own staff in measuring lipoproteins accurately. A new branch follow-up 7.4 years), LDL-C was reduced by 20% which resulted in
of the NHLBI, the Lipid Research Branch, was established with Dr a 19% reduction in the primary end-points (CAD death or nonfatal
Levi as its head. Twelve university centers across the country were MI). The benefits were even greater for the secondary end-points
successful in the competition to receive the grants for this purpose, (20% reduction in the development of angina and 25% reduction in
thus, lipid research clinics became a reality. the development of positive exercise ECG). On a brighter side, those
who fully adhered to the medication had a 35% reduction in LDL-C
LRC-CPPT (CORONARY PRIMARY and a 49% reduction in CAD.35,36 Overall, a 1% reduction in LDL-C
reduced the CAD events by 1%.
PREVENTION TRIAL)
This landmark study which was conceived in 1970 and
As of the early 1980s, despite the wealth of evidence—from experi- completed in 1984 at a cost $150 million ($40,000 per person) fi-
mental animal models, the extensive epidemiologic evidence, the nally proved the lipid hypothesis, 70 years after it was proposed by
powerful genetic evidence, and the strongly suggestive clinical in- Anitschkow. Major medical journals around the world hailed the
tervention trial results—most clinicians still remained unpersuaded results. The Medical Journal of Australia wrote “the lipid hypothesis
regarding the relevance of the lipid hypothesis. What was needed was is proven…the LRC-CPPT has given a new respectability and cred-
a well-designed, large-scale, long-term, double-blind study dem- ibility to the dietary and pharmacological management of hypercho-
onstrating a statistically significant impact of treatment of elevated lesterolemia”. For the first time, preventing coronary heart disease
blood cholesterol on CAD events. The NIH had laid the groundwork became a national public health goal.1 The NIH went on record to
for such a study as early as 1970, but the study was not completed advocate the screening for hypercholesterolemia and urged aggres-
and the results were not published until 1984. This trial has been sive treatment for those at high-risk.
described as the key stone in the arch evidence linking blood cho- The conviction and enthusiasm was not shared by a few vocal
lesterol to CAD.1 skeptics. Michael Oliver, wrote an editorial for British Medical Jour-
By far the greatest consumer of cholesterol is the liver which nal entitled “Hypercholesterolemia and Coronary Artery Disease: An
needs lots of cholesterol for the bile acid it makes. The liver is also Answer”. With characteristic pessimism, he warned that the CPPT
the only organ that can actually excrete cholesterol—that is when the results only applied to men with very high blood cholesterol values,
bile acids leave the body. Most of the bile acids, though, are reab- that there was no guarantee that other drugs would be of benefit and
sorbed from the intestine and recycled. The bile acid sequestering that the study did nothing to really settle the diet-heart problem.
resins can interrupt this cycle ferrying the cholesterol out of the body Some other experts were even more cynical (Table 27.2) since the
resulting in increase in the liver’s demand for cholesterol and its pool study did not demonstrate a reduction in all-cause mortality. It is
of LDL receptors.1 worth highlighting that the study was not designed to demonstrate a
The agent chosen for the CPPT was cholestyramine—a bile- reduction in all-cause mortality which would have necessitated the
acid-binding resin which was previously shown to reduce LDL-C by recruitment of least 20,000 subjects and a billion dollar expenditure
30–35% at full dose (24 g/d). Because it was totally nonabsorbable, it that was beyond the budget of NIH and NHLBI. Another concern was
would predictably be free from systemic toxic side effects. However, an unexplained increase in traumatic deaths (homicide, suicide and
most subjects experienced bloating, constipation or diarrhea due accidents) in the treatment group.
reduction in blood cholesterol contributing the most for this

THE 1984 NIH CONSENSUS
decline.
DEVELOPMENT CONFERENCE The NCEP guidelines may underestimate the risk among Asians
The results of the CPPT provided the impetus for the NIH to convene and Indians. For example, when patients were stratified by the num-
a National Consensus Development Conference on Lowering Blood ber of risk factors present and their 10-year CAD risk, 60% of Kore-
Cholesterol to Prevent Heart Disease. Twenty the foremost experts ans diagnosed with an acute MI did not qualify for drug therapy.37
from various fields were chosen with Dr Steinberg and Farquhar as The Australian and European guidelines have specific modifications
the chairpersons. After an exhaustive review of all available data, the with a lower threshold of intervention for South Asians—a popula-
panel concluded that the relationship between blood cholesterol tion with the highest rate of premature CAD.38 The Indo-US Health
level and CAD was causal and that the reduction in blood cholesterol Summit has recommended a 30 mg lower LDL-C cut-point for ini-
level would help prevent CAD. The panel recommended the forma- tiating therapy for Asian Indians than that recommended by NCEP.
tion of NCEP under NHLBI, involving all major medical and public The 2004 revision to the NCEP III has standardized LDL-C 40 mg/dl
health associations to educate both physician and the public about as optimum and LDL-C less than 70 mg/dl as the therapeutic target
the importance of controlling blood cholesterol levels. The confer- for very high-risk patients (CAD with diabetes).6 The NCEP-ATP IV is
ence was extremely well-received by the medical and scientific anticipated to be published before the end of 2010.
community except for a few arch antagonists. Michael Oliver wrote
a sarcastic editorial titled “Consensus or Nonsensus Conference on AKIRA ENDO AND THE ERA OF STATINS—
Coronary Heart Disease”. However, the conclusions of the consen-
THE UNDERUSED WONDER DRUGS
sus conference were so convincing that the FDA started approving
cholesterol-lowering medications without demonstration of benefits When the cells need more cholesterol, they respond by not only in-
on cardiovascular outcome. creasing the number of LDL receptors, but also by turning on HMG
CoA reductase. As discussed earlier, bile acid resins (that produces
THE NATIONAL CHOLESTEROL a drain on cholesterol) have been shown to decrease LDL-C and
reduce CAD events. An important weakness of this medication is the
EDUCATION PROGRAM
stepped up production of cholesterol partially negating its cholester-
Armed with the results of CPPT and a consensus among leaders ol lowering effect. A search for an inhibitor of cholesterol synthesis
in the field, the NIH made lowering blood cholesterol level a high began in early 1950s. Triparanol the first such drug came to market in
national priority. The NHLBI launched the NCEP in November 1985. 1959, but was soon withdrawn due to dangerous side effects such as
The coordinating committee had representatives from 24 important hair loss, eye damage and even blindness in rats and dogs.1
national health professional organizations and ten federal agencies, Konrad Bloch and Feodor Lynen were awarded the Nobel Prize
with James Cleemen as the chair. The goal of the NCEP is to contrib- for deciphering the cholesterol biosynthesis pathway in 1965. Gould,
ute to reducing morbidity and mortality from CAD by reducing the Taylor and Popjak are credited with discovery of the rate limiting
percentage of Americans with high blood cholesterol. Through edu- step—HMG CoA reductase step—the conversion of hydroxymeth-
cational efforts directed at health professionals and the public, the ylglutarate to mevalonate. This opened the possibility of lowering
NCEP aims to raise awareness and understanding about high blood the blood cholesterol by inhibiting this rate limiting step. This then
cholesterol as a risk factor for CAD and the benefits of lowering blood became the logical target for inhibitors that might lower the blood
cholesterol levels as a means of preventing CAD. In 1988, the first cholesterol levels.
Adult Treatment Panel (ATP) published its detailed guidelines. The In 1976, Akira Endo working at Sankyo in Tokyo discovered from
ATP classified blood cholesterol level of less than 200 mg/dl desirable a fungal broth (compactin) the first statin. This powerful inhibitor of
as and more than 240 mg/dl as high blood cholesterol—a far cry from HMG CoA reductase was effective in lowering blood cholesterol in
330 mg/dl previously considered normal. animals and humans. He collaborated with Goldstein and Brown
National Cholesterol Education Program has made significant and jointly reported dramatic increases in the amount of HMG CoA
strides towards its goal of reducing the prevalence of high blood reductase enzyme induced in cells by statin treatment (because of
cholesterol in the US. The latest Cholesterol Awareness Survey competitive inhibition). This resulted in a huge build-up of endoplas-
(CAS) of physicians and the public shows that from 1983 to 1995, the mic reticulum, (the organelle in which the reductase resides) causing
percentage of the public who had ever had their blood cholesterol the cells to look markedly abnormal. Because of this, compactin was
checked rose from 35% to 75%. The NCEP had a profound impact on erroneously interpreted as carcinogenic and Sankyo abruptly aban-
the blood cholesterol level and CAD mortality in the US population. doned clinical trials of compactin. At about the same time, in the UK,
The average blood cholesterol level among US adults have fallen Beecham Labs also discovered compactin independently. Beecham,
from 233 mg/dL to 199 mg/dl and the prevalence of high blood cho- too, abandoned further research for a different reason—their scien-
lesterol (> 240 mg/dl) has declined from 26 to 16%. Coronary artery tists could not produce blood cholesterol reduction in rats. We came
disease mortality in the US has declined by 69% since 1968, with close to losing statins—the wonder drugs of the century.
In 1978, Alfred W Alberts working for Merck, Sharp and Dohme a young age and/or for a longer duration (lifetime) is likely to yield
in the US discovered lovastatin—a statin with a structure very similar substantially greater benefit.
to compactin. Almost simultaneously, but independently, Endo also
discovered lovastatin. Despite widespread rumors of cancer risk of BLOOD CHOLESTEROL, STROKE
the first statin, Merck went ahead with human clinical trials at the
AND STATINS
request of numerous experts in the field of lipidology. Merck got the
US Food and Drug Administration (FDA) approval and brought lov- Although the relationship between blood cholesterol and stroke is
astatin to market in 1987 for the benefit of millions of patients. This weak on epidemiological studies, clinical trials with intensive statin
formally ushered the statin era in clinical practice. During the course therapy have clearly demonstrated substantial decrease in stroke
of the past 23 years, more than a billion prescriptions of statins have incidence and mortality. Blood cholesterol levels are also related to
been written worldwide and we can now say with absolute confi- the entire spectrum of ASCVD and its complications.41 Aggressive
dence that neither lovastatin nor any other statin on the market is lowering of LDL-C (more than 50%) was not associated with any
carcinogenic either in animals or in humans. increase in hemorrhagic stroke.42
STATIN MEGA TRIALS AND REVOLUTION HOW SAFE ARE STATINS?

IN PREVENTIVE CARDIOLOGY
The benefits of statin therapy far outweigh the risk by a factor of 1,000
A series of randomized, double-blind, clinical trials in quick succes- or more. Abnormal liver functions are a major concern for many
sion demonstrated dramatic benefits of lowering blood cholesterol. patients taking statins. Recent studies indicate that liver enzyme
But the cholesterol antagonists remained unconvinced because ini- elevation is probably due to decrease in the blood cholesterol per se
tial trials did not reduce all-cause mortality. This changed once and rather than toxic effect of statins, as evidenced by such abnormalities
for all when the unambiguous results of the 4S study were published in long-term follow-up POSCH subjects.43 Throughout the 23 years
in 1994. of statin use and a billion prescriptions worldwide, no liver failure
The Scandinavian Simvastatin Survival Study (4S) randomized death has been reported that are attributable to statins. Fatal rhab-
4,444 survivors of MI with very high blood cholesterol to either a domyolysis, the most dreaded complication of statin therapy, occurs
placebo or simvastatin 20–40 mg. The goal was to reduce blood cho- infrequently. For example, a million person-years of statin use would
lesterol to less than 200 mg/dl with simvastatin. The primary end- cause only three deaths from rhabdomyolysis while preventing
point was all-cause death and not cardiac death alone. The study was 10,000–20,000 CVD events (death, stroke, MI, coronary angioplasty,
continued until 10% of the study participants died (444 deaths)—a stent and/or bypass surgery).
unique feature that would never be repeated in any future studies. Statins are far safer than aspirin—even high dose statins are hun-
This landmark study reported a 35% reduction in LDL-C and 42% dred times safer than low dose aspirin. In primary prevention, statin
reduction in CAD mortality in the simvastatin group. For the first therapy prevents 700 deaths per million person-years of use com-
time, a clear and unequivocal 30% reduction in total mortality with pared to 100 for aspirin. Furthermore, aspirin significantly increases
statin therapy was demonstrated, converting most nonbelievers into the risk of hemorrhagic stroke and gastrointestinal bleeding—fea-
true believers of lipid hypothesis. Subsequent studies demonstrated tures not shared by statins.44
that the benefits of lowering LDL-C are not limited to people with
CAD and high blood cholesterol. The British Heart Protection Study HOW LOW IS LOW LDL-C?
(n = 20,000) demonstrated the safety and benefits of statin therapy
even among people with low pretreatment LDL-C less than 100 Steinberg and Grundy have reported a 67-year-old person with unu-
mg/dl.39 sually low levels of LDL-C (only 4–8 mg/dl). Many of his kindred also
An astonishing array of clinical trials have conclusively demon- had very low LDL-C (10–15 mg/dl). Yet, they not only failed to show
strated the benefit of statin therapy in virtually all patient groups: any ill-effects, they actually showed an increased longevity.45 Today,
women as well as men; the old as well as the young; those with initial in the spectacular era of statins, most cardiologists believe not only in
low LDL-C levels as well as those with high LDL-C levels; diabetics lowering the blood cholesterol level but fully subscribe to the theory
as well as nondiabetics; patients with/without heart disease; and “the lower the better”.
patients with/without stroke. A recent meta-analysis of 14 rand- The JUPITER Study (n = 17,802) has demonstrated the benefits
omized statin trials with a total of more than 90,000 middle-aged of intensive statin therapy in people with near normal LDL-C with-
and older individuals (using lovastatin, pravastatin, simvastatin, flu- out CAD or risk factors. All subjects had LDL-C less than 130 mg/dl
vastatin and atorvastatin) showed that every 80 mg/dl decrease in and the mean LDL-C was 108 mg/dl. Compared to placebo, rosuv-
LDL-C resulted in a 40% reduction in major vascular events and 24% astatin 20 mg/dl reduced the LDL-C by 50%. An astonishing 4,451
reduction in total mortality over a 5-year period.40 Statin therapy at subjects had an LDL-C less than 55 mg/dl; 2,225 had LDL-C less than
44 mg/dl; and 2,047 had LDL-C less than 40 mg/dl—without any se- LDL-C lowering confers a 54% reduction in CAD when started at age
rious adverse effects.7 The overall reduction in coronary events was of 35 and continued; the benefit progressively decreases to 20% when
44%, which increased to 55% in those with LDL-C less than 70 mg/ started at 65 years of age.52
dl and to 79% in those who also had CRP less than 1 mg/dl. These Conversely, children with LDL-C more than 400 mg/dl can
results strongly support the current standardization of 40 mg/dl as develop advanced CAD before 10 years of age.1 As mentioned earlier,
the optimum LDL-C level and the LDL-C target of less than 70 mg/dl it was the pursuit of a young brother and sister, ages 6 and 8 with
in high risk patients.6,46 The price of statins has plummeted with the advanced atherosclerosis and history of heart attacks that led to the
arrival of generic statins. Many statins are available in the US at a cost discovery of LDL receptors and the centrality of blood cholesterol in
of ` 11 cents/d and in India for ` 5/d—an affordable price for vast ASCVD.10 In children 8–18 years of age, statin treatment has been
segments of society. Those interested in learning more about inten- shown to reduce the progression of atherosclerosis with no adverse
sive statin therapy are encouraged to read the comprehensive review effects on growth, hormone levels or sexual maturation.53 In recog-
on the subject.47 nition of the overwhelming safety and benefits, several statins are
approved for use in boys and girls 8 years and older.54
DOES LOW CHOLESTEROL INCREASE
NON-CVD MORTALITY? SUMMARY
Several epidemiological studies have shown a higher non-CVD Cumulative evidence over a hundred years from several different
mortality among subjects with low blood cholesterol levels (< 160 kinds of studies—epidemiologic, genetic, dietary intervention and
mg/dl). This led to the erroneous argument that lowering blood randomized double-blind clinical trials—have clearly established
cholesterol might be dangerous and that no attempt should be made to the dominant causative role of blood cholesterol level in ASCVD.
lower the blood cholesterol in the general population even by dietary High blood cholesterol level increases the risk of ASCVD regardless
measures.26 According to Stamler, widely recognized as the Father of of its cause—genetic, endocrine or nutritional. The CAD incidence
preventive cardiology, the low blood cholesterol observed in most of and mortality in populations are proportional to blood cholesterol
the prospective cohorts was due to underlying health status such as levels, which in turn are proportional to the dietary saturated fat
occult malignancy, heavy smoking (causing lung cancer or chronic intake (rather than genetic factors). The dietary saturated fat intake
obstructive lung disease), and heavy alcohol use (resulting in liver is indeed the primary determinant of elevated blood cholesterol
cirrhosis or suicide). In other words, low blood cholesterol is a mark- among individuals and populations. Contrary to common belief, the
er of other causative factors rather than a cause itself.48 The proof contribution of the dietary cholesterol to blood cholesterol eleva-
comes from the 14-year follow-up of NHANES, which has document- tion is small. Likewise, total fat intake is not related to elevated blood
ed the disappearance of excess deaths in the low blood cholesterol cholesterol except when saturated fat intake is also increased. More
group after 10 years.48 A similar observation was made among the importantly, increased consumption of both polyunsaturated fats
29,093 men in the Alpha-Tocopherol-Beta- Carotene Cancer Preven- and monounsaturated fats significantly decrease blood cholesterol
tion Study followed for 18 years.49 level. Thus, reducing saturated fat intake and replacing them with
unsaturated fats is the foundation of dietary approach to lower the
WHEN TO START LDL-C blood cholesterol level.
Low-density lipoprotein cholesterol is the principal atherogenic
LOWERING THERAPY?
lipoprotein and 40 mg/dl LDL-C is standardized as the optimum
All evidence supports the current dictum “the earlier the better”. This level. The LDL-C target is less than 70 mg/dl in very high-risk indi-
dictum is supported by recent findings of a dramatic reduction in viduals. The newer potent statins can lower LDL-C up to 60% and are
CAD risk in subjects with a genetic trait (PCSK9 seen in 3% of the poised to perform greater wonders in the 21st century than antibiot-
population) that results in lifelong reduction in LDL-C. This genetic ics did to infectious diseases in the last century.47
trait results in an 11–16% lifelong reduction in LDL-C levels and con- Atherosclerosis is a disease of multiple etiologies. Proper clinical
fers a 30% reduction in CAD risk in whites. The impact of this genetic management should include intervention on all of them: high LDL-
trait is even greater in blacks among whom the reduction in LDL-C is C; low HDL-C; tobacco use; hypertension; obesity; diabetes mellitus;
28% and the reduction in CAD risk is 88%.50,51 Together, these studies metabolic syndrome; lack of exercise and low intake of fruits and
indicate that a lifelong 10% reduction in LDL-C confers a 30% reduc- vegetables. Yet, the 30–45% reduction in coronary events with LDL-C
tion in CVD — far greater than the 5–10% reduction observed in sta- lowering indicates the dominant role of LDL-C in CAD. There is com-
tin trials (that usually lasts only for 5 years). In other words, having a pelling data that supports the idea that early and intensive medical
low LDL-C from birth triples the benefit compared to lowering it in attention to dyslipidemia along with equally intensive attention to
middle age and beyond. Earlier initiation of LDL-C lowering therapy other major risk factors will eventually reduce sharply the need for
has been shown to derive greater benefit. For example, a 40 mg/dl interventional cardiology.
• The contribution of total fat and dietary cholesterol intake to

Key Points
blood cholesterol level is small. A low-fat diet can help people with
• Raising blood cholesterol level produces atherosclerosis in humans elevated chylomicrons while people with elevated VLDL or triglyc-
and in several experimental animals—baboons, cats, chickens, erides need to restrict their intake of carbohydrates.
chimpanzees, dogs, goats, guinea pigs, hamsters, monkeys, mice, • The arrival of statin medications led to a revolution in preventive
parrots, pigs, pigeons, rabbits and rats. cardiology. These medications are remarkably safe, easy to use and
• Elevated blood cholesterol is a sufficient risk factor for CAD—indi- can lower LDL-C up to 60% conferring a 50–60% reduction in CAD
viduals with very high LDL-C develop CAD at a young age in the risk.
absence of other risk factors. Several children (6–8 years of age) • Intensive statin therapy begun earlier in life (rather than waiting till
with very high blood cholesterol levels due to FH, have had multiple middle age or a cardiac event) would confer even greater benefit.
heart attacks and even bypass surgeries and heart transplants. Many statins have been studied in children with no adverse effects
• Elevated blood cholesterol is a necessary risk factor for CAD—indi- on growth, hormone levels or sexual maturation and approved for
viduals and populations with high levels of traditional risk factors use boys and girls as young as 8 years of age.
do not develop ASCVD in the absence of some elevation in blood • Drastic reduction in LDL-C to less than 40 mg/dl in more than 3,000
cholesterol level. subjects in randomized statin trials showed no evidence of serious
• LDL-C is the principal atherogenic lipoprotein and 40 mg/dl adverse effects. There is no evidence that low or reduced serum cho-
LDL-C is standardized as the optimum level (total cholesterol of lesterol concentration increases mortality from any cause.
110–120 mg/dl). The LDL-C target is <70 mg/dl in very high-risk • Although epidemiological studies have shown an association be-
individuals. An individual with LDL-C 70 mg/dl has a 30% higher tween low blood cholesterol and hemorrhagic stroke, aggressive
CAD risk than one whose LDL-C is 40 mg/dl. LDL-C lowering with intensive statin therapy has shown no increase
• All dietary fats are not created equal. Saturated fat intake signifi- in hemorrhagic stroke but a greater decrease in ischemic stroke.
cantly increases the blood cholesterol whereas, unsaturated fats • The association between cancer and low cholesterol is real, but is
significantly decreases it. Dietary intervention to lower blood cho- explained by reverse causality, cancer producing low blood choles-
lesterol should focus on decreasing saturated fat intake and substi- terol level and not the other way around. In fact, the blood choles-
tuting with mono and poly unsaturated fats. terol level starts decreasing 5 years before cancer is diagnosed.
REFERENCES
1. Steinberg D. The Cholesterol Wars: The Skeptics versus the Preponderance of Evidence. San Diego: Academic press; 2007.
2. Hanke H, Lenz C, Finking G. The discovery of the pathophysiological aspects of atherosclerosis—a review. Acta Chir Belg. 2001;101(4):162-9.
3. Frantz IDJ, Moore RB. The sterol hypothesis in atherogenesis. Am J Med. 1969;46(5):684-90.
4. Ahrens EHJ, Insull W, Blomstrand R, et al. The influence of dietary fats on serum-lipid levels in man. Lancet. 1957;272(6976):943-53.
5. Reed DM. The paradox of high-risk of stroke in populations with low-risk of coronary heart disease. Am J Epidemiol. 1990;131(4):579-88.
6. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment
Panel III guidelines. Circulation. 2004;110(2):227-39.
7. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of
rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373(9670):1175-82.
8. Dock W. Research in arteriosclerosis; the first fifty years. Annals of internal medicine. 1958;49(3):699-705.
9. Schmidt HH, Hill S, Makariou EV, et al. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozy-
gous familial hypercholesterolemia. Am J Cardiol. 1996;77(8):575-80.
10. Deweerdt SE. Vital Signs: Discoveries in diseases of heart, lungs, and blood. Bethesda; 1998.
11. Gofman JW, Lindgren F. The role of lipids and lipoproteins in atherosclerosis. Science (New York, NY). 1950;111(2877):166-71.
12. Kris-Etherton PM, Lichtenstein AH, Howard BV, et al. Antioxidant vitamin supplements and cardiovascular disease. Circulation. 2004;110(5):637-
41.
13. Enas EA, Chacko V, Pazhoor SG, et al. Dyslipidemia in South Asian patients. Curr Atheroscler Rep. 2007;9(5):367-74.
14. Enas EA, Chacko V, Senthilkumar A, et al. Elevated lipoprotein(a)—a genetic risk factor for premature vascular disease in people with and without
standard risk factors: a review. Dis Mon. 2006;52(1):5-50.
15. Erqou S, Thompson A, Di Angelantonio E, et al. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involv-
ing 58,000 participants. J Am Coll Cardiol. 2010;55(19):2160-7.
16. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the Framingham study. JAMA. 1987;257(16):2176-80.
17. Connor WE, Connor SL. Dietary cholesterol and coronary heart disease. Curr Atheroscler Rep. 2002;4(6):425-32.
18. Kern F. Normal plasma cholesterol in an 88-year-old man who eats 25 eggs a day. Mechanisms of adaptation. N Engl J Med. 1991;324(13):896-99.
19. Hu FB, Stampfer M, Manson J, et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;337(21):1491-9.
20. Uusitalo U, Feskens EJ, Tuomilehto J, et al. Fall in total cholesterol concentration over five years in association with changes in fatty acid composi-
tion of cooking oil in Mauritius: cross sectional survey. BMJ. 1996;313(7064):1044-6.
21. Dowse GK, Gareeboo H, Alberti KG, et al. Changes in population cholesterol concentrations and other cardiovascular risk factor levels after
five years of the non-communicable disease intervention programme in Mauritius. Mauritius Non-communicable Disease Study Group. BMJ.
1995;311(7015):1255-59.
22. Hulley SB, Newman TB. Position statement: cholesterol screening in children is not indicated, even with positive family history. J Am Coll Nutr.
1992;11(Suppl):20S-22S.
23. Mann GV. Diet-Heart: end of an era. N Engl J Med. 1977;297(12):644-50.
24. Ahrens EHJ. Dietary fats and coronary heart disease: unfinished business. Lancet. 1979;2(8156-7):1345-8.
25. Oliver MF. Serum cholesterol—the knave of hearts and the joker. Lancet. 1981;2(8255):1090-5.
26. Hulley SB, Walsh JM, Newman TB. Health policy on blood cholesterol. Time to change directions. Circulation. 1992;86(3):1026-9.
27. Keys A. Diet and the epidemiology of coronary heart disease. J Am Med Assoc. 1957;164(17):1912-9.
28. Enas EA. Cooking oils, cholesterol and CAD: facts and myths. Indian Heart J. 1996;48(4):423-7.
29. Enas EA, Senthilkumar A, Chennikkara H, et al. Prudent diet and preventive nutrition from pediatrics to geriatrics: current knowledge and practi-
cal recommendations. Indian Heart J. 2003;55(4):310-38.
30. Buchwald H, Campos CT, Boen JR, et al. Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholes-
terolemia: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH). J Am Coll Cardiol. 1995;26(2):351-7.
31. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with
hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323(14):946-55.
32. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol.
1986;8(6):1245-55.
33. Stamler J. Coronary heart disease: Doing the “right things”. N Engl J Med. 1985;312(16):1053-5.
34. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the
American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613.
35. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-
64.
36. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to
cholesterol lowering. JAMA. 1984;251(3):365-74.
37. Yoon YE, Rivera JJ, Kwon DA, et al. National Cholesterol Education Panel III guidelines performance role in preventing myocardial infarction in a
large cohort without a history of coronary artery disease: Korea Acute Myocardial Infarction Registry study. Prev Cardiol. 2009;12(2):109-13.
38. Enas EA, Singh V, Gupta R, et al. Recommendations of the Second Indo-US Health Summit for the prevention and control of cardiovascular dis-
ease among Asian Indians. Indian heart J. 2009;61:265-74.
39. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial.
Lancet. 2002;360(9326):7-22.
40. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 par-
ticipants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-78.
41. Paciaroni M, Bogousslavsky J. Statins and stroke prevention. Expert review of cardiovascular therapy. 2009;7(10):1231-43.
42. Amarenco P, Goldstein LB, Szarek M, et al. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient
ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2007;38(12):3198-204.
43. Buchwald H, Williams SE, Matts JP, et al. Lipid modulation and liver function tests. A report of the Program on the Surgical Control of the Hyper-
lipidemias (POSCH). J Cardiovasc Risk. 2002;9(2):83-7.
44. Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled
trials involving 65,229 participants. Arch Intern Med. 2010;170(12):1024-31.
45. Steinberg D, Grundy SM, Mok HY, et al. Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypolphali-
poproteinemia and fasting chylomicronemia. J Clin Invest. 1979;64(1):292-301.
46. O’Keefe JH, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll
Cardiol. 2004;43(11):2142-46.
47. Enas EA, Hancy Chennikkara Pazhoor, Arun Kuruvila, et al. Intensive Statin Therapy for Indians:Part I Benefits. Indian Heart J. 2010;(In press).
48. Stamler J, Stamler R, Brown WV, et al. Serum cholesterol. Doing the right thing. Circulation. 1993;88(4 Pt 1):1954-60.
49. Ahn J, Lim U, Weinstein SJ, et al. Prediagnostic total and high-density lipoprotein cholesterol and risk of cancer. Cancer Epidemiol Biomarkers
Prev. 2009;18(11):2814-21.
50. Cohen JC, Boerwinkle E, Mosley TH, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med.
2006;354(12):1264-72.
51. Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independ-
ent studies and meta-analyses. J Am Coll Cardiol. 2010;55(25):2833-42.
52. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart
disease? BMJ. 1994;308(6925):367-72.
53. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized con-
trolled trial. JAMA. 2004;292(3):331-37.
54. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement
from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the
Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115(14):1948-67.
Past, Present and Future of
28 Cardiovascular Dysmetabolic
Syndrome
Srikanth S, Deedwania P
cated that any given patient may have some or all of the components
HISTORICAL PERSPECTIVE
of the syndrome.
Cardiovascular dysmetabolic syndrome (CDS) or metabolic syn-
drome is a major public health problem. It is estimated that as much EVOLUTION OF THE DEFINITION
as 30–40% of the adult population in the developed countries have
CDS/metabolic syndrome (MS). Although CDS has been widely rec- Several groups have attempted to develop diagnostic criteria for the
ognized in recent years, the historical perspectives indicate that the diagnosis of metabolic syndrome. In 1998, the American Diabetes
understanding of this syndrome has been evolving for quite some Association proposed that metabolic syndrome is comprised of glu-
time. The evolution of the concept of the CDS traces its roots back cose intolerance, central obesity, dyslipidemia [increased triglycer-
nearly 70 years when insulin sensitivity and changes in insulin sen- ides, decreased high-density lipoprotein cholesterol (HDL-C), and
sitivity were first reported upon in a series of Goulstonian Lectures increased small dense low-density lipoprotein cholesterol (LDL-C)],
to the Royal College of Physicians in London by Himsworth in 1939.1 hypertension, increased prothrombotic and antifibrinolytic factors
About 5 decades later, Reaven reported on the pathophysiologic fea- and risk for atherosclerotic disease. However, no specific thresholds
tures of the insulin resistant state.2 In his Banting lecture, he noted were established to define the syndrome. The first concrete attempt
the clustering of multiple abnormalities of hyperglycemia, hyperten- to develop diagnostic criteria was made by a World Health Organiza-
sion and dyslipidemia and called it the “syndrome-X or the insulin tion (WHO) diabetes group in 1999, which proposed that the meta-
resistance syndrome”. Reaven proposed that insulin resistance was bolic syndrome is defined by insulin resistance or its surrogates as
the predominant abnormality underpinning this syndrome. He did essential components co-existing with at least two of the following
not include obesity or visceral obesity as a component of the insulin clinical abnormalities: raised blood pressure, hypertriglyceridemia
resistance syndrome. However, as we presently understand, the epi- and/or low HDL cholesterol, obesity as measured by body mass
demic of obesity is primarily responsible for preponderance of cases index (BMI) or waist-hip ratio and microalbuminuria.
with CDS. Whether it is valuable to assess insulin resistance in addition to
Obesity is associated with resistance to the effects of insulin in more readily measured traits of the syndrome is uncertain. Since the
the muscle tissue and results in hyperinsulinemia, hyperglycemia, traits of metabolic syndrome co-exist, patients identified with one or
dyslipidemia, hypertension and endothelial dysfunction. A similar just a few traits are likely to have other traits, as well as insulin re-
profile is seen in individuals with Type 2 diabetes mellitus.2-5 The sistance. The guidelines developed by the 2001 National Cholesterol
occurrence of metabolic risk factors common to both Type 2 diabe- Education Program (NCEP) took this approach to heart and focused
tes and cardiovascular disease (CVD) suggested the existence of a explicitly on the risk of CVD in coming up with a pragmatic definition
metabolic syndrome. Various names were proposed to identify the for the metabolic syndrome.7 These criteria were updated in 2005 in a
conglomeration of metabolic abnormalities namely hyperglycemia, statement from the American Heart Association (AHA) and National
dyslipidemia, obesity and hypertension. Some of the names include Heart Lung and Blood Institute (NHLBI).8,9 Current Adult Treatment
the deadly quartet and the obesity dyslipidemia syndrome. Issues Panel (ATP) III criteria define the metabolic syndrome as the pres-
relating to these metabolic abnormalities and attendant CVD were ence of any three or more of the five traits as noted in Table 28.1.
discussed in a round table in November 1997 by the Western Work- The International Diabetes Foundation (IDF) revised the guide-
ing Group, which came up with the name of the “Cardiovascular lines to address disparities related to ethnic differences in different
Dysmetabolic Syndrome”.6 This name was thought to best describe populations.10 The IDF maintained the less glucocentric approach to
the clinical impact of the associated group of abnormalities, because defining the metabolic syndrome. Central obesity is an essential ele-
it emphasized the cardiovascular consequences of the components ment in the definition with waist circumference thresholds modified
of CDS, recognized them as distinguishable abnormalities and indi- to reflect the population norms of different ethnic groups (Table 28.2).
TABLE 28.1 Updated ATP III criteria for metabolic syndrome (AHA/NHLBI)
• Abdominal obesity, defined as a waist circumference in men more
than 102 cm (40 in) and in women more than 88 cm (35 in)
• Serum triglycerides more than or equal to 150 mg/dL (1.7 mmol/L)
or drug treatment for elevated triglycerides
• Serum HDL cholesterol less than 40 mg/dL (1 mmol/L) in men and
less than 50 mg/dL (1.3 mmol/L) in women or drug treatment for
low HDL-C
• Blood pressure above or equal to 130/85 mm Hg or drug treatment
for elevated blood pressure
• Fasting plasma glucose (FPG) more than or equal to 100 mg/dL (5.6
mmol/L) or drug treatment for elevated blood glucose.
Figure 28.1: Prevalence of metabolic syndrome in an Indian
urban population. Source: Gupta R, Deedwania P, et al. Int J Cardiol.
2004;97:257-61
TABLE 28.2 International diabetes foundation definition of CDS

Central obesity Ethnic specific tion in the early 1990s.15 At baseline, the prevalence of the metabolic
according to the waist South Asians: Men ≥ 90 cm; Women ≥ 80 cm syndrome was 26.8% in men and 16.6% in women. Ford reported
circumference plus any Europids: Men ≥ 94 cm; Women ≥ 80 cm 39% prevalence in the USA using data from NHANES 1999–2002
two of the following Chinese: Men ≥ 90 cm; Women ≥ 80 cm participants, using IDF criteria as compared to 34.5% prevalence
four risk factors Japanese: Men ≥ 85 cm; Women ≥ 90 cm using the ATP III criteria.13 Prevalence of metabolic syndrome in
South and Central Americans: as South Asians ethnic groups, such as Native Americans and Hispanics is higher
Raised triglycerides ≥ 150 mg/dL and is partly related to higher prevalence of obesity in these groups.
Reduced HDL < 40 mg/dL in men; < 50 mg/dL in women Additionally, they also have insulin resistance out of proportion to the
cholesterol severity of obesity.16 Various studies in Europe based on NCEP, IDF
Raised blood pressure Systolic ≥ 130 mg/dL and WHO criteria have revealed the prevalence to be approximately
25% in the European population. IDF criteria usually give a higher
Distolic ≥ 85 mg/dL
prevalence due to the lower threshold for abnormal waist circumfer-
Raised fasting plasma ≥ 100 mg/dL
ence.
glucose Preriously diagnosed type 2 diabetes
Reported prevalence of the metabolic syndrome in the India var-
ies between 13%17 and 41%.18 In a study of 1,800 adults over the age
of 20 years with population proportionate distribution from Jaipur,
the prevalence of metabolic syndrome was 31.6% (22.9% in men and
PREVALENCE 39.9% in women) using the ATP III definition19 (Fig. 28.1).
Metabolic syndrome is widely prevalent worldwide. The prevalence Prevalence of 41% in the study from Chennai used obesity cri-
appears to be increasing and parallels the rise in the number of over- teria suitable for Indians.18 It appears that within the same ethnic
weight and obese individuals in the population. There is also pro- population group, there can be significant differences in the preva-
gressive increase in prevalence with advancing age.11 A large number lence of both the individual factors that constitute the metabolic syn-
of studies have been carried out to determine the prevalence of the drome and the metabolic syndrome itself. While the prevalence of
metabolic syndrome in different populations, but the various defini- metabolic syndrome in India is high, less than one-fifth of the stud-
tions for the metabolic syndrome have led to difficulty in comparing ied population in Southeast Asia has the metabolic syndrome. This
data from studies using the different criteria. The majority of epide- might be largely due to the fact that most reports from India have
miological studies have used NCEP criteria,12 but there have been utilized NCEP ATP III criteria which might not be appropriate for
several comparisons of NCEP criteria with WHO and IDF recom- Asian populations and might underestimate the prevalence when
mendations for estimating prevalence. compared to the IDF criteria for central obesity. Additionally, overall
In the National Health and Nutrition Examination Survey 1999– younger age of the Southeast Asian population as compared to the
2002 database, 34.5% of participants met ATP III criteria for the meta- European population might also have a bearing. In China, the preva-
bolic syndrome compared with 22% in NHANES III (1988–1994).13,14 lence is relatively low specially when using the NCEP threshold for
In addition, metabolic syndrome, defined by the 2005 revised ATP III waist circumference. In Latin America, one-fourth of the adult popu-
criteria, was assessed in 3,323 Framingham Heart Study participants, lation has the metabolic syndrome and may be even higher in some
ages 22–81, who did not have diabetes or CVD at a baseline examina- countries with a large proportion of migrant Japanese population.20
Chapter 28  Past, Present and Future of Cardiovascular Dysmetabolic Syndrome 197
dent CVD (RR ranging from 1.53 to 2.18) and all cause the mortality
CLINICAL IMPLICATIONS
(RR 1.27–1.60).25-27 The most recent report by Gami et al. included
Metabolic syndrome is associated with increased risk of develop- 172,573 people from 37 longitudinal cohort studies. Pooled analysis
ing diabetes mellitus and CVD. Intuitively it is not surprising the of these studies demonstrated that the metabolic syndrome con-
that the risk of developing diabetes in the presence of the metabolic ferred cardiovascular risk beyond that associated with its individual
syndrome is higher since insulin resistance or surrogate markers of component risk factors. The ongoing controversy is whether CDS/
insulin resistance are generally incorporated in the definition. Multi- MS contributes incremental risk compared to risk related to the indi-
ple prospective observational studies demonstrate a strong associa- vidual components of CDS/MS.
tion between the metabolic syndrome and the risk for subsequent
development of Type 2 diabetes. In meta-analysis by Ford et al. of 16 UNDERSTANDING PATHOPHYSIOLOGY
multiethnic cohort studies, the relative risk of developing diabetes
OF CDS
ranged from 3.53 to 5.17, depending upon the definition of metabolic
syndrome and the population studied.21 Higher number of abnormal The insulin signaling pathway involving the insulin receptor, insu-
components was strongly related to incident diabetes. Compared lin receptor substrate (IRS) proteins, PI3-kinase, pyruvate dehydro-
with participants without an abnormality, estimates of relative risk genase kinase (PDK1) and Akt regulates GLUT4 translocation and
for those with four or more abnormal components ranged from 10.88 glucose uptake in skeletal muscle and adipose tissue while the same
to 24.4. The risk of diabetes appears to increase with increasing com- pathway is involved in production of NO in the endothelium (Fig.
ponents of the metabolic syndrome.22-24 Nevertheless there is limited 28.2).
evidence suggesting that fasting glucose alone may be as good a pre- In the last decade, animal studies using tissue-specific knock-
dictor for diabetes mellitus as metabolic syndrome.21 out mice have shed some light into the molecular mechanisms
Only recently have there been studies assessing the risk of of insulin resistance. Knockout of insulin receptor in liver (LIRKO)
incident CVD events in the presence of metabolic syndrome. Three is associated with increased hepatic glucose production and
recent meta-analyses, which included many of the same stud- decreased insulin clearance, leading to hyperinsulinemia and in-
ies, found that the metabolic syndrome increases the risk for inci- creased peripheral insulin resistance, but decreased triglyceride
Figure 28.2: PI 3-kinase branch of insulin signaling regulates GLUT4 translocation and glucose uptake in skeletal muscle and NO production
and vasodilation in vascular endothelium. MAP kinase branch of insulin signaling generally regulates growth and mitogenesis and controls
secretion of ET-1 in vascular endothelium. Source: Kim JA, Montagnani M, Koh KK, et al. Reciprocal relationships between insulin resistance
and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113:1888-904.
secretion.28,29 This ultimately produces hyperglycemia with de- neogenesis in addition to other metabolic, vascular and mitogenic
creased triglycerides and free fatty acids. Mice with knockout of effects. Typically in disease states associated with insulin resistance
insulin receptor in muscle (MIRKO), show decreased muscle glucose different tissues show varying levels of insulin resistance and hence
uptake with overall normal glucose homeostasis.29 Knockout of the not all insulin regulated processes show a uniform degree of insu-
insulin receptor in adipocytes (FIRKO) decreases glucose uptake lin resistance. Thus, when plasma insulin levels increase to maintain
into fat and induces favorable changes in adipocyte morphology and euglycemia in the insulin resistant state, the mitogenic effects of
gene and protein expression.30 Combination of defects in multiple insulin on cell growth and differentiation might become more pro-
tissues have been studied to examine their interaction. When insulin nounced leading to hypertriglyceridemia, hypertension and hyper-
receptors are knocked out simultaneously in the liver and pancreatic androgenism.34 Classically, insulin resistance in muscle, liver and fat
beta cells, mice become markedly diabetic. tissues has been viewed as central to the pathogenesis of the “insulin
While these studies have been instructive, pure insulin resist- resistance syndromes”.
ance with dysfunctional insulin receptors is seen rarely in genetic Obesity is a risk factor for excess cardiovascular events. However,
conditions. Defects at multiple sites in the insulin signaling cascade the excess risk is related to the insulin resistance associated with the
are more likely to mediate insulin resistance31 (Fig. 28.3). metabolic syndrome rather than simple obesity. This is illustrated in
At each step in the cascade, there are several isoforms capable the Framingham population where obese individuals without meta-
of transducing signal, each having some overlapping function apart bolic syndrome did not have a significantly increased risk of diabetes
from some discrete effects. Diminishing the activity of any single or CVD.35 Obese people with the metabolic syndrome had a 10-fold
component of the signaling cascade may produce a distinct type of increased risk for diabetes and a two-fold increased risk for CVD
insulin resistance. Not surprisingly concurrent endothelial dysfunc- relative to normal weight people without the metabolic syndrome.
tion is observed in the presence of impaired insulin signaling in People with normal weight, meeting revised 2005 ATP III criteria for
metabolic tissues.32,33 This is related to predominance of MAP-kinase the metabolic syndrome had a four-fold increased risk for diabetes
induced activity of insulin in insulin resistant states. and a three-fold increased risk for CVD.
Actions of insulin at the whole organ level include its ability to Excess abdominal fat is predictive of insulin resistance and related
lower circulating glucose, stimulating glucose utilization in muscle metabolic abnormalities that comprise the metabolic syndrome.
and adipose tissues and suppression of hepatic and renal gluco- However, the evidence for causal relationship between abdominal
Figure 28.3: Mechanism of insulin resistance. Multiple mechanisms exist such as decreased synthesis, increased degradation, inhibitory serine
phosphorylation, interaction with inhibitory proteins and alteration of the ratios of different signaling molecules. Source: Biddinger SB, Kahn CR.
From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol. 2006;68:123-58.
fat and metabolic syndrome is still lacking. Imaging studies using resistance. Thus positive energy balance in the adipose tissue may
measurements of abdominal adiposity suggest that it is the excess mediate insulin resistance by “lipotoxicity” in various tissues.
of visceral adipose tissue as opposed to the amount of subcutane- More recently the significant role of the endocannabinoid sys-
ous abdominal fat tissue that is closely correlated with the metabolic tem in the control of food intake and energy balance has been appre-
syndrome. In fact individuals matched for subcutaneous abdominal ciated. Multiple mechanisms of action, not solely limited to the cen-
fat quantity, but with varying amounts of visceral adipose tissue have tral nervous system are involved in the endocannabinoid-mediated
been shown to have varying levels of insulin resistance; higher resist- control of food intake and energy balance. Control of metabolic func-
ance being associated with higher visceral fat content.36-39 Whereas tions in peripheral tissues such as adipocytes, hepatocytes, gastroin-
when matched for visceral adiposity, individuals with varying levels testinal tract and possibly skeletal muscle by the endocannabinoid
of subcutaneous fat tissue do not have varying insulin resistance.37,38 system is being actively investigated.43
Thus not all obesity is associated with increased cardiovascular risk.
Studies suggest that it is the obese individual with excess visceral fat IDENTIFICATION
who is at higher risk for cardiovascular complications. Adipose tis-
sue secretes many biologically active intermediaries that mediate Although the NCEP criteria allow for identification of the CDS, the
insulin resistance (Fig. 28.4). The engendering of metabolic disease phenotypic pattern can be recognized by a simple look at the patient
states with adiposity is a net result of dysfunctional adaptations in and basic laboratory studies. In this regard the mnemonic D-R-O-
the adipose tissue and other body organs. Organ systems that are af- P where D stands for Dyslipidemia, R for insulin Resistance, O for
fected by signaling from adipose tissue include the nervous system, Obesity and P for high blood Pressure helps in easier identification
immune system, skeletal muscle, cardiovascular system and the liver. (Table 28.3).44
In addition to impaired communication, non-adipose tissues Other abnormalities that may be associated include elevated
may have inherent or acquired abnormalities leading to the risk of serum uric acid and elevated plasminogen activator inhibitor-1
insulin resistance. Individuals may have an inability to metabolize (PAI-1) levels. Insulin resistance is thought to be central to the meta-
intramuscular fat due to genetic or acquired “inflexibility” in the bolic abnormalities, but all of the mechanisms are not established
oxidation of free fatty acids released from adipose tissue.40 In these and other etiologies are possible. A diagnosis of CDS requires the
individuals, fat cell hypertrophy and/or increase in visceral adipose presence of criteria for at least two of the first three components
tissue results in the intramuscular accumulation of intramyocellu- (dyslipidemia, insulin resistance and obesity). Any component is a
lar lipids, such as diacylglycerol, fatty acyl CoA and ceramides pro- risk factor for macrovascular disease (coronary, cerebral or peripher-
moting insulin resistance by down-regulating the PI 3-K pathway.41 al vascular). Additional components confer additional risk, although
Individuals with hepatic inflexibility in free fatty acid (FFA) oxida- some, such as diabetes mellitus, confer more risk than others. These
tion, develop insulin resistance and hyperlipidemia with increased risk factors are in addition to, but not necessarily completely inde-
release of FFA from adipose tissue accumulation.42 Hepatic insulin pendent of, other traditional risk factors, such as established vascular
resistance leads to triglyceride synthesis and decreased FFA oxida- disease, smoking, age, gender, elevated LDL cholesterol, sedentary
tion. This contributes to the hypertriglyceridemia seen with insulin lifestyle and positive family history of vascular disease.
TABLE 28.3 The cardiovasculer dysmetabolic syndrome

D I. Dyslipidemia
– Fasting triglycerides > 140 mg/dL OR
– HDL cholesterol < 40 mg/dL OR
– LDL particle size < 260 A
R II. Insulin resistance
– Fasting plasma glucose ≥ 110 mg/dL OR
– Type 2 diabetes mellitus
O III. Obesity
– Body mass index > 25 kg/m2 OR
– Waist/Hip > 0.85 OR
– Waist > 100 cm
Figure 28.4 Adipocyte role in insulin resistance, metabolic syndrome
P IV. High blood pressure
and CVD. Source: Deedwania PC, Volkova N. Current treatment options
for the metabolic syndrome. Curr Treat Options Cardiovasc Med. – Systolic blood pressure ≥ 140 mm Hg OR
2005;7:61-4 – Diastolic blood pressure ≥ 90 mm Hg
The therapeutic goals for management of metabolic syndrome

THERAPY
have been outlined by the AHA and the Endocrine Society45,46
Obesity (particularly central obesity) is central to the pathophysiol- (Table 28.4). They include reduction of abdominal obesity, increas-
ogy of CDS. As such therapy should be primarily directed towards ing physical activity, dietary modification and treatment of specific
this central process. Additionally, insulin resistance and endothelial cardiovascular risk factors if present.
dysfunction play an important role in the pathogenesis of metabolic
and CVD including diabetes, obesity, atherosclerosis, hypertension LIFESTYLE MODIFICATION
and coronary heart disease. Many complex molecular and cellu-
lar mechanisms and tissue and organ level interactions contribute Current evidence suggests that the first step in the management of
to the reciprocal relationship between insulin resistance, adipos- patients with metabolic syndrome should be focused weight loss and
ity and endothelial dysfunction. These mechanisms include parallel increased physical activity. Lifestyle modifications including diet,
insulin signaling pathways in metabolic and vascular tissues, cross- weight loss and physical exercise reduce insulin resistance, obesity
talk between inflammatory and insulin signaling, pathway-specific and improve endothelial function. The benefit of weight manage-
insulin resistance, coupling of blood flow with glucose metabo- ment in preventing worsening of CDS is highlighted by the coro-
lism, cross-talk between metabolic and vascular tissues and shared nary artery risk development in young adults (CARDIA) study.47 In
stressors contributing to insulin resistance and endothelial dysfunc- this observational study of more than 5,000 young individuals for 15
tion, which explain epidemiological data suggesting links between years between the ages of 18 and 30 years, increasing BMI was as-
metabolic and cardiovascular disorders. Results from various phar- sociated with progression of components of metabolic syndrome as
macological and nonpharmacological therapeutic interventions to opposed to those who maintained a stable BMI over the same period.
treat metabolic and cardiovascular conditions have been shown to Obese individuals can lose up to 0.5 kg/week by restricting calories
improve insulin sensitivity and endothelial function. While most to less than 500–1,000 kcal below daily requirements.48 Combining
of the therapeutic interventions have been developed with the in- calorie restriction with regular exercise can lead to a weight loss of
tention of metabolic control, adequate symptomatic control with 5–10% from baseline over a 6 month period. A realistic goal for weight
improved long-term outcomes of any salubrious intervention ap- reduction is a target of 7–10% over a 6–12 month period. Such reduc-
pears to correlate with improved insulin sensitivity and endothe- tions in body weight are associated with much greater loss of visceral
lial dysfunction. Medications with pleiotropic effects that favorably adiposity (the central problem in CDS). This marginal weight loss
influence these various interactions might offer a better outcome. results in improvement of many of the metabolic abnormalities.49
TABLE 28.4 Therapeutic goals and clinical recommendations for management of CDS
Target Goal Recommendations
Abdominal obesity 10% weight loss in the first and continued weight loss Diet control and increased physical activity.
thereafter
Physical inactivity Regular moderate physical activity 30–60 minutes of exercise daily.
Atherogenic diets Reduced intake of saturated fats, trans fats and cholesterol Total fats 25–35% of total calories, saturated fats < 7% of
calories.
Smoking Complete cessation Complete cessation
High LDL cholesterol LDL cholesterol < 100 mg/dl in moderate risk patients and < Lifestyle change and cholesterol lowering drugs to achieve
70 mg/dl in high-risk patients targets
High triglycerides Insufficient data. possibly triglycerides < 100 mg/dl in high Lifestyle change and triglyceride lowering drugs (fenofibrate)
risk patients to achieve targets.
Low HDL cholesterol Insufficient data Lifestyle change and HDL-raising drugs (nicotine acid, CETP
inhibitors) to achieve targets
High blood pressure Blood pressure < 135/< 85 mm Hg. In diabetes and chronic Lifestyle therapy and antihypertensive drugs to achieve
kidney disease < 130/80 mm Hg. targets
Elevated glucose Reduction and maintenance of fasting glucose < 90 mg/dl. Lifestyle therapy and hypoglycemic drugs if required
HBA1C < 7.0% for diabetes.
Prothrombotic state Reduction of prothrombotic state. Low-dose aspirin in all high and moderate risk patients.
Consider clopidogrel if aspirin not tolerated.
Proinflammatory state Reduction of proinflammatory state. No specific therapies. Aspirin and/or statins are being
evaluated.
Diet Intervention
Several dietary approaches have been advocated for treatment of the

metabolic syndrome. A Mediterranean diet which is high in fruits,
vegetables, nuts, whole grains and olive oil results in improved
lipid profile and insulin resistance as compared to a low-fat diet.50,51
Objective data on other weight reducing diets such as high-protein
low carbohydrate diet is limited. In a study of 132 obese individuals
with BMI of 35 or more over a year, the subjects were randomized to
receive counseling to restrict carbohydrate intake to less than 30 g/d
or to restrict caloric intake by 500 calories/day with less than 30%
of calories from fat (conventional diet). Subjects on the low-carbo-
hydrate diet had more favorable outcomes at 1 year than those on
a conventional diet. Weight loss was similar between groups, but Figure 28.5: DPP: benefit of diet/exercise or metformin on diabetes
effects on atherogenic dyslipidemia and glycemic control were more prevention in at-risk patients. Source: DPP research group, Stephane
favorable with a low carbohydrate diet after adjustment for differences Garrigue, Philippe Bordier, Pierre Jaïs, et al. Benefit of atrial pacing in
sleep apnea syndrome. N Eng J Med. 2002;346:393-403.
in weight loss.52 Foods with low glycemic index may be beneficial.
In a cross-sectional analysis of carbohydrate-related dietary factors,
insulin resistance and prevalence of metabolic syndrome in nearly
3,000 subjects from the Framingham Offspring Study, dietary glyce- of the metabolic syndrome including hyperglycemia, dyslipidemia,
mic index was positively associated with prevalence of the metabolic hypertension and abnormal coagulation.
syndrome.53
Antiobesity Drugs
Exercise
Medications that are used for weight loss may potentially be benefi-
Current guidelines recommend practical, regular and moderate cial. Metabolic benefits associated with sibutramine induced weight
regimens for exercise. The standard exercise recommendation is a loss were reported by Krejs et al.56 Orlistat has also been shown in
daily minimum of 30 minutes of moderate-intensity (such as brisk a few studies to improve individual components of metabolic syn-
walking) physical activity. The Diabetes Prevention Program (DPP) drome in addition to promoting weight loss and mobilizing visceral
study showed that multiple metabolic risk factors can be controlled fat.57,58 The problem with these drugs continues to be a relatively
and Type 2 diabetes prevented or delayed by controlling weight with high rate of adverse side effects leading to poor compliance.
regular exercise. The discovery of the endocannabinoid system and its role in feed-
The DPP study enrolled 3,234 normotensive subjects who were ing and energy balance promised the potential of a new therapeutic
mostly obese and randomized them to intensive lifestyle modifica- approach to the problem of insulin resistance and obesity. Inhibition
tion, metformin, troglitazone or placebo (Fig. 28.5). The metabolic of cannabinoid (CB1) with rimonabant in humans is associated with
syndrome (using ATP III criteria) was present in 53% of DPP partici- weight loss, reduced waist circumference, improvements in athero-
pants at baseline. In the remaining subjects, both intensive lifestyle genic dyslipidemia, blood pressure, glycemia and adiponectin levels.
intervention and metformin therapy reduced the risk of develop- Initial manufacture sponsored clinical trials to study the effects the
ing the metabolic syndrome. The rate of development of diabetes/ cannabinoid receptor CB1-antagonist rimonabant, on body weight
metabolic syndrome was least in the intensive lifestyle modification and the metabolic syndrome in overweight patients showed clini-
group, which consisted of low-fat diet and 150 minutes of walking per cal benefit (RIO-LIPIDS and RIO-Europe trials). The Rimonabant in
week.54 Exercise may be beneficial beyond its effect on weight loss by Obesity–Lipids (RIO-Lipids) study examined the effects of rimona-
more selectively removing abdominal fat, at least in women.55 bant on metabolic risk factors, including adiponectin levels, in high-
risk patients who were overweight or obese and had dyslipidemia.59
PHARMACOLOGICAL OPTIONS In 1,036 patients with BMI 27–40 and untreated dyslipidemia
were randomly assigned to double-blinded therapy with either pla-
Although exercise and weight loss ameliorate insulin resistance cebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months,
and may prevent or delay onset of disease, therapy that will reverse in addition to a hypocaloric diet. Results of the trial showed that, as
insulin resistance in individuals unable to make changes to lifestyle compared with placebo, rimonabant at a dose of 20 mg was associ-
is required. Pharmacologic approaches include drugs that combat ated with a significant mean weight loss, reduction in waist circum-
obesity and medications that address the individual components ference, increase in HDL cholesterol and reduction in triglycerides
Figure 28.6: RIO-Lipids: Percent change in HDL-C and TG levels at 1 year. Source: Adapted with permission from Després JP, Golay A, Sjöström L,
Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med.
2005;353:2121-34.
(Fig. 28.6). Rimonabant also decreased HOMA insulin resistance

index and significantly increase plasma adiponection levels in the
nondiabetic population of RIO-LIPIDS.
The RIO-North America trial evaluated the efficacy and safety
of rimonabant in conjunction with a hypocaloric diet in promoting
reductions in body weight and waist circumference, long-term
weight maintenance, and amelioration of cardiometabolic risk
factors in obese and higher-risk overweight patients. A total of
3,045 obese (BMI ≥ 300) or overweight (BMI > 27), patients were
randomized to double-blind treatment with placebo, 5 mg rimona-
bant or 20 mg rimonabant. At year 1, the 20 mg rimonabant group
produced greater mean reductions in weight, waist circumference
and level of triglycerides compared with the placebo group, and a Figure 28.7: RIO-North America: Change in metabolic syndrome
greater increase in level of HDL-C. The prevalence of the metabolic status. Source: Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect
syndrome significantly declined in patients receiving 20 mg rimona- of rimonabant, a cannabinoid-1 receptor blocker, on weight and
bant (from 34.8% to 21.2%), compared with patients receiving pla- cardiometabolic risk factors in overweight or obese patients: RIO-North
America: a randomized controlled trial. JAMA. 2006;295:761-75.
cebo (31.7–29.2%) (Fig. 28.7). Benefits were largely maintained at 2
years by participants who remained on 20-mg rimonabant.60
The favorable effects of rimonabant in Type 2 diabetes were also
shown in SERENADE, a 6 month placebo-controlled trial in over- drug or similar compounds can be used widely for weight reduction
weight subjects with recent onset diabetes mellitus on diet.61 How- in populations, larger and definitive safety trials need to be conduct-
ever rimonabant use is associated with many side effects including ed to demonstrate long-term safety.
upset stomach, nausea, diarrhea, dizziness, fatigue, sweating, back
pain, muscle spasms and tendon inflammation. Serious psychiat- Lipid Management
ric side effects were also reported including suicidal thoughts, hal-
lucinations, anxiety, panic, depression, irritability, mood swings The lipid abnormalities in the metabolic syndrome were originally
and insomnia. Due to concerns regarding adverse effects, including described as atherogenic dyslipidemia by Grundy.62 The definition
depression rimonabant was never approved for use in the United included borderline high LDL cholesterol and apolipoprotein B,
States and the European since then all trials with this drug have been increased small dense LDL particles, raised triglycerides and low
stopped and other pharmaceutical companies have also terminated HDL cholesterol levels. The ATP III guidelines emphasize that LDL
trials of other potential CB1 receptor antagonist drugs. Before this reduction is the primary target in lipid management even in the
metabolic syndrome with low HDL and triglycerides being second- tor blockers (ARB) and a low dose thiazide diuretic to achieve these
ary targets.63 The more aggressive target of LDL less than 70 mg/dL goals. The value of ACE inhibitors and ARBs in hypertensive patients
is supported by the recent TNT-Metabolic syndrome study showing with the metabolic syndrome who do not have CVD or diabetes is
greater reduction in coronary events in the group that achieved LDL not clear. Several large clinical trials on hypertension, such as the
levels of 70 mg/dL as opposed to the group that attained levels of Losartan Intervention for Endpoint (LIFE) reduction in hypertension
less than 100 mg/dL.64 In TNT, 10,001 patients with clinical CAD study and the Heart Outcomes Prevention Evaluation (HOPE) study,
were randomized to receive daily atorvastatin at either 10 mg (LDL which used ramipril in patients at high risk of cardiovascular events
goal, 100 mg/dL) or 80 mg (LDL goal, 75 mg/dL). Fifty-six percent have shown the benefit renin-angiotensin-aldosterone system
of subjects had the metabolic syndrome, according to NCEP ATP III (RAAS) blockade with ACE-I and ARB by demonstrating lower inci-
criteria. Post-hoc data show that the number needed to treat with 80- dence of new onset diabetes mellitus.66,67 Animal studies have shown
mg atorvastatin to avoid adverse cardiovascular event over 5 years is improvement in insulin resistance, reduction of ROS production and
28 among nondiabetic TNT subjects with the metabolic syndrome increased mitochondrial biogenesis with enalapril and losartan.68,69
and 167 among all TNT subjects without the metabolic syndrome65 Studies have also shown significant increase in adiponectin levels
(Fig. 28.8). with inhibition of RAAS with ACEI or ARB, which is associated with
The use of intensive lipid lowering therapy attenuated the prog- improved insulin sensitivity.70 ACEI and ARBs might increase per-
nostic impact of each component of MS (Fig. 28.9). oxisome proliferators-activated receptor (PPAR) activity which might
While the efficacy of statins in reducing LDL cholesterol is well promote adipogenesis thus improving metabolic perturbations.71 In
established, combination therapy has been suggested for achiev- the diabetes reduction Assessment with ramipril and rosiglitazone
ing LDL targets and reducing triglycerides, apolipoprotein B and medication (DREAM) study, there was a nonsignificant trend to-
increasing HDL cholesterol. wards a reduction in the incidence of diabetes in the ramipril group,
with 449 patients who had diabetes in the ramipril group, as com-
Antihypertensive Therapy pared with 489 in the placebo group (hazard ratio, 0.91; 95% CI, 0.80
to 1.03; P = 0.15), over a median follow-up period of 3 years.72 In the
The blood pressure goal for patients with known CVD or diabe- nateglinide and valsartan in impaired glucose tolerance outcomes
tes is less than 130/80. These individuals are often treated with an research (NAVIGATOR) study, a single daily dose of the ARB vals-
angiotensin-converting-enzyme (ACE) inhibitor/angiotensin recep- artan (up to 160 mg), when added to lifestyle intervention reduced
Figure 28.8: Time to first major cardiovascular event in metabolic syndrome patients without diabetes. Source: Deedwania P, Barter P, Carmena
R, et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the treating
to new targets study. Lancet. 2006;368:919-28.
Figure 28.9: Incidence of major cardiovascular events by number of metabolic syndrome components. Source: Deedwania P, Barter P, Carmena
R, et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the treating
to new targets study. Lancet. 2006;368:919-28
the risk of diabetes, but not of cardiovascular events in patients with tolerance to Type 2 diabetes. In the Finnish study and the DPP per-
impaired glucose tolerance and established CVD or risk factors. The sonalized recommendations about diet and exercise reduced inci-
relative reduction of 14% in the risk of diabetes in the valsartan group dence of new onset diabetes by 58% compared to the group receiving
was consistent across all subgroups that were examined.73 usual instructions. These findings mirror the results of studies evalu-
Sympathetic activation in obese hypertensive patients seems to ating diet and exercise in the Malmo study78,79 and Da Qing trial80 in
contribute to elevated blood pressure and cardiovascular and meta- the previous decade. Diet and exercise in the Malmo study reduced
bolic consequences of the metabolic syndrome. In theory drugs diabetes incidence by 50% and at 12-year follow-up the group that
inhibiting the sympathetic nervous system could be useful, but the achieved normoglycemia had similar mortality as normal subjects.
evidence of efficacy of central imidazoline receptor binding agents The Da Qing trial demonstrated that diet alone, exercise alone or
and peripheral b-adrenergic blocking agents is not convincing. In their combination significantly reduced the incidence of diabetes.
fact a diabetogenic effect has been unequivocally demonstrated for In obese insulin resistant individuals stratified by glucose tolerance
both thiazide diuretics and older b-blockers such as atenolol. There- after weight loss in response to low calorie diet combined with mod-
fore these drugs may not be suitable as first line therapy for hyperten- erate physical exercise, insulin sensitivity has been shown to improve
sion in subjects with metabolic syndrome. significantly especially among diabetic subjects.81,82
Although exercise and weight loss ameliorate insulin resistance
Insulin Resistance and may prevent or delay onset of disease, therapy that will reverse
insulin resistance in individuals unable to make changes to lifestyle
Approaching CDS from the aspect of insulin resistance (IFG, IGT, is required. Pharmacologic approaches to address insulin resist-
DM) is conceptually reasonable. Practically this translates into treat- ance potentially can control hyperglycemia, dyslipidemia, abnormal
ment of individuals with impaired fasting glucose or impaired glu- coagulation and possibly even hypertension. Metformin which was
cose tolerance before overt hyperglycemia develops. Recent stud- first described in 1922, improves hyperglycemia primarily through
ies targeting individuals with dysglycemia using aggressive lifestyle its suppression of hepatic glucose production. In addition metform-
interventions or pharmacotherapy have reduced the incidence of in increases insulin sensitivity, enhances peripheral glucose uptake,
diabetes and the risk of CVD. The Finnish Diabetes Prevention fatty acid oxidation and decreases absorption of glucose from the
Study74 and the US-DPP75-77 showed that diet and exercise had a sig- gastrointestinal tract. Increased peripheral utilization of glucose
nificant effect on reducing the progression from impaired glucose may also be due to improved insulin binding to insulin receptors.
Metformin was included in one of the treatment arms along with therapeutic option to lower vascular events.88 It is also important to
lifestyle advise in DPP. While metformin was effective in reducing note that RAS inhibition also reduces PAI-1 levels and inflammatory
the incidence of diabetes as compared with placebo, it was not as cytokines and thus potentially reduces risk of increased thrombotic
effective as intensive lifestyle intervention. events in patients with metabolic syndrome.89
Acarbose, an inhibitor of a-glucosidase slows the digestion of
carbohydrates in the intestine and reduced postprandial glucose SURGICAL MANAGEMENT
levels. The Study to Prevent Non-Insulin Dependent Mellitus (STOP-
NIDDM) was a randomized trial to evaluate whether acarbose would Bariatric surgery techniques using laparoscopic adjustable band-
prevent development of Type 2 in subjects with impaired glucose ing of stomach along with Roux-en-Y and other forms of gastric by-
tolerance.83 In the acarbose group as compared to placebo group pass are now fairly well established for severe and morbid obesity
significantly less developed diabetes (32% vs 42%, p = 0.0015) and resulting in weight loss of 25–30% and rapid normalization of glucose
probability of reverting to normal glucose tolerance was significantly handling and blood pressure in patients with diabetes and hyperten-
greater. There was also a reduction in risk of developing cardiovascu- sion.90 Marked reductions in the prevalence of the metabolic syn-
lar events. drome have also been observed after RYGBP at greater than 1 year of
One of the first drugs to address all the abnormalities existent follow-up.91-93 In a recently published study from Australia fifty obese
in the insulin resistance state are the thiazolidinediones (TZDs). adolescents (mean BMI, 41) were randomized to undergo gastric
TZDs are insulin-sensitizing drugs, that act via the nuclear PPARg banding with instructions on diet and exercise or to participate in a
to change activation of a plethora of genes and the levels of vari- supervised lifestyle intervention focused on diet, exercise and behav-
ous expressed proteins.84 Some of these proteins are involved in ior modification.94 At 2 years, significantly more teens in the band-
glucose and lipid metabolism including adipogenesis, while others ing group than in the lifestyle group had lost at least half their excess
participate in a variety of molecular cascades, including inflamma- weight (84% vs 12%). In addition, banding led to complete resolution
tion, which have a favorable effect on insulin resistance. The DREAM of the metabolic syndrome, as well as some improvements in qual-
study evaluated rosiglitazone for its ability to preserve insulin sensi- ity of life. However, long-term results are not available and there are
tivity.85 In this study rosiglitazone at 8 mg per day reduced the three reports of substantial mortality and morbidity related to these proce-
year incidence of Type 2 diabetes significantly by 60% in patients dures. It is to be noted that studies have shown no improvement in
with IGT or IFG who were taking the medication at the time of test- biomarkers despite significant weight loss with liposuction.
ing. Pioglitazone has been shown to reduce multiple components of
metabolic syndrome, such as high blood pressure, high blood glu- CURRENT CONTROVERSIES
cose and triglycerides in addition to a decrease in urinary albumin/
AND FUTURE DIRECTION
creatinine ratio.86 The prospective pioglitazone clinical trial in mac-
rovascular events (PROACTIVE) study evaluated secondary preven- Questions regarding the clinical utility of identifying the CDS have
tion of macrovascular events in patients with Type 2 diabetes using been raised by few investigators including Reaven.95 Khan et al. pro-
pioglitazone in a RCT. Pioglitazone reduced composite of all-cause pose that the primary focus should remain on the individual meta-
mortality, nonfatal myocardial infarction and stroke.87 There is how- bolic risk factors and that aggregating them into a syndrome adds
ever as yet no strong evidence that TZDs reduce CVD endpoints and little to clinical management.96 Criticism includes the fact that there
in particular there are no data on such risk reduction for people with have been multiple definitions for the CDS raising questions about
metabolic syndrome. Moreover, as evidenced by recent controversy the uniformity and general applicability of results from various stud-
rosiglitazone may even be associated with an increased risk of CV ies. Additionally, there are multiple different phenotypes included
events. within the metabolic syndrome making it a heterogenous collection
of different clinical entities; this might be a reflection of the varying
Prothrombotic State pathophysiologic factors not limited to insulin resistance. Moreover,
there is contamination of data by inclusion of patients with clinical
The CDS is characterized by a procoagulant state with increased CVD or diabetes as part of the syndrome, which is intended to define
levels of fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and the risk for these diseases. There is also the valid critique of the cur-
other coagulation factors. They also have a proinflammatory state rent metabolic syndrome construct that treatment of the syndrome
characterized by elevated cytokines-tumor necrosis factor and is no different than treatment for each of its components. However,
interleukin-6, and acute phase reactants, such as CRP and fibrino- the counter argument is that there is undeniable clustering of risk
gen. Aspirin is widely recommended in patients with established factors for diabetes and CVD. Inclusion of CDS in routine clinical
CVD although its role in prevention of events in diabetes is not well assessment makes it easier for the clinician to put this cluster togeth-
established. In patients with CDS and a high risk of future cardio- er and identify it for the patient as a disease entity which can then be
vascular events, aspirin in a dose of 75–150 mg/day is an attractive addressed in an effective manner. There is also general agreement
that the presence of any one component of the CDS should lead to visceral adiposity) and metabolic susceptibility as manifested by
a search for other risk factors. Identification of risk-factor cluster- insulin resistance. In addition, to dyslipidemia, hypertension, and
ing changes the clinical focus to underlying causes, which calls for hyperglycermia, the syndrome carries a prothrombotic state and
greater emphasis on lifestyle therapies to reduce long-term risk for a proinflammatory state. Despite the ongoing controversy, clini-
CVD. The key clinical implication of the diagnosis of the CDS in a cal identification of CDS is quite helpful for the clinicians to put
patient is the need for aggressive lifestyle modification focused on the individuals with clustering of these components of CDS/MS in
weight reduction and increased physical activity. Additionally if the proper perspective. Presence of the CDS identifies an individual at
major purpose of defining the CDS is to shift emphasis to earlier twice the risk for CVD compared with those without the syndrome.
intervention with lifestyle therapies, it is reasonable to extend the It also raises the risk for Type 2 diabetes by about five-fold. While
concept to obese children and adolescents where the syndrome is some investigators favor keeping risk factors separate for purposes
already beginning to take hold. of clinical management, there is general agreement that identifying
individuals with an aggregation of risk factors provides additional
CONCLUSION useful information to guide clinical management. Current guide-
lines emphasize therapies that will reduce all of the risk factors
The CDS is a compilation of multiple established risk factors that simultaneously. This approach involves lifestyle therapies (weight
occur due to metabolic abnormalities. The etiopathogenesis of the reduction and increased exercise), which target all of the risk
CDS appears to be due to complex interplay of obesity (primarily factors.
REFERENCES
1. Himsworth HP. The mechanism of diabetes. Lancet. 1939;2:1-6.
2. Reaven G. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
3. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and athero-
sclerotic cardiovascular disease. Diabetes Care. 1991;14:173-94.
4. Lindsay RS, Howard BV. Cardiovascular risk associated with the metabolic syndrome. Curr Diab Rep. 2004;4:63-8.
5. Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome insights from therapeutic interventions. J Am Coll Cardiol.
2005;46:1978-85.
6. Fagan TC, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med. 1998;105(1A):77S-82S.
7. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And
Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.
8. Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160-7.
9. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National
Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735.
10. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366:1059-62.
11. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world–a growing challenge. N Engl J Med. 2007;356:213-5.
12. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood choles-
terol in adults (Adult Treatment Panel III). Final Report. Circulation. 2002;106:3143-421.
13. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the US. Diabetes Care.
2005;28:2745-9.
14. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition
Examination Survey. JAMA. 2002;287:356-9.
15. Wilson PW, D’Agostino RB, Parise H, et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation.
2005;112:3066-72.
16. Lillioja S, Mott diabetes, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes
mellitus: prospective studies of Pima Indians. N Engl J Med. 1993;329:1988-92.
17. Gupta A, Gupta R, Sarna M, et al. Prevalence of diabetes, impaired fasting glucose and insulin resistance syndrome in an urban Indian population.
Diab Res Clin Pract. 2003;61:69-76.
18. Ramachandran A, Snehalatha C, Satyavani K, et al. Metabolic syndrome in urban Asian Indian adults-a population study using modified ATP III
criteria. Diabetes Res Clin Pract. 2003;60:199-204.
19. Gupta R, Deedwania PC, Gupta A, et al. Prevalence of metabolic syndrome in an Indian urban population. Int J Cardiol. 2004;97(2):257-61.
20. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008;28:629-36.
21. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care. 2008;31:1898-904.
22. Sattar N, McConnachie A, Shaper AG, et al. Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from
two prospective studies. Lancet. 2008;371:1927-35.
23. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and
diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003;108:414-9.
24. Hanson RL, Imperatore G, Bennett PH, et al. Components of the “metabolic syndrome” and incidence of type 2 diabetes. Diabetes. 2002;51:
3120-7.
25. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence.
Diabetes Care. 2005;28:1769-78.
26. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med. 2006;119:812-9.
27. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-
analysis of longitudinal studies. J Am Coll Cardiol. 2007;49:403-14.
28. Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dys-
function. Mol Cell. 2000;6:87-97.
29. Bruning JC, Michael MD, Winnay JN, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM
without altering glucose tolerance. Mol Cell. 1998;2:559-69.
30. Bluher M, Michael MD, Peroni OD, et al. Adipose tisssue selective insuiln receptor knockout protects against obesity and obesity regulated glucose
intolerance. Dev Cell. 2002;3:25-38.
31. Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799-806.
32. Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium.
Curr Diab Rep. 2003;3:279-88.
33. Federici M, Pandolfi A, De Filippis EA, et al. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human
endothelial cells. Circulation. 2004;109:399-405.
34. Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts and different goals. Endocrinol Metab
Clin North Am. 2004;33:283-303.
35. Meigs JB, Wilson PW, Fox CS, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol
Metab. 2006;91:2906-12.
36. Despre´s JP, Moorjani S, Lupien PJ, et al. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis.
1990;10:497-511.
37. Ross R, Aru J, Freeman J, et al. Abdominal adiposity and insulin resistance in obese men. Am J Physiol Endocrinol Metab. 2002;282:E657-E663.
38. Ross R, Freeman J, Hudson R, et al. Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. J Clin Endocrinol
Metab. 2002;87:5044 -51.
39. Nieves DJ, Cnop M, Retzlaff B, et al. The atherogenic lipoprotein profile associated with obesity and insulin resistance is largely attributable to
intra-abdominal fat. Diabetes. 2003;52:172-9.
40. Storlien L, Oakes ND, Kelley DE. Metabolic flexibility. Proc Nutr Soc. 2004;63(2):363-8.
41. Adams JM, Pratipanawatr T, Berria R, et al. Ceramide content is increased in skeletal muscle from obese insulin-reistant humans. Diabetes.
2004;53(1):25-31.
42. Nadler ST, Attie AD. Please pass the chips: genomic insights into obesity and diabetes. J Nutr. 2001;131(8):2078-81.
43. Pagotto U, Marsiscano G, Cota D, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endo Rev.
2006;27(1):73-100.
44. Fagan TC, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med. 1998;105(1A):77S-82S.
45. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National
Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-52.
46. Rosenzweig JL, Ferrannini E, Grundy SM, et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008;93:3671-89.
47. Lloyd-Jones DM, Liu K, Colangelo LA, et al. Consistently stable or decreased body mass index in young adulthood and longitudinal changes in
metabolic syndrome components: the Coronary Artery Risk Development in Young Adults Study. Circulation. 2007;115:1004-11.
48. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med. 2002;346:591-602.
49. Haslam DW, James WPT. Obesity. Lancet. 2005;366:1197-1209.
50. Esposito K, Marfella R, Ciotola M, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in
the metabolic syndrome: a randomized trial. JAMA. 2004;292:1440-6.
51. Tortosa A, Bes-Rastrollo M, Sanchez-Villegas A, et al. Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN
prospective cohort. Diabetes Care. 2007;30:2957-9.
52. Stern l, Iqbal N, Seshadri P, et al. The effects of low carbohydrate versus conventional weight loss diets in severely obese adults: one year follow-up
of a randomized trial. Ann Intern Med. 2004;140:778-85.
53. McKeown NM, Meigs JB, Liu S, et al. Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham
Offspring Cohort. Diabetes Care. 2004;27:538-46.
54. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J
Med. 2002;346:393-403.
55. Thompson PD, Buchner D, Pina IL, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease:
a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition,
Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation. 2003;107:3109-16.
56. Krejs GJ. Metabolic benefits associated with sibutramine therapy. Int J Obesity. 2002;26(Suppl 4):S34-S37.
57. Didangelos TP, Thanapoulou AK, Bousboulas SH, et al. The orlistat and cardiovascular risk profile in patients with the metabolic syndrome and
type 2 diabetes (ORLICARDIA) study. Curr Med Res Opin. 2004;20:1393-1401.
58. Torgerson JS, Hauptman J, Boldrin MN, et al. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study or
orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-61.
59. Despres JP, Golay A, Sjostrom L. Rimonabant in Obesity-Lipids Study Group. Effects on metabolic risk factors in overweight patients with dyslipi-
demia. N Engl J Med. 2005;353:2121-34.
60. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. For the RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on
weight and cardiometabolic risk factors in overweight or obese patients. RIO-North America: A randomized controlled trial. JAMA. 2006;295:761-
75.
61. Rosenstock J, Iranmanesh A, Hollander PA. Improved glycemic control with weight loss plus beneficial effects on atherogenic dyslipidemia with
rimonobant in drug-naïve type 2 diabetes: the SERENADE trial (Abstract). Diabetes. 2007;56(Suppl 1):A49-A50.
62. Grundy SM. Small LDL, atheogernic dyslipidemia and the metabolic syndrome. Circulation. 1997;95:1-4.
63. Grundy SM, Cleeman JI, Merz CN, et al. National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart
Association. Implications of recent clinical trials for the National Cholesterol Education Program ATP III guidelines. Circulation. 2004;110(2):227-
39. Review. Erratum in: Circulation. 2004;110(6):763.
64. Deedwania PC. TNT study and metabolic syndrome. Circulation. 2005;112(Suppl A):Abstract.
65. Deedwania P, et al. For the Treating to New Targets Investigators. Lancet 2006;368:919-28.
66. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular event in high-risk patients. The
heart outcomes prevention evaluation study investigators. N Engl J Med. 2000;342:145-53.
67. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hyperten-
sion study (LIFE): a randomized trial against atenolol. Lancet. 2002;359(9311):995-1003.
68. De Cavanagh EM, Piotrkowski B, Basso N, et al. Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J. 2003;17:1096-8.
69. De Cavanagh EM, Inserra F, Toblli J, et al. Enalapril attenuates oxidative stress in diabetic rats. Hypertension. 2001;38:1130-6.
70. Furuhashi M, Ura N, Higashiura K, et al. Blockade of the rennin-angiotensin system increases adiponectin concentrations in patients with essen-
tial hypetenstion. Hypertension. 2003;42:76-81.
71. Engeli S. Role of the renin-angiotensin-aldosterone system in the metabolic syndrome. Contrib Nephrol. 2006;151:122-34.
72. The DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551-62.
73. NAVIGATOR study group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1463-76.
74. Toumilheto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus with lifestyle intervention or metformin. N Engl J Med.
2001;344:1343-50.
75. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J
Med. 2002;346:393-403.
76. Knowler WC, Hamman RF, Edelstein SL, et al. Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the
diabetes prevention program. Diabetes. 2005;54:1150-56.
77. Diabetes Prevention Program Research Group. Role of insulin sensitivity and secretion in the evolution of type 2 diabetes in the diabetes preven-
tion program. Diabetes. 2005;54:2404-14.
78. Eriksson KF, Lindgrade F. Prevention of type 2 diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia.
1991;34:891-8.
79. Eriksson KF, Lindgrade F. No excess of 12-year mortality in men with impaired glucose tolerance who participated in the Malmo preventive trial
with diet and exercise. Diabetologia. 1998;41:1010-6.
80. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and
Diabetes Study. Diabetes Care. 1997;20:537-44.
81. Monzillo LU, Hamdy O, Horton ES, et al. Effects of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Obes Res.
2003;11:1048-54.
82. Hotta K, Funashashi T, Arita Y, et al. Plasma conocentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterio-
scler Thromb Vasc Biol. 2000;20:1595-9.
83. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: STOP-NIDDM randomized trial. Lancet. 2002;359:
2072-7.
84. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106-18.
85. DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, et al. Ef-
fect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled
trial. Lancet. 2006;368(9541):1096-105.
86. Rajagopalan R, Iyer S, Khan M. Effect of pioglitazone on metabolic syndrome risk factors: results of double boind, multi-center, randomized clini-
cal trials. Curr Med Res Opin. 2005;21:163-72.
87. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive
study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet. 2005;366:1279-89.
88. Patrono C, Garcia-Rodriguez LA, Landolfi R, et al. Low dose aspirin for the prevention of atherothrombosis. NEngl J Med. 2005;353:2373-83.
89. Deedwania PC, Fonesca VA. Diabetes, prediabetes, and cardiovascular risk: shifting the paradigm. Am J Med. 2005;118:939-47.
90. Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes and cardiovascular riks factors 10 years after bariatric surgery. N Engl J Med.
2004;351:2683-93.
91. Lee WJ, Huang MT, Wang W, et al. Effects of obesity surgery on the metabolic syndrome. Arch Surg. 2004;139:1088-92.
92. Mattar SG, Velcu LM, Rabinovitz M, et al. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic
syndrome. Ann Surg. 2005;242:610-7.
93. Madan AK, Orth W, Ternovits CA, et al. Metabolic syndrome: yet another co-morbidity gastric bypass helps cure. Surg Obes Relat Dis. 2006;2:48-
51.
94. O’Brien PE, Sawyer SM, Laurie C, et al. Laparoscopic adjustable gastric banding in severely obese adolescents: a randomized trial. JAMA.
2010;303(6):519-26.
95. Reaven GM. The metabolic syndrome: is this diagnosis necessary? AmJ Clin Nutr. 2006;83:1237-47.
96. Kahn R, Buse J, Ferrannini E, et al. American Diabetes Association; European Association for the Study of Diabetes. The metabolic syndrome: time
for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes
Care. 2005;28:2289-304.
29 History of Obesity and
Cardiovascular Disorder
Manoria PC, Pankaj M, Verma RK, Manoria P
Obesity is a highly prevalent and complex chronic disease that angina and obesity was emphasized later. In 1811, Robert Thomas
results from the accumulation of the excessive adipose tissue. wrote:
Obesity is changing, but its origins can be traced 30,000 years back It is found to attack men much more frequently than women, par-
to our prehistoric ancestors. The Darwin theory of “The survival of ticularly those who have short necks, who are inclinable to corpulency
fittest” dictated that individuals who stored energy in the most and who at the same time lead an inactive or sedentary life he should
efficient way would survive the inevitable fast and famine that endeavor to counteract any disposition to obesity, which has been con-
would follow times of plenty. But, natural selection has turned on sidered a predisposing cause.5
us. Life now favors inefficient phenotypes who fail to store energy in The other main comorbidity linked to obesity is diabetes, a
adipose depots, while those who lay down fat in the abdomen are condition probably known to doctors since 1552 BC when the Ebers
condemned to premature death. papyrus refers to “excessive urination”, and “a medicine to drive
Acceptance of obesity as a medical phenomenon has been slow. away the passing of too much urine”.6 In Hindu writings, black ants
For thousands of years, obesity was prized, indicating status and detected diabetes thousands of years ago. Records describe a mys-
wealth. Only the richest had the means to become obese and girth terious, deadly disease causing intense thirst, enormous urine out-
advertised wealth more effectively than the richest clothing or jew- put and wasting of the body. A diagnostic sign was the attraction
els. Hippocrates (ca 460–370 BC) was one of the first to warn of the of ants and flies to the victims’ urine. It is claimed that up to 80%
dangers of obesity when he wrote,1 “It is very injurious to health to of Type 2 diabetes is linked to excess weight, but it is only relatively
take in more food than the constitution would bear, when at the same recently that the connection was highlighted. Nathan Buchan, in
time, one uses no exercise to carry off this”. 1795, blamed “hard drinking” but not corpulence. In 1811, Robert
Thomas noted not only the presence, but also the site of body fat in
OBESITY AND RELATION WITH cases of diabetes, highlighting dangerous metabolically active vis-
ceral fat. Dr Robert Thomas of Salisbury linked “paralysis” or stroke,
VARIOUS DISEASES
in 1811, with “full plethoric habit”.5 In 1795, Dr Nathan Buchan docu-
George Cheyne (1671–1743) was the foremost physician of his day, mented the effect on the skin in ‘sedentary and studious’ individu-
who himself suffered from gross obesity, weighing 32 stone (203.2 kg) als.7 Sleep apnea was documented as being linked with obesity in the
at his peak, and feeling “excessively fat, short-breath’d, lethargick and 4th century BC. Dionysius, himself obese, lived in fear of suffocating
listless”. He required a servant to walk behind him carrying a stool on while asleep, and employed attendants to thrust needles through his
which to recover every few paces. Cheyne wrote of “The Fat, unwieldy sides to awaken him every time he slept. Hippocrates also described
and over-grown”, saying ‘tis easier to preserve health than to recover it, abnormal sleep patterns: “Others, when their diet bears too great a
and to prevent diseases than to cure them without due labor and exer- proportion to their exercise, not only do not sleep well at night, but are
cise, the juices will thicken, the joints will stiffen, the nerves will relax, likewise drowsy in the day; the repletion still increases, and their nights
and on these disorders, chronical distempers, and a crazy old age must begin to grow restless; their sleep afterwards becomes disturbed with
ensue”.2 The fact was becoming noted that obesity was not an isolated frightful dreams of battles”. 8
disorder and that other conditions occurred more readily in obese
patients coronary heart disease commonly coexists with obesity. DIFFERENT BODY SHAPES
The condition now called angina was described by Edward Hyde (in
AND OBESITY RISK
1759).3 The term “angina” was first used by Heberden in 1768. “There
is a disorder of the breast, marked with strong and peculiar symptoms, Morgagni, in 1765, highlighted the importance of abdominal fat
considerable for the kind of danger belonging to it. The seat of it and by postmortem dissection. More recently, in the 19th century, the
sense of strangling and anxiety with which it is attended may make it link between maleness and obesity has been more clearly defined.
not improperly be called angina pectoris”.4 The connection between According to the famed writer and wit, Brillat-Savarin: There is one
kind of obesity that centers round the belly; I have never noticed it in moderate size in a short time, by making him run every morning
women: since they are generally made up of softer tissues, no part of until he fell into a profuse sweat; I then had him rubbed hard, and
their body is spared when obesity attacks them. I call this type of fat- put into a warm bath; after which I ordered him a small break-
ness gastrophoria, and its victims gastrophores. I myself am in their fast, and sent him to the warm bath a second time. Some hours
company; but although I carry around with me a fairly prominent after, I permitted him to eat freely of food, which afforded but lit-
stomach, I still have well-formed lower legs, and calves as sinewy as tle nourishment; and lastly, set him to some work which he was
the muscles of an Arabian steed. He is describing the typical and dan- accustomed to for the remaining part of the day.10 The ancient
gerous apple shape which obese men tend to assume, as opposed Egyptians method of limiting food intake was primitive. They
to the ‘pear’ shape of obese women who often carry their weight were said by Diodorus Siculus to: “prevent distempers by glisters,
harmlessly on the thighs and buttocks. French Physician Jean Vague purging, vomiting or fasting every second, third or fourth day”,
revisited the same territory, and first described the now traditional because “the greatest part of the aliment we take is superfluous,
“apples” and “pears” of android and gynoid obesity respectively and which superfluity is cause of our distempers”.11 Herodotus agreed:
gave an explanation as to the underlying metabolic derangements.9 “Egyptians vomit and purge themselves thrice every month, with
a view to preserve their health, which in their opinion is chiefly
OBESITY AND SYNDROME X injured by their ailment”.12
In the early spring of 1988, Gerald Reaven, Professor of Medicine at THE SITUATION TODAY
Stanford University, was struggling to prepare his Banting Award ad-
dressed for the American Diabetes Association Conference, when The world wide prevalence of obesity is currently estimated at over
“the notion of Syndrome X sprung almost full-blown into my mind”. 300 million individuals with an additional 800 million people clas-
Diseases, once seemingly unconnected, were drawn together under sified as overweight writers and physicians over many centuries
the banner of insulin resistance and presented as one life-threaten- have dedicated their life’s work to teach the preservation of health,
ing syndrome. For the first time, the clustering together of illnesses and warn of the dire consequences of ignoring good diet and
including heart disease, stroke, diabetes and dyslipidemia was activity. However, their wisdom has been disregarded. In modern
explained clearly and scientifically. times the continued rise in obesity threatened to reverse the gains
made in prolonging life expectancy and reducing the morbidity
TREATMENT OF OBESITY from CAD and other chronic health problems. Instead of spending
precious resources inventing novel scientific gadgets, the works of
IN THE EARLY DAYS
our forefathers should be revisited, and the simple lessons learned
Galen, wrote on food and diet, recounting one of the earliest case from history used to once again prioritize the preservation of
studies of obesity Management, “I reduced a huge fat fellow to a health.
REFERENCES
1. Hippocrates 400 C e Priscina Medicina.
2. Cheyne G. An Essay of Health and Long Life George Strahan. London, 1724.p.1.
3. Hyde E. Edward Hyde. Life of Edward, 1st Earl of Clarendon, by himself Clarendon. Oxford; 1759.
4. Heberden W. ‘Some Account of a Disorder of the Breast’ presented at the Royal College of Physicians July 21st 1768, Vol. II of Medical Transactions
of the College of Physicians, 1772. London: Royal College of Physicians; 1768.
5. Thomas R. The Modern Practice of Physic. New York: Collins and Co; 1811.
6. Diabetes in the Eberspapyrus. [online] Available from http://wwwunix.oit.umass.edu/~abhu000/diabetes/ebers.html. [Accessed 2006].
7. Buchan N. Domestic Medicine (American Edition) Dobson: Philadelphia, PA; 1795.
8. Hippocrates -440 BC De Vict Rat in Morb Acut. lib 3.
9. Vague J. Sexual differentiation, a factor affecting the forms of obesity. Presse Med. 1947;30:339-40.
10. Galen -AD 160 De Sanitate Tuenda. lib 6 cap 8.
11. Siculus. Bibliotheca historica.
12. Herodotus. Euterpe, section 77.
30 History of Dilated Cardiomyopathy
Bahl A, Nahar U, Talwar KK
Nonspecific endocardial thickening is often found and thrombus

DILATED CARDIOMYOPATHY
may or may not be superimposed. Patchy fibrosis, limited to the
General Features and History inner-third of the myocardium, may also be present.9,10 The coronary
arteries are generally normal.
The term dilated cardiomyopathy (DCM) describes a clinical
syndrome of primary heart muscle disease, forms a considerable Histopathology
part of the total cardiac diseases causing congestive heart failure
(CHF) and was called as congestive cardiomyopathy in the older Histological examination shows regularly arranged myocardial fibers
times (Goodwin et al.).1 One of the earliest reports of the DCM of apparently normal dimension due to attenuation, but showing nu-
was communicated to the British Cardiac Society by Bedford and clear changes of hypertrophy, such as pyknosis, blunting or vesicular
Konstam in 1946 which are presently described as endomyocar- changes.9,10 Small foci of necrosis and small accumulation of chronic
dial fibrosis and idiopathic DCM.2 This was followed by a series inflammatory cells are occasionally found (Goodwin et al., 1961).1
of descriptions of cardiomyopathies by Davies3 from Uganda in Small vessels in over sixty cases personally examined have not
1948 and from South Africa by Gillanders4 in 1951 and Becker5 shown any abnormalities. The overlying endocardium is thickened
et al. in 1953. with an often prominent increase of the smooth muscle component
There has been a dramatic increase in the number of cases of which denotes severe dilatation of some duration. Histochemically,
chronic myofascial pain (CMP) between 1970 and 1982 in United changes consist of an apparent patchy increase in enzyme systems,
States, probably because of the changes in the diagnostic criteria such as succinic dehydrogenase reflecting an increased number of
and/or classification.6,7 The term DCM was applied to all those suba- mitochondria, glycogen, acid phosphatase and nonspecific esteras-
cute or chronic disorders of the myocardium associated with con- es, reflecting an increased number of lysosomes (van Noorden, 1971;
gestive cardiac failure with cardiomegaly in absence of valvular heart Olsen, 1973).9-11
disease, hypertension, coronary artery disease or any observable
cause at autopsy. Some CMPs are congenital, others acquired; some Ultrastructure
have a specific morphology while others do not. The cause of some
is known but presently many do not have a definite etiology. Eventu- Electron microscopy does not show distinguishing features other
ally and ideally, a pathologist makes a diagnosis based on histomor- than those of hypertrophy. Increase in glycogen is confirmed the
phological features. This is done after studying the clinical, echocar- myocyte show degenerative and hypertrophic changes in the form
diographic data and endomyocardial biopsy or tissue from autopsy. of mitochondrial hyperplasia with distortion of cristae, loss of myofi-
A careful light microscopy, histochemistry, electron microscopy, brils and increase in myelin figures.10,11
immunohistochemistry and molecular studies need to be done in
each case to ascertain the cause of cardiomyopathy. Etiology
Pathology Various etiological factors have been implicated as causative agent

for DCM. The most common being postviral infection causing myo-
Gross carditis and persistent myocardial damage.11 Other caused include
postpartum myocardial failure,12 alcohol, chronic protein energy
The macroscopic features reveal an overweight heart (400–500 g) malnutrition, ischemia and chronic diabetes.13 In the past familial
which may go up to 750 g, severe dilatation of all chambers and cases were thought to be rare, however presently, it accounts for
flabby myocardium without any abnormality in valves or septae.8,9 nearly 25% of the cases.
Myocarditis is described as “an inflammatory infiltrate of the members with a similar condition, termed familial dilated cardiomy-
myocardium with necrosis and/or degeneration of adjacent myo- opathy (FDC). Michels in 1992, using the most stringent diagnostic
cytes”.14 It usually manifests in an otherwise healthy person and criteria (a formal diagnosis of IDC in relatives) demonstrated that
can result in rapidly progressive (and often fatal) heart failure and FDC was present in 20% of patients with IDC.26 When less stringent
arrhythmia. In the clinical setting, myocarditis is synonymous with diagnostic criteria other than a formal diagnosis of IDC in relatives
inflammatory cardiomyopathy. Incidence is usually estimated at was used (such as isolated left ventricular enlargement, or explained
1–10 cases per 100,000 persons. Lieberman15 proposed clinico- heart failure and/or sudden cardiac death in young relatives), two
pathologic classification as fulminant myocarditis, acute myocardi- of the largest studies suggested that 35–48% of all patients with IDC
tis, chronic active myocarditis and chronic persistent myocarditis in have relatives with a similar condition (The McKenna and co-work-
tissue specimen. ers report, London, 1998; The Heidelberg report, 1998).
Pathophysiology Inheritance
Myocarditis is likely caused by a wide variety of infectious organisms, Familial dilated cardiomyopathy most commonly exhibits familial
autoimmune disorders, and exogenous agents, with genetic and transmission consistent with autosomal dominant (AD) inheritance
environmental predisposition. Myocarditis cases usually fall into (approximately 90%), but X-linked (5–10%) and much less com-
four main categories: infection, postviral autoimmune related, auto- monly autosomal recessive (AR) or mitochondrial inheritance have
immunity [lupus myocarditis, giant cell myocarditis (GCM)], and as- been reported. The important mutations involve cardiac troponin T,
sociated with drugs (hypersensitivity and toxic myocarditis). In over lamin A/C, muscle LIM protein, presenilin 1 (PSEN1) and presenilin
50% of the cases, myocarditis is considered idiopathic and is believed 2 (PSEN2).
to be postviral immune related, even in the absence of demonstrable
viral antigens. Cases of viral myocarditis have an identifiable infec- TREATMENT
tious organism ranging from 10% to 100% in several studies.16-21
Klugman et al. found that 82% of the pediatric cases studied were Treatment paradigms of heart failure and DCM have demonstrated
considered idiopathic.22 The investigators also determined that 3% of major paradoxical shifts over the last 40 years. Drugs like b-blockers
cases in the study had a known bacterial or viral etiology, and that 6% that were considered to be contraindicated earlier, form the main-
of cases were related to other diseases. stay of treatment today whereas inotropic agents now have a much
In idiopathic cases, a viral etiology is often suspected but more limited role. Therapeutic options in patients with heart failure
unproved, even with sophisticated immunohistochemical and and DCM were by and large limited to diuretics and digoxin till 3
genomic studies. Studies on patients with idiopathic DCM found decades back. Though these drugs resulted in significant sympto-
evidence of viral particles in endomyocardial biopsy specimens in up matic improvement especially early in the course of disease, these
to two-thirds of the patients.23 drugs did not slow the progression of disease, nor did they result in
The Dallas criteria for the biopsy diagnosis of myocarditis, estab- improved outcomes. Today, there are a wide range of treatment
lished in 1987, consist of myocyte necrosis and inflammation. A posi- options available for these patients. Apart from more effective drug
tive biopsy, however, does not correlate with clinical symptoms; for therapy, device therapy, assist devices and cardiac transplantation
example, fulminant from chronic myocarditis, which is diagnosed represent major therapeutic advances.
clinically and may respond to immunosuppressive therapy, may Digitalis was one of the first drugs used for the treatment of heart
show only minimal inflammation because of sampling. The Dal- disease. It is isolated from the garden herb foxglove (Digitalis purpu-
las criteria include a “borderline” category for the first biopsy and rea). Though foxglove has been known to be an herbal remedy since
“resolving myocarditis” for subsequent ones with no necrosis24 cur- ancient Roman times, it is William Withering of Birmingham, Eng-
rently; any chronic inflammation in heart biopsy for new onset heart land who introduced digitalis into the practice of medicine in 1775.
failure is diagnostic of myocarditis. The introduction of digitalis was one of the landmarks in the history
In a documented study as many as 12.8% of patients with idi- of cardiac disease. Digitalis remained one of the most widely used
opathic DCM had presumed prior myocarditis. This indicates that cardiac medications until recently. Digitalis has been described as
adults may present with heart failure years after initial index event of the most valuable cardiac drug ever discovered and even considered
myocarditis.25 to be one of the most valuable drugs in the entire pharmacopeia.
Withering and the early researchers used the leaf extract of the fox-
THE GENETICS OF DILATED glove herb. In 1869, a French pharmacist, Claude Adolphe Nativelle,
isolated a much-purified material he called “digitalin” from foxglove.
CARDIOMYOPATHY
Six years later, German chemist Oswald Schmiedeberg, whom many
From scattered case reports prior to 1985, it was suggested that 1–2% consider the father of pharmacology isolated the first pure glyco-
of patients with idiopathic dilated cardiomyopathy (IDC) had family side in crystal form from foxglove, which he called digitoxin. These
Chapter 30  History of Dilated Cardiomyopathy 213
discoveries contributed significantly to the launch of pharmacology improvement in her heart failure.31 The first series of b-blocker use
as a modern science. in heart failure was reported in 1975 and consisted of only seven
However, the side effects of digoxin use came to be realized even patients.31 All seven patients reported had improvement in their
in the 18th century soon after its initial use. Even Withering himself clinical condition and improvement in the left ventricular function
was bluntly honest about his own mistakes in determining effective over a mean period of 5.4 months. Based on these reports, the first
and safe dosages for the drug. He confessed to years of overmedicat- open label study of b-blockers in congestive cardiomyopathy was
ing patients to dangerous levels with a host of painful side effects, conducted. This study included 28 patients and used several differ-
sometimes leading to more rapid death. Even he realized that digox- ent b-blockers.32 b-blocker use resulted in improvement in func-
in has a narrow therapeutic window. tional status and ejection fraction and reduced mortality. The first
In the 1980s, there was renewed interest in digoxin because of a major multinational trial of b-blocker use in DCM was the meto-
decrease in the incidence of digoxin toxicity since a lower dose was prolol in dilated cardiomyopathy.33 This trial confirmed an impor-
being used and newer inotropic drugs were shown to be associated tant role of b-blockers in DCM. From these beginnings several large
with poorer survival rates.27 In the mid-1990s, the results of the Ran- multicenter trials of different b-blockers (carvedilol, bisoprolol, sus-
domized Assessment of Digoxin on Inhibitors of the Angiotensin- tained release metoprolol and nebivolol) have conclusive shown that
Converting Enzyme (RADIANCE) trial and the Digitalis Investigation b-blockers are well tolerated in all stages of heart failure, improve
Group (DIG) trial were carried out. The RADIANCE trial showed that most end points and reduce mortality.34-37 The mechanism of ben-
the discontinuation of digoxin was associated with an increase by a efit of b-blockers was clarified in the mid-1980s when Bristow et
factor of five in the rate of worsening heart failure within 3 months al. showed that the adenylatecyclase response to b-blockade was
and a decrease in exercise tolerance, in spite of the continuation of attenuated in patients with heart failure compared with controls.38
therapy with diuretics and angiotensin-converting enzyme inhibitors The Carvedilol Or Metoprolol European Trial (COMET) showed that
(ACEI).28 The Digitalis Investigation Group trial was the first large trial all b-blockers are nor the same. In this trial, carvedilol was supe-
whose main objective was to assess the effect of digoxin therapy on rior to metoprolol tartrate.39 The Multicenter Oral Carvedilol Heart
overall mortality in patients with heart failure. At around 3 years, there failure Assessment (MOCHA) trial suggested that the benefit of
was no difference in overall mortality between the placebo group and b-blockers was dose dependent.40
the digoxin group. There was a reduction in the rate of death due to Along with b-blockers ACEI forms the mainstay of treatment
pump failure with digoxin that was offset by an increase in the rate of of DCM today. It was in 1987 that Co-operative New Scandinavian
death presumably due to arrhythmias.29 Current recommendations Enalapril Survival Study (CONSENSUS) I showed that ACEI enalapril
on the use of digoxin are largely based on these trials. improves survival in patients with heart failure.41 Soon after Veterans
Diuretics have long been used for the treatment of DCM and Heart Failure Trial II (V-HEFT II) and Studies of Left Ventricular Dys-
heart failure. Organomercurials were first introduced in 1920. Their function (SOLVD) confirmed that enalapril alters the natural history
use was limited by their side effects. Furosemide and other loop diu- of heart failure with a significant improvement in long-term progno-
retics are today most often used for relieve congestion and symptoms sis.42,43 The clinical benefit of these drugs to patients is beyond doubt
in heart failure. Despite their widespread use and major symptomatic and they now represent a cornerstone in the treatment of heart fail-
benefit, diuretics were not considered to be disease modifying drugs. ure.
This changed with the publication of the Randomized Aldosterone
Evaluation Study (RALES) in 1999.30 In this trial, aldosterone antago- Prognosis
nist was found to reduce mortality in patients with heart failure and
left ventricular systolic dysfunction who were already being treated Despite advances, drug therapy has proved to be inadequate for
with an ACEI. Aldosterone antagonists today form an important many patients with DCM. Cardiac transplant was first performed
armamentarium in the treatment of DCM patients. by Christian Barnard in 1967. Since then it has been an important
b-blockers were traditionally considered contraindicated in therapeutic option for end stage DCM patients. Cardiac transplant
patients with DCM. It was felt that their negative inotropic effect is however limited by donor heart availability and side effects of
would aggravate heart failure. In addition, many patients with DCM immunosuppressive therapy. Ventricular assist devices, implantable
have conduction abnormalities especially left bundle branch block. cardioverter-defibrillators and cardiac resynchronization therapy
Many physicians feared that b-blockers could aggravate these con- have proved to be beneficial for a subset of DCM patients. Despite
duction blocks. It was in early 1970s that a potential role for the use of all these therapeutic options, the long-term outcome of many DCM
b-blockers in DCM was considered. A patient with DCM, tachycardia patients remains poor since none of these strategies forms a true
and acute pulmonary edema received a bolus of intravenous prac- “cure” for DCM. Many new therapies still need to be tested before a
tolol followed by oral b-blocker therapy. This patient had marked truly satisfactory cure can be offered to DCM patients.
REFERENCES
1. Goodwin JF, Gordon H, Hollman A, et al. Clinical aspects of cardiomyopathy. Br Med J. 1961;1:69.
2. Bedford D, Konstam G. Obscure heart disease in West African Troops. Br Heart J. 1946;8:236.
3. Davies JNP. Endomyocardila fibrosis in East Africa. East African J. 1948;25:10.
4. Gillanders AD. Nutritional heart disease. Br Heart J. 1951;13:177.
5. Becker BJ, Chatgidakis CB, van Lingen B. Cardiovascular collagenosis with parietal endocardial thrombosis. Circulation. 1953;7:345.
6. Olsen EG. Cardiomyopathies. In: Brest AN, Edwards JE (Eds). Cardiovascular Clinics, 4, No. 2. Philadelphia: FA Davis; 1972. p. 240.
7. Olsen EG. The Pathology of the Heart. New York: Intercontinental Medical Book Corporation; 1973. p. 171.
8. Olsen EG. Pathological recognition of cardiomyopathy. Postgrad Med J. 1975;51:277-81.
9. Van Noorden S, Olsen EG, Pearse AG. Hypertrophic obstructive cardiomyopathy: a histological, histochemical and ultrastructural study of biopsy
material. Cardiovasc Res. 1971;5(1):118.
10. Van Noorden S, Pearse AG. Histochemistry and electron microscopy of the heart in hypertrophic obstructive cardiomyopathy. Hypertrophic Ob-
structive Cardiomyopathy: Ciba Foundation Study Group No. 37. London: Churchill; 1971. p. 192.
11. Bengtson E. Myocarditis and cardiomyopathy: clinical aspects. Cardilogia. 1968;52:97.
12. Stuart KL. Cardiomyopathy of pregnancy and puerperium. Q J Med. 1968;52:36.
13. Oakely C. Clinical definitions and classification of cardiomyopathies. Postgrad Med J. 1972;48:703.
14. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Pathol. 1987;1(1):3-14.
15. Feldman AM, McNamara D. Myocarditis. N Engl J Med. 2000;343(19):1388-98.
16. Venteo L, Bourlet T, Renois F, et al. Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute
myocarditis. Eur Heart J. 2010;31(6):728-36.
17. Bowles NE, Towbin JA. Molecular aspects of myocarditis. Curr Opin Cardiol. 1998;13(3):179-84.
18. Badorff C, Knowlton KU. Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside. Med
Microbiol Immunol (Berl). 2004;193(2-3):121-6.
19. Karjalainen J, Heikkila J. Incidence of three presentations of acute myocarditis in young men in military service. A 20-year experience. Eur Heart
J. 1999;20(15):1120-5.
20. Durani Y, Egan M, Baffa J, et al. Pediatric myocarditis: presenting clinical characteristics. Am J Emerg Med. 2009;27(8):942-7.
21. Wakafuji S, Okada R. Twenty year autopsy statistics of myocarditis incidence in Japan. Jpn Circ J. 1986;50(12):1288-93.
22. Klugman D, Berger JT, Sable CA, et al. Pediatric patients hospitalized with myocarditis: a multi-institutional analysis. Pediatr Cardiol.
2010;31(2):222-8.
23. Kuhl U, Pauschinger M, Noutsias M, et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idi-
opathic” left ventricular dysfunction. Circulation. 2005;111(7):887-93.
24. Al-Mallah M, Kwong RY. Clinical application of cardiac CMR. Rev Cardiovasc Med. 2009;10(3):134.
25. Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol. 1987;18(6):619-24.
26. Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopa-
thy. N Engl J Med. 1992;326:77-82.
27. Eichhorn EJ, Gheorghiade M. Digoxin—New Perspective on an Old Drug. N Engl J Med. 2002;347:1394-5.
28. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-33.
29. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-
enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993;329:1-7.
30. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med.
1999;341:709-7.
31. Waagstein F, Hjalmarson A, Varnauskas E, et al. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J.
1975;37:1022-36.
32. Swedberg K, Hjalmarson A, Waagstein F, et al. Beneficial effects of long-term b blockade in congestive heart failure. Br Heart J. 1980;44:117-33.
33. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993;342:1441-6.
34. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS).
Circulation. 1994;90:1765-73.
35. Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. U.S. Carvedilol
Heart Failure Study Group. Circulation. 1996;94:2800-6.
36. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
37. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
Lancet. 1999;353:2001-7.
38. Bristow MR, Herschenberger RE, Fowler M, et al. b1- and b2-adrenergic receptor subpopulations in normal and failing human ventricular
myocardium: coupling of both receptor subtypes to muscle contraction and selective b1 receptor down-regulation in heart failure. Circ Res.
1986;59:297-309.
39. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart
failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7-13.
40. Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects
with chronic heart failure. MOCHA Investigators. Circulation. 1996;94:2807-16.
41. The CONSENSUS (Co-operative New Scandinavian Enalapril Survival Study) Trial Study Group. Effects of enalapril on mortality in severe heart
failure. N Engl J Med. 1987;316:1429-35.
42. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with isosorbidedinitrate in the treatment of chronic congestive heart failure. (V-
HEFT II-Veterans Heart Failure Trial II). N Engl J Med. 1991;325:303-10.
43. The SOLVD (Studies of Left Ventricular Dysfunction) Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection
fractions and congestive cardiac failure. N Engl J Med. 1991;325:293-302.
31 History of Hypertrophic
Cardiomyopathy
Parakh N, Bhargava B
“History is who we are and why we are the way we are.”

—David C McCullough
Timeline by the scientific community to this condition during the course of

Hippocrates (400 BC): First descriptions suggestive of sudden cardiac evolving knowledge for HCM.1 The diversity of presentation of HCM
death. has delayed its appropriate recognition by the researchers and
scientists. Apparently, HCM might have been recognized much
Liouville and Hallopeau (1869): Described hypertrophied septum
causing LVOTO. earlier than believed but the credit for its first ever modern and sci-
entific description goes to an English forensic pathologist Dr Donald
Krehl (1891): Recognized this entity as primary myocardial disease. Robert Teare.2
Schmincke (1907): Described two cases of septal hypertrophy and
LVOTO. THE FIRST CITATION
Davies (1952): Described a family with history of sudden cardiac
death and systolic murmur. Autopsy of one patient showed diffuse Dr Donald Teare, while working at St George’s hospital, London,
subaortic stenosis. described clinical and histopathological findings in a cohort of nine
patients, where he found asymmetrical septal hypertrophy with bi-
Brock (1957): Showed subaortic stenosis and hypertrophied nondi-
zarre arrangement of muscle fibers. He termed this as muscular
lated left ventricle.
hamartomas of the heart. He established association of this condi-
Teare (1958): First scientific description of HCM; then recognized as tion with sudden death in young people. He also appreciated pres-
cardiac tumor in a series of nine patients. ence of systolic murmur and history of recurrent syncope in some of
Cleland (1958): First septal myectomy. these patients. Though he submitted his article to British Heart Jour-
nal in January 1957, it was published in the journal next year only.2
Morrow (1960): Myotomy-myectomy.
In his earlier publication in 1951, he reported, ‘‘I have seen three
Braunwald (1960): First detailed clinical, hemodynamic and angio- cases of rhabdomyoma of the myocardium causing sudden death in
graphic description; coined the term idiopathic hypertrophic sub- young and healthy adults in as many months.’’ These cases are likely
aortic stenosis. to be some of the cases in the series he described later.3 Dr Teare’s
Lawrence Brent (1960): Mendelian autosomal dominant inheritance. observations were not the earliest historical descriptions of HCM
but, the reason, for crediting Dr Teare as first descriptor of HCM was
Seidman (1990): HCM described as first inherited cardiovascular
his scientific recognition and description of this unusual condition.
disorder to be successfully genotyped.
Dr Teare not only described the autopsy findings of the diseased
Sigwart (1994): First alcohol septal ablation. myocardium but he also described the cardinal symptoms like chest
pain, palpitations, dyspnea and syncope. He also noted electrocar-
INTRODUCTION diographic findings of T-wave inversion and pathological Q waves.
Dr Teare recognized sudden cardiac death as the most devastating
Hypertrophic cardiomyopathy (HCM) as a clinical entity remains an complication of this condition and a possibility of familial linkage.
enigma for researchers and scholars worldwide. The history of HCM The completeness and accuracy of his description was the reason
is not less interesting. The interest or confusion regarding HCM can behind the recognition of Dr Teare’s work above his predecessors
be exemplified by the fact that more than 75 names has been assigned and contemporary scientists.
included 213 pages of original work describing various aspects of

HISTORY BEFORE HISTORY
HCM.16 Brent recognized the familial nature of the disease, compat-
Today we know that HCM is the most common cause of sudden ible with Mandelian dominant gene and termed it as familial mus-
cardiac death in young people. Sudden cardiac death in young cular subaortic stenosis.17 Wigle identified the role of asymmetrical
people has been described almost 2400 years ago in Aphorisms of septal hypertrophy in producing muscular subaortic stenosis.18 He
Hippocrates (Those who are subject to frequent and severe fainting also determined that increased muscle mass was associated with
attacks without obvious cause die suddenly).4 The description of reduced ventricular compliance and diastolic dysfunction.
sudden death in apparently healthy people and also in patients with
history of recurrent syncope in the absence of other symptoms fits THE FIRST SURGERY
the diagnosis of HCM reasonably well. In 1869, two French patholo-
gists, Hallopeau and Liouville, described the classic appearance of In 1958, William P Cleland performed first myectomy at Hammer-
asymmetrical hypertrophy of the interventricular septum compat- smith hospital, London for hypertrophic obstructive cardiomyopa-
ible with what we know today as HCM.5,6 They postulated that hyper- thy (HOCM).19 The 42-year-old patient had a 4-year history of exer-
trophied septum is the cause for left ventricular outflow obstruction. tional chest pain and syncope. This patient was clinically evaluated
Hallopeau also described abnormal thickening of the anterior mitral preoperatively by Dr Paul Wood who inferred some form of dynamic
leaflet in one of his patient. Later on, Dutch and French researchers subvalvular obstruction from his findings.10 On percutaneous punc-
published articles narrating similar conditions. Krehl in 1891 recog- ture, a systolic gradient of 60 mm Hg was measured between the left
nized that the condition described by Hallopeau and Liouville is a ventricle and the brachial artery. Postoperatively, patient’s electro-
primary myocardial disorder.7 Schmincke coined the term ‘‘primary cardiogram (ECG) showed left bundle branch block. His symptoms
muscular left sided conus stenosis’’ and suggested it may remain improved markedly and maintained for many years. The concept
asymptomatic throughout life, and may also account for many cas- of subaortic ventriculomyotomy for HOCM was pioneered and first
es of unexplained idiopathic cardiac hypertrophy in the literature.8 performed by Dr Andrew Glenn Morrow who himself had the disease
In 1952, Davies recognized a family with history of sudden cardiac and this procedure is rightly called as Morrow’s procedure after him.20
death and systolic murmur. Autopsy of one member of the family
showed diffuse subaortic stenosis.9 JOURNEY TO GOLDEN JUBILEE
Dr Paul Wood described a clinical condition with jerky pulse,
double apex beat and ejection systolic murmur. From his clini- In 1966, Ross and associates presented angiographic and hemody-
cal findings, he inferred that this condition is because of muscular namic evidence that obstruction is caused by an abnormal position
hypertrophy leading to left ventricular outflow obstruction. He also of the mitral valve in the left ventricular outflow tract during systo-
suggested that this obstruction is dynamic and dependent on chang- le.21 Lawrence Brent and colleagues in their description of a family
es in preload and afterload. His accurate identification of pathophys- with muscular subaortic stenosis suggested familial nature of the
iology of underlying disorder on the basis of clinical findings was disease. They examined the pedigree and remarked on apparent
quite remarkable.10,11 Mendelian autosomal dominant inheritance. In 1966, Fix et al.22 in
In 1957, Russel Claude Brock operated upon a 58-year-old female Stockholm and Dinsmore and colleagues23 in Boston on angiogra-
who presented with signs and symptoms of severe aortic stenosis. phy. Two years later, Pravin Shah and his co-workers confirmed sys-
At operation, the aortic valve was normal, but withdrawal pressure tolic anterior movement (SAM) of the mitral leaflet as the cause of
readings showed a gradient of 93 mm Hg and subvalvular stenosis. left ventricular outflow obstruction, using simultaneous recordings
An attempt was made to relieve the stenosis by dilating the stenotic of the ECG, phonocardiogram, carotid artery pulse, and reflected
part but it failed. Unfortunately, patient died on operation table and cardiac ultrasound.24,25 In 1995, Robert Levine, Arthur Weyman and
later on autopsy confirmed muscular subvalvular stenosis 2.5 cm be- colleagues reported that obstructive variety of HCM was associated
low the aortic valve. Brock labeled this as functional subvalvular ob- with primary structural abnormalities of the mitral valve apparatus.
struction and attributed it to systemic hypertension.12 Almost simul- The most important abnormality was anterior displacement of the
taneously, researchers from other places also started recognizing this papillary muscles which is now considered as one of the hallmark
entity. Bercu used the term pseudoaortic stenosis13 while Braunwald findings for HOCM.26
called it idiopathic hypertrophic subaortic stenosis.14 Teare’s seminal Thirty two years after Donald Teare’s description of the disease,
paper was published almost simultaneously. HCM became the first inherited cardiovascular disorder to be suc-
cessfully genotyped. A disease-causing mutation was identified in
THE JOURNEY AFTER TEARE the gene encoding cardiac beta-myosin heavy chain (MYH7).27 A
distinct missense mutation in MYH7 was subsequently isolated in
In 1964, Braunwald reported extensive clinical and operative stud- the family originally reported by Hollman, Goodwin and Teare.28 In
ies on 64 patients.15 This American Heart Association monograph the decade that followed, various other sarcomeric proteins were
Chapter 31  History of Hypertrophic Cardiomyopathy 217
implicated in HCM, including tropomyosin, cardiac troponin T, successful ASA on 16 June 1994. This patient and two additional
troponin I, myosin binding protein-C, regulatory myosin light chain, patients who underwent successful ASA were reported in 1995.33 A
essential myosin light chain, cardiac actin, titin, cardiac myosin family history of sudden death and the presence of nonsustained
heavy chain and troponin C.29 ventricular tachycardia on ambulatory ECG monitoring were recog-
A major breakthrough in the treatment of HOCM occurred with nized as the first risk factors for sudden cardiac death in HCM.34,35 A
alcohol septal ablation (ASA). The idea of septal ablation originated noninvasive risk prediction algorithm for HCM with a negative pre-
in early 80s, at the University of Lausanne in Switzerland. While stud- dictive value exceeding 95%, was also proposed. A consensus state-
ying the hemodynamics of left-sided cardiac chambers in patients ment for HCM was published in 2003 highlighting the various risk
with HCM, Sigwart and Late Dr Grbic found significant reduction factors for sudden cardiac death.36
in left ventricular outflow tract gradient, when angioplasty balloon
was inflated in the first septal artery.30 This was further supported by CONCLUSION
disappearance of the typical auscultatory findings, carotid pulse, and
echocardiographic manifestations of obstruction of HOCM following The history of HCM is one of the most illustrative saga in the modern
myocardial infarction (MI).31,32 Subsequently, Sigwart considered cardiology. Even though there are suggestions from the history that
instilling alcohol into the septal artery to create a controlled infarc- this disease was there and acknowledged even thousands of years
tion. It took more than a decade for this revolutionary idea to get ago, its real nature and scientific basis evolved with the evolution
ethical clearances and finally materialized. A 68-year-old lady, unre- of scientific concepts and methodology. The never ending story of
sponsive to DDD pacemaker and optimal medical therapy for HCM, HCM truly represents the evolution and growth of present days’ sci-
agreed to become the first patient for ASA. This lady underwent ence and cardiology.
REFERENCES
1. Maron BJ, Salberg L. Historical perspective and names. In: Maron BJ, Salberg L (Eds). Hypertrophic Cardiomyopathy: For Patients, Their Families
and Interested Physicians. Blackwell-Synergy publications; 2007. pp. 1-4.
2. Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J. 1958;20:1-8.
3. Teare R. Some reflections on 25,000 autopsies. St George’s Hospital Gazette 1951;36:433-37.
4. Mirchandani S, Phoon CK. Sudden cardiac death: a 2400-year old diagnosis? Int J Cardiol. 2003;90:41-8.
5. Hallopeau H. Retrecissement ventriculo-aortique. Gazette de Medicine (Paris). 1869;24:683.
6. Liouville I. Retrecissement cardiaque sous-aortique. Gazette de Medicine (Paris). 1869;24:161.
7. Krehl L. Beitrag zur Kenntniss der idiopathischen Hertzmuskelerkrankungen. (Dtsch.) Arch Klin Med. 1891;48:414-31.
8. Schmincke A. Ueberlinksseitigemuskuloseconusstenosen. Dtsch Med Wochenschr. 1907;33:2082.
9. Davies LG. A familial heart disease. Br Heart J. 1952;14:206-12.
10. Wood P. Diseases of the heart and circulation. London: Eyre and Spottiswood; 1956. pp. 937-47.
11. Somerville J. Paul Wood Lecture. The master’s legacy: the first Paul Wood Lecture. Heart. 1998;80:612-8.
12. Brock R. Functional obstruction of the left ventricle (acquired aortic subvalvar stenosis). Guys Hosp Rep. 1957;106:221-38.
13. Bercu B, Diettert G, Danforth W, et al. Pseudoaortic stenosis produced by ventricular hypertrophy. Am J Med. 1958;25:814-8.
14. Morrow AG, Braunwald E. Functional aortic stenosis; a malformation characterized by resistance to left ventricular outflow without anatomic
obstruction. Circulation. 1959;20:181-9.
15. Braunwald E, Lambrew GT, Morrow AG, et al. Idiopathic hypertrophic subaortic stenosis. American Heart Association Monograph #10. Circula-
tion. 1964;29-30(suppl):4-212.
16. Braunwald E, Morrow AG, Cornell WP, et al. Idiopathic hypertrophic subaortic stenosis: clinical, hemodynamic and angiographic manifestations.
Am J Med. 1960;29:924-45.
17. Brent LB, Aburano A, Fisher DL, et al. Familial muscular subaortic stenosis: an unrecognized form of ‘‘idiopathic heart diseases’’, with clinical and
autopsy observations. Circulation. 1960;21:167-80.
18. Wigle ED, Heimbecker RO, Gunton RW. Idiopathic ventricular septal hypertrophy causing muscular subaortic stenosis. Circulation. 1962;26:325-
40.
19. Goodwin JF, Hollman A, Cleland WP, et al. Obstructive cardiomyopathy simulating aortic stenosis. Br Heart J. 1960;22:403-14.
20. Morrow AG, Brockenbrough EC. Surgical treatment of idiopathic hypertrophic subaortic stenosis: technique and hemodynamic results of subaor-
tic ventriculomyotomy. Ann Surg. 1961;154:181-9.
21. Ross J, Braunwald E, Gault JH, et al. The mechanism of the intraventricular pressure gradient in idiopathic hypertrophic subaortic stenosis. Circu-
lation. 1966;34:558-78.
22. Fix P, Moberg A, Soederberg H, et al. Muscular subvalvular aortic stenosis; abnormal anterior mitral leaflet possibly the primary factor. Acta Radiol
Diagn (Stockh). 1964;2:177-93.
23. Dinsmore RE, Sanders CA, Harthorne JW. Mitral regurgitation in idiopathic hypertrophic subaortic stenosis. N Engl J Med. 1966;275:1225-8.
24. Shah PM, Gramiak R, Adelman AG, et al. Role of echocardiography in diagnostic and hemodynamic assessment of hypertrophic subaortic steno-
sis. Circulation. 1971;44:891-8.
25. Shah PM, Gramiak R, Kramer DH. Ultrasound localization of left ventricular outflow obstruction in hypertrophic obstructive cardiomyopathy.
Circulation. 1969;40:3-1.
26. Levine RA, Vlahakes GJ, Lefebvre X, et al. Papillary muscle displacement causes systolic anterior motion of the mitral valve. Experimental valida-
tion and insights into the mechanism of subaortic obstruction. Circulation. 1995;91:1189-95.
27. Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain
gene missense mutation. Cell. 1990;62:999-1006.
28. Hollman A, Goodwin JF, Teare D, et al. A family with obstructive cardiomyopathy (asymmetrical hypertrophy). Br Heart J. 1960;22:449-56.
29. Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc
Med. 2008;5:158-68.
30. Sigwart U, Grbic M, Payot M, et al. Ventricular wall motion during balloon occlusion. In: Sigwart U, Heintzen PH (Eds). Ventricular Wall Motion.
New York: George Theime; 1983. pp. 206-10.
31. Come PC, Riley MF. Hypertrophic cardiomyopathy, disappearance of auscultatory, carotid pulse, and echocardiographic manifestation of ob-
struction following myocardial infarction. Chest. 1982;82:451-4.
32. Waller BF, Maron BJ, Epstein SE, et al. Transmural myocardial infarction in hypertrophic cardiomyopathy: a cause of conversion from left ventricu-
lar asymmetry and from normal-size to dilated left ventricular cavity. Chest. 1981;79:461-5.
33. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet. 1995;346:211-4.
34. McKenna W, Deanfield J, Faruqui A, et al. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemody-
namic features. Am J Cardiol. 1981;47:532-8.
35. McKenna WJ, England D, Doi YL, et al. Arrhythmia in hypertrophic cardiomyopathy. I: Influence on prognosis. Br Heart J. 1981;46:168-72.
36. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document
on hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;42:1687-713.
32 History of Restrictive
Cardiomyopathy
Venugopal K
INTRODUCTION GEOGRAPHICAL DISTRIBUTION

Restrictive cardiomyopathy is an idiopathic or systemic disorder The fascinating aspect of EMF is its geographical distribution. The
characterized by restrictive filling, normal or reduced left ventricular disease tends to cluster in areas within 20° latitude on either side of
(LV) and right ventricular (RV) volumes and normal or near normal the equater.2 There is no other systemic involvement and the disease
LV systolic function.1 The involvement can be myocardial or endo- occurs in the low socioeconomic group. The areas where the disease
myocardial. is prevalent are Uganda, Brazil, Nigeria, Ivory Coast and Kerala in
The causes of myocardial restrictive cardiomyopathy could be India.
due to scleroderma, pseudoxanthoma elasticum, amyloidosis, sar-
coidosis, Gaucher’s disease, hemochromatosis, Fabry’s disease or HISTORY OF ENDOMYOCARDIAL FIBROSIS
due to idiopathic causes. Obliterative restrictive cardiomyopathy is
seen in endomyocardial fibrosis (EMF) and hypereosinophilic syn- The earliest report of this unusual type of cardiac disease was by
drome. Nonobliterative endomyocardial disease is seen in carcinoid, Arthur Williams in 1938.3 Then came the reports of Bedford and
malignant infiltration, radiation or drugs. Constam in 1946.4 The major contribution to understanding of EMF
Though a large number of causes have been identified, most was by the pioneering studies of JNP Davies in Uganda.5,6 It was the
common conditions are EMF, amyloidosis, sarcoidosis and the subject of his MD thesis. The subject of EMF was not described in
idiopathic variety. the textbook of cardiology by Paul Dudley White. The condition was
clearly separate from Lofflers endocarditis seen in temperate region.
THE ENIGMA OF ENDOMYOCARDIAL The predominantly right-sided EMF could easily mimic constric-
tive pericarditis. The electrocardiogram (ECG) abnormalities and the
FIBROSIS
nature of atrioventricular (AV) valve incompetence was discussed by
The most common restrictive cardiomyopathy that has been exten- Somers and William in 1960.7 The first catheterization studies in EMF
sively studied is EMF. The etiology of the disease remains unclear was published in British Heart Journal in 1961.8 Abrahams et al. pos-
even today though the pathological changes have been well docu- tulated that an acute carditis progressing to endocarditis or fibrosis
mented. as a result of rheumatic process was responsible for EMF.9 In 1965,
The pathological changes of fibrosis and calcification of the World Health Organization (WHO) sponsored a meeting in Kampala,
endocardium and the myocardium typically affect the apices of the Uganda for the nomenclature, definition and diagnostic criteria for
ventricle and the inflow and usually spares the outflow region. This EMF, dilated cardiomyopathy and chagas heart disease.10
fibrotic replacement causes restrictive physiology in the ventricle Cardiac catheterization studies and pressure pattern differentia-
and also results in tricuspid and mitral incompetence. The fibrotic tion of constrictive pericarditis from EMF was published by Somers.11
areas may undergo calcification and thrombus formation may also Intracardiac electrophysiological studies were also performed at that
occur. Disease may involve right or left ventricle selectively or it time.12 Endomyocardial biopsy was first performed by Professor
may involve both ventricles simultaneously. Clinical picture varies Souji Konno of Japanese Heart Institute and endomyocardial biopsy
according to type of involvement. The left ventricular EMF would findings in EMF were first reported by Somers et al.13,14 Immuno-
present with features of mitral incompetence, pulmonary congestion logical basis for EMF was proposed by Hugo van der Geld.15 Dr John
and pulmonary hypertension. Right ventricular endomyocardial Fowler from University College, London redefined the auscultatory
fibrosis (RVEMF) produces tricuspid regurgitation, systemic venous and phonocardiographic features of left ventricular endomyocar-
congestion, ascites and cardiac failure. dial fibrosis (LVEMF).16 The longer survival pattern of patients with
RVEMF as compared to LVEMF was demonstrated by Dr D’ Arbela.17 Friedreich and Kekule in 1859 found out that the material did not
There was an opinion that both EMF and nontropical EMF (Loffler contain starch or cellulose but the term amyloid was not changed.
endocarditis) had the same factor of eosinophilia, especially by Dr First description of cardiac involvement in a case of primary amy-
Olsen and colleagues.18,19 But this was not agreed upon other groups loidosis was by Wild in 1886.32 Bennhold (1922) introduced Congo
involved in the study of EMF. red staining for amyloid tissue. Divry and Florkin (1927) described
apple green birefringence of amyloid when viewed under polarized
ENDOMYOCARDIAL FIBROSIS IN INDIA light. Cohen and Calkins (1959) recognized nonbranching fibril-
lar structure of amyloid when viewed under electron microscope.33
Kerala with its closeness to equator was the first state in India to Eanes and Glenner (1968) demonstrated the crossed β-pleated sheet
report EMF.20 The first documented case was by Professor CK Gopi in structure formed by amyloid polypeptide chain by X-ray diffraction
1962 in an autopsy specimen.20 The disease was confined to the poor studies.34
socioeconomic class. Dr DV Nair from Aleppey presented his early Amyloidosis is a heterogenous group of disorders resulting from
experience between 1965 and 1982.21 Other centers in Kerala from extracellular deposition of amyloid fibrils. Amyloid proteins are
South to North had also started recording the increased incidence derived from normal or abnormal serum proteins.35 Amyloidoses
of EMF in the state. Endomyocardial fibrosis was extensively stud- that frequently involve the heart are primary amyloidosis, senile
ied by invasive as well as noninvasive techniques. Echocardiography systemic amyloidosis and familial amyloidosis. Myocardial infiltra-
introduced in 1980s became the standard tool to diagnose the dif- tion is less with secondary amyloidosis. Clinical presentations of
ferent spectra of EMF. Dr Vijayaraghavan et al. described the echo- cardiac amyloidosis can be restrictive cardiomyopathy, systolic heart
cardiographic features of EMF in 1983.22 In 1981, an Indian Coun- failure, orthostatic hypotension, conduction system disease in the
cil of Medical Research (ICMR) workshop on EMF was conducted form of malignant arrhythmias or conduction block.36
by Dr RP Sapru in Trivandrum.23 Clinical course of a large series of In primary amyloidosis, monoclonal light chains from plasma
EMF patients from Sree Chitra Institute Trivandrum was published cells form the protein subunits of amyloid fibril. Kyle and Bayrd rec-
in 1989.24 Difference in clinical presentation, hemodynamics and ognized the association between plasma cell disorders and primary
angiography between RVEMF and Ebstein’s anomaly was presented amyloidosis.37 Glenner et al. proved that amyloid fibrils in primary
by Balakrishnan KG et al. in 1982.25 amyloidosis are homologous in sequence to monoclonal light chains,
Etiological factors of EMF still remain unelucidated and con- and monoclonal light chains can form amyloid fibril in vitro.38,39
troversial. Abnormal eosinophils were implicated in pathogenesis In a series by Kyle et al. 15–21% of patients with multiple myeloma
as per Olsen and his group. Various theories that have been pro- develop primary amyloidosis and 25–31% of them have cardiac
posed are rheumatic etiology, malnutrition, viral infection, filariasis, involvement.40,41
dietary toxin, etc. A geochemical basis for pathogenesis has been First probable description of senile systemic amyloidosis was
proposed by Sree Chitra Institute, Trivandrum.26 An excess of by Soyka in 1876.42 King et al. estimated 21% incidence of senile sys-
thorium and caesium in the soil is correlated with the geographical temic amyloidosis in age group above 80.43 Familial amyloid cardio-
distribution of the disease in India. The excess is pathogenic when myopathy was reported in a Danish family by Frederiksen et al. in
there is associated hypomagnesemia. The exact etiology of EMF as 1962.44 Another age-related amyloidosis, particularly involving Afri-
mentioned earlier still remains elusive. can Americans associated with point mutations in transthyretin gene
Surgical management of EMF has differed for LVEMF and at codon 122 (isoleucine replaces valine) is recently described.45
RVEMF. Left ventricular endocardiectomy and AV valve replacement Larsen in 1930 noted that low QRS voltage in ECG was a feature
has been done for LVEMF.27 Isolated right ventricular involvement of cardiac amyloidosis.46 Lindsay estimated that 50% of patients with
has been treated by bidirectional Glenn procedure.28 Rarely, cardiac amyloidosis had low QRS voltages.47 Increased cardiac echogenicity
transplantation has also been done. is 87% sensitive for amyloidosis and when in association with intera-
Decline in the incidence of EMF has been noted in India, espe- trial septal thickness greater than 6 mm is 100% specific for amyloi-
cially Kerala.29 The age of presentation has also changed to older age dosis.48 Specimens obtained by endomyocardial biopsy were first
groups. However, the disease still continues to be prevalent in Sub- used in 1975 to diagnose amyloidosis.49
Saharan Africa.30 The decline in incidence in Kerala may reflect the Kyle RA et al. showed that a regimen with melphalan and pred-
improved socioeconomic and dietary standards in the state. nisolone improved prognosis in primary amyloidosis.50 Alkylat-
ing agents may be used alone or in combination with autologous
CARDIAC AMYLOIDOSIS bone marrow stem cell transplantation. Heart transplantation with
autologous bone marrow transplantation is associated with variable
The term amyloid was coined by Schleiden, a German botanist.31 It success as amyloidosis recurs in transplanted heart. In transthyretin
was used by Rudolph Wirchow in 1854 to describe a macroscopic amyloid, liver transplantation may remove the source of the abnor-
tissue abnormality with characteristic starch like reaction to iodine. mal protein.36
Chapter 32  History of Restrictive Cardiomyopathy 221
18F-fluorodeoxyglucose (FDG) positron emission tomography

OTHER INFILTRATIVE AND
(PET) are most sensitive investigative modalities to detect cardiac
STORAGE DISORDERS sarcoidosis. Steroids are the mainstay of treatment. Resistant cases
may require hydroxychloroquine, methotrexate, cyclophosphamide
Sarcoidosis
or infliximab.61 Implantable cardioverter defibrillator (ICD) is appro-
Jonathan Hutchinson is credited with the first clinical description priate for patients at risk of sudden cardiac death.
of sarcoidosis in 1869.51 Boeck, a Norvegian dermatologist, named
it sarcoidosis as he thought that the lesions resembled sarcoma Fabry Disease
cells.52 Bernstein in 1929 demonstrated that sarcoidosis can involve
the heart.53 In 1952, Longcope and Freiman estimated 20% myocar- Fabry disease (OMIM301500) is an X-linked recessive lysosomal
dial involvement in an autopsy series of patients with sarcoidosis.54 storage disorder resulting from deficiency of alpha galactosidase-A
Prevalence varies according to ethnicity being higher in blacks and activity.62 The disease was first described in 1898 by Anderson and
Scandinavians. Japanese sarcoid patients are reported to have high- Fabry.63,64 Brady et al. is credited with demonstration of the enzyme
est cardiac involvement around 80%.55 defect.65 Enzyme replacement therapy for Fabry disease became
Clinical manifestations of sarcoid heart disease include con- available in 2001.66,67 Histological evaluation of the heart shows
duction disturbances, arrhythmias and congestive cardiac failure diffuse involvement of myocardium, endothelium, conduction sys-
(CCF).52 They may also present with restrictive cardiomyopathy.37 tem and valves, particularly mitral valve. Clinical presentation may
Complete heart block is the most common manifestation of clinically be angina, mitral regurgitation (MR), diastolic dysfunction, CCF, AV
evident sarcoidosis, seen in 23–30%. Sudden cardiac death caused by block or hypertrophic cardiomyopathy.
arrhythmia is the terminal event in 67% of patients with cardiac sar-
coidosis.56 Ventricular tachycardia is the most common arrhythmia Gaucher’s Disease
with a reported incidence of 23%,57 while atrial arrhythmias occur
in 15–17%.56 Congestive cardiac failure accounts for 25% of deaths First clinical description of this disease dates back to 1882.68 Brady
in these patients. Sarcoid granuloma may involve all three layers of et al. is credited with the demonstration of the enzyme defect in
heart, myocardial involvement being most common. Gaucher.69 Barton et al. in 1990 demonstrated clinical response of
In 1993, Japanese ministry of Health and Family Welfare pub- enzyme replacement therapy.70 Cardiac involvement can be in the
lished guidelines for diagnosing cardiac sarcoidosis.58 Thallium form of restrictive cardiomyopathy, LV failure, hemorrhagic pericar-
scintigraphy perfusion defects exhibiting reverse distribution (de- dial effusion, or sclerosis and calcification of left-sided valves.
fects improving on exercise) are characteristic of myocardial sar- Restrictive cardiomyopathies, especially EMF have been fasci-
coidosis.59 Okayama showed that gallium-67 uptake in scintigraphy nating disease processes, and the painstaking research and observa-
indicate active disease and is predictive of improval on steroid treat- tions by master clinicians and pathologists have enriched our knowl-
ment.60 Contrast-enhanced magnetic resonance imaging (MRI) and edge of these rare disease entities.
REFERENCES
1. Hoit BD, Gupta S. Restrictive, obliterative and infiltrative cardiomyopathies. In: Fuster V et al. (Eds). Hurst’s The Heart, 12th edition. New York:
McGraw-Hill Medical. pp. 851-63.
2. Ramankutty V, Abraham S, Kartha CC, et al. Geographical distribution of endomyocardial fibrosis. Int J Epidemiol. 1996;25:1202-7.
3. Williams AW. Heart disease in the native population of Uganda. East Afr Med J. 1938;15:279.
4. Bedford DE, Konstam GLS. Heart failure of unknown aetiology in Africans. Br Heart J. 1946;8:236.
5. Davies JNP. A heart disease of obscure aetiology in Africans. MD Thesis. University of Bristol; 1948.
6. Davies JNP. Endocardial fibrosis in Africans. A heart disease of obscure aetiology in Africans. East Afr Med J. 1948;25:10.
7. Williams AW, Somers K. The electrocardiogram in endomyocardial fibrosis. Br Heart J. 1960;22:311.
8. Shillingford JP, Somers K. Clinical and hemodynamic patterns in endomyocardial fibrosis. Br Heart J. 1961;23:344.
9. Parry EH, Abrahams DG. The natural history of endomyocardial fibrosis. Q J Med. 1962;31:1.
10. Hutt MS, Ikeme AC, Lukas AO, et al. Cardiomyopathies. Bull World Health Organ. 1965;33:257.
11. Somers K, Brenton DP, DArbela PG, et al. Hemodyamic features of severe endomyocardial fibrosis of right ventricle, including comparison with
constrictive pericarditis. Br Heart J. 1968;30:332.
12. Emslie-Smith D, Somers K. Intracardiac electrocardiogram in endomyocardial fibrosis. Br Heart J. 1968;30:696.
13. Konno S, Sakakibara S. Intracardiac heart biopsy. Dis Chest. 1963;44:345.
14. Somers K, Hutt MS, Patel AK, et al. Endomyocardial biopsy in diagnosis of cardiomyopathies. Br Heart J. 1971;33:822.
15. Van der Geld H, Peetom F, Somers K, et al. Immunohistological and serological studies in endomyocardial fibrosis. Lancet. 1966;2:1210.
16. Fowler JM, Somers K. Left ventricular endomyocardial fibrosis and mitral regurgitation. a new syndrome. Lancet. 1968;1:227.
17. DArbela PG, Mutazindwa T, Patel AK, et al. Survival after first presentation with endomyocardial fibrosis. Br Heart J. 1972;34:403.
18. Report of the WHO expert committee. Cardiomyopathies. Technical report series. No.697. WHO Geneva, 1984.
19. Olsen EG, Spry CJ. The pathogenesis of Loffler endomyocardial disease and its relationship in endomyocardial fibrosis. In: Yu PN, Goodwin JF
(Eds). Progress in Cardiology. Lea and Feliger; 1979. pp. 281-303.
20. Gopi CK. Endomyocardial fibrosis in idiopathic cardiomegaly. WHO Bulletin. 1968;38:979-92.
21. Nair DV, Kurian S. Ecological study of endomyocardial fibrosis in children in Kerala. In: Sapru RP (Ed). Endomyocardial Fibrosis in India. Indian
Council of Medical Research; 1983. p. 187.
22. Vijayaraghavan G, Davies J, Sadanandan S, et al. Echocardiographic features of tropical endomyocardial disease in South India. Heart. 1993;50:450-
9.
23. Sapru RP. Endomyocardial fibrosis in India. ICMR workshop proceedings 1981. In: Sapru RP (Ed). Endomyocardial Fibrosis in India. Indian Coun-
cil of Medical Research; 1983.
24. Gupta PN, Valiathan MS, Balakrishnan KG, et al. Clinical course of endomyocardial fibrosis. Heart. 1989;62:450-4.
25. Balakrishnan KG, Sapru RP, Sasidharan K, et al. A comparison of the clinical, haemodynamic and angiographic features in right ventricular endo-
myocardial fibrosis and Ebstein’s anomaly of the tricuspid valve. Cardiology. 1982;69(5):265-75.
26. Kartha CC. Endomyocardial fibrosis, a case for the tropical doctor. Cardiovasc Res. 1995;30(5):636-43.
27. Metraz D, Outtara K, Coulibaly AO, et al. LVEMF with severe mitral insufficiency: the case for mitral valve repair. A report of four cases. Thorac
Cardiovasc Surg. 1983;31:297-300.
28. Anbarasu M, Manohar SR, Titus T, et al. One and a half ventricular repair for right ventricular endomyocardial fibrosis. Asian Cardiovasc Thorac
Ann. 2004;12:363-5.
29. Tharakan J, Bohora S. Current Perspectives in endomyocardial fibrosis. (in press).
30. Mayosi BM. Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa. Heart.
2007;93(10):1176-83.
31. Kyle RA. Amyloidosis: a convoluted story. Br J Haematol. 2001;114:529-38.
32. Sipe JD, Cohen AS. History of the the amyloid fibril. J Struct Biol. 2000;130(2-3):88-98.
33. Cohen AS, Calkins E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature. 1959;183:1202-3.
34. Eanes ED, Glenner GG. X-ray diffraction studies on amyloid filaments. J Histochem Cytochem. 1968;16:673-7.
35. McCarthy RE, Kasper EK. A review of the amyloidoses that infiltrate the heart. Clin Cardiol. 1998;21:547-52.
36. Hare JM. The dilated, restrictive and infiltrative cardiomyopathies. In: Libby et al. (Eds). Braunwald’s Heart Disease. A Textbook of Cardiovascular
Medicine, 8th edition; 2008. pp. 1739-62.
37. Kyle RA, Bayrd ED. Primary systemic amyloidosis and myeloma: discussion of relationship and review of 81 cases. Arch Intern Med. 1961;107:344-
53.
38. Glenner GG, Terry W, Harada M, et al. Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analysis. Sci-
ence. 1971;172:1150-1.
39. Glenner GG, Ein D, Eanes ED, et al. Creation of amyloid fibril from Bence Jones proteins in vitro. Science. 1971;174:712-4.
40. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45-59.
41. Kyle RA, Greipp PR. Amyloidosis: clinical and laboratory features in 229 cases. Mayo Clin Proc. 1983;58:665-3.
42. Pomerance A. Senile cardiac amyloidosis. Br Heart J. 1965;27:711-8.
43. King LS. Atypical amyloid disease with observations on a new silver stain for amyloid. Am J Pathol. 1948;24:1095-114.
44. Frederiksen T, Gotzsche H, Harboe N, et al. Familial primary amyloidosis with severe amyloid heart disease. Am J Med. 1962;33:328-48.
45. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant sequence transthyretin (isoleucine 122) in late onset cardiac amyloidosis in black Ameri-
cans. N Eng J Med. 1997;336:466-73.
46. Larsen RM. Apathological study of primary myocardial amyloidosis. Am J Pathol. 1930;6:147-60.
47. Lindsay S. The heart in primary systemic amyloidosis. Am Heart J. 1946;32:419-37.
48. Falk RH, Plehn JF, Deering T, et al. Sensitivity and specificity of echocardiographic features of cardiac amyloidosis. Am J Cardiol. 1987;59:418-22.
49. Schroeder JS, Billingham ME, Rider AK. Cardiac amyloidosis: diagnosis by transvenous endomyocardial biopsy. Am J Med. 1975;59:269-73.
50. Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis colchicines alone, melphalan and prednisone and melpha-
lan, prednisone and colchicine. N Eng J Med. 1997;336:1202-7.
51. Hutchinson J. Cases of Mortimer’s malady, a form of lupus pernio. Arch Surg. 1898;9:307-15.
52. Doughan AR, Williams BR. Cardiac sarcoidosis. Heart. 2006;92:282-8.
53. Bernstein M, Konzelman FW, Sidlick DM. Boeck’s sarcoid: report of a case with visceral involvement. Arch Intern Med. 1929;4:721-34.
54. Longcope WT, Freiman DG. A study on sarcoidosis; based on a combined investigation of 160 cases including 30 autopsies from the John Hopkins
hospital and Masachusetts general hospital. Medicine (Baltimore). 1952;31(1):1-132.
55. Lagana SM, Parwani AV, Nichols LC. Cardiac sarcoidosis: a pathology-focused review. Arch Lab Pathol Med. 2010;134:1039-46.
56. Robert WC, McAllister HA, Ferrans VJ. Sarcoidosis of the heart: a clinicopathologic study of 35 patients (group 1) and review of 78 previously de-
scribed necropsy patients (group 2). Am J Med. 1977;63:86-108.
57. Sekiguchi M, Numao Y, Imai M, et al. A clinical and histopathological profile of sarcoidosis of the heart and acute idiopathic myocarditis. Jpn Circ
J. 1980;44:249-63.
58. Hiraga H, Yuwai K, Hiroe M, et al. Guidelines for diagnosis of cardiac sarcoidosis. Japanese ministry of health and family welfare; 1993. pp. 23-24.
59. Fields CL, Ossorio MA, Roy TM, et al. Thallium scintigraphy in the diagnosis and management of myocardial sarcoidosis. South Med J. 1990;83:339-
42.
60. Okayama K, Kurata C, Tawarahara K, et al. Diagnostic and prognostic value of myocardial scintigraphy with thallium-201 and Gallium 67 in car-
diac sarcoidosis. Chest. 1995;107:330-4.
61. Syed J, Myers R. Sarcoid heart disease. Can J Cardiol. 2004;20(1):89-93.
62. Deegan PB, Baehner AF, Barba Romero MA, et al. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet.
2006;43(4):347-52.
Chapter 32  History of Restrictive Cardiomyopathy 223
63. Fabry J. Ein Beitrag zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch Dermatol Syph.
1898;43:187-200.
64. Anderson W. A case of “angeiokeratoma”. Br J Dermatol. 1898;10:113-7.
65. Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N Engl J Med. 1967;276:1163-7.
66. Schiffmann R, Kopp JB, Austin HA, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285:2743-9.
67. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A—replacement therapy in Fabry’s disease. N
Engl J Med. 2001;345:9-16.
68. Gaucher PCE. De l’épithélioma primitive de la rate. Thèse de Paris; 1882.
69. Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides. II Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys
Res Commun. 1965;18:221-5.
70. Barton NW, Furbish FS, Murray GJ, et al. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease.
Proc Natl Acad Sci USA. 1990;87:1913-6.
33 Peripartum Cardiomyopathy
Deshpande NV
INTRODUCTION cytokines. Recently, there have been reports of familial cardiomyo-

pathy being unmasked by pregnancy. Some of the proposed mecha-
Peripartum cardiomyopathy (PPCM) is a rare form of heart failure nisms are discussed below:
which affects healthy young women with devastating consequences.
Although described as early as 1849 by Richie,1 Seftel et al.2 recog- Myocarditis
nized the occurrence of heart failure in late pregnancy and used the
term “peripartum cardiomyopathy” in their paper presented in Brit- Presence of myocarditis on endomyocardial biopsy was reported first
ish Heart Journal. However, the condition was not well-characterized by Melvin and colleagues7 in three consecutive patients of PPCM.
until 1971 when Demakies et al.3,4 established the current diagnostic However, the incidence of myocarditis in the subsequent reports has
criteria. A workshop by National Heart, Lung, and Blood Institute varied probably due to difficulties in establishing the diagnosis by
(NHLBI) in 1997 standardized the definition of PPCM as “onset of endomyocardial biopsy and variable interval between presentation
cardiac failure with no identifiable cause in last month of pregnan- and timing of the biopsy. During pregnancy, the immune response
cy or within five months after delivery in absence of heart disease is depressed which may allow unchecked viral replication leading to
before the last month of pregnancy”.5 Left ventricular (LV) systolic a greater likelihood of developing myocarditis. Studies in pregnant
dysfunction demonstrated by echocardiography is essential for mice have shown enhanced susceptibility to viral myocarditis due to
diagnosis of PPCM. coxsackievirus and echoviruses.8
EPIDEMIOLOGY Abnormal Immune Response

Peripartum cardiomyopathy has an incidence of 1:1,500 to 1:4,000 It is postulated that fetal cells may escape in maternal circulation and
live births. In United States, the estimated prevalence is 1 case per remain there without being rejected due to weak immunogenecity.
1,300–1,500 live births, while in Japan, it is 1 case per 6000 live births. These chimeric hematopoetic cells may take up residence in the car-
The condition appears to be more prevalent in South Africa with re- diac tissue during the immunosuppressed pregnant state. Following
ported prevalence of 1 case per 1,000 live births. Reports from Haiti postpartum recovery of immune system, they are recognized as non-
show a relatively high incidence of 1 case per 350–400 live births.6 self, and this can trigger a pathologic autoimmune response medi-
The risk factors identified include older maternal age, multiparity, ated through release of cytokines and similar signaling molecules
multiple gestations and black race. African American women seem to inducing a nonspecific bystander myocytotoxicity and myocarditis.
be at higher risk of developing PPCM. African Americans have higher This hypothesis is supported by the observation that in patients with
incidence of hypertension and it is unclear whether race is an inde- PPCM, autoantibodies against select cardiac proteins are elevat-
pendent risk factor or it is the interaction of the race and hypertension. ed.9,10
ETIOLOGY AND PATHOGENESIS Hemodynamic Stress

Peripartum cardiomyopathy is considered as a distinct entity as The hemodynamic stresses of pregnancy are considered as a possible
the incidence is higher than the incidence of idiopathic dilated car- cause of PPCM. Hemodynamic alterations during pregnancy include
diomyopathy (DCM) unmasked by pregnancy. The exact etiology is a reversible decrease in LV systolic function during second and third
not known but various factors have been proposed which include trimester which persists during early postpartum period, return-
myocarditis, abnormal immune response to pregnancy, maladap- ing to baseline thereafter. It is possible that PPCM is an exaggerated
tive response to hemodynamic stress of pregnancy, stress-activated response in decrease in systolic function.11
Chapter 33  Peripartum Cardiomyopathy 225
Inflammation and Oxidative Stress Chest X-ray shows cardiomegaly with pulmonary venous con-
gestion. Electrocardiogram (ECG) exhibits sinus tachycardia LV
A proinflammatory response in PPCM is described by Sliwa et al. hypertrophy and nonspecific ST-T changes. PR interval may be pro-
from South Africa. Studying a large cohort of PPCM, they have longed and some patients demonstrate widening of QRS complex
described elevated plasma levels of tumor necrosis factor-alpha indicating intraventricular conduction disturbances. Bundle branch
(TNF-alpha), Fas/Apo-1 and interleukin-6 (IL-6) and a positive cor- blocks are present occasionally.
relation between c-reactive protein levels, LV end-diastolic and end- Echocardiography is the most important diagnostic tool which
systolic diameters at the diagnosis.12 usually shows a dilated globally hypokinetic left ventricle. The
Enhanced oxidative stress is reported in a mouse model of diagnostic echo criteria include (a) left ventricular ejection fraction
PPCM. It is postulated that in PPCM, enhanced oxidative stress trig- (LVEF) less than 45% (b) fractional LV shortening less than 30% and
gers activation of cathepsin D, a ubiquitous lysosomal enzyme which (c) LV end-diastolic dimensions greater than 2.7 cm per square meter
subsequently cleaves serum prolactin to its antiangiogenic and of body surface area. Echo also helps to define the severity of mitral
proapoptotic 16 kDa form. This metabolite is also shown to promote and tricuspid valve regurgitation.
endothelial inflammation and impair cardiomyocyte metabolism
and contraction.13 Full length 23 kDa form of prolactin is upregulated MANAGEMENT
post delivery and has been implicated in cardiac tissue injury and
modulation of autoimmune response. Thus, unbalanced oxidative The medical management of patients with PPCM is similar to those
stress and generation of 16 kDa form of prolactin may represent a with left heart failure due to LV systolic dysfunction except that the
crucial step in initiation of PPCM. In fact, pharmacological inhibition potential effects of the medications on the fetus or lactation become
of prolactin release has been shown to prevent PPCM in mice studies the primary concern in these patients.
and to be beneficial in patients in preliminary studies. For women presenting in the last month of pregnancy with
Recent reports from the Netherlands strongly suggest that a symptoms of congestion, loop diuretics in appropriate doses can be
subset of PPCM is actually an initial manifestation of familial DCM. started. Generally, a small daily dose of digoxin can be added with
The authors suggest that PPCM develops as a complex interaction good benefits. Hydralazine and nitrates can be safely used as vaso-
between pregnancy associated and genetic factors. On the back- dilators to reduce afterload in pregnancy. Although use of b-blockers
ground of genetic susceptibility, factors associated with pregnancy generally appears safe during pregnancy for treatment of hyperten-
could lead to PPCM.14 Indeed, another recent paper has identified sion, less is known about their effect in patients with PPCM. Angio-
mutation in six genes in patients with PPCM.15 tensin-converting enzyme (ACE) inhibitors are the most important
drugs to treat LV systolic dysfunction otherwise, cannot be used dur-
CLINICAL PRESENTATION ing pregnancy due to the unwanted effects on the fetus.
For patients presenting following delivery, ACE inhibitors form
The women suffering from PPCM have generally no significant his- the cornerstone of therapy. Loop diurectics and digoxin can be
tory except that in the last month of pregnancy, they may complain added to ACE inhibitors to decrease pulmonary congestion. Ad-
of dyspnea, fatigue and peripheral edema. More than 80% patients dition of b-blockers would be important in patients who remain
develop cardiac symptoms postpartum while 7% of them develop symptomatic despite optimization of these drugs. Caution needs to
symptoms during last month of pregnancy. About half of the patients be exercised in occasional patient presenting with severe systolic
are more than 30 years of age and 71% are in their third or subse- dysfunction without significant ventricular dilatation, who may
quent pregnancy. Twins and toxemia occur in 7% and 22% of these tolerate b-blockers poorly.
patients.3,4 Thrombotic and embolic complications may occur in PPCM, like
Patients present with features of left heart failure including they occur in other forms of heart failure. Anticoagulation must be
fatigue, dyspnea and orthopnea. Peripheral edema and abdominal considered in patients presenting with systemic embolism or those
discomfort occur in about half of them. Coughing and hemoptysis with mural LV thrombi. During pregnancy, heparin therapy must be
are features of pulmonary embolism to which these patients are considered as oral anticoagulation is contraindicated. Role of low
particularly predisposed. Clinical signs include moderate to severe molecular weight heparin (LWMH) or newer drugs like fondaparin-
respiratory distress, elevated jugular venous pressure, pedal edema aux is not established as yet. Anticoagulation needs to be continued
and hepatomegaly. The heart is enlarged with an active LV impulse. for at least 6 months postpartum. Need for continued therapy can be
Enlarged right ventricle may give left parasternal impulse. Murmurs reassessed according to recovery of LV function at 6 months.
of mitral and tricuspid regurgitation are common and tend to disap- Ventricular arrhythmias can occur as in other forms of heart fail-
pear as the LV function improves. Left ventricular third heart sound ure and need to be managed conventionally with use of b-blockers
is noted in majority of the patients. and adequate doses of amiodarone. Occasionally, implantable car-
dioverter defibrillator (AICD) may be needed in patients with malig- for PPCM. A single dose of cabergoline, a strong and long acting
nant ventricular arrhythmia despite conventional therapy. The risk prolactin antagonist has been shown to be beneficial in treating a
of arrhythmia decline with recovery of LV function and therapy may patient of PPCM has been reported by deJong et al.22 Heart transplant is
be withdrawn after 6 months when the LV function normalizes com- another option for end-stage heart failure due to PPCM, and occa-
pletely. sional transplanted patient has been reported to have undergone
Physical activity is encouraged as much as the functional sta- successful subsequent pregnancy.23
tus of the patients allows; however, aerobic activities and heavy lift-
ing are discouraged for at least 6 months. Breastfeeding is strongly NATURAL HISTORY AND PROGNOSIS
discouraged due to heavy metabolic demands of lactation. Some of
the drugs may also be secreted in the breast milk causing untoward Historic data from the series of Demakis et al.3,4 shows that 50% of the
effects to the baby. patients with PPCM showing complete regression of cardiomegaly
at 6 months have good prognosis. Long-term mortality in patients
Newer Therapeutic Agents showing complete regression of heart size was 14% in their series
(significantly higher than those without PPCM). Patients having per-
Immune modulation therapy is considered by some authors due to sistent cardiomegaly beyond 6 months have a worse prognosis with
inflammatory nature of PPCM. Medei et al. used prednisone and a very high mortality rate exceeding 75% in next 2–3 years. Modern
azathioprine in a small series of patients and were able to show treatment with ACE inhibitors, b-blockers has improved the survival
marked improvement in 9 out of 10 patients treated.16 Similarly, of patients with PPCM. Recent data from Felker et al.24 shows very
Bozkurt et al.17 in a retrospective analysis found that patients with good long-term survival of patients with PPCM (94% at 5 years) (Fig.
PPCM when treated with intravenous (IV) immune globulin given 33.1), which is significantly higher than survival for any other form of
in a dose of 2 g/kg over 2 days significantly improved LV function at DCM. Recent data from Forster et al.25 shows that levels of serum N-
6 months. Results of both these studies need to be interpreted with terminal prohormone brain natriuretic peptide (NT pro BNP), inter-
caution as other studies of immune modulation therapy in active feron-gamma, oxidized low-density lipoprotein (LDL) and prolactin
myocarditis have failed to show significant improvement so far.18,19 correlate with outcome. Persistently high levels of these inflamma-
Treatment with pentoxifylline, a xanthine derivative has been tory markers spell worse prognosis as compared to those who show
shown to inhibit production of TNF-alpha and improves func- reduction in the levels of these markers.
tional class in LV function in patients with idiopathic DCM. Sliwa Subsequent pregnancy in patients with PPCM is the real con-
et al.20 studied effects of addition of pentoxifylline to 30 consecutive cern. Although pregnancy in patients who show normalization of LV
patients with PPCM in a dose of 400 mg TID in addition to stand- function can be considered, almost 20% of them develop symptoms
ard therapy. A lower mortality rate and better functional class was of heart failure during subsequent pregnancy.26 It appears that even
observed in patients treated with pentoxifylline. Significant reduc- though the LV function at rest is normal, patients who have suffered
tion in LV diameters was also observed in this group of patients. PPCM in previous pregnancy have impaired contractile reserve.
The same group recently studied effects of prolactin block- Lampert et al.27 have demonstrated this phenomenon using dobu-
ade with bromocriptine (a dopamine 2D agonist) in patients with tamine stress echocardiography. For those who show only partial
PPCM.21 In this small open label randomized study of 20 patients (10 improvement, the risk is considerably higher with more than 50%
standard therapy and 10 with bromocriptine 2.5 mg twice daily for 2 developing heart failure in the subsequent pregnancy. Short-term
weeks followed by 2.5 mg OD for 6 weeks), a significant improvement mortality for this group remains high at 19% and they tend to have
in functional class, LV systolic and diastolic function and degree of unfavorable fetal outcome with 50% premature deliveries and 25%
functional mitral regurgitation was observed. Use of bromocriptine therapeutic abortions.28 In view of the above observations, subse-
was based on their recent observation that oxidative stress of preg- quent pregnancy in a patient who has suffered PPCM needs to be
nancy converts prolactin to its 16 kDa form which leads to myocar- strongly discouraged. For those who get pregnant again, a system-
dial toxicity. Although encouraging, it should be remembered that atic care in tertiary care institute with close cardiologic monitoring is
bromocriptine is known to cause cerebral and cardiovascular com- mandatory to avoid catastrophic outcome.
plications including stroke, seizure and coronary artery thrombosis.
Risk of thrombosis is already high in the postpartum phase due to CONCLUSION
altered coagulation system. However, in this small study, no throm-
botic complications were noted in the nine surviving patients. Fur- Peripartum cardiomyopathy remains a rare but devastating com-
ther, bromocriptine-treated women cannot breastfeed and there plication of pregnancy. Current recommended therapy remains
is a risk of malnutrition of the infant, especially in the developing the standard of care therapy for LV systolic dysfunction. Almost
countries. Hence, these promising results need to be replicated in half of the patients tend to recover their LV function in 6 months
larger studies before bromocriptine is used as a standard therapy following delivery, however, almost 20% of them can develop heart
Chapter 33  Peripartum Cardiomyopathy 227
Figure 33.1: Adjusted Kaplan—Meier Estimates of survival according to the underlying cause of cardiomyopathy. Only idiopathic cardiomyopathy
and cardiomyopathy, due to causes for which survival was significantly different from that in patients with idiopathic cardiomyopathy are shown.
Source: Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N
Eng J Med. 2000;342:1077-84
failure during subsequent pregnancy. Patients showing incomplete group. Given the rarity of the condition, an international collabora-
recovery of LV function need to be discouraged strongly from get- tive registry is essential to gain further knowledge in management
ting pregnant again as maternal and fetal outcomes are worse in this of these patients.
REFERENCES
1. Ritchie C. Clinical contributions to the pathology, diagnosis and treatment of certain chronic diseases of the heart. Edinburgh Med Surg J.
1849;12:333.
2. Seftel H, Susser M. Maternity and myocardial failure in African women. Br Heart J. 1961;23:43-52.
3. Demakis JG, Rahimtoola SH. Peripartum cardiomyopathy. Circulation. 1971;44:964-8.
4. Demakis JG, Rahimtoola SH, Sutton GC, et al. Natural course of peripartum cardiomyopathy. Circulation. 1971;44:1053-61.
5. Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung and Blood Institute and Office of Rare Diseases
(National Institutes of Health) workshop recommendations and review. JAMA. 2000;283:1183-8.
6. Gentry MB, Dias JK, Luis A, et al. African American women have a higher risk for developing peripartum cardiomyopathy. J Am Coll Cardiol.
2010;55:654-9.
7. Melvin KR, Richardson PJ, Olsen EG, et al. Peripartum cardiomyopathy due to myocarditis. N Eng J Med. 1982;307:731-4.
8. Farber PA, Glasgow LA. Viral myocarditis during pregnancy: encephalomyocarditis virus infection in mice. Am Heart J. 1970;80:96-102.
9. Nelson JL, Binachi DW, Maloney S, et al. Microchimerism and HLA compatible relationships of pregnancy in scleroderma. Lancet. 1998;351:559-
62.
10. Ansari AA, Neckelmann N, Wang YC, et al. Immunological dialogue between cardiac myocytes, endothelial cells and mononuclear cells. Clin Im-
munol Immunopathol. 1993;68:208-14.
11. Julian DG, Szekeley P. Peripartum cardiomyopathy. Prog Cardiovasc Dis. 1985;27:233-46.
12. Sliwa K, Forster O, Libhaber E, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied
patients. Eur Heart J. 2006;27:441-6.
13. Sliwa K, Skudicky D, Bergemann A, et al. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of
cytokines and Fas/Apo-1. J Am Coll Cardiol. 2000;35:701-5.
14. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy.
Circulation. 2010;121:2169-75.
15. Morales A, Painter T, et al. Mutations in 6 genes identified in patients with Peripartum cardiomyopathy. JACC. 2010;55(10A):A131.
16. Midei MG, DeMent SH, Feldman AM, et al. Peripartum myocarditis and cardiomyopathy. Circulation. 1990;81:922-8.
17. Bozkurt B, Villaneuva FS, Holubkov R, et al. Intravenous immune globulin in the therapy of perpartum cardiomyopathy. J Am Coll Cardiol.
1999;34:177-80.
18. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Eng J Med. 1995;333:269-75.
19. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent onset dilated cardiomyopathy. Circula-
tion. 2001;103:2254-9.
20. Sliwa K, Skudicky D, Candy G, et al. The addition of pentoxyphylline to conventional therapy improves outcomes in patients with peripartum
cardiomyopathy. Eur J Heart Failure. 2002;4:305-9.
21. Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof of con-
cept pilot study. Circulation. 2010;121:1465-73.
22. de Jong JS, Rietveld K, van Lochem LT, et al. Rapid left ventricular recovery after cabergoline treatment in a patient with peripartum cardiomyopa-
thy. Eur J Heart Fail. 2009;11:220-2.
23. Carvalho AC, Almeida D, Cohen M, et al. Successful pregnancy, delivery and puerperium in a heart transplant patient with previous peripartum
cardiomyopathy. Eur Heart J. 1992;13:1589-91.
24. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Eng
J Med. 2000;342:1077-84.
25. Forster O, Hilfiker-Kleiner D, Ansari AA, et al. Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in
patients with peripartum cardiomyopathy. Eur J Heart Fail. 2008;10:861-8.
26. Reimold SC. Peripartum cardiomyopathy. N Engl J Med. 2001;344(21):1629-30.
27. Lampert MB, Weinert L, Hibbard J, et al. Contractile reserve in patients with peripartum cardiomyopathy and recovered left ventricular function.
Am J Obstet Gynaecol. 1997;176:189-95.
28. Elkayam U. Pregnant again after peripartum cardiomyopathy: to be or not to be? Eur Heart J. 2002;23:753-6.
34 History and Clinical Implications of
Myocarditis and Pericarditis
Tewari S, Jain V, Pancholia AK
diversity of clinical manifestations has made the true incidence of

MYOCARDIUM
myocarditis difficult to determine. Recent prospective postmortem
Myocardium is a thick contractile middle layer of uniquely con- data have implicated myocarditis in sudden cardiac death of young
structed and arranged muscle cells that forms the bulk of the heart adults at rates of 8.6–12%.1 Furthermore, it has been identified as a
wall. The myocardium contains a minimum of other tissue, except cause of dilated cardiomyopathy in 9% of cases in a large prospective
blood vessels, and is covered interiorly by the endocardium. The series.2 Recent molecular techniques have facilitated new insights
contractile tissue of the myocardium is composed of fibers with the into inflammatory autoimmune processes that affect the myocardi-
characteristic cross-striations of muscular tissue. The fibers are about um and ultimately result in acute or chronic dilated cardiomyopathy.
one-third as large in diameter as those of skeletal muscle and contain Despite the well-established morbidity and mortality associated with
more sarcoplasm. They branch frequently and are interconnected to myocarditis, clinical practice guidelines with regard to its evaluation
form a network that is continuous except where the bundles and the and treatment are lacking. The wide variety of etiologies implicated
laminae are attached at their origins and insertions into the fibrous in myocarditis and its heterogeneous clinical presentations have
trigone of the heart. Myocardial muscle contains less connective tis- impeded patient identification and consensus on the most appropri-
sue than does skeletal muscle. Specially modified fibers of myocar- ate diagnostic criteria.
dial muscle constitute the conduction system of the heart, including The Dallas pathological criteria, published in 1986, served as the
the sinoatrial node, the atrioventricular (AV) node, the AV bundle first attempt to develop standardized diagnostic guidelines for the
and the purkinje fibers. Most of the myocardial fibers function to histopathological classification of myocarditis. Active myocarditis
contract the heart. The metabolic processes of the myocardium are is characterized by an inflammatory cellular infiltrate with evidence
almost exclusively aerobic. of myocyte necrosis, whereas borderline myocarditis demonstrates
an inflammatory cellular infiltrate without evidence of myocyte
MYOCARDITIS injury. The inflammatory infiltrate should be further described as
lymphocytic, eosinophilic or granulomatous. The amount of inflam-
Myocarditis is clinically and pathologically defined as “inflamma- mation may be mild, moderate or severe, and its distribution may be
tion of the myocardium”. Despite its rather clear-cut definition, the focal, confluent or diffuse, respectively.
classification, diagnosis and treatment of myocarditis continue to
prompt considerable debate. The more routine use of endomyo- ETIOLOGY
cardial biopsy (EMB) has helped to better define the natural history
of human myocarditis and to clarify clinicopathological correla- Myocarditis most commonly results from an external inflammatory
tions. The precise incidence of myocarditis is difficult to ascertain, trigger, such as a virus, including a host immune response that may
depending on inclusion and diagnostic criteria applied. One range from minimally transient response to fulminant, overwhelm-
estimate has been 8–10 per 100,000 of the population. However, ing inflammation.
because of failure to make the appropriate diagnosis or failure to • Viruses: Enteroviruses (including Coxsackie virus), adenovirus,
detect subclinical cases, many deaths caused by myocarditis may go parvovirus, hepatitis C virus, human immunodeficiency virus
unrecognized. This suggests that clinical myocarditis is not clinically (HIV), influenza, mixed viral infection
suspected in large number of cases, leading to deaths or severe heart • Bacteria: Clostridia, diphtheria, streptococcal infection, tuber-
failure. culosis, Whipple disease, lyme carditis
Clinical presentations of the disease range from nonspecific sys- • Protozoal infection: Chagas disease
temic symptoms (fever, myalgias, palpitations or exertional dyspnea) • Toxins: Anthracyclines, cocaine
to fulminant hemodynamic collapse and sudden death. The extreme • Hypersensitivity: Clozapine, sulfonamides, penicillins
• Autoimmune disorders: Giant cell myocarditis, Sjogren syn- heart failure or hemodynamic collapse; symptoms recede with drug
drome, celiac disease systemic lupus erythematosus (SLE), Ta- cessation with or without administration of corticosteroids. Autoim-
kayasu arteritis mune diseases that are associated with active myocarditis include
Although a broad array of etiologies have been implicated as celiac disease and Whipple’s disease, rheumatoid diseases, such as
causes of myocarditis, viral myocarditis remains the prototype for SLE, mixed connective tissue disease, systemic sclerosis and certain
the study of the disease and its evolution. Enteroviruses, specifically hematologic abnormalities such as thrombocytopenic purpura.
Coxsackie group B serotypes, have traditionally been perceived as
the predominant viral cause. Early studies suggested a causal rela- PATHOGENESIS
tionship between symptomatic presentation and rising serum Cox-
sackie B viral titers. However, Keeling et al.3 subsequently reported Our current understanding of the pathogenesis of myocarditis de-
similar levels of serotype-specific Coxsackie virus B IgM antibodies rives largely from animal models. Three essential pathways have
in household contacts and myocarditis cases. Molecular techniques, been elucidated. Direct myocardial invasion by cardiotropic virus
such as polymerase chain reaction (PCR) have facilitated extensive or other infectious agents rapidly progresses to a second phase of
testing of myocardial tissue for potential viral etiologies. Nested PCR immunologic activation. In the last phase, prompts clonal expansion
analyses of adult and pediatric myocardium have demonstrated the of B cells, resulting in further myocytolysis, additional local inflam-
presence of adenoviral genome in patients with idiopathic left ven- mation, and production of circulating anti-heart antibodies. All three
tricular (LV) dysfunction with a greater frequency than enterovirus. mechanisms may interact within the same host, the predominant
Hepatitis C has been more frequently reported in Japanese patients, pathogenic mechanism may vary according to host defenses and the
whereas parvovirus B19 genome is more commonly identified via specific infectious agent. During the period of active viremia, car-
nested PCR techniques in German cases. Kuhl et al.4 have reported diotropic RNA viruses, such as Coxsackie B or encephalomyocardi-
identification of more than two different viral genomes in more than tis virus are taken into myocytes by receptor-mediated endocytosis
25% of cases when genome could be amplified. These findings sug- and are directly translated intracellularly to produce viral protein.
gest that age-related and regional differences in viral etiology may be Viral genomic persistence via incorporated double-stranded RNA
more important in the causation of acute and chronic myocarditis may also contribute to myocyte dysfunction by cleaving dystrophin
than previously appreciated. or eukaryotic initiation factor-4. The next phase is characterized by
Hepatitis C virus (HCV) has also been associated with myocardi- inflammatory cellular infiltration, including natural killer cells and
tis by identification of HCV antibodies and ribonucleic acid (RNA) in macrophages, with the subsequent expression of proinflammatory
sera and cardiac tissue of patients with biopsy-proven myocarditis. cytokines, particularly interleukin-1, interleukin-2, TNF and inter-
The causative relationship between HCV infection and dilated car- feron-TNF activates endothelial cells, recruits additional inflam-
diomyopathy remains ambiguous; increased tumor necrosis factor matory cells, further enhances cytokine production, and has direct
(TNF) and cytokine expression have been implicated. negative inotropic effects. Cytokines also activate inducible nitric
Human immunodeficiency virus has been associated with car- oxide (NO) synthase (NOS) in cardiac myocytes. The role of NO in the
diotropic viral infection resulting in myocarditis and LV dysfunction. development and progression of myocarditis is complex. Nitric ox-
In a postmortem study of HIV-infected patients, 14 of 21 patients ide can inhibit viral replication by targeting specific viral proteases,
(67%) had myocarditis by histopathological criteria.5 Human immu- and peroxynitrate formation has potent antiviral effects. Mice defi-
nodeficiency virus-related myocarditis is associated with a signifi- cient in NOS have greater viral titers, a higher viral mRNA load and
cantly poorer prognosis than is lymphocytic myocarditis; multivari- more widespread myocyte necrosis. Conversely, in experimental
ate modeling has identified HIV-related myocarditis as the strongest myosin-induced autoimmune myocarditis, NOS expression in myo-
predictor of death among a large cardiomyopathy population. Small- cytes and macrophages is associated with more intense inflamma-
pox vaccination has recently been recognized as causing myoperi- tion, whereas NOS inhibitors have been shown to reduce myocarditis
carditis. Cases have been identified by their close proximity to small- severity. Cell-mediated immunity also plays an important role in
pox vaccination (4–30 days), clinical manifestations, and elevation of viral clearing. Cytotoxic (CD8+) cells recognize degraded viral
cardiac biomarkers. protein fragments that are presented by major histocompatibil-
Numerous medications have been implicated in hypersensitivity ity (MHC) complex class I antigens on the myocyte surface. Finally,
myocarditis including antidepressants (tricyclics), antibiotics (peni- circulating autoantibodies directed against contractile, structural
cillins, cephalosporins, sulfonamides) and antipsychotics (clozap- and mitochondrial proteins have been described in both murine and
ine). A hypersensitivity reaction may be heralded by fever, peripheral human myocarditis.
eosinophilia, sinus tachycardia, and a drug rash that occurs days to The relationship of myocarditis to idiopathic dilated cardiomyo-
weeks after administration of a previously well-tolerated agent. Myo- pathy has been partially clarified by molecular techniques. Detec-
cardial involvement varies but usually does not result in fulminant tion of viral RNA at early, intermediate and late stages of myocardial
Chapter 34  History and Clinical Implications of Myocarditis and Pericarditis 231
infection has been demonstrated in animal models of myocarditis,

DIAGNOSTIC EVALUATION
particularly those produced by Coxsackie virus B3. The presence of
low levels of ongoing viral replication may result in continued myo- Biopsy
cardial damage, including apoptotic cell death, as a component of
the immunologic response to infection. The presence of HIV- and The Dallas criteria9 have standardized the histopathological defini-
HCV-infected myocytes at autopsy argues that these infections are tion of myocarditis. Despite its considerable limitations, yielding
capable of producing ongoing myocardial injury that ultimately re- diagnostic information in only 10–20% of cases, EMB findings
sults in an acute or chronic dilated cardiomyopathy. remain the gold standard for unequivocally establishing the diagno-
sis. The largest case series of patients with an unexplained cardiomy-
CLINICAL PRESENTATION opathy used biopsy findings to diagnose 111 of 1,230 patients (9%)
with myocarditis. Fewer than 10% of 2,233 patients with idiopathic
Clinical manifestations range from asymptomatic electrocardio- heart failure referred to the Myocarditis Treatment Trial10 had EMBs
gram (ECG) abnormalities to cardiogenic shock. Transient ECG deemed positive by the Dallas criteria. However, multiple investiga-
abnormalities suggesting myocardial involvement commonly occur tors have described strong clinical, ventriculographic, and labora-
during community viral endemics; most patients remain entirely tory evidence of myocarditis among patients with negative biopsies.
asymptomatic. In contrast, myocarditis can also result in fulminant Biopsies performed within weeks of symptom onset have a higher
heart failure presenting as new-onset cardiomyopathy. Patients may yield than those undertaken when symptoms have been more long-
report a viral prodrome of fever, myalgias, respiratory symptoms standing.11 Current American College of Cardiology/American Heart
or gastroenteritis followed by an abrupt onset of hemodynamic Association (ACC/AHA) guidelines for the treatment of heart failure
collapse. The incidence of a reported infectious viral prodrome describe EMB as a class IIb recommendation. Biopsy is generally
is highly variable, ranging from 10% to 80% of patients with docu- reserved for patients with rapidly progressive cardiomyopathy
mented myocarditis. refractory to conventional therapeutic management or an unex-
Acute dilated cardiomyopathy is one of the most dramatic and plained cardiomyopathy that is associated with progressive conduc-
clinically relevant presentations of acute lymphocytic myocarditis. tion system disease or life-threatening ventricular arrhythmias.
The link between clinical myocarditis and acute dilated cardiomyo-
pathy is most convincingly provided by EMB findings. The two largest Cardiac Biomarkers
biopsy series have confirmed myocarditis in 9–16% of cases of new-
onset dilated cardiomyopathy.6,7 The Giant Cell Myocarditis Study Serum cardiac biomarkers [creatine kinase (CK), troponin I and T]
Group identified heart failure symptoms as the primary presentation are routinely measured when myocarditis is suspected. Creatine
in 75% of patients with giant cell myocarditis. Neither symptoms nor kinase or its isoform (CK-MB) is not generally useful for noninvasive
clinical course of myocarditis has been shown to correlate with his- screening because of its low predictive value. Lauer et al.12 reported
topathological features, such as the extent of lymphocytic infiltrate that only 28 of 80 patients (35%) with suspected myocarditis had
or fibrosis. The classification of Lieberman et al.8 differentiates fulmi- elevated troponin levels. Using a serum troponin T cutoff great-
nant from active myocarditis. Fulminant myocarditis, manifested by er than 0.1 ng/ml, these investigators reported a sensitivity for
severe hemodynamic compromise requiring high dose vasopressor detecting myocarditis of 53%, a specificity of 94%, a positive predic-
support or mechanical circulatory support, was identified in 15 of tive value of 93%, and a negative predictive value of 56%. Smith and
147 patients (10.2%) in the largest prospective study to use this classi- coworkers also examined the value of troponin I in a subgroup of the
fication system. Fulminant cases were additionally characterized by Multicenter Myocarditis Treatment trial. Although the sensitivity of
a distinct viral prodrome, fever, and abrupt onset (generally < 3 days) an elevated troponin I for the entire group was low (34%), its specific-
of advanced heart failure symptoms. These patients typically have ity was high (89%). Not surprisingly, a short duration of symptoms
severe global LV dysfunction and minimally increased LV end-dias- (< 4 weeks) was associated with a significantly higher sensitivity for
tolic dimensions. Of note, either borderline or active lymphocytic detecting biopsy-proven disease. More importantly, the positive pre-
myocarditis can produce this dramatic clinical presentation. dictive value was acceptable at 82%. Most clinicians now routinely
Myocarditis can produce variable effects on the cardiac conduc- measure either troponin T or I whenever a clinical diagnosis of myo-
tion system. Ventricular tachycardia is an uncommon initial manifes- carditis is considered.
tation of myocarditis but often develops during long-term follow-up.
The Giant Cell Myocarditis Study Group reported an initial incidence Immunologic Markers
of ventricular tachycardia of less than 5% in a multicenter cohort.
Ventricular tachycardia due to either lymphocytic or granulomatous Advances in immunology have expanded the diagnostic capabili-
myocarditis may infrequently result in sudden cardiac death. ties of the EMB. Immunohistochemical staining has enabled more
precise characterization of infiltrating lymphocytes subtypes and almost universally results in a full recovery of cardiovascular status
can accurately define and help quantify upregulation of MHC in previously healthy adults. Individuals with smallpox vaccine-asso-
antigens. Some investigators have adopted myocyte-specific MHC ciated myocarditis have also been shown to have rapid resolution of
expression as an essential criterion for diagnosing inflammatory clinical, laboratory, and echocardiographic abnormalities. Patients,
cardiomyopathy. who present with heart failure may have mildly compromised ven-
tricular function [left ventricular ejection fraction (LVEF) of 40–50%]
Myocardial Imaging and typically improve within weeks to months. Alternatively, a small-
er cohort of patients will present with more advanced LV dysfunc-
Noninvasive diagnostic myocardial imaging techniques for detection (LVEF > 35%, LV end-diastolic dimension > 60 mm). Among this
tion of myocarditis may include echocardiography, nuclear imaging group, 50% of patients will develop chronic ventricular dysfunction,
with gallium-67- or indium-111-labeled antimyosin antibodies and and 25% of patients will progress to transplantation or death; how-
magnetic resonance imaging (MRI). Echocardiography is currently ever, the remaining 25% of patients will have spontaneous improve-
recommended in the initial diagnostic evaluation of all patients with ment in their ventricular function. A small minority of these patients
suspected myocarditis. Several studies have specifically evaluated will present with cardiogenic shock requiring mechanical circulatory
the role of transthoracic echocardiography for diagnosing myocar- support as a bridge to cardiac recovery or transplantation.
ditis. Echocardiographic findings can be varied but relatively non-
specific. Serial studies have been shown to be useful in assessing the TREATMENT
response to treatment of several forms of myocarditis. Resolution of
marked concentric LV hypertrophy in eosinophilic myocarditis after Supportive care is the first line of treatment. A minority of patients
corticosteroid treatment has been reported. Although anatomic fea- who present with fulminant or acute myocarditis will require an
tures on echocardiography [i.e. chamber dimensions, ejection frac- intensive level of hemodynamic support and aggressive pharmaco-
tion (EF), wall motion abnormalities] are insufficient to differentiate logical intervention, including vasopressors and positive inotropic
myocarditis from other forms of cardiomyopathy but ultrasonic tis- agents, similar to other patients with advanced heart failure due
sue characterization may prove to be more useful. Transmission and to profound LV dysfunction. Elevated ventricular filling pressures
reflection of ultrasound energy depends on tissue density, elasticity should be treated with intravenous diuretics and vasodilators (when
and acoustical impedance. Changes in one or more of these factors feasible), such as nitroprusside or intravenous nitroglycerin. A ven-
lead to different ultrasonic backscatter and an altered image texture. tricular assist device or extracorporeal membrane oxygenation may
More recent techniques, particularly tissue Doppler imaging and rarely be required to sustain patients with refractory cardiogenic
myocardial velocity measurements are better able to characterize shock. These devices favorably alter ventricular geometry, reduce
tissue changes in acute myocarditis and to monitor changes in these wall stress, decrease cytokine activation, and improve myocyte
parameters over time. Additional validation studies will be required contractile function. Although the data on survival after ventricular
to determine their clinical utility. assist device or extracorporeal membrane oxygenation implantation
Indium-111-labeled monoclonal antibody fragments (directed are largely observational, the high likelihood of spontaneous recov-
against heavy chain myosin) bind to cardiac myocytes that have lost ery of ventricular function argues for aggressive short-term hemody-
the integrity of their sarcolemmal membranes and have exposed namic support.
their intracellular myosin to the extracellular fluid space. Unlike gal- After initial hemodynamic stabilization, treatment should fol-
lium, which detects the extent of myocardial inflammation, antimyo- low current ACC/AHA recommendations for the management of LV
sin cardiac uptake reflects the extent of myocyte necrosis. systolic dysfunction and include an angiotensin-converting enzyme
Contrast-enhanced MRI appears to be the most promising tech- inhibitor and adrenergic blocking agent in all patients and the selec-
nique for diagnosing myocardial inflammation and myocyte injury tive use of an aldosterone antagonist in patients with persistent New
on the basis of small, observational clinical studies. Besides pro- York Heart Association (NYHA) functional class III or IV symptoms.
viding anatomic and morphological information, MRI can provide The decision to prophylactically implant an implantable cardiovert-
accurate tissue characterization by measuring T1 and T2 relaxa- er-defibrillator in patients with advanced LV dysfunction should be
tion times and spin densities. Because active myocarditis is typically deferred for several months whenever possible to allow sufficient
associated with myocyte injury including edema and cellular swell- time for recovery of ventricular function. Because the long-term
ing, assessment of relaxation times provides a sensitive measure for sequelae of viral myocarditis appear to be related to abnormal cellu-
its detection. lar and humoral immunity, many clinicians believe that immunosup-
pression should be beneficial for myocarditis treatment. Although
NATURAL HISTORY AND PROGNOSIS greater than 20 uncontrolled observational studies have reported
success with the use of a variety of immunosuppressive agents14 and
The natural history of myocarditis is as varied as its clinical presen- several caveats should be emphasized. First, histological resolution
tations.13 Myocarditis masquerading as myocardial infarction (MI) of myocardial inflammation does not closely correlate with improve-
ment in ventricular function. Second, the high incidence of sponta- myocytes. Its precise characterization and natural history have been
neous improvement in contractile function supports the need for a limited by the extraordinary variability of its clinical presentations,
control group whenever treatment success is evaluated. Finally, the laboratory findings, and the diversity of etiologies. The relatively low
specific viral agent (e.g. adenovirus, enterovirus or parvovirus) and incidence and difficulties in unequivocally establishing a diagnosis
the immunologic state of the host may result in different response have limited the conduct of large-scale, randomized clinical trials to
rates to immunosuppression. Despite these considerable obstacles, evaluate treatment strategies.
several controlled clinical trials have been completed successfully. Treatment of myocarditis remains largely supportive. Immuno-
Intravenous immune globulin has been used to treat both giant suppression has not been shown to be effective as routine treatment
cell and lymphocytic myocarditis in uncontrolled studies. The Inter- for acute lymphocytic myocarditis. Early trials of antiviral therapies,
vention in Myocarditis and Acute Cardiomyopathy Study was a dou- such as interferons, suggest a potential therapeutic role but require
ble-blind, randomized, controlled trial of intravenous immune glob- further investigation. Currently, the standard of care from acute
ulin in 62 patients with recent-onset (< 6 months) heart failure and cardiomyopathy remains hemodynamic and cardiovascular sup-
unexplained dilated cardiomyopathy. No treatment-related differ- port, including use of ventricular assist devices and transplantation
ences were observed in all-cause mortality or improvement in LVEF when necessary. Pharmacological therapy should consist of a heart
at 6 or 12 months. Both groups demonstrated substantial increases failure regimen demonstrated to improve hemodynamics and symp-
in LVEF (> 10 EF units) during the study period. The spontaneous toms. Although the high rate of spontaneous improvement in acute
increase in LVEF observed in the control group once again limited myocarditis and cardiomyopathy provides some optimism, patients
the ability of a small trial to detect meaningful differences between who progress to chronic dilated cardiomyopathy experience 5-year
treatment regimens. survival rates greater than 50%. Ongoing clinical trials should help
Immunohistochemical studies have recently led to a reformula- to clarify whether immune-modulating strategies can improve this
tion of our therapeutic paradigm by focusing on the presence of an prognosis.
inflammatory cardiomyopathy rather than biopsy-proven myocardi-
tis per se. A more recent observational analysis examined the role of
circulating cardiac autoantibodies and viral genomic expression in a PERICARDITIS
cohort of 41 patients with biopsy-proven active lymphocytic myocar-
ditis who had failed to respond to conventional therapy. All patients Anatomy and Physiology
were treated empirically with azathioprine and prednisone immu-
nosuppression. Patients were subsequently classified as respond- The pericardium is composed of two layers, the visceral pericar-
ers or nonresponders after 1 year of follow-up. Cardiotropic viral dium, a membrane composed of a single layer of mesothelial cells
genome was present in 17 of 20 (85%) of nonresponders compared adherent to epicardial surface of heart, and the fibrous parietal layer,
with only 3 of 21 responders (14%). In addition, cardiac autoanti- which is about 2 mm thick in normal humans and surround most of
bodies were found in the sera of 19 of 21 responders (91%) and none the heart. The parietal pericardium is largely acellular and contains
of the nonresponders in this study. The lack of randomization and both collagen and elastin fibers. The pericardial space or sac is con-
lack of a control group limit, the generalizability of these potentially tained between these two layers and normally contains up to 50 ml of
important observations and call for additional studies to evaluate serous fluid. The pericardium normally restrain cardiac volume (i.e.
their significance. the force it exerts on the surface of the heart can significantly limit
Finally, both interferon-a and interferon-b have been described filling, with a component of intracavitary filling pressure represent-
as producing hemodynamic and clinical improvement in dilated car- ing transmission of pericardial pressure. The pericardium maintains
diomyopathy and myocarditis. Interferon-a benefit was described in the position of the heart relatively constant. It also functions as a
a case study15 and in a single-center, randomized trial comparing its barrier to infection and provides lubrication between visceral and
efficacy to placebo or thymomodulin. Although mortality did not dif- parietal layers. The normal pericardium also contributes to dias-
fer, LVEF rose significantly more in the treatment than the placebo tolic interaction, the transmission of intracavitary filling pressure to
group. Interferon-b has also been shown to produce benefit in a adjoining chambers.
phase II, single-center study of patients with PCR-detected enterovi-
ral or adenoviral genome on EMB.16 Data on the efficacy of interfer- Acute Pericarditis
on-a or -b have yet to be confirmed in large-scale, multicenter clini-
cal trials. Acute pericarditis is a common disorder in several clinical settings,
which include primary care as well as emergency and subspecialty
FUTURE DIRECTIONS departments, such as cardiology, rheumatology and nephrology.
The disease is recorded in 0.1% of hospitalized patients and 5% of
Myocarditis is the end result of both myocardial infection and patients admitted to the emergency department for nonacute MI
autoimmunity that results in active inflammatory destruction of chest pain.17
In clinical practice and with a traditional diagnostic approach, On this basis, knowledge of the epidemiological data is essential for
idiopathic and viral acute pericarditis is found in 80–90% of cases in the development of a rational management program for the disease.
immunocompetent patients from developed countries. Acute viral The varied causes of pericarditis suggest that the diagnostic ap-
or idiopathic pericarditis typically follows a brief and benign course proach should be targeted at the individual patient and background.
after empirical treatment with nonsteroidal anti-inflammatory
drugs (NSAID). As a result, it does not seem appropriate to perform Clinical Poor Prognostic Predictors
a full diagnostic evaluation in all patients because no specific treat-
ments exist for viral diseases. In many cases, both the performance Presumptive indicators of poor prognosis of acute pericarditis
of tests to establish a specific causal diagnosis and hospitalization of (fever > 38°C, subacute onset, immunodepression, trauma, oral
patients may be unnecessary. On this basis, it has been proposed anticoagulant therapy, myopericarditis, large pericardial effusion
that a patient with simple uncomplicated acute pericarditis could and cardiac tamponade), derived from literature review, have been
undergo initial evaluation in a same-day hospital facility or clinic and proposed to identify patients who should be admitted to a hospital
follow-up might be accomplished on an outpatient basis. Although and submitted to a full etiological search. However, additional risk
no absolute clinical features exist that will definitely differentiate factors may be considered. Another important feature of high-risk
between specific and idiopathic pericarditis, possible “indicators may be the lack of response to a NSAID after at least 1 week of thera-
of poor prognosis” of acute pericarditis have been reported. These py. In fact, failure to respond to a NSAID may imply the possibility of
negative clinical features are considered more frequently associ- a specific cause. For instance, the lack of response to NSAID, an in-
ated with an increased risk of short-term complications or a specific cessant or recurrent course, and cardiac tamponade at presentation
diagnosis. They included fever greater than 38°C, subacute onset, were found to be risk factors for neoplastic origin of acute pericardial
immunodepression, trauma, oral anticoagulant therapy, yoperi- disease. A recent open-label study on the use of colchicine in acute
carditis, large pericardial effusion, and cardiac tamponade. Further pericarditis has shown that corticosteroid use was a risk factor for
studies have also reported that the lack of initial response to aspi- recurrences, and so corticosteroids may also be considered within
rin could identify a group of patients at greater risk of relapses and poor prognostic predictors.
complications, and corticosteroids have been found as possible risk
factor for recurrences in acute pericarditis. Although previous find- PERICARDIAL EFFUSION
ings have shown that the clinical subsets of patients with unfavorable
clinical evolution after medical therapy and cardiac tamponade may Etiology
have a higher probability of a specific cause, all other features have
been derived from literature review but are not validated by pro- Idiopathic pericarditis and any infection, neoplasm, autoimmune
spective cohort studies. Acute pericarditis risk stratification based or inflammatory process can cause pericarditis leading to effusion.
on clinical and echocardiographic evaluation is important in clini- Effusions can also occur following surgeries, trauma, post-MI, cardiac
cal practice, because it could be useful to select the appropriate care procedures and a long list of noninflammatory causes of the diseases
setting (outpatient vs hospitalization) as well as to identify high-risk that can cause effusion; those with high incidence of progression to
cases to be admitted and thoroughly investigated. tamponade are infections (bacterial, fungal and viral, especially HIV)
and neoplasms. Although large effusions caused by acute idiopathic
Etiology pericarditis are unusual, because of its high frequency this form of
pericarditis accounts for significant number of tamponade cases.
In Europe and the US, the main specific causes to consider are Approximately 20% of large, symptomatic effusions without any
autoimmune (pericardial injury syndromes and connective tissue obvious cause on routine investigations constitute early manifesta-
diseases), neoplastic and tuberculous. Bacterial pericarditis other tions of undiagnosed cancers.
than tuberculosis is rare (< 1%). Although the relative frequency
of tuberculous pericarditis seems almost unchanged over years in Pathophysiology
Western countries, the causes of acute pericarditis are completely
different in developing countries with a high prevalence of specific The pericardial space normally contains 15–50 ml of fluid, which
forms related to tuberculosis (e.g. 70–80% of cases in subSaharan serves as lubrication for the visceral and parietal layers of the peri-
Africa, and even up to > 90% when pericarditis is associated with cardium. This fluid is thought to originate from the visceral peri-
HIV-infection). The incidence of tuberculous pericarditis is increas- cardium and is essentially an ultrafiltrate of plasma. Total protein
ing in Africa as a result of the HIV epidemic. In developed countries, levels are generally low; however, the concentration of albumin is
tuberculous pericarditis is less frequent, but a possible increase may increased in pericardial fluid owing to its low molecular weight. The
be expected in the near future as a result of immigrants from areas pericardium and pericardial fluid provide important contributions
with a high prevalence of tuberculosis and HIV-infected patients. to cardiac function. The parietal pericardium contributes to resting
diastolic pressure, and is responsible for most of this pressure in the • Cardiovascular
right atrium and ventricle. Through their ability to evenly distribute – Classic Beck triad of pericardial tamponade (hypotension,
force across the heart, the pericardial structures assist in ensuring muffled heart sounds, jugular venous distension)
uniform contraction of the myocardium. – Pulsus paradoxus: Exaggeration of physiologic respiratory
The normal pericardium can stretch to accommodate a small variation in systemic blood pressure, defined as a decrease
amount of fluid without significant change in intrapericardial pres- in systolic blood pressure of more than 10 mm Hg with inspi-
sure. However, once this pericardial reserve volume is surpassed, ration, signaling falling cardiac output during inspiration
the pressure-volume curve becomes steep. With slow increases in – Pericardial friction rub
volume, pericardial compliance can increase to lessen the increase – Tachycardia
in intrapericardial pressure. Clinical manifestations of pericardial – Hepatojugular reflux: This can be observed by applying
effusion are highly dependent upon the rate of accumulation of fluid pressure to the periumbilical region. A rise in the jugular
in the pericardial sac. Rapid accumulation of pericardial fluid may venous pressure (JVP) of greater than 3 cm H2O for more
cause elevated intrapericardial pressures with as little as 80 ml of than 30 seconds suggests elevated central venous pressure.
fluid, while slowly progressing effusions can grow to 2 l without symp- Transient elevation in JVP may be normal.
toms. Understanding the properties of the pericardium can help • Respiratory
predict changes within the heart under physiologic stress; during hy- – Tachypnea/dyspnea
pervolemic states, the pericardium limits acute cardiac cavitary dila- – Ewart sign: Dullness to percussion beneath the angle of left
tation. By distributing forces across the heart, the pericardium plays scapula from compression of the left lung by pericardial fluid
a significant role in the physiologic concept of ventricular interde- • Gastrointestinal: Hepatosplenomegaly
pendence, whereby changes in pressure, volume and function in one • Extremities
ventricle influence the function of the other. The pericardium plays a – Weakened peripheral pulses
pivotal role in cardiac changes during inspiration. As the right atrium – Edema
and ventricle fill during normal inspiration, the pericardium, by lim- – Cyanosis
iting the ability of these chambers to dilate, contributes to the bowing
of the atrial and ventricular septums to the left. This reduces LV filling LABORATORY INVESTIGATIONS
volumes, which lead to the drop in cardiac output. As intrapericar-
dial pressures rise, this effect becomes pronounced, eventually lead- Electrocardiogram
ing to the finding of pulsus paradoxus, heralding the development of
pericardial tamponade. The electrocardiogram shows diffuse low voltage, with a suggestion
The cause of abnormal fluid production depends on the un- of electrical alternans in the precordial leads. Early in the course of
derlying etiology, but it is usually secondary to injury or insult to acute pericarditis, the ECG typically displays diffuse ST elevation in
the pericardium (i.e. pericarditis). Transudative fluids result from association with PR depression. The ST elevation is usually present
obstruction of fluid drainage, which occurs through lymphatic in all leads except for aVR, but post-MI pericarditis, the changes may
channels. Exudative fluids occur secondary to inflammatory, infec- be more localized. Classically, the ECG changes of acute pericarditis
tious, malignant or autoimmune processes within the pericardium. evolve through four progressive stages:
1. Stage I: Diffuse ST-segment elevation and PR-segment depres-
Clinical Picture sion
2. Stage II: Normalization of the ST and PR segments
A patient with pericardial effusion may report the following symp- 3. Stage III: Widespread T-wave inversions
toms: 4. Stage IV: Normalization of the T waves
• Cardiovascular chest pain, pressure, discomfort: characteristi-
cally, pericardial pain may be relieved by sitting up and leaning Chest X-ray
forward and is intensified by lying supine, light-headedness,
syncope, palpitations. Findings include enlarged cardiac silhouette (so-called water-bottle
• Respiratory-cough, dyspnea, hoarseness heart) and pericardial fat stripe. A third of patients have a coexisting
• Gastrointestinal-hiccoughs pleural effusion. Radiography is unreliable in establishing or refuting
• Neurologic-anxiety, confusion diagnosis of pericardial effusion.
Physical Echocardiography
Upon examination, a patient with pericardial effusion may have the Echocardiography is the imaging modality of choice for the diagnosis
following signs: of pericardial effusion, as the test can be performed rapidly and in
unstable patients. Most importantly, the contribution of pericardial Intracardiac Echocardiography

effusion to overall cardiac enlargement and the relative roles of tam-
ponade and myocardial dysfunction to altered hemodynamics can Intracardiac echocardiography (ICE) is generally reserved for the
be evaluated with echocardiography.18 assessment of pericardial effusion in the setting of percutaneous
• Pericardial effusion appears as an echo-free space between the interventional or electrophysiology procedure. Phased array ICE
visceral and parietal pericardium. Early effusions tend to accu- systems can perform both 2D and Doppler interrogations.
mulate posteriorly owing to expandable posterior/lateral peri-
cardium. Large effusions are characterized by excessive motion Computed Tomography
within the pericardial sac. Small effusions have an echo-free
space of less than 10 mm, and are generally seen posteriorly. • Computed tomography (CT) can potentially determine compo-
Moderate-sized effusions range from 10 mm to 20 mm and are sition of fluid and may detect as little as 50 ml of fluid.
circumferential, and greater than 20 mm indicates a large effu- • Computed tomography results in fewer false-positive results
sion. Fluid adjacent to the right atrium is an early sign of pericar- than echocardiography.
dial effusion. Severe cases may be accompanied by diastolic col- • Computed tomography can be problematic in patients, who are
lapse of the right atrium and right ventricle (and in hypovolemic unstable given the time required to transport to and from the
patients, the left atrium and left ventricle), signaling the onset of scanner and perform the test.
pericardial tamponade.
• Doppler echocardiography Magnetic Resonance Imaging
– Transmitral and transtricuspid inflow velocities should
be interrogated to assess for respiratory variation. • Magnetic resonance imaging can detect as little as 30 ml of
Decreases in flow during inspiration (transmitral) or pericardial fluid.
expiration (transtricuspid) should raise the suspicion of • May be able to distinguish hemorrhagic and no hemorrhagic
clinically significant interventricular dependence and fluids, as hemorrhagic fluids have high signal intensity on T-1
tamponade physiology. Pulmonic vein inflow may show weighted images, whereas no hemorrhagic fluids have low signal
a decrease in early diastolic flow with hemodynamically intensity.
significant effusions. Hepatic vein diastolic flow reversal • Nodularity or irregularity of the pericardium seen on MRI may
may also be seen. be indicative of a malignant effusion.
– False-positive echocardiograms can occur in pleural effu- • Magnetic resonance imaging is more difficult to perform than
sions, pericardial thickening, increased epicardial fat tissue, CT scan acutely, given the length of time the patient must remain
atelectasis and mediastinal lesions. Epicardial fat tissue is in the scanner.
more prominent anteriorly but may appear circumferen- Both MRI and CT scan may be superior to echocardiography in
tially, thus mimicking effusion. Fat is slightly echogenic and detecting loculated pericardial effusions, especially when located
tends to move in concert with the heart, two characteristics anteriorly.19 Also, these modalities allow for greater visualization of
that help distinguish it from an effusion, which is generally the thoracic cavity and adjacent structures, and therefore may iden-
echolucent and motionless. In addition to its mimicry, peri- tify other abnormalities relating to the cause of the effusion.
cardial fat accumulation is a source of bioactive molecules,
is significantly associated with obesity-related insulin resist- Other Tests
ance and may be a coronary risk factor.
In patients with pericardial effusion, imaging from low to The following lab studies may be performed in patients with
midposterior thorax can provide additional diagnostic echo- suspected pericardial effusion:
cardiographic images and should be used in patients in whom • Electrolytes: Metabolic abnormalities (e.g. renal failure)
conventional images are technically difficult or require additional • Complete blood count (CBC) count with differential: Leukocy-
information. tosis for evidence of infection, as well as cytopenias, as signs of
underlying chronic disease (e.g. cancer, HIV)
Transesophageal Echocardiography • Cardiac enzymes
• Thyroid-stimulating hormone: Thyroid-stimulating hormone
Transesophageal echocardiography (TEE) maintains all of the screen for hypothyroidism
advantages of transthoracic echocardiography and is useful in • Rheumatoid factor, immunoglobulin complexes, antinuclear
characterizing loculated effusions. However, this may be difficult to antibody test (ANA), and complement levels (which would be
perform in patients with symptomatic effusions due to hemodynam- diminished)—In suspected rheumatologic causes
ic instability, making the required sedation more difficult. • Purified protein derivative (PPD) and controls
Pericardial Fluid Analysis – Cultures: Signals and identifies infectious etiology

– Fluid hematocrit for bloody aspirates: Hemorrhagic fluid
• Routine tests (these should be considered part of the standard hematocrits usually significantly less than simultaneous
pericardial fluid analysis) peripheral blood hematocrits
– Lactic acid dehydrogenase (LDH), total protein: The Light cri- • Special tests (these should be considered individually based on
teria (for exudative pleural effusion) found to be as reliable in the pretest probability of the coexisting condition under con-
distinguishing between exudative and transudative effusions cern)
– Total protein fluid-to-serum ratio greater than 0.5 – Viral cultures
– Lactic acid dehydrogenase fluid-to-serum ratio greater than – Adenosine deaminase
0.6 – Polymerase chain reaction
– Lactic acid dehydrogenase fluid level exceeds two-thirds of – Culture for tuberculosis; smear for acid-fast bacilli in sus-
upper-limit of normal serum level pected tuberculosis infection, especially in patients with
Other indicators suggestive of exudate: HIV
– Specific gravity greater than 1.015 A definite diagnosis of tuberculous pericarditis is based on the
– Total protein greater than 3.0 mg/dl demonstration of tubercle bacilli in pericardial fluid or on a histo-
– Lactic acid dehydrogenase greater than 300 U/dl logical section of the pericardium. Probable tuberculous pericardi-
– Glucose fluid-to-serum ratio less than 1 tis is based on the proof of tuberculosis elsewhere in a patient with
– Cell count: Elevated leukocytes (i.e. > 10,000) with neutro- otherwise unexplained pericarditis, a lymphocytic pericardial exu-
phil predominance suggests bacterial or rheumatic cause, date with elevated adenosine deaminase levels, and/or appropriate
although unreliable response to a trial of antituberculosis chemotherapy.
– Gram stain: Specific but insensitive indicator of bacterial Tumor markers: Elevated carcinoembryonic antigen (CEA) lev-
infection els in pericardial fluid have a high specificity for malignant effusions.
REFERENCES
1. Fabre A, Sheppard MN. Sudden adult death syndrome and other non ischaemic causes of sudden cardiac death: a UK experience. Heart.
2006;92(3):316-20.
2. Felker GM, Hu W, Hare JM, et al. The spectrum of dilated cardiomyopathy: the Johns Hopkins experience with 1,278 patients. Medicine (Balti-
more). 1999;78:270-83.
3. Keeling PJ, Poloniecki LA, Caforio AL, et al. A prospective case-control study of antibodies to Coxsackie B virus in idiopathic dilated cardiomyo-
pathy. J Am Coll Cardiol. 1994;23:593-8.
4. Kuhl U, Pauschinger M, Noutsias M, et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idi-
opathic” left ventricular dysfunction. Circulation. 2005;111:887-93.
5. Hofman P, Drici MD, Gibelin P, et al. Prevalence of toxoplasma myocarditis in patients with the acquired immunodeficiency syndrome. Br Heart
J. 1993;70:376-81.
6. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl
J Med. 2000;342:1077-84.
7. Herskowitz A, Campbell S, Deckers J, et al. Demographic features and prevalence of idiopathic myocarditis in patients undergoing endomyocar-
dial biopsy. Am J Cardiol. 1993;71:982-6.
8. Lieberman EB, Hutchins GM, Herskowitz A, et al. Clinicopathologic description of myocarditis. J Am Coll Cardiol. 1991;18:1617-26.
9. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Pathol. 1987;1:3-14.
10. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial In-
vestigators. N Engl J Med. 1995;333:269-75.
11. Hauck AJ, Kearney DL, Edwards WD. Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocardi-
tis: implications for role of sampling error. Mayo Clin Proc. 1989;64:1235-45.
12. Lauer B, Niederau C, Kuhl U, et al. Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol. 1997;30:1354-9.
13. Magnani JW, Suk-Danik HJ, Dec GW, et al. Survival in biopsy-provenmyocarditis: a long-term retrospective analysis of the histopathologic, clini-
cal, and hemodynamic predictors. Am Heart J. 2006;151:463-70.
14. Frustaci A, Chimenti C, Calabrese F, et al. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of
responders versus nonresponders. Circulation. 2003;107:857-63.
15. Daliento L, Calabrese F, Tona F, et al. Successful treatment of enterovirus-induced myocarditis with interferon-alpha. J Heart Lung Transplant.
2003;22:214-7.
16. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function
in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation. 2003;107:2793-8.
17. Hoit BD. Pericardial disease and pericardial tamponade. Crit Care Med. 2007;35(8 Suppl):S355-64.
18. Horowitz MS, Schultz CS, Stinson EB. Sensitivity and specificity of echocardiographic diagnosis of pericardial effusion. Circulation. 1974;50:239-
47.
19. Karia DH, Xing YQ, Kuvin JT, et al. Recent role of imaging in the diagnosis of pericardial disease. Curr Cardiol Rep. 2002;4(1):33-40.
35 History of Infective Endocarditis
and Future Directions
Sankardas MA, Subban VK
vanni Battista Morgagni of Italy in 1769, attempted to link the symp-

INTRODUCTION
toms during life with anatomical lesions found at autopsy. In the De
Infective endocarditis (IE) is a serious disease involving the inner sedibus, he mentioned about a patient who died of virulent gonor-
layer of the heart, particularly of the valves.1 The knowledge of histo- rhea. At autopsy, he noticed a large number of outgrowths on the
ry of this disease is long and is spread over 5 centuries with contribu- aortic valve and in addition he found multiple lesions in the spleen.
tion from different generations. Even in the modern era of advanced But no clear relation was established between the symptoms and
diagnostic imaging, improved antimicrobial chemotherapy and anatomical lesions.5 Sandifort published an illustration of a case of
potentially curative surgery, IE is associated with a persistently ventricular septal defect with IE on the aortic valve in 1784.6 In 1797,
high morbidity and mortality. With increasing number of patients Matthew Baillie in England correlated rheumatic carditis and later
with congenital heart disease surviving into adulthood, growing occurrence of deformities of the valves.5
population of elderly with degenerative valve diseases, liberal use of In 1806, Jean Nicolas Corvisart was the first person to use the
intravascular devices, ever rising nosocomial infections and marked- word “vegetations” to refer to the outgrowths on the inner layer
ly expanding number of immunosuppressed individuals, IE contin- of the heart. He liked the appearance of the outgrowths to that of
ues to be a major health issue.2 The first part of this chapter reviews venereal warts and proposed syphilitic virus as the possible cause of
the evolution of endocarditis over the years and the later part deals these abnormalities. Further, he suggested antivenereal treatment, if
with the current trends and emerging issues. the diagnosis could be established.7 However in 1808, Englishman
Allen Burns expressed different views on the formation of vegeta-
HISTORICAL PERSPECTIVE tions in his discussion on polyps of the heart. According to him, the
vegetations were not “outgrowths” or “buds”, but aggregation of parti-
The earliest recorded reference to endocarditis is given by Jean cles adhering to the heart.8 Invention of the “cylindrical stethoscope”
Francois Fernel, physician to Henri II of France, in his book called by Théophile-Hyacinthe Laënnec, a pupil of Corvisart, in 1816 was
“Universa Medicini” published in three parts in the middle of the a major step forward in clinical cardiology. Improvement in cardiac
16th century.3 auscultation further enhanced the clinicopathological correlation.
Towards the end of the 17th century and early 18th century, Laënnec also questioned the venereal etiology of vegetation pro-
understanding of cardiac abnormalities significantly improved with posed by Corvisart, as he could not find a history of syphilis during
the anatomical observations from autopsy studies. A number of ana- life in many of the patients with vegetations. This observation was
tomical abnormalities of the inner membrane of the heart and the confirmed later by James Hope in 1832.4
valve were noticed during this period.4
In 1646, Lazare Rivière, professor of Medicine at the University Bouillaud’s Endocarditis
of Montpellier made one of the first pathological descriptions of the
heart. In the autopsy of a patient who presented to him with features Jean-Baptiste Bouillaud, a French physician, labeled the inner layer
suggestive of cardiac failure, he observed multiple round outgrowths of the heart as “endocardium” in his book Traité Clinique Des Mal-
of varying sizes in the left ventricle and a larger one obstructing the adies Du Coeur, published in 1835. He was well aware of the vari-
aortic valve.5 Next reference to endocarditis was given by the Italian ous infections of the endocardium. He proposed that inflammation
clinician Giovanni Maria Lancisi who in 1708, discussed an unusual of the endocardium could be the cause of the lesions on the valves.
structure at the entrance into the aorta and proposed these as pro- Following his autopsy observations, he divided endocarditis into
jections of fibers and valvular tissue.5 Similar valvular abnormalities four phases: (1) Normal heart, (2) Redness and thickening, (3) Valvu-
were also enlightened in 1715 by Raymond Vieussens and later in lar vegetations and (4) Valvular damage. He also described the clini-
1749 by Jean-Baptiste Sènac in France.4 In the same century, Gio- cal features associated with valvular vegetations in the form of high
Chapter 35  History of Infective Endocarditis and Future Directions 239
temperature and “bellows murmur”. He later classified endocarditis In 1878, Edwin Klebs, a well-known microbiologist from Prague,
into two broad clinical categories: (1) Simple, a purely inflammatory expressed that all cases of endocarditis were of infectious origin. In
affection, which either developed independently or became evident his microscopic study of vegetations from 27 autopsy cases, he could
during acute rheumatoid arthritis, pleurisy or pleura-pneumonia find micrococci in the septic endocarditis, and the structures, which
and (2) Septic, endocarditis modified by coexistent typhoid state.4 he called “monads” in the remaining cases, due to rheumatic endo-
carditis. But, he did not explain the mode of colonization of micro-
Embolic Phenomena organism on the valve. In the same year, Karl Koester proposed that
the affection began in the inner aspect of the valve before being more
Rudolph Virchow, in 1846, was the first to recognize the occurrence superficial. Joseph Hamburg, a student of Virchow in 1879, differed
of embolic events during IE. He described a case of a young man who on this and said that the parasites carried by the blood entered the
presented to him with several weeks of fever and incoherent speech. vegetation from outside to inside and the portal of entry was either
After a few days, he developed pain in the left foot and a month later the healthy lungs or intestines or from a point of infection. He later
he succumbed. The autopsy showed mitral valve vegetations and undertook detailed microscopic study of 14 autopsy cases. In that
emboli in right carotid, left femoral and popliteal arteries. He stud- study he could find micrococci only in four cases and according to
ied microscopically the embolized material and the organ infarct. him the remaining cases were inflammatory similar to any paren-
He later named this phenomenon as “embolism”.9 In 1852, William chymatous inflammation. Germain Sée in France, was also in favor
Senhouse Kirkes, the English physiologist, published his classic work of infectious theory and he was the first to talk about the treatment:
on embolic manifestations of endocarditis. He described autopsy “If future therapeutics provides us with more effective means of
findings of four endocarditis patients. In three of the patients, who fighting endocarditis, it will certainly come from attacking the root
died of cerebral embolism, in addition he noted emboli in other ves- cause, i.e. parasitic infection”. However, Michel Peter believed that
sels along with infarcts in spleen and kidneys. The other patient had microorganisms were not the cause, but were the result.4
tricuspid valve endocarditis and his lungs showed minute hemor- During that period, it was very difficult to prove either the
rhages throughout. He correctly correlated the type of the vessel oc- infectious or the inflammatory theory as there was no conclusive
cluded to the size of the emboli. Further, he also attributed the pro- evidence for either. It was impossible to show the existence of the
duction of typhoid or phlebitic symptoms of endocarditis to minute bacteria in the bloodstream and their growth in the vegetations
particles mingled with blood—the early concept, microemboli and during the patient’s lifetime.
immune complexes.10 In 1870, Samuel Wilks proposed scarlet fever
as a possible cause for the endocardial lesions and postulated that BIRTH OF BLOOD CULTURE
the poisoning of blood by particulate materials released from veg-
etations were the cause of death rather than the vegetation per se.11 The birth of bacteriology, thanks to the works of Louis Pasteur in
France and that of Robert Koch and others in Germany in the later
PATHOPHYSIOLOGY OF ENDOCARDITIS— part of the 19th century made a major impact on the understanding
of the pathophysiology of IE. To prove Winge’s postulates on trans-
INFECTIOUS OR INFLAMMATORY
portation of parasites from cutaneous lesions to the heart and from
In 1869, Emmanuel Winge of Norway, made a landmark contribution there to other parts of the body, it was essential to establish the pres-
to the understanding of endocarditis by his theory on its pathophysi- ence of microorganisms in blood. This leads to the idea of cultivation
ology. He described elegantly the chronology of events in a case of of blood to identify the organisms. However, it was very demanding
a healthy male who developed a local abscess following removal of to obtain and cultivate blood without contamination. It was Pasteur
a corn from the sole of his feet. The patient died a month later. In who obtained the first pure bacterial culture from a woman with
the autopsy study, he found vegetations on both sides of the heart puerperal sepsis, by using a finger prick. He also proposed the idea
and embolisms in the lungs, left kidney and the spleen. Microscopic of taking blood from different points of the body to track the germs
examination of the vegetation showed organisms in the form of mesh circulated in the blood. In 1880, Jacques Doleris, an obstetrician
of threads together with rods and round bodies. Similar organisms obtained systematic blood cultures in the hospital context and he
were noticed in the renal artery embolus. He linked the systemic also noted that the cultures were frequently positive when there was
events to the suppuration of the wound and transmission of parasites a marked increase in patient’s body temperature or when there was
to the heart through veins and later to other organs. He called this shivering. However, single finger prick did not yield enough blood
affection as “mycosis endocardii”.12 In 1872, another Norwegian, and it necessitated multiple pricks over different parts of the body.
Hjalmar Heiberg, reported a case of puerperal endocarditis. His au- Development of various syringe designs, particularly piston syringe
topsy study on that patient found similar organisms in both the mitral in France, syringe with a glass body and asbestos piston by Lüer in
valvular vegetation and embolisms. As with Winge, he claimed that Germany and later completely glass syringe by Malassez in France
uterine wound as the portal of entry of the microorganism.13 Many simplified the technique of sterile collection of adequate quantity
similar observations followed in the subsequent years from Europe. of blood directly from the circulation in a single prick. This made it
possible to discover the microorganisms responsible for the disease ing blood in the heart cavity rather than through small blood vessels
in a living patient.4 inside the valves and (3) Only certain types of bacteria were likely to
In 1880s, Arnold Netter, an intern working under Joseph adhere to the valves, especially the Streptococcus and the Staphylo-
Grancher, did systematic sampling of blood of patients with clinically coccus. He also believed that negative culture results could be due to
proven endocarditis. He observed the germs under the microscope death of the bacteria before or during culture. Thus, the experimental
and the sample was then incubated in chicken broth culture media. endocarditis contributed immensely to further understanding of the
After incubation for 48 hours, he could recognize the growth of colo- pathophysiology of the disease.4
nies of microorganism. In the series of blood cultures, he noticed a
diversity of microorganisms. Based on these observations, he con- CLASSIFICATION OF ENDOCARDITIS
cluded that endocarditis was an anatomical and clinical symptom,
which could appear during various infections. It contradicted the Based on the knowledge that had been accumulated on this disease,
idea that one single microorganism had to correspond to one dis- by combining the clinical and bacteriological approaches, classi-
ease. This made Grencher to use the term “infectious endocarditis” fication of endocarditis was attempted toward the end of the 19th
for this entity in 1884. Subsequently, in a patient with clinical en- century.
docarditis, he did serial blood cultures and later autopsy. He found William Osler of United States, one of the greatest clinicians at
micrococci in both the cultures when the patient was alive and in the the turn of the century, synthesized the work of others relating to
vegetations obtained during autopsy.4 endocarditis and presented three Gulstonian lectures on the topic
Even though, microorganisms were consistently demonstrated of “malignant endocarditis”, in which he gave a comprehensive
to be associated with endocarditis, it was impossible to prove its account of the seriousness of the disease and the grave prognosis
causative role. It was deemed necessary to reproduce the disease attached to it. He classified endocarditis into “acute”—characterized
in an animal. However, attempted injection of pathogenic bacteria by vegetations and exudation on the endocardial surface with loss of
into an animal failed to reproduce the disease. It became clear that substance and “chronic”—characterized by slowly progressive scle-
endocarditis cannot be transmitted from one person to other and the rosis resulting in deformation, but no vegetation. He also mentioned
portal of entry remained unknown. “simple” and “malignant” endocarditis.
Osler addressed the major features of “slow” type endocardi-
EXPERIMENTAL REPRODUCTION tis in great detail: previous valvular abnormality either from acute
rheumatoid arthritis or congenital valvular abnormality; irregular
OF ENDOCARDITIS
and intermittent fever; sweating; heart murmur; embolism; certain
Edwin Klebs, in 1876, published his study on hemodynamic con- skin manifestations from embolism; prolonged illness lasting for 3–4
sequences of experimental valvular regurgitation. For this experi- months. He linked the local and general manifestations to the growth
ment, he induced mitral valve damage in a dog by passing a special of bacteria on heart valves and its transportation away from the origi-
type of catheter through the carotid artery into the left ventricle.14 nal point of affection.17
Influenced by this experiment and experiments to study the trans- In 1899, Hermann Lenhartz described staphylococcal, strepto-
mission of infectious diseases in 1878, Ottomar Rosenbach of Bre- coccal, pneumococcal and gonococcal endocarditis. He believed
slau, established the first endocarditis animal model. His model that acute and chronic types of endocarditis were caused by different
resulted from the combination of animal models of “experimental types of Streptococci. In 1910, Hugo Schottmüller distinguished these
physiology” and “experimental infection”, which could not produce two organisms by their hemolytic properties and named the Strepto-
endocarditis separately. By pushing a stylet covered with septic coccus causing the chronic endocarditis as “Streptococcus mitior seu
matter through the rabbit’s carotid artery, he induced mechani- viridians” as it produced a greenish pigment. He identified this entity
cal injury to the aortic valve, which later resulted in endocarditis. as “endocarditis lenta”.18
He could not induce endocarditis by producing mechanical injury A few years later, Emanuel Libman an endocarditis specialist
with a sterile stylet or the injection of microorganism in the absence from New York, United States, published his work on the slow form
of valvular damage.15 This and latter works by Vladimir Wyssokow- of endocarditis and proposed a new name “subacute endocarditis”
itsh in Russia, concluded that IE always developed on a previously even though, Osler’s name was given to this form of endocarditis. In
damaged valve.16 his article, he gave a detailed account on the clinical features of suba-
Similar work was conducted in Austria by Weichselbaum, cute endocarditis and clearly differentiated it from the acute variety,
professor of Histopathology and Bacteriology at the University of which was fatal within a matter of days.19 Libman along with Benja-
Vienna. He came out with some important observations such as: (1) min Sacks in 1924, described another variety of endocarditis “atypi-
Experimental endocarditis needs a previous valvular lesion, (2) The cal verrucous endocarditis”, which was found to be associated with
microorganisms enter the valves from outside through the circulat- systemic lupus erythematosus.20
ANTIBIOTIC ERA DIAGNOSTIC CRITERIA

In his descriptions of a case of IE, Bouillaud wrote: Infective endocarditis is a syndrome diagnosis based on a constel-
“…. Prescription: Blood-letting in two bleeding bowls, herbal tea, lation of findings, rather than a single laboratory test. So, a uniform
starvation diet. The following day we recommended that two scari- case definition was then essential for the clinicians and researchers
fied cupping glasses be placed at the back of the chest. There was who studied this complex disease. The first criteria for the diagnosis
some improvement but suddenly, on December 31, the suffocation of IE, developed in 1977 by Pelletier and Petersdorf, were specific,
became so great that the patient died during the day ….”4 but lacked sensitivity.25 Subsequently, in 1982 Von Reyn et al. pub-
This shows the incurable nature and the uniform fatality of IE. lished their criteria (Beth Israel criteria) based on the clinical and
Numerous treatment modalities, like antibacterial vaccines and microbiologic features.26 These criteria quickly became the stand-
various types of dyes were employed with no success. The first ard by which the diagnosis of IE was established. Though Von Reyn
sulfonamide, sulfanilamide, though available in 1936, did not make criteria improved the specificity, the sensitivity remained low. In
much difference. With the availability of penicillin in 1944 for the 1994, with emphasis on echocardiography the newer Duke’s criteria
first time, the fatal disease was treated successfully. Slowly the hos- has become the standard,27 which was later approved by the AHA.
tile nature of the vegetation was realized and prolonged treatment Recently, modifications were made in the original Duke’s criteria to
with higher doses of antibiotics came into practice. Newer antibiotics further improve the specificity.28
developed subsequently to cope with the need to treat more virulent
and resistant organisms.21 CURRENT TRENDS AND
FUTURE CHALLENGES
ANTIBIOTIC PROPHYLAXIS
Although, IE is known for the past 450 years, it still remains an enig-
The second-half of the 20th century witnessed the concept of pre- matic disease. Despite major diagnostic and therapeutic advances,
vention of major diseases and endocarditis was no exception to this. the incidence remains the same over decades.29 However, there has
Antimicrobial prophylaxis to prevent IE was based on the principle been a marked change in the epidemiological patterns of IE since
that certain cardiac conditions were more prone to develop IE and 1960.
by using antibiotics prior to procedures involving bacteremia with Infective endocarditis has now become a disease of the elderly
organisms known to cause IE, serious infection can be prevented. with more than half of the patients older than 60 years. “Wear and
In 1955, the first American Heart Association (AHA) document on tear” degenerative valve diseases, as well as the proliferation of
this subject was published in Circulation. Subsequently, nine more intravascular devices have largely contributed towards this “graying”
documents were published till 2007 with modification of the indica- trend.1
tions and antibiotic regimens. In the latest guidelines, prophylaxis In most of the developed countries, mitral valve prolapse has
has been restricted to only a small number of cardiac conditions with supplanted rheumatic heart disease as the primary underlying
very high-risk for adverse outcomes from IE and is no more indicated condition and it accounts for up to 30% of the cases of native valve
for gastrointestinal and genitourinary procedures.22 endocarditis. About 20% have one or more prosthetic valves in place.
Calcific aortic stenosis contributes up to 50% valvular infection in the
ECHOCARDIOGRAPHY AND elderly.1
An important growing trend is healthcare-associated IE, which
INFECTIVE ENDOCARDITIS
accounts for about 25% of the IE population. It correlates with
Even though diagnosis of endocarditis was made from the clinical increasing employment of intravascular devices, like dialysis cathe-
scenario and positive blood cultures, intracardiac developments ters, hyperalimentation lines and pacemakers. Much of this is related
were known only during autopsy. The dramatic change in diagnos- to the bacteremia associated with infection of intravascular catheters
tic evaluation occurred in 1973 with the first M-mode description of and other devices and fewer than 50% of patients had underlying
valvular vegetations.23 With the advent of two-dimensional and Dop- structural heart disease.30 Device related IE, particularly from pace-
pler modalities and later addition of transesophageal imaging, echo- makers, defibrillators and ventricular assist devices has gone up by
cardiography has become virtually indispensible in the diagnosis 124%. With expanding application of these devices, this might still go
and management of these patients. In 1994, the Duke Endocarditis up in the future.1
Service included the echocardiographic appearance of vegetations The most significant observation in the recent prospective
as one of the major diagnostic criteria.24 studies on IE is that Staphylococcus aureus has superseded
Streptococcus as the most common cause of IE in much of the world. also be used to identify the organism well, before the culture reports
The rapid growth of intravascular devices and increasing number of become available so that appropriate antibiotics can be started
invasive procedures on hospitalized patients are the major contribu- early. In future, identification of antimicrobial resistance genes ena-
tors to this change. As a direct result the cases of acute IE have in- bles a targeted and cost-effective approach to antibiotic treatment.
creased to the point that they now outnumber subacute ones.30 Improvements in diagnostic imaging (e.g. three-dimensional echo-
The number of immunosuppressed individuals has risen mark- cardiography, intracardiac echocardiography computed tomogra-
edly over the last 25 years. The patients belong to this category are phy and cardiac magnetic resonance) to better assess the intracar-
those with acute immunodeficiency syndrome, organ transplant diac anatomy may further improve patient management.
recipients, and those on aggressive therapy for hematologic and solid Development of intracardiac devices like prosthetic valves
malignancies.31 and pacemaker leads using biomaterials resistant to infection may
Resistance of the common bacteria to conventional antibiotic reduce the risk of IE.
regimens is a growing concern of the present medical community. Vaccines targeting specific bacterial adhesins, may inhibit colo-
Streptococcal resistance to penicillin and other β-lactam antibiot- nization of valves with pathogenic bacteria. Encouraging results have
ics, mediated by decreased affinity of the penicillin binding proteins been reported with antistreptococcal and antistaphylococcal vacci-
to the β-lactams increasingly being reported. Methicillin resist- nations in hemodialysis patients.2
ance among staphylococci is now widely prevalent in most hospital Newer antibiotics currently available or in development may
environments. Adding to this, chromosomal mutation acquired help to overcome multidrug resistance among Gram-positive cocci.
vancomycin resistance is an emerging problem. Similarly, multidrug Quinupristin-Dalfopristin, linezolid, daptomycin and tigecycline
resistant enterococci are also commonly encountered. This puts lot have already shown excellent activity against vancomycin-resistant
of pressure to develop newer and more potent antibiotic regimens isolates. Dalbavancin, telavancin and oritavancin are new lipogly-
to cope with the rapidly growing resistance. Another concern is that copeptide agents with superior pharmacodynamics properties and
in future, we may be in a situation in which we may not be able to excellent activity against Gram-positive cocci are currently being
treat even a simple infection resulting from pan-antibiotic resistant evaluated.33
organisms.2 The recently reported New Delhi Metallo-beta-lacta- Till date, there are no large-scale prospective studies on any of
mase (NDM-1) gene acquired bacterial resistance to a broad range of the aspects of IE. The current knowledge is largely based on small,
frontline antibiotics is an example of this situation.32 uncontrolled, single center studies. An International Collaboration
Current era is witnessing the emergence of IE due to newer on Endocarditis (ICE) was initiated in 1999 to establish a global
organisms, like Tropheryma, Bartonella spp., Finegoldia spp., database of IE patients to further the understanding of this disease.
Gemella spp., Abiotrophia defectiva, etc. These organisms pose prob- International Collaboration on Endocarditis has already merged its
lems in both diagnosis and treatment. Even though diagnosis can be existing databases, which have given a pool of 2,200 well character-
established with newer serological methods, it remains very difficult ized patients with definite IE by the Duke’s criteria. The purpose of
to culture and device antibiotic regimens for these.29 this project was to assess the regional differences in endocarditis and
to provide a large sample of patients that would permit various sub-
NEW DEVELOPMENTS group analyses. The hypotheses generated from these analyses may
be tested in future randomized, prospective cohort studies by ICE.
Newer molecular techniques like polymerase chain reaction have The forthcoming information will allow evidence based decision
enhanced the reliability of detection of fastidious and noncultur- making for difficult areas of treatment, such as antibiotic prophylax-
able agents in blood and surgical materials of patients with IE. It may is, surgical indications and the treatment of unusual causes of IE.34
REFERENCES
1. Brusch JL. Epidemiology. In: Brusch JL (Ed.). Infective Endocarditis: Management in the Era of Intravascular Devices. New York: Informa Health-
care USA, Inc; 2007. p. 1.
2. Prendergast BD. The changing face of infective endocarditis. Heart. 2006;92(7):879-85. Epub 2005.
3. Fye WB. Jean François Fernel. Clin Cardiol. 1997;20(12):1037-8.
4. Contrepois A. Towards a history of infective endocarditis. Med Hist. 1996;40(1):25-54.
5. Major RH. Notes on the history of endocarditis. Bull Hist Med. 1945;17:351-9.
6. Long ER. A history of pathology. Baltimore, MD: Williams and Wilkins; 1928. p. 118.
7. Kerr A. History. Subacute Bacterial Endocarditis. Springfield, Illinois: Charles C Thomas Publisher Ltd; 1955. pp. 3-30.
8. Burns A. Observations on the formation of polypi in the heart. In: Observations on Some of the Most Frequent and Important Diseases of the
Heart. Edinburgh: T Bryce and Co; 1809. pp. 191-202.
9. Virchow R. Ueber Capillaire Embolie. Arch Path Anat. 1856;9:307-8.
10. Kirkes WS. On some of the principal effects resulting from the Detachment of Fibrinous Deposits from the interior of the heart, and their mixture
with the circulating blood. Med Chir Trans. 1852;35:281-324.
11. Wilks S. Select clinical cases. Guy’s Hosp Rep. Series 3. 1870;15:29-35.
12. Winge E. Mycosis endocardia. Hyg Med Farm Man. 1870;32:172-5.
13. Heiberg H. Ein Fall von Endocarditis ulcerosa puerperalis mit Pilzhildungen in Herzen (Mycosis endocardii). Virchows Arch Path Anat.
1872;56:407-15.
14. Jarcho S. Edwin Klebs on experimental valvulotomy (1875). Am J Cardiol. 1967;19(4):572-6.
15. Jarcho S. Artificial insufficiency of heart valves (Rosenbach, 1878). Am J Cardiol. 1967;19(6):850-3.
16. Jarcho S. Experimental endocarditis (Wyssokowitsch, 1886). Am J Cardoil. 1969;24(6):876-9.
17. Osler W. The Galstonian Lectures, on Malignant Endocarditis. Br Med J. 1885;1(1262):467-70;1(1263)522-6;1(1264)577-9.
18. Schottmuller H. Endocarditis lenta. Munch Med Wochenschr. 1910;1:617-20.
19. Libman E, Celler HL. The etiology of subacute infective endocarditis. Am J Med Sci. 1910;140:516-27. Reprinted in Am J Med Sci. 1973;266(1):44-
52.
20. Libman E, Sacks B. A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med. 1924;33:701-37.
21. Weinstein L, Brusch JL. The historical development of antimicrobial and surgical therapy of infective endocarditis. In: Weinstein L, Brusch JL
(Eds). Infective Endocarditis. 1st edition. New York: Oxford University Press; 1996. p. 17.
22. Wilson W, Taubert KA, Gewitz M, et al. Prevention of Infective Endocarditis. Guidelines from the American Heart Association: A guideline from
the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the
Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Re-
search Interdisciplinary Working Group. Circulation. 2007;116(15):1736-54.
23. Dillon JC, Feigenbaum H, Konecke LL, et al. Echocardiographic manifestations of valvular vegetations. Am Heart J. 1973;86(5):698-704.
24. Evangelista A, Gonzalez-Alujas MT. Echocardiography in infective endocarditis. Heart. 2004;90(6):614-7.
25. Pelletier LL Jr, Petersdorf RG. Infective endocarditis: a review of 125 cases from the University of Washington Hospitals, 1963-72. Medicine (Balti-
more). 1977;56(4):287-313.
26. Von Reyn CF, Levy BS, Arbeit RD, et al. Infective endocarditis: an analysis based on strict case definitions. Ann Intern Med. 1981;94(4 pt 1):505-18.
27. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke En-
docarditis Service. Am J Med. 1994;96(3):200-9.
28. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633-
8. Epub 2000.
29. Millar BC, Moore JE. Emerging issues in infective endocarditis. Emerg Infect Dis. 2004;10(6):1110-6.
30. Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International
Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169(5):463-73.
31. Brusch JL. Cardiac infections in the immunosuppressed patients. Infect Dis Clin North Am. 2001;15(2):613-38, xi.
32. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular,
biological, and epidemiological study. Lancet Infect Dis. 2010;10(9):597-602. Epub 2010.
33. Manfredi R, Sabbatani S. Novel pharmaceutical molecules against emerging resistant Gram-positive cocci. Braz J Infect Dis. 2010;14(1):96-108.
34. Cabell CH, Abrutyn E. Progress toward a global understanding of infective endocarditis. Lessons from the International Collaboration on Endo-
carditis. Cardiol Clin. 2003;21(2):147-58.
The History of Deep Vein
36 Thrombosis and Pulmonary
Thromboembolism
Deb PK, Chatterjee A
developed a permanently swollen leg following child birth and went

INTRODUCTION
on to live 38 years with it. Richard Wiseman, a famous surgeon in the
Dalen and Alpert1 estimated that there are 630,000 symptomatic court of Charles II, described DVT following child birth. He correctly
episodes of pulmonary embolism (PE) per year in the US, making postulated that the clots are formed because of stagnation of blood
it half as common as acute myocardial infarction (AMI) and three in the vessel as a result of dependency, external pressure or some
times as common as cerebrovascular accident. This is an underesti- abnormality in the composition of blood.6
mate, because nearly three out of four cases of autopsy proven PE are Since fluid accumulation was seen to occur in the limbs of
not detected clinically.2 patients having DVT, humoral theories became fashionable among
The phenomenon of deep vein thrombosis (DVT) was probably a section of the medical fraternity. Given the fact that DVT is
known to Hippocrates (460–377 BC), the celebrated Greek physician. common in pregnancy, it was thought to result from the accumula-
In a relief preserved at the National Archaeological Museum, Athens, tion of lochia in the lower limbs. Others believed that it is caused by
Greece, Hippocrates is seen examining a hugely swollen lower limb the accumulation of milk. Charles White of Manchester contested
of a patient who also possessed varicose veins.3 these assertions and put forth the alternative hypothesis that the
head of the fetus caused rupture of lymphatic channels; accumula-
ETIOLOGY tion of lymph in the limb followed and gives rise to phlegmasia alba
dolens puerperium. Incidentally, he believed that such an event
Ask and it will be given to you; seek and you will find; knock and the can only occur in women, hence the name. But his successors soon
door will be opened to you.4 discovered that similar findings can be seen in nonpregnant women
Rudolph Virchow,5 the famous German pathologist, is generally and also in men.6
credited as the first man to postulate the cardinal factors responsi- In the years that followed, eminent physicians began to doubt the
ble for the pathogenesis of DVT, namely, hypercoagulability, stasis humoral theories and put forth alternative explanations that went on
and endothelial injury. He was a keen observer and had an analyti- to form Virchow’s triad. Albrecht Haller (1786) believed that pressure
cal mind: the principles that he postulated in 1855 started receiving on the veins cause slowing of blood flow, which ends up with DVT.
attention from the scientific world nearly a 100 years later as a result Similar concepts were favored by Mathew Baillie (1798), John Fer-
of accumulation of scientific evidence in their favor. Nevertheless, his riar (1810) and Laennec (1819). Although the concept of endothelial
triad of factors was discovered in various permutations and combi- damage was not heard of in those days, two surgeons, Joseph Hogd-
nations by various scientists in the 600 years that preceded the pub- son (1815) and Alexander Copland Hutchinson (1829) believed that
lication of his thesis.6 DVT results from damage to the walls of the veins. A brilliant idea
The earliest available publication is that of Raoul of Norman- struck Andral: he guessed that DVT can result from some intrinsic
dy (1271), who described a 20 years old man who presented with defect in the blood. It took more than a century to prove Andral’s
swelling of the right ankle that gradually extended up to the thigh; guesswork right when it was shown that thrombophilia can give rise
the contralateral limb was perfectly healthy. This man prayed to the to DVT (Egeberg 1965).6
saints and got cured in about a year’s time.6 The fact that venous thrombosis is related to cancer was reported
Child birth began to be recognized as a possible cause in the 17th by Bouilland (1823) and Trosseau.7
century. Incidentally, it was about this time that doctors—instead of Immobilization, especially in the sitting position, causes kink-
midwives—began to conduct labor. Good doctors, by education and ing of the popliteal veins and gives rise to DVT. A six-fold increase
habit, record the history and findings of their patients. It is through in the incidence of venous thromboembolism was reported at the
the meticulous documentation of some of our illustrious predeces- time of the air raids in London during World War II; most of the af-
sors that we have come to know that they knew the phenomenon fected ones were those who sat in deck chairs in the different stations
of DVT. Francois Mauriceau (1668) of Paris described an aunt who of the underground railway. The incidence fell dramatically when
Chapter 36  The History of Deep Vein Thrombosis and Pulmonary Thromboembolism 245
the deck chairs were replaced by bunk beds. In the years that fol- geal echocardiography has been done by several workers. Enlarge-
lowed the World War II, prolonged sitting in long distance flights was ment of the right-sided cardiac chambers or Doppler documenta-
recognized as a cause of DVT. It earned the dubious distinction of tion of pulmonary hypertension are common when the embolism
economy class syndrome or travel associated venous thrombosis.7 is hemodynamically significant. McConnel’s sign (1976) involves
Venous thrombosis of the upper limbs can result when they are the demonstration of hypokinesia of the mid free wall, but normal
subjected to unaccustomed exercise. This is known as Paget Schrotter motion of the apex of the right ventricle.17
syndrome and is accompanied by temporary or permanent swelling
of the scalenus anterior muscle.7 Chest X-ray
Smoking increases the risk of DVT two- to three-fold as proved
by the Nurses’ Health Study and study of Men Born in 1913. The risk The development of the X-ray as a tool for investigation was vital
of DVT is nine times greater in smoking women who also use the oral in the diagnosis of PTE for many years. Wilhelm Conrad Roentgen,
contraceptive pill.7 Professor of Physics at Warberg, Germany pored over his laborato-
Factor V Leiden was found to be associated with DVT in 1994.7 ry table on a cold November day in 1885. He was studying cathode
ray fluorescence by passing electricity through tubes that contained
CLINICAL PICTURE rarified gas. All of a sudden, his gaze became fixed on a strange
glow emanating from a small fluorescent screen, which was at some
Haeger (1969) proved that clinical assessment of DVT is inaccurate distance away. He was surprised, because the screen was not a part
and only 40% of the suspected subjects have venographic confirma- of the apparatus that he was experimenting with, and correctly
tion of the condition. postulated that some invisible light came out of the cathode ray tube
John Homans (1877–1954),8,9 a surgeon of Boston, showed and fell on the screen, thus causing it to glow. He called the invis-
that there is pain on dorsiflexion of the foot in a patient of DVT. He ible light X-rays; the letter ‘X’ stood for something unknown. He was
was aware of the limitation of his finding and did not attach much thrilled to find that he could see outlines of his bones if he placed his
importance to it. Other eponymous findings include: Moses’s sign10 hand between the cathode ray tube and the screen. In the 7 weeks
in which there is more pain during anteroposterior compared to that followed, he merrily worked on his experiment day and night,
lateral compression; Lowenbereg’s sign11 in which there is pain in the and took numerous pictures of his own bones and those of his wife,
calf when the sphygmomanometer cuff is inflated to 180 mm Hg on completely unaware of the fact that they were exposing themselves to
the thigh; Pratt’s sign12 in which there is distension of the pretibial unacceptable levels of radiation.
veins; and Peabody’s sign13 in which there is spasm of the calf mus- Other scientists took the cue from Roentgen and began to refine
cles when the leg is elevated with the foot strongly dorsiflexed.14 the technique of taking X-rays. Williams FH took the first chest X-ray
in 1896 at Boston. In the very same year, Carl Sclleussner developed
INVESTIGATIONS the first silver bromide coated photographic X-ray plate in Frank-
furt, Germany. Pasche EAO built a collimator in 1903 to suppress
Electrocardiography scattered radiation. In 1916, Gustav Buck developed a scatter radia-
tion grid in Berlin, Germany. This eliminated scattering of the rays
John Burden Sanderson and Frederick Page (1878) obtained the before it struck the X-ray screen and thereby produced vastly improved
tracings of the cardiac electrical activity of a frog. Augustus D Waller images.18
(1887) took the graph from a human subject. The technique under- All this facilitated the X-ray diagnosis of PTE. Several eponymous
went further refinement and was called “electrocardiogram” by Wil- signs developed; these bear testimony to the keen observation pow-
helm Einthoven (1893), who, later claimed that his friend Waller was ers of their proponents. Pulmonary artery enlargement (Fleischner’s
the man who first coined the term. Ever since its discovery till the sign) may be a result of elevation of pulmonary artery pressure, the
present day, the test has found application in numerous cardiovascu- clot per se or pulmonary artery aneurysm. Focal oligemia (Wester-
lar disorders one of which is pulmonary thromboembolism (PTE).15 mark’s sign) results from dilatation of the vessels proximal to the clot
McGinn and White (1935) described the S1Q3T3 pattern in PTE. and collapse of the vessels distal to it. Pulmonary thromboembolism
This is a nonspecific finding and may be found in many acute lung can cause infarction of the lung parenchyma; the chest X-ray shows
conditions.16 a triangular consolidation in the periphery of the lung (Hampton’s
hump).19
Echocardiography
Contrast Venography
This has not proved to be a particularly useful diagnostic modality
in the diagnosis of PTE. Transient demonstration of clots passing Contrast venography was discovered by Berberisch and Hirsch
through the right-sided cardiac chambers, or documentation of clots (1923).20 Iodinated contrast was first employed by Moniz et al. in the
in the main pulmonary artery either by transthoracic or transesopha- 1930s.21
Pulmonary Angiography were jointly awarded the Nobel Prize in 1979. Incidentally, the
initial scanners took several hours to acquire the raw data for a
Forssmann was a surgical resident at the Auguste Victoria Home in “slice” of the brain, and several days to process this raw data and
Eberswalde. He watched with horror how intracardiac injections produce a picture.26
of life-saving drugs were avoided in patients suffering from cardiac The currently available multidetector row CT scanners are capa-
arrest until they were beyond medical treatment; this was because ble of providing submillimeter resolution and can show emboli even
of the fear of causing pneumothorax or cardiac tamponade. He de- in the sixth order vessels. These emboli are so small that it is doubtful
cided that a novel way of circumventing the problem would be to whether they are of any clinical significance. Computed tomography
pass a catheter into the right-sided cardiac chambers and inject the venography has made phlebography redundant.
drug. To explore this novel idea, he made a venesection on himself
introduced a catheter in his right atrium and injected 20% sodium Magnetic Resonance Imaging
iodide in the right atrium, right ventricle and pulmonary artery. He
was taken to task by the consultant under whom he was working as a Nuclear magnetic resonance was discovered by Isidor Rabi in 1938.27
junior doctor and thrown out of the hospital. However, the consult- He was awarded the Nobel Prize for his work in 1944. Felix Bloch
ant was generous enough to mention that he had made a discovery of the Stanford University and Edward Mills Purcell of the Harvard
worthy of immediate publication, and even referred him to a big hos- University, discovered the effects of Nuclear Magnetic Resonance
pital in Berlin to work on it. However, Forssmann did not seem to be on solids and liquids for which they too got the Nobel Prize in 1952.
bothered about cardiology or cardiac catheterization thereafter and They found out that magnetic fields and radio waves caused atoms to
lived and died as urosurgeon. He was awarded the Nobel Prize in give out small radio signals.27 This technique was employed by Paul
Medicine in 1956 as recognition of his seminal contribution to medi- C Laterbur and Peter Mansfield to construct a magnetic resonance
cal science.22 imaging (MRI) scanner for which they were awarded the Nobel Prize
Bolt et al. introduced the concept of selective pulmonary angi- in Medicine in 2003.31
ography, while the degree of pulmonary vascular obstruction was The currently available machines allow excellent demonstration
objectively assessed by Miller, Walsh and Simon.23 of the clot, allows clot age determination, pulmonary hypertension,
blood flow quantification, vessel distensibility and concomitant
Ventilation Perfusion Scan DVT.
Ventilation imaging was started in 1955 with the inhalation of 133Xe D-dimer
gas by Knipping et al. (1955).24 Nearly 10 years later, regional blood
flow was imaged with radioactive agents (Wagner et al. (1964).25 Ven- This investigation owes its existence to the fact that in PTE, there is
tilation imaging is now done with 99mTc-diethylenetriamine penta always some spontaneous fibrinolysis. While this may be insufficient
acetic acid. Perfusion imaging is done on the principle of trapping to give hemodynamic and symptomatic relief, it breaks down fibrin
of a radiotracer in the lungs following intravenous injection and pas- into enough D-dimer to be detected by a simple blood test. Discov-
sage through the right atrium and right ventricle. It employs micro- ered in the 1970s by Gaffney,28 this test has a good negative predictive
particulate human protein labeled with 99mTc. value and is used to rule out significant PTE.
The ventilation perfusion scan has largely been supplanted by
the computed tomography (CT) angiography. There are only three MEDICAL MANAGEMENT
valid reasons to do the former investigation in current day medical
practice, viz, renal impairment, anaphylaxis to intravenous contrast It was realized that dissolution of the clot was the cornerstone of suc-
that cannot be overcome by large doses of corticosteroids and preg- cess in the treatment of PTE. This requirement was met by the discov-
nancy. ery of heparin, dicoumarol and their analogues.
In the year 1916, Jay McLean,29 a young second year student
Computed Tomography at Johns Hopkins University Medical School walked into the of-
fice of William H Howell with a beaker of cat’s blood in which he
The development of CT scan technology has been instrumental in had added some canine liver homogenate, and asked him to pre-
the correct diagnosis of DVT and PTE in many patients. dict when it would clot. Instead of acting, like thromboplastin and
Rohann Radon (1917) demonstrated that it is possible to accelerating coagulation, this sample of blood never clotted. Since
reconstruct the image of a three-dimensional object by taking an clotting was prevented by the liver extract, the substance that pre-
infinite number of two-dimensional projections. In the year 1971, vented clotting was named heparin (Greek hepar, liver). By the
British engineer, Godfrey Houncefield and US physicist, Allan 1930s, heparin was purified and produced in sufficient quantity
Cormack independently discovered the CT scanner for which they for clinical use. In 1976, Johnson et al.30 and Andersson et al.31
Chapter 36  The History of Deep Vein Thrombosis and Pulmonary Thromboembolism 247
independently discovered low-molecular-weight heparin. Fon-

daparinux was discovered by Sanofi Synthelabo in collaboration
SURGICAL MANAGEMENT
with Akzo Nobel subsidiary Organon Pharmaceuticals. It got the
US Food and Drug Administration approval for hip fracture sur- Acute Pulmonary Thromboembolism
gery, hip replacement surgery and knee replacement surgery for Trendelenburg (1908)37 was the first surgeon to attempt operative
the prevention of DVT in 2007. removal of the pulmonary clot in the early hours of PTE. None of his
The discovery of dicoumarol by Karl Paul Link was an three patients survived. Long-term recovery was reported by Kirsch-
important landmark in the management of DVT and PTE. On a chilly ner (1924).38 Allison (1960)39 performed the operation with total
morning in February 1933, Ed Carlson, a farmer who hailed from body hypothermia and circulatory arrest. In the years that followed,
Deer Park, Wisconsin came to Link’s laboratory carrying milk can cardiopulmonary bypass proved to be a much better technique.
full of blood that would not coagulate. Outside the building, he had a
truck carrying a dead heifer and a bundle of spoilt sweet clover hay. Chronic Thromboembolic Pulmonary
Link discovered that the clover became rotten when attacked by a
Hypertension
fungus. As a result, coumarin, a normal constituent of sweet clover
or sweet grass that is responsible for the sweet smell, is converted to Holister and Cull (1956)40 performed the first thromboendarterec-
dicoumarol, which is a competitive antagonist of vitamin K and tomy operation. There have been anecdotal reports of having per-
hence an anticoagulant. Chemical manipulation of dicoumarol formed this operation ever since its discovery. However, the largest
produced a 4-hydroxycoumarin, which came to be known as war- series till date is that of Nina Starr Braunwald41 who started doing this
farin (Wisconsin Alumni Research Foundation; the terminal—arin operation in the 1970s and performed more than 2,300 operations.
indicates its relationship with coumarin).
While it is true that the anticoagulants described above pre- PREVENTION
vent the formation of clot in the deep veins and cause dissolution of
clots in the legs, as well as the pulmonary artery, this is a long drawn Sigel et al. (1973)42 showed that graduated compression stockings
process. Massive and submassive PTE are medical emergencies in significantly improved blood flow in the lower limbs. Intermittent
which it is frequently necessary to get rid of the clot quickly. In other pneumatic compression was introduced by Blackshear et al. (1987).
words, some form of thrombolysis is desirable. John Hunter (1784)43 realized that an effective way of prevent-
William Smith Tillet (1933)32 made a chance of discovery of ing PE would be to interrupt the pathway of the lower limb DVT. He
streptokinase. Many years of painstaking research established its ligated the femoral vein in a patient of DVT to prevent PTE. Mobin-
role as a thrombolytic agent in AMI (1958). Its application in the Uddin introduced the inferior vena cava filter for the prevention of
field of PTE was not until the early 1970s. McFarlane33 pioneered the PTE in the 1970s.44 At least nine different types have been invented
discovery of urokinase from human urine in 1947. The therapeutic till date, but many of these models have fallen out of favor.
effect of urokinase was proved in the Urokinase Pulmonary Embo-
lism Trial (1974). A combination of streptokinase and heparin proved EPILOGUE
to be better than heparin alone (1995). Several teams discovered tis-
sue plasminogen activator from various sites of the body beginning The past century and a half has seen remarkable developments in
in the 1940s.34 Intravenous recombinant tissue plasminogen activa- our understanding and management of DVT and PTE. One area of
tor was successfully tried in PTE in 1988. concern is that clinical assessment is notoriously untrustworthy; the
Percutaneous catheter fragmentation and dispersal of the proxi- disease often exists where it is unsuspected, and does not exist where
mal pulmonary embolus was attempted by Brady et al. (1991).35 it is suspected. And even with treatment in the best of centers, the
Koizumi et al. (1998)36 placed a Z-stent in the pulmonary artery mortality and morbidity are high. It is important, therefore, for the
to compress the clot and restore blood flow. medical fraternity not to lower its guard.
REFERENCES
1. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis. 1975;17(4):259-70.
2. In: van Beek EJR, Buller HR, Oudkerk M (Eds). Deep Vein Thrombosis and Pulmonary Embolism. Oxford: John Wiley & Sons Ltd; 2009. p. 513.
3. In: van Beek EJR, Buller HR, Oudkerk M (Eds). Deep Vein Thrombosis and Pulmonary Embolism. Oxford: John Wiley & Sons Ltd.; 2009. p. 58.
4. The New Testament. Mathew; 7:7.
5. Virchow R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI—Atheromatous affection of arteries. 1858.
Nutr Rev. 1989;47(1):23-5.
6. Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol. 2008;143(2):180-90. Epub 2008.
7. In: van Beek EJR, Buller HR, Oudkerk M (Eds). Deep Vein Thrombosis and Pulmonary Embolism. Oxford: John Wiley & Sons Ltd.; 2009. pp. 3-16.
8. Barker WF. To the memory of John Homans, M.D. 1877-1954. Major Probl Clin Surg. 1966;4:v-vii.
9. Crawford ES. The seventh John Homans Lecture: heroes in vascular surgery. J Vasc Surg. 1992;15(2):417-23.
10. Moses WR. The early diagnosis of phlebothrombosis. N Engl J Med. 1946;234:288-91.
11. Lowenberg RI. Early diagnosis of phlebothrombosis with aid of a new clinical test. J Am Med Assoc. 1954;155(18):1566-70.
12. Pratt GH. An early sign of femoral thrombosis. J Am Med Assoc. 1949;140(5):476.
13. Peabody CN. An objective sign of thrombophlebitis. Angiology. 1964;15:434-5.
15. Electrocardiogram. [online] Available from www.ecglibrary.com. [Accessed July, 2012].
16. McGinn S, White PD. Acute cor pulmonale resulting from pulmonary embolism. J Am Med Assoc. 1935;104:1473-80.
17. McConnell MV, Solomon SD, Rayan ME, et al. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embo-
lism. Am J Cardiol. 1996;78(4):469-73.
18. Radiography [online] Available from www.wikiradiography.com. [Accessed July, 2012].
19. In: van Beek EJR, Buller HR, Oudkerk M (Eds). Deep Vein Thrombosis and Pulmonary Embolism. Oxford: John Wiley & Sons Ltd.; 2009. pp. 67-68.
20. Berberich J, Hirsch S. Die roentgenologische Darstellung der Arterien und Venen im lebenden Menschen. Klin Wschr. 1923;49:2226.
21. Moniz E. Diagnostic des tumeurs cerebrales et epreuve de l’encephalographie arterielle. Paris: Masson & Cie; 1931. p. 1174.
22. Mueller RL, Sanborn TA. The history of interventional cardiology: cardiac catheterization, angioplasty, and related interventions. Am Heart J.
1995;129(1):146-72.
23. Ludwig JW. Heart and coronaries- the pioneering age. In: Rosenbuscg G, Oudkerk M, Ammann E, Winter PF (Eds). Radiology in Medical Diagnos-
tics: Evolution of X-ray Applications 1895-1995. Cambridge, Mass: Blackwell Science, Inc; 1995. pp. 213-24.
24. Knipping HW, Bolt W, Venrath H, et al. [A new method of heart and lung function testing, the regional functional analysis in the lung and heart
clinic by the radioactive noble gas xenon 133 (isotope thoracography)]. Dtsch Med Wochenschr. 1955;80(31-32):1146-7.
25. Wagner HN Jr, Sabiston DC Jr, Mcafee JG, et al. Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Eng J Med.
1964;271:377-84.
26. Computed tomography [online] Available from www.wikiradiography.com/page/CT. [Accessed July, 2012].
27. Magnetic resonance imaging. [online] Available from www.en.wikipedia.org/wiki/Magnetic_resonance_imaging. [Accessed July, 2012].
28. Gaffney PJ. D-dimer: History of the discovery, characterization and the utility of this and other fibrin fragments. Fibrinolysis. 1993;7:2-8.
29. McLean J. The thromboplastic action of heparin. Am J Physiol. 1916;41:250-7.
30. Johnson EA, Mulloy B. The molecular-weight range of mucosal-heparin preparations. Carbohydr Res. 1976;51(1):119-27.
31. Andersson LO, Barrowcliffe TW, Holmer E, et al. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound
antithrombin iii and by gel filtration. Thromb Res. 1976;9(6):575-83.
32. Tillett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med. 1933;58(4):485-502.
33. Urokinase [online] Available from www.en.wikipedia.org/wiki/Urokinase. [Accessed July, 2012].
34. Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost. 2004;2(4):541-6.
35. Brady AJ, Crake T, Oakley CM. Percutaneous catheter fragmentation and distal dispersion of proximal pulmonary embolus. Lancet.
1991;338(8776):1186-9.
36. Koizumi J, Kusano S, Akima T, et al. Emergent Z stent placement for treatment of cor pulmonale due to pulmonary emboli after failed lytic treat-
ment: technical considerations. Cardiovasc Intervent Radiol. 1998;21(3):254-5.
37. Trendelenburg F. Uber die operative Behandlung der Embolie Lungenarterie. Arch Klin Chir. 1908;86:686-700.
38. Kirschner M. Ein durch die Trendelenburgsche Operation genheilter Fall von Embolie der Arterien Pulmonalis. Arch Klin Chir. 1924;133:312.
39. Allison PR, Dunnill MS, Marshall R. Pulmonary embolism. Thorax. 1960;15:273-83.
40. Hollister LE, Cull VL. The syndrome of chronic thrombosis of the major pulmonary arteries. Am J Med. 1956;21(2):312-20.
42. Sigel B, Edelstein AL, Felix WR Jr, et al. Compression of the deep venous system of the lower leg during inactive recumbency. Arch Surg.
1973;106(1):38-43.
43. Hunter J. Observations on inflammation of internal coat of veins. Trans Soc Improvement Med Chir Knowledge. 1793;1:18.
44. Mobin-Uddin K, Utley JR, Bryant LR. The inferior vena cava umbrella filter. Prog Cardiovasc Dis. 1975;17(5):391-9.
37 Lessons Learnt from History of
Rheumatic Heart Diseases
Vijayalakshmi IB
to joint, lasting in one spot for a few days or a week before moving
INTRODUCTION
to another location. His family put him to bed for several weeks and
Hippocrates in 400 BC provided the first description of arthri- he recovered completely after each bout. Despite the considerable
tis. Since then thousands of studies have contributed to the better debility during the active stage of the disease, he had been left with
understanding of the disease. The earliest concept of rheumatic no permanent handicap. Therefore Rheumatism in the 18th century
heart disease (RHD) began as “articular rheumatism” in the 17th consisted of only fever and migratory arthritis (Fig. 37.1).
century. Guillaume de Baillou (France) is credited with the first Lesson learnt is arthritis in RF is characteristically flitting in na-
description of “acute rheumatism” in the 17th century. Since then ture and recovers completely without permanent handicap.
this disease has ravaged the world for the past 4 centuries, afflict- The clinicians, by the last years of the 18th century, appreciated
ing the children, adolescents and young adults. It has been diag- cardiac involvement in ills also characterized by “rheumatism”. Mr
nosed and treated more effectively since the 20th century, thanks TM’s 10th bout began in the accustomed way: knees and ankles red,
to the lessons learnt from centuries of experience of clinicians. Still swollen and tender, occurring after an unfortunate submersion into
it has remained as a burning problem in many developing coun- a cold spring pond. What set this episode apart from earlier ones
tries, where the clinicians, society and governments have not learnt was an “oppression in his chest” and the palpitation of his heart.
lessons from the history. Therefore the history of rheumatic fe- After three weeks, these chest complaints led to extreme breathless-
ver (RF) is of relevance to modern medicine, so that lessons learnt ness and a feeling that he was “about to expire”. So different was this
from the past experience can help to evolve appropriate preventive addition to his regular rheumatic complaints that he travelled to
strategies in countries where the disease is still endemic. London to consult a hospital-based physician. There he met Dr
The striking and progressive changes that were seen with post William Charles Wells at St. Thomas’s Hospital. Wells listened to
streptococcal infections—acute arthritis, pericarditis, endocarditis, the young man’s story and quickly confirmed that Mr TM had what
chorea, myocarditis are quite distinct. The history of RF has taught us physicians in the late 18th century called “acute rheumatism”. What
much about the pathophysiology and epidemiology of this autoim- was entirely new in Wells’s experience was the history of “oppression
mune disease. It has also taught us the methods of prevention. How- in the chest”, heart palpitations and breathlessness. Wells confirmed
ever, in spite of much research the link between “the throat and the that the heart was involved by palpating the pulse and feeling the
heart” remains elusive. Unless this is established full control of the heart bound against Mr TM’s chest wall. Wells believed that he was
disease may not be possible. seeing a new aspect of a common disease; he called it “rheumatism
of the heart’’.1 Mr TM, like most sufferers from acute rheumatism,
HISTORY IN THE 18TH CENTURY survived even repeated attacks of this disease.
Syndenham (England) separated “articular rheumatism” from gout HISTORY IN THE 19TH CENTURY
and although he gave a masterly description of chorea, he did not
recognize its rheumatic nature! In April 1798, Mr TM was struck In early 19th century, Wells called attention to the experience of
down with rheumatism while travelling in England. He was very David Dundas, sergeant-surgeon to the king, who reported nine
familiar with the beginning stages of this illness, for he had been
afflicted with rheumatism yearly since the age of nine. There was a
preliminary period of fever and chills, which he and his family attrib-
uted to a needless exposure to dampness and cold weather, followed
by considerable swelling, redness, and tenderness of his knees, an-
kles and wrists. This arthritis had a peculiar twist: it moved from joint Figure 37.1: Rheumatism in the 18th century
patients with heart disease and rheumatism in 1809. Most had suf- after a sore throat, chill and cough. Suddenly she was overwhelmed
fered chest pains, anxiety and increased pulse, ascites (fluid in the by a “great oppression” in her chest and shortness of breath so severe
abdomen), pleural fluid or peripheral edema following one or more that she could not lie down and a week later she was dead.6 Similar
attacks of acute rheumatism. Seven of the nine were under 22 years case reports increased over the next decade so that a Parisian medi-
of age and seven died, usually after a period of several months. He cal student, Joseph-Irénée Itard, was able to sustain a 24-page thesis
autopsied six and found the heart enlarged in most and excess peri- for graduation from medical school, entitled ‘’Considérations sur
cardial fluid surrounded one heart and in several others the pericar- le Rhumatisme de Coeur” in 1824.7
dium adhered to the surface of the heart.2 Initially, sounds emanating from the lungs received most at-
When later Wells published Mr TM’s history with 13 additional tention and only by the 1830s did clinicians begin to sort out which
cases in 1812, he did not claim priority for his observation linking abnormal heart sounds came from a particular chamber or valve of the
heart disease with rheumatism. Rather, he credited David Pitcairn, heart.8 Jean-Baptiste Bouillaud, a Parisian clinician who had been a
a prominent British physician, with the initial association in 1788. student of Laennec, applied this new instrument to rheumatic patients
Pitcairn failed to publish his remarks on the subject, so Wells consid- in 1837, greatly enhancing the ability to describe cardiac injury while
ered his paper to be serving the purpose of recording Pitcairn’s idea, the patient lived. Significantly, the stethoscope also permitted Bouil-
to which he added his own cases. laud to discover patients with asymptomatic heart disease.9
Wells, provided an early description of the new face of rheuma-
tism. One of his case histories gave details of Miss AL, a 16-year-old Bouillaud and the Stethoscope
girl who had been well until her current affliction. Her fatal illness
began in early August 1806. Wells also remarked that Matthew Baillie, Most initial reports resulted from specific and striking complaints of
a Scottish pathologist, had made the initial autopsy investigation of a patients, external inspection of chest and pulse, followed by confirm-
patient with rheumatism dying from heart disease.3 Following Wells’s atory autopsies. The stethoscope changed this. While René Laen-
lead some practitioners began looking for heart disease in cases of nec’s introduction of the stethoscope in 1816 has been well stud-
rheumatism. James Russell, a surgeon from Birmingham, provided ied by historians, a great deal less is known about the reception by
an example from 1814. Seth Bassett, a 22-year-old wagoner, came to practitioners of this technological breakthrough. The acquisition of
Russell with painful joints. Russell, aware of the writings of Baillie, skills among practitioners that correlated sounds at the bedside with
Dundas, and Wells, took a special interest when Bassett developed structural changes at the autopsy table took time. The best histori-
chest pain, shortness of breath and a rapid pulse several weeks later. cal accounts demonstrate that the stethoscope received a slow, but
Russell confidently believed that Bassett had an inflamed heart.4 steady welcome from clinicians, especially among those physicians
Following René Laennec’s introduction of the stethoscope in who had been trained in Paris.
1816, practitioners’ acquisition of auscultatory skills that correlated Using a stethoscope, Jean-Baptiste Bouillaud (1796–1881), who
sounds at the bedside with structural changes at the autopsy table had been a student of Laennec,10 argued convincingly in 1836 that
took decades. Rheumatic fever has not been a static disease, which there was a “constant coincidence either of endocarditis or of peri-
patients and physicians have viewed from different vantages over the carditis with acute articular rheumatism.”9
past two centuries. Technology thus confirmed rheumatism’s change Over the 19th century, RF’s biological changes and the progres-
in biological character. Bouillaud’s use of the stethoscope followed sion of clinical thinking shifted emphasis from fever and joints to the
Wells’s observation by more than a quarter of a century and initial heart. Individual cases showed that cardiac injury was part of rheu-
reports of cardiac involvement by nearly 50 years. This is not to ar- matism and hospital studies showed that most debility and death
gue that technology played no role. The stethoscope cemented car- resulted from heart disease. The “typical” case demonstrated that
diac damage to acute rheumatism in the minds of many practition- heart involvement was the most vital element in rheumatism from
ers by contributing fresh bedside evidence. And it extended the link the point of view of prognosis (Fig. 37.2).
between heart injury and rheumatism to include the many asympto- Despite the growing association of heart disease with acute
matic cases in which the injury was so mild that it went unnoticed by rheumatism, clinicians still gave central importance to fever and
the patient. By mid-century, then, experience and technology were joint pains. These were the complaints that brought the patient to
available to diagnose whether the pericardium or endocardium was the practitioner. These were the criteria needed to make a diagnosis;
involved in acute rheumatism; the stethoscope was not, of course, as these were the objects of therapy. But heart damage had joined fever
helpful in determining myocardial damage, which was often silent. and joint pains as an associated manifestation and death resulted
In 1821, René Laennec listed “gouty or rheumatic affections” as an from heart disease.
occasional cause of pericarditis.5 In September 1835, Bouillaud had been called to consult in the
William Potts Dewees, a physician from Philadelphia, described case of a 19-year-old boy who had been admitted to La Charité Hos-
the case of AB, an 8-year-old girl: in mid-November, the young girl pital 2 weeks earlier. The boy’s admitting physician asked Bouillaud’s
developed swelling and redness of her wrists and ankles shortly advice when the young man developed chest pains in addition to
Chapter 37  Lessons Learnt from History of Rheumatic Heart Diseases 251
ing sound, and when desired to put out his tongue it was protruded
with all the forced grimace and difficulty observed in chorea.” A
rapid and irregular heartbeat “led to suspicions” that the heart was
also affected. Sixteen days later, the boy died. At autopsy, Bright
discovered that both the pericardium and the endocardium were
involved. Careful dissection of the brain failed to yield any
perceptible abnormalities.13
RHEUMATISM’S NEW FACE

Figure 37.2: Acute rheumatism in the 1830s
Rheumatism was a quite familiar health concern for patients and
physicians at the end of the 18th century. Thomas Sydenham, who
his joint complaints. On this initial visit, Bouillaud placed his hand had turned his revolutionary zeal from Puritan causes to the many
on the chest and felt a “very distinct vibration, which immediately epidemic fevers plaguing his practice among London’s poor, defined
led him to announce the existence of the bellows, file or saw sound,” rheumatism in the late 17th century in a fashion that continued to
which he confirmed when he applied his ear to the boy’s chest. He serve practitioners a century later.
interpreted his findings to mean that the boy had the valvular dam- This disease happens at any time, but especially in Autumn and
age of endocarditis. He visited weekly, each time recording his cardi- chiefly affects such as are in the prime of life. It is generally occasioned
ac findings. A month after his initial visit, he found the boy improved. by exposing the body to the cold, or immediately after having heated it
This time he examined his patient with a stethoscope and discovered by violent exercise or some other way. It begins (1) with chillness and
that the abnormal heart sounds had largely disappeared. This and shivering, which are soon succeeded (2) by heat, restlessness, thirst and
other experiences led Bouillaud to observe that “in auscultating the the other concomitants of a fever (3) in a day or two and sometimes
sounds of the heart in some individuals still laboring under or con- sooner, there arises an acute pain in some or other of the limbs, es-
valescing from acute articular rheumatism, I was not a little surprised pecially in the wrists, shoulders, and knees; which, shifting between
to hear a strong, full, saw or bellows sound, such as I had often met in whiles, affects these parts alternatively, leaving a redness swelling
chronic or organic induration of the valves, with contractions of the in the part last affected. (4) In the beginning of the illness, the fever
orifices of the heart.’’9 and the aforementioned symptoms do sometimes come together, but
In a short monograph devoted entirely to the subject, Bouillaud the fever goes off gradually whilst the pain continues, and sometimes
gave a systematic approach to examining the heart in patients with increase[s], occasioned by the derivation of the febrile matter to the
rheumatism. Like other members of the Paris School, the term often limbs, which the frequent return of the fever, from the repulsion of the
used by historians of medicine to describe extraordinarily creative morbific matter by external remedies sufficiently shews.14
hospital-based medicine, which grew out of educational and clinical Cullen had appreciated that joint complaints separated into
innovations of the French Revolution, Bouillaud made extensive use two distinct clusters: “acute rheumatism” in teenagers and young
of percussion and auscultation and he followed unsuccessful cases adults with short-lived arthritis that left no permanent disability, and
to the autopsy room.11 Hospital-based, Bouillaud saw enough cases “chronic rheumatism” in older adults, in their fifties and sixties, with
to estimate that nearly one-half of people with acute rheumatism persistent joint complaints that often resulted in crippling arthritis.
suffered from either pericarditis or endocarditis or both. Bouillaud’s Ideas about RF evolved from what Cullen called “acute rheumatism,”
observation of the frequency of cardiac injury was another piece of a term that others enlarged to “acute articular rheumatism,” to place
evidence of the malignant transformation and increasing severity of emphasis on the painful joints. In First Lines of the Practice of Physic,
acute rheumatism. Cullen stated that rheumatism “seldom appears either in the very
In 1838 Richard Bright (1789–1858), a prominent London phy- young or elderly persons, and most commonly occurs from the age
sician had encountered so many patients with rheumatism, called of puberty to that of 35 years.” He concurred with Sydenham that “the
attention in his Lumleian Lectures at the College of Physicians to the pains affect several joints, often at the very same time, but for the
occasional association of chorea with diseases of the pericardium.12 most part shifting this place, and, having abated one joint, become
Each patient also suffered from acute rheumatism. The following more violent in another”.15
year he reported in detail three case histories. The initial case was
a 17-year-old boy who 12 days earlier “had begun to complain of DEATH FROM ACUTE RHEUMATISM:
general rheumatic symptoms; pains in the limbs, with puffiness and
A NEW OUTCOME
swelling of the wrists and some other joints”. Six days later, he de-
veloped chorea: “his head was constantly thrown from one side of Beginning in the middle of the 18th century, physicians began to re-
the bed to the other; his lips were closed, and opened with a smack- cord a few who died from their bouts with rheumatism. These deaths
contrasted sharply with the complete recovery that both patients and WELLS AND “RHEUMATISM OF THE HEART”
physicians anticipated with acute rheumatism. As with any new phe-
nomenon, these deaths begged explanation. The precise reason for Despite difficulty in defining acute rheumatism precisely, Wells had
the deaths perplexed physicians because it was not at all clear why no trouble diagnosing acute rheumatism in Mr TM.1 Wells recalled
a temporary joint complaint should suddenly turn fatal. When this that two colleagues, David Pitcairn and Matthew Baillie, had men-
unusual event occurred, physicians would explain that the rheu- tioned similar cardiac difficulties in patients with acute rheumatism.
matism had moved somehow from the joints to a vital organ. For After scouring the available medical literature, he could find only one
example, Gerhard van Swieten, the great Viennese physician of the or two additional references. Nevertheless, it is clear from accounts
mid-18th century, noted in his commentaries upon Boerhaave’s of patients suffering from acute rheumatism that practitioners were
Aphorisms, “while the rheumatism attacks only the joints, it is rarely becoming aware of the cardiac connection before Wells. For exam-
fatal; but when it seizes the brains or lungs, it is highly dangerous ple, van Swieten had reported that “sometimes, when the pain in
and sometimes occasions sudden death.” Van Swieten gave only the limbs ceases, there arise an anxiety in the breast, a palpitation of
a cursory explanation of how rheumatism could move around the the heart, an intermitting pulse”.16 Despite this observation, van Swi-
body. Early in his discussion, he claimed that “rheumatism derives eten did not connect the rare involvement of the heart with the few
its name from (the Greek word) to flow”.16 He had a vague notion that patients he treated who died from rheumatism. Cullen, too, had
a misdirected rheumatic ‘’poison” could flow from the joints to pro- called attention to the “full and hard pulse” that accompanied rheu-
duce havoc elsewhere. matism on occasion.16 In the first extensive statistical analysis of
Sydenham and Cullen had spoken of diseased joints in a gen- rheumatism, John Haygarth noted in 1805 that 55 of 93 patients with
eral way. Other observers sought to locate the site of disease more acute rheumatism who had their pulse recorded had a heart rate
precisely within the joint itself. For example, William Balfour, a phy- greater than 96 beats per minute. Haygarth did not make the connec-
sician writing on the pathology of rheumatism early in the 19th cen- tion between heart damage and rheumatism and an elevated pulse
tury, claimed that the location of rheumatism was in the “cellular does not always mean heart disease (fever alone can raise the pulse).
membrane” of the joints, by which he meant the connective tissue But Haygarth’s observation indicated that physicians were beginning
surrounding the joints. Balfour based his notion on his examination to look at the heart when confronted with patients with rheuma-
of living patients and not on dissection.17 tism. Twelve of Haygarth’s patients died. His detailed case histories
Cullen, who was known for his meticulous classification of indicate that three died with either severe chest pain or shortness of
diseases, had struggled over, where exactly to locate “acute rheu- breath. While it is not possible to be certain of the exact anatomical
matism.” It shared many characteristics with inflammation. Acute cause of the deaths, it is likely that diseased hearts were responsi-
rheumatism produced swollen, painful joints that appeared to the ble.19
examiner just like joints in other illnesses that were filled with pus Lesson learnt was RF does not deform the joints but kills the pa-
or suppuration. In these latter conditions, the joints frequently were tient due to involvement of heart. Hence “RF licks the joints but bites
destroyed, leaving the patient crippled. In contrast, Cullen noted that the heart”.
the affected joints in rheumatism never contained pus and never Wells presented the experiences of nine of his patients, plus five
were permanently damaged: “The acute rheumatism, though it has from colleagues. Miss AL, the young woman who died from cardiac
much of the nature of the other phlegmasiae (inflammation), differs complications that was Wells’s fifth case. Eleven of these patients
from all these hitherto mentioned in that it is not liable to terminate were teenagers, two were in their twenties, and the oldest was 36.
in suppuration.”15 Acute rheumatism also differed from other forms With fever and migrating arthritis, each clearly suffered from acute
of inflammation in that it moved from one joint to another without rheumatism. Like the cases of Mr TM and Miss AL, each had com-
affecting the tissue in between. plaints explicitly related to the heart: chest pain breathlessness,
The practitioners began to realize that the umbrella of “rheu- palpitations, irregular heartbeat, forcible or violent heartbeat or
matism” often covered many conditions that Sydenham and Cullen an enlarged heart. In each case, Wells or his colleagues confirmed
had never intended. Edward J Seymour, a physician at St. George’s cardiac involvement with examination of the pulse and inspection
Hospital in London, noted that practitioners loosely used the term to and palpation of the chest wall. Six patients died, a highly unusual
cover many ills, both trivial and serious: growing pains in children, outcome for acute rheumatism. The autopsies revealed that peri-
the limb pains that accompanied many febrile illnesses the pain of carditis, a collection of fluid resulting from an inflamed pericardi-
nerves damaged by hemorrhage, debilitated constitutions, abuse of um, was the cause of each of the deaths. One of the older patients
mercury, any pain stemming from muscles, bones or joints, as well as had the additional finding of “excrescences” attached to the mitral
the joint pain in rheumatism.18 heart valve, indicating injury to another of the heart’s tissues, the
endocardium. Of passing interest was Wells’s finding that one ous brain injury. Bright believed, although his postmortem dissec-
patient, Martha Clifton, also had “many of the tendons of the super- tions failed to demonstrate it, that rheumatic inflammation spread
ficial muscles studded with numerous hard tumors,” the first clear from the pericardium to the spinal cord then on to the brain, leading
description of subcutaneous nodules, another ailment later associ- to chorea.13
ated commonly with acute rheumatism. Prompted by Bright’s observation, Dr Yonge of Plymouth con-
When Alfred Stillé discussed the death of a 23-year-old man from sulted Bright in 1840 about the case of Francis Hill, a 19-year-old gar-
rheumatism, he stated to his listeners at the Pathological Society of dener whom we met in the prologue, who struggled with his bout of
Philadelphia in 1839 that examination of the heart in rheumatism rheumatism, endocarditis and chorea.23 Francis was so afflicted with
had become routine.20 In the same year that Bouillaud published, his chorea that he could not walk, eat or drink and required a strait-
Henry Shuckburgh Roots (1785–1861) described a man he admitted jacket to prevent him from harming himself. After Francis’s death,
to St. Thomas’s Hospital in London who suffered from acute rheuma- Yonge and Bright discovered that his mitral valve was seriously dam-
tism and pericarditis, a diagnosis he made with the use of a stetho- aged; the spinal cord and brain, while carefully dissected, yielded no
scope.21 visible abnormalities.
There was a similar historical trail leading from rheumatism Richard Bright thought his linkage of chorea with the now car-
to chorea. Beginning in the 1830s, doctors began commenting on diac expanded acute rheumatism was a new observation. In its 19th
patients with rheumatism, some of them with heart disease in addi- century form, chorea overwhelmed the observer. Rheumatism had
tion, who also suffered from uncontrollable movements or chorea. altered its biology again.
One early example came from Dr Yonge of Plymouth, England, in
his 1840 description of Francis Hill, a 19-year-old boy who had suf- ACUTE RHEUMATISM CHANGES
fered from rheumatism for 2 weeks before developing severe chest
AGAIN WITH CHOREA
pains. What caught Dr Yonge’s attention was: irregular twitching of
the muscles of the mouth and right side of the face; which is increased There was a comparable path leading from acute rheumatism to cho-
by speaking, and occasions some hesitation: seemed unconscious of rea, a dramatic movement disorder. In the middle-third of the 19th
this till it was noticed, but says, on being asked whether it was habitual century, chorea began to afflict some patients of acute rheumatism,
that it has come on during the previous week.(One week later) Has another indication that rheumatism was changing its biological
walked from his lodgings; but with great difficulty, from the very un- character. Again, it was Thomas Sydenham who gave chorea its clas-
controllable state of the voluntary muscles throughout the body: great sic description in 1686: This is a kind of convulsion, which attacks
difficulty in making himself understood; cannot remain for any time boys and girls from the 10th year to the time of puberty. It first shows
in one posture; and although there is no spasm or violent action of the itself by limping or unsteadiness in one of the legs, which the patient
muscles, he is very unmanageable, and gives his friends a great deal drags. The hand cannot be steady for a moment. It passes from one
of trouble. His gait is unsteady and tottering and he drags rather than position to another by a convulsive movement; however, much of the
lifts his feet. Francis worsened the next day and was hospitalized. The patient may strive to the contrary. Before he can raise a cup to his lips
muscular agitation continues to increase; he occasionally strikes him- he makes as many gesticulations as a mountebank; since he does not
self against objects, from inability to control or regulate movements. move it in a straight line, but has his hand drawn aside by spasms,
(His) articulation is almost unintelligible; the tongue is jerked out. (Of until by some good fortune he brings it at last to his mouth. He then
note, one doctor heard a heart “bruit” on auscultation with a stetho- gulps off at once, so suddenly and so greedily as to look as if he were
scope, but Francis’s violent movements prevented accurate description trying to amuse the lookers-on.24 In Sydenham’s practice, chorea and
of the heart’s injury). rheumatism did not occur together in the same patient.
Over the next week, his chorea deteriorated. He died 11 days after Lesson learnt is though Chorea is part of rheumatism it does not
entering the hospital. At autopsy, Dr Yonge concluded that the cause occur at the same time as joint pain.
of death was the marked pericarditis (the cause of the chest pain) and
endocarditis (which had produced the bruit, an extra sound heard PATIENTS AND DOCTORS
when listening with a stethoscope that indicated disease). His brain
appeared entirely normal. Chorea was a most dramatic punctuation At mid-century, changing biology dictated a significant shift in the
of Francis’s rheumatism, but it did not kill him.22 Similar descriptions way practitioners approached patients with acute rheumatism. When
increased over the next decades until chorea joined heart injury as confronted with patients with fever and joint pains, physicians rou-
another new feature of rheumatism. tinely examined the heart, often with a stethoscope whether or not
Bright suggested a linkage between acute rheumatism, heart dis- the person complained of chest pains. In addition, practitioners an-
ease and chorea. This observation confronted him with a conundrum ticipated the possible onset of chorea. What was important was that
similar to the one that had faced Cullen and Wells: how to explain the physicians began to assign greater significance to heart damage. The
connection between a minor, self-limited form of arthritis and a seri- rising prominence of the heart in rheumatism came from the grow-
ing clinical appreciation, backed up by autopsy reports that deaths From the mass of individual cases and hospital studies available,
from acute rheumatism resulted not from arthritis or fever, but from Cheadle identified RF’s common elements in 1886: fever, arthritis,
injury done to the heart. Chorea, although seldom a cause of death pericarditis, endocarditis, pleurisy, tonsillitis, erythematous rashes,
and never accompanied with an autopsy finding, added complex- chorea and nodules. This expanded list of symptoms alone signaled
ity, misery, and certainly drama to acute rheumatism. While neither how far RF had travelled in a century. Over the course of this relaps-
heart disease nor chorea occurred in every case of rheumatism, their ing illness, Cheadle believed that most patients would suffer from
presence was anticipated in the minds of practitioners (Fig. 37.3). most symptoms. Despite this expectation, Cheadle understood that
Lesson learnt along with arthritis, carditis and chorea also were not every patient experienced every possible complaint. He organ-
part of acute rheumatism. ized these symptoms or “manifestations,” into 10 common temporal
The final-third of the 19th century witnessed another shift in sequences, or “series.” For one example, in chart form he described
clinical thinking about RF. Individual case histories showed the the case of WS, aged four and half, that Cheadle thought “typical’’ of
considerable variability of the illness. Hospital-based analysis dem- many who suffered from RF.25
onstrated in a general way how RF affected populations. Neither
approach was entirely helpful to the practitioner when confronted Cheadle’s Series VIII
with sick patients and a mutating disease. What emerged in the
1880s was the concept of the “typical” case, which allowed for the • Chorea probably accompanied by endocarditis (Nov. 1886)
necessary biological variability yet possessed common elements. interval of 11 months
Employing an epidemiological approach, which clustered elements • Arthritis (Oct. 1887)
from many cases, enabled physicians to make a certain diagnosis in • Chorea (second attack), subcutaneous nodules, endocarditis,
a disease that was most uncertain in its presentation. Another advan- erythema marginatum (Nov. 1887)
tage of this strategy was to follow patients over longer periods of time, • Emotional attacks, chorea (continued), fresh nodules (Dec.
demonstrating that RF was an illness of relapses and remissions, with 1887)
increasing debility with each episode. Pioneering in this strategy was • Erythema marginatum, fresh eruption of nodules, chorea
Walter Butler Cheadle, physician to the hospital for sick children, (relapse), arthritis (second attack) (Jan. 1888)
Great Ormond Street, London. • Fresh eruption of erythema, fresh crop of nodules, tonsillitis
In mid-century, hospital-based physicians in Great Britain, with (Feb. 1888)
access to 100 patients with the new biologically expanded rheuma- • Death, March 1888
tism, were able to analyze more carefully RF’s changing character. Cheadle’s clinical organization of thinking about RF provided
Using numbers and statistics, these physicians enumerated precisely practitioners with a helpful guide to diagnosis (Fig. 37.4).
how often heart injury and chorea joined fever and arthritis, what Indeed, no one has improved upon his general approach. Even
age groups were most vulnerable, what time of year rheumatism was T Duckett Jones’s diagnostic criteria created in response to RF’s
most likely to attack and which therapies were most likely to suc- continuing biological evolution in the 20th, which medical students
ceed. Large hospital-based studies also noted that rheumatism was began to memorize after 1944, were solidly based on Cheadle’s
continuing to change: subcutaneous nodules sometimes appeared, efforts.
erythematous rashes joined in some cases and tonsillitis had struck
most victims. Significantly, these hospital-based reports recorded
that heart disease gravely sickened patients.
Figure 37.3: Acute rheumatism in 1850 Figure 37.4: Cheadle’s rheumatic state (1889)
Although Bouillaud supported substantial bloodletting, other

SOCIAL SETTING OF ACUTE RHEUMATISM
physicians worried that such measures actually weakened their
Practitioners in the 18th century, before the advent of heart dis- patients.30 In opium, Corrigan found a drug that worked well.
ease and chorea, observed that people who succumbed to rheu- Some physicians turned to cinchona bark to treat the fever of
matism often belonged to families who seemed to have a consti- acute rheumatism. This use was prompted by the perceived similari-
tutional weakness that predisposed them to this disease. Several ties between rheumatism and malaria, i.e. high fever and a tendency
children in one house would have rheumatism at the same time; to recur. After John Haygarth published his favorable experience
parents had suffered similarly when children themselves. In peo- using cinchona bark with 170 patients with rheumatism in 1805,
ple so prone, rheumatism was thought to follow a chill brought the drug enjoyed several decades of popularity.29 Many physicians
on by exposure to cold and wet, reflecting the usual onset of the combined standard therapies for inflammation with drugs for pain
disease in fall, winter or early spring. Physicians thus noted a and fever.
social dimension to rheumatism. Not too infrequently, the victim, Perceptions of physicians and patients that a variety of therapies
often poor and living in crowded circumstances, was described as worked quite well in acute rheumatism were enhanced by the nature
intemperate in drinking, eating or sleeping. As such, physicians of the disease to remit frequently on its own. In general, physicians
thought that rheumatism had seasonal, familial and social dimen- stuck by traditionally favorite remedies and normally the patient
sions. recovered. When confronted with a patient who developed a serious
case of chorea or heart disease, most physicians “threw the book” at
THERAPY FOR RHEUMATISM IN the patient, hoping that one or all remedies would prevent death. The
treatment of acute rheumatism was very much an open question in
THE EARLY 19TH CENTURY
mid-century.
Changing biology challenged therapeutics with its new injuries, Through anatomical analysis of those who died from rheuma-
but initially led to only a few fundamental changes. Until the end tism, “acute rheumatism” became an inflammatory illness in most
of the 18th century, doctors and patients addressed the complaints classification schemes. Yet it never comfortably fit into any nosologi-
that brought patients to physicians like joint distress and fever. In cal niche, largely because the joints and brains of victims, clearly
addition, doctors worried about an underlying, but poorly defined, diseased in life, appeared normal at autopsy. In a footnote, Baillie
phlegmasiae or inflammation. Bed rest, always a pillar in the care of recorded that “Dr Pitcairn has observed this in several cases”.
any debilitating illness, formed the mainstay of treatment for acute Deformities of the heart valves were noted by Morgagni (Italy) in
rheumatism. Enforced rest, it was thought, prevented permanent 1861, in autopsies of patients with history of articular rheumatism.
damage to hurting joints. Physicians also directed attention to local, Just prior to Cheadle’s reorganization of “clinical thinking”.
external care. Painful joints were frequently wrapped. Some doc-
tors preferred linen; others flannel; still others a variety of plasters.26 Clinical Thinking
Opium became the prime drug for alleviating joint pain and, after
the march of acute rheumatism to the heart, for chest pain as well.27 Repeatedly over the 19th century, RF’s changing biology forced phy-
Reports from the first years of the 19th century indicated that opium sicians to sort out common and useful patterns in a disease that was
was administered in doses large enough and frequent enough (of- becoming increasingly complex in its presentation. This sorting out
ten hourly) to relieve pain. Whether opium speeded the course of occurred in distinct phases and was clearly reflected in clinical re-
acute rheumatism or merely lessened troublesome symptoms was a porting. Early in the century, practitioners, such as Wells and Yonge,
debated point.28 wrote about individual cases that stressed elements peculiar to that
Physicians at the end of the 18th century also treated acute rheu- patient. The focus centered on fever and the joint disease, but other
matism with depletive therapies commonly employed to lessen any manifestations, such as cardiac damage and chorea, were added to
form of inflammation: bleeding, purging, sweating and local irrita- the picture in a supporting role.
tion. These measures continued during the first decades of the 19th As observations linking acute rheumatism and heart disease
century. Although he had altered how physicians thought about mounted, postmortem examinations showed that the pericardium
rheumatism, Bouillaud advocated these traditional treatments. Sig- was the main site of cardiac injury. An early exception was Dewees’s
nificantly, Bouillaud directed some of these customary remedies at findings at the autopsy of AB. He discovered that both pericardium
heart injury, for example, cupping the chest wall over the heart in and myocardium were involved: “heart twice as large as usual, and
an effort to draw off inflammation around the heart. Pericarditis and adhering by a thick coat of lymph to the pericardium, two ounces
endocarditis thus were treated both systemically with bleeding and of straw-colored serum in pericardium. The texture of the heart was
locally with application of leeches or other locally applied medicines sensibly altered in the crispy semicartilaginous manner peculiar to
to the chest wall.29 Physicians treated chorea with bed rest, restraint inflamed muscles. I did not detect any inflammation of its lining
and occasionally sedatives. membrane.”6
Wells’s earlier single description of endocardial injury indicated that salicylate effectively lowers fever, reduces joint pain and swell-
that acute rheumatism was capable of attacking all three tissues of ing, eliminates some of the pericardial inflammation that leads to
the heart. Wells believed that his and others’ recent observations the painful accumulation of fluid and probably (although doubt still
coupling heart injury to acute rheumatism were new at the end of exists) cuts some early endocardial inflammation. In other words, sa-
the 18th century.1 Is it possible that Pitcairn, Wells, Dundas, Dewees, licylate eased both the distresses that brought patients to doctors and
and others simply observed what others had overlooked in the past? the forms of heart disease that doctors most feared at the end of the
This is unlikely acute rheumatism was rarely a fatal disease until the 19th century. Salicylate did not influence myocarditis, which eventu-
end of the 18th century. Patients’ new chest complaints were strik- ally led to the undeserved conclusion that it was ineffective in RF.35
ing and demanded attention. Physicians confirmed with their usual
examinations that the heart was behaving improperly and autopsies Coburn “Activity” and Aspirin
demonstrated definite cardiac injury. Careful physicians could not
fail to miss either patient demands for alleviation of symptoms or the The concept of rheumatic “activity”, which combined clinical evalua-
result of examination or autopsy. Even Haygarth, van Swieten and tion with laboratory confirmation, provided a novel way of assessing
Cullen who did not associate rheumatism with heart disease never- the value of aspirin. Helen Taussig, a pediatrician at Johns Hopkins
theless did remark on these “unusual” symptoms. In the 18th cen- who began her career studying RF before shifting her interests to
tury, patients with acute rheumatism were not discomforted except congenital heart disease as RF waned, was among the first to sug-
from their joint pains and fever, and they did not die. A close look at gest that aspirin speeded the return of the sedimentation rate to its
the individual case reports from Wells and Dundas shows that these normal value.36 Alvin Coburn developed this idea.
early patients were dramatically symptomatic. Coburn argued that the treatment should be directed at “activ-
What was likely that acute rheumatism had changed its biologi- ity”, not symptoms. In his view, physicians had erred in giving aspi-
cal nature to include injury to the heart. Wells treated only nine parin only as long as patients complained of fever, chest discomfort
tients with the new rheumatic heart complication in the span of 12 or joint pain. Overt symptoms ended long before the cessation of
years; Dundas encountered a like number of patients over the course “activity”, measured by the sedimentation rate. Withdrawing aspirin
of 36 years. The observation that took Wells and Dundas years to too soon permitted ongoing cardiac damage. Coburn estimated that
repeat became commonplace later in the 19th century. For example, nearly 40% of patients relapsed when doctors and patients stopped
a physician at St. Bartholomew’s Hospital, PM Latham, tabulated aspirin at the point when fever and joint pain ended. Breaking new
that 13% of all patients admitted between 1836 and 1840 with the ground, Coburn proposed administering large doses of aspirin, up to
diagnosis of acute rheumatism suffered from pericarditis.31 The pro- 10 grams a day, as soon as the diagnosis was made and continuing
portion of patients with pericarditis as part of their rheumatism grew the drug until all signs of “activity” were extinguished for at least 2
to 22% at Middlesex Hospital between 1853 and 185932 and 24% at weeks. This often meant that aspirin needed to be taken for months.
Guy’s Hospital between 1870 and 1872.33 The prevalence of endocar- To ensure that patients received sufficient aspirin, he advocated giv-
ditis in some hospitals was even higher. ing it intravenously at least at the beginning of therapy and measur-
ing blood levels to make certain that the physician had not overshot
HISTORY OF DRUGS IN ACUTE or undershot his therapeutic mark.37 When aspirin was used in this
fashion, the patient experienced comfort from reduced fever and
RHEUMATIC FEVER
cessation of joint pain. In Coburn’s hands, aspirin also dampened
Thomas Maclagan discovered in 1876 that salicin quickly lowered the effect of rheumatic carditis. None of his patients relapsed.
fever, eased joint pain and swelling, and lessened chest pain by Coburn’s advice to treat “activity” was heeded almost without
decreasing pericardial fluid.34 It had no effect on chorea. Shortly, question and continues to serve as one guidepost for therapy in
many salicylates with slightly varying chemical constituents became RF. His innovation provided a rationale for length and efficacy of
available, including aspirin, which formed a mainstay of therapy for therapy. And most doctors accepted that the best, and safest, way of
RF in the early 20th century. Relief from joint illness, prolonged fe- monitoring aspirin was with guidance from the serum level. Some
ver, and chest pain brought excitement to doctors and patients alike; early reports supported Coburn’s findings.38 Not all were convinced,
virtually overnight older therapies were cast aside. So effective was however, that his high-dose regimen of aspirin effectively treated
salicylate in alleviating distress that almost no physician critically heart disease. From Coburn’s Presbyterian Hospital came reports
analyzed its value to the injury that doctors feared most: endocar- that colleagues could not improve outcomes with Coburn’s more
ditis at the end of the 19th century and myocarditis in the 20th cen- aggressive approach.39 Some encountered serious overdosing de-
tury. When these studies were carried out, some nearly a half cen- spite careful monitoring of the serum aspirin levels.40 Others could
tury after the introduction of salicylate, the drug was found wanting not verify that aspirin hurried the return of the sedimentation rate to
in healing myocarditis, the heart injury then common. Here we see normal values.41 Still others argued that high-dose aspirin benefited
another consequence of the biological mutation of RF. We now know only pericarditis.42
this fashion, children’s heart disease actually worsened.45 The nar-

row range between effective dose and overdose in children proved
a difficult one to achieve, but when it was attained, victims of RHD
benefited.46
Physicians at the House of the Good Samaritan worked out
Figure 37.5: Coburn’s phases of rheumatic fever (1936) the details. The first line of therapy for congestive heart failure was
restricting fluid intake and lowering dietary salt. If the child remained
symptomatic, doctors added a mercurial or xanthine diuretic, both
What seems likely is that Coburn’s more precise use of aspirin drugs with side effects in the 1940s. When these efforts were not
and “activity” collided with RF’s biological evolution. Always effective enough, they added digitalis, carefully monitoring for ill effects. In this
for fever, joint complaints and pericardial fluid, salicylate, when first manner, most children showed signs of improvement.47
employed at the end of the 19th century, seemed more effective The concept of “activity,” sulfonamide prophylaxis and care-
against heart disease simply because pericarditis was then more fully monitored aspirin provided physicians with tools to combat RF.
common. Aspirin was far less capable in treating the newer form of Without question, they improved the lot of victims of the disease. One
heart disease. Thus, as pericarditis waned, the perception waxed that cannot leave this conclusion without a parting, sympathetic remem-
aspirin was worthless in any form of heart injury. Nevertheless, when brance for all those children who spent months or years in conva-
Coburn developed his aggressive high dose aspirin treatment, RF lescent homes, some exposed to cold and the elements, in enforced
injured the heart far less seriously than it had when Thomas Maclagan bed rest, with few visits from parents and family. Some endured rigor
first used salicin 75 years earlier. This lessening of impairment may producing fever for chorea; others serious side effects from early sul-
well have left the impression of the benefits of Coburn’s treatment fonamide or digitalis; a few overdosage of radiation; most had tonsils
(Fig. 37.5). removed. Their travail is part of the history of RF.
Lessons learnt are the concept of “rheumatic activity” and
remarkable improvement of the symptoms with Asprin. HISTORY IN THE 20TH CENTURY
Radiation Moderating biology of RF in the 20th century is easy to spot. A close

look at the central feature of RF carditis reveals the outline. Dramatic
A few physicians approached chronic myocardial inflammation pericarditis and endocarditis of the late 19th century largely disap-
with an entirely different therapeutic strategy. Beginning in the mid- peared, replaced by myocarditis that was often clinically subtle and
1920s, Robert Levy, also at Presbyterian Hospital in New York, used which might even smolder for decades with minimal perceived mor-
radiation. His rationale was that X-ray killed inflammatory cells; in bidity. In the last-third of the 20th century, few, if any, streptococcal
RF Aschoff bodies were sites of inflammation. Over a period of many infections treated or not injured the heart. We can see the diminish-
years, Levy selected a small number of patients with evidence of my- ing of other symptoms. By the time that Jones published his diag-
ocarditis and gave them 4–25 radiation treatments for a total dose of nostic scheme in 1944, painful, migratory swollen joints had yielded
about 1,500 rad, which in itself was capable of injuring the heart’s to mildly sore joints without much swelling or arthralgia, melting
muscle. Although Levy believed that his patients benefited from away over the next decades to insignificant aches and pains. Chorea,
radiation, he was unable, of course, to obtain myocardial biopsies once a major movement disorder with verbal and even psychiatric
to verify his claims.43 Never widely accepted, radiation nevertheless involvement, also disappeared, witnessed now, if at all, with only
was assessed during World War II among naval personnel hospital- an occasional twitch. Subcutaneous nodules and erythema mar-
ized with RF. Giving much lower doses, naval physicians could detect ginatum have also largely disappeared. In contrast to Cheadle, who
no benefit.44 anticipated that most patients would suffer most symptoms at some
point in their illness, for Jones the clinical problem was the difficulty
TREATMENT FOR CONGESTIVE of making a diagnosis in a disease of increasing rarity and diminish-
ing severity. Most of his patients suffered from only one or two of RF’s
HEART FAILURE
many symptoms. To surmount these new hurdles, Jones separated
Treating congestive heart failure with digitalis offered the hope of the diverse complaints of RF into “major” manifestations and “mi-
shortening the time a child spent in bed. Heart failure made the nor” manifestations. The presence of only two “major” or one “ma-
experience of RF even more desperate for victims. Shortness of jor” and two or more “minor’’ manifestations was sufficient to make
breath, swollen legs and greatly enlarged livers worsened the quality a diagnosis (Chart 37.1).
of life. Some of the earliest trials of digitalis pushed the dose to the Lesson learnt: Jones”major” and “minor” manifestations were
point where toxic effects were evident on the electrocardiogram. In helpful to make the diagnosis.
CHART 37.1: Jones criteria for the diagnosis of rheumatic fever (1944) that these antibodies were identical to streptococcus-induced anti-
Major manifestations Carditis bodies. In other words, a constituent of the streptococcus produced
antibodies that “cross-reacted” with heart tissue. These antibodies,
Arthralgia
in theory, were the agents of cardiac injury.54 Subsequent laboratory
Chorea
research demonstrated similar cross-reactivity between the strepto-
Subcutaneous nodules coccus and glycoprotein in heart valves, heart muscle, neurons in the
Prior bout with rheumatic fever caudate and subthalamic nuclei of the brain, and joint tissues mo-
Minor manifestations Fever lecular evidence linking the streptococcus to each part of the body at-
Arthritis tacked by RF. Different components of the streptococcus, usually clas-
sified as M proteins, appeared responsible for antibodies targeting
Abdominal pain
distinct tissues, accounting in theory for the variable symptomatic
Chest pain
expression of RF in diverse people that has characterized so much of
Rashes (erythema marginatum, among others) its history.
Nosebleeds Epidemiologists in the 1930s did more than just provide evi-
Lung disease dence that streptococcal sore throats preceded RF. They recorded
Abnormal laboratory tests, such as elevated how prevalent the disease had become and, as startling, showed
erythrocyte sedimentation rate, high white that its continuing biological evolution had started its march toward
blood count extinction. In an exhaustive study that summarized virtually all rel-
Source: Reference 48 evant epidemiological knowledge in 1930, John R Paul determined
that approximately 840,000, or just less than 1% of Americans, suf-
fered significant and permanent heart damage from RF.55 A decade
later, Philip Hench estimated that the number had grown to 1 mil-
MOLECULAR BIOLOGY
lion, with an estimated 40,000 deaths each year.56 Mortality did not
The prevention of rheumatic recurrences by antistreptococcal medi- tell the whole story. School health doctors in the United States and
cation was confirmed in 1929 by Coburn and Moore. The relationship Britain calculated that between 1% and 2% of all school-age children
between Group A streptococcus (GAS) and RF was established only had perceptible cardiac scars with varying degrees of handicap,57
in 1931 by Collis (England) and Coburn (USA).49 By 1935, variations impediments that mandated special educational programs in most
in GAS resistance to phagocytosis of virulent, attenuated and aviru- communities.58
lent strains were clearly confirmed and were summarized by Ward
and Lyons.50 They wrote, “the resistance to phagocytosis of the viru- ADRENOCORTICOTROPIC HORMONE
lent variants appears to be associated with the presence of capsules
AND CORTISONE
on the organisms. No capsule can be demonstrated on the avirulent
variant”. The appearance of the colony depends to some extent on the “A new era in the study and treatment of rheumatic diseases began
length of incubation time. The younger colonies—6 to 8 hours—are on April 13, 1949,” Benedict Massell precisely proclaimed, when
of the mucoid type, being smooth, watery and of regular contour”. Philip Hench and colleagues at the Mayo Clinic first gave patients
The prevention of first attacks of RF by the treatment of GAS Pharyn- cortisone and adrenocorticotropic hormone (ACTH).59 Cortisone
gitis was done in 1949 by Massell and Wannamaker.49 Later interest and ACTH hormones, known to physiologists for over a decade as
in RF waned, but curiosity about the streptococcus and its fascinat- “compound E” and “compound F”, had not been available in suffi-
ing biology continued strong. With Lancefield’s discovery of the GAS cient amounts for human trials until 1948. The first patients to receive
surface M protein as a major virulence factor and the type-specific the hormones were victims of Addison’s Disease, who lacked normal
protection afforded by its homologous M antibody51, the capsule was levels of cortisone. Hench, who had edited annual critical surveys of
relegated to a secondary level of interest, especially because it ap- literature dealing with rheumatological diseases since 1935, turned
peared to be nonantigenic.52,53 However, to select GAS clones likely his attention to the potent anti-inflammatory characteristics of these
to be most mouse virulent and to contain a large amount of M pro- compounds. Hench proposed their use, at much higher doses, in
tein, Lancefield advised picking only the most highly mucoid colo- degenerative arthritis in adults and RF in children. His supposition
nies from the surface of a blood agar culture. was that both drugs should lower fever, lessen the pain and swell-
In the late 1950s, pathologists discovered that antibodies were ing of arthritis and reverse the carditis all signs of inflammation in
attached to heart tissue removed during surgical repair of rheumat- RF. Hench understood that giving pituitary ACTH resulted in pa-
ic heart valves. This provided molecular evidence that myocarditis tients’ secreting higher than normal amounts of adrenal cortisone. In
smoldered long after the initial bout with RF and suggested that these essence, giving either preparation resulted in increasing the level of
antibodies mediated cardiac damage. In the early 1960s came proof cortisone available to lessen inflammation. At first, Hench treated
just seven patients. He was impressed with the prompt response in in improving the general “well-being” of the patient, for example,
abating symptoms and urged further study.60 improving appetite. At issue, did hormone benefit the heart? In a
Massell and physicians at the House of the Good Samaritan i discussion that bore striking resemblance to the debate on the value
mmediately accepted the task of exploring the effects of hormones of salicylate 75 years earlier, the Bellevue doctors thought cortisone
and later in 1949 they administered ACTH to ten of their sickest helped with pericarditis, perhaps aided myocarditis, but almost cer-
patients. Like many physicians who regularly treated those seriously tainly did not prevent damage to heart valves.63 Several groups con-
ill with RF, Massell understood that aspirin had serious limitations, cluded again from the perspective of their small numbers of patients
especially in healing carditis. His initial experience with hormones that hormone produced no benefit to the heart, but ladened the
rendered him an ardent convert. He had good reason for his pas- patient with serious side effects.64
sion: even in these precariously ill patients fever vanished in a day, Lesson learnt is cortisone has serious side effects and a distressing
joint pain in 1–3 days, joint swelling in 2–3 days, pericarditis and “flare” or “rebound” of symptoms once medication was stopped.
congestive heart failure in less than 2 weeks. The sedimentation rate A clear mandate to remove the triggering streptococcus with pen-
returned to normal in less than 1 month; nodules melted in less than icillin seemed the unavoidable conclusion to laboratory research.
2 months. Large doses of ACTH had side effects: acne, stretch marks, Here the dramatic moderating of streptococcal diseases in general
headache and in a few cases psychiatric disturbances. More immedi- and RF in particular hindered efforts. Office-based research pointed
ately, ACTH promoted fluid retention that initially worsened conges- to obstacles. Much streptococcal infection was now asymptomatic.
tive heart failure. To Massell, the benefits of hormone were “striking” Some streptococcal disease mimicked the common cold. Only a frac-
and far outweighed the complications, hitting a chord that was struck tion of streptococcal illnesses produced the “classical” symptoms of
again and again throughout the medical profession.59 sore throat with accompanying signs of fever, swollen lymph nodes
What followed was a cascade of reports from many hospitals that and exudative pharyngitis. In most office practice, only 1% of strepto-
treated children with RF. For the most part they described experi- coccal throat infections progressed to cause RF. And these few cases
ences with a small number of patients, often just during the period were far milder by every measure than cases of a generation earlier.
when the drug was administered. In part, the small numbers were With the simple office throat culture, physicians had the means of
dictated by the epidemiological downswing of the disease: no hos- diagnosing streptococcal disease quickly and accurately, but deter-
pital had enough patients, especially with life-threatening carditis, mining which patients required culturing was problematic. With
to conduct a study that would achieve statistical significance. There every epidemiological study pointing toward the marked reduction
were other problems. What was the appropriate dose, for how long in the incidence of RF, some physicians in the 50s began to question
should treatment last, what signs should the clinician follow, how whether close surveillance of the streptococcus in the office setting
many side effects could be tolerated? Treatment with cortisone was was even necessary. Even parents of the children at greatest risk,
often followed by a new phenomenon: a distressing “flare” or “re- those with prior episodes of RF, often neglected to take their offspring
bound” of symptoms once medication was stopped. What did these to the physician’s office for monthly injections of penicillin. Most
new symptoms mean for the prognosis of the patient? Despite short- children did not suffer negative consequences.
comings, these early reports were uniformly enthusiastic, especially
in the treatment of the sickest patients those with pericarditis (for- PENICILLIN
tunately now rare) and myocarditis complicated by congestive heart
failure.61 Penicillin altered RF’s clinical landscape. Although Alexander Flem-
Corticosteroid offered the hope of accomplishing what peni- ing had observed the bacteria-killing nature of the penicillium mold
cillin and aspirin could not: treating myocarditis. This potent anti- in 1928,65 penicillin largely remained for the next decade an effec-
inflammatory steroid hormone ran headlong into RF’s changing tive laboratory tool for sorting out bacteria on blood agar plates. In
biology and epidemiology. Fewer critically ill patients made drug the late 1930s, Howard Florey and Ernest Chain at Oxford revitalized
trials more difficult. Fewer deaths and those occurring decades after Fleming’s idea and systematically explored it. The older drugs like
initial illness made pathological evidence of success or failure nearly sulfonamide could prevent streptococci from multiplying, but could
impossible. In some instances, steroids appeared to provide quick not eliminate them from the pharynx. When physicians had stopped
relief to myocarditis, but new problems swiftly arose. Side ef- giving sulfonamide to patients, streptococci lingered in the throat
fects were prompt and serious, preventing long-term use. Grave to trigger RF. In sharp contrast, penicillin promptly killed all strep-
“rebound” occurred when the drug was withdrawn.62 A careful tococci. The question was one of timing: would penicillin overcome
multinational comparison between aspirin and steroids, carried out the necessary delay between the acquisition of bacteria on the ton-
by the American Heart Association and the British Medical Research sils and the start of antibiotic? Older studies had implied that strep-
Council, demonstrated no superiority for hormones! tococci needed some time to initiate the rheumatic havoc (Coburn’s
At Bellevue Hospital in New York City, physicians confirmed that Phase II), but the span of the therapeutic window of opportunity was
hormones were strikingly effective in treating fever and arthritis and uncertain.
A close look at one of the initial investigations reveals the Massell was able to culture throats thrice weekly of patients conva-
power of their method. They enrolled over 1,600 recruits who lescing from RF. As soon as streptococci appeared (whether or not
suffered from sore throats severe enough to produce exudates of pus they produced symptoms in the child), he started penicillin. When
on their tonsils. Researchers cultured all for streptococci and tested he did so, only 6% of patients relapsed compared with nearly half of
all serially for antistreptolysin O. Randomly, they divided the recruits patients who served as controls. The lesson drawn was that penicillin
into a group that received penicillin and a control group that re- used in this fashion was beneficial, but not as effective as continu-
ceived no antibiotic, which was, of course, the prevailing approach in ous prophylaxis with sulfadiazine, which, when followed, eliminated
1949 to the initial management of streptococcal tonsillitis. This ran- most relapses. In marked contrast to physicians at Fort Francis War-
dom assignment eliminated a bias that had entered Caroline Bedell ren, Massell studied only 46 patients.72
Thomas’s earlier studies with sulfonamide when only those patients A natural consequence of the Fort Francis Warren investigations
who were compliant received the drug. Only two men in the penicil- was to see whether penicillin would also be effective in a scheme of
lin group subsequently developed RF compared with 17 in the con- continuous prophylaxis. Initially, penicillin was available only in
trol group. Penicillin was clearly more effective than no treatment. A injectable form and as such was considerably less attractive for daily
crucial benefit to this study was the calculation that 2% of patients use than oral sulfadiazine. In the early 1950s, penicillin became avail-
with untreated streptococcal sore throats ultimately went on to de- able in oral tablets. Dosage was five times the intramuscular route and
velop RF, a prediction subsequently refined upward to 3%.66 to be effective penicillin had to be given three or four times a day on
Almost immediately, the treatment of streptococcal throat in- an empty stomach, no mean task for parents to accomplish. Despite
fections with penicillin became the recommendation of the Ameri- obstacles, penicillin proved highly efficacious. Its advantage over
can Heart Association (AHA). Because many physicians’ offices did sulfadiazine was that physicians did not need to follow white blood
not have ready access to definitive culture techniques in the early counts looking for early signs of drug induced toxicity.73, 73a The ques-
1950s, the AHA encouraged giving penicillin even in “suspected” tion arose whether patients and their families would be able to follow
cases.67 With a similar study design, the Fort Francis Warren group such a schedule for years. As a more palatable alternative, some doc-
determined that recruits benefited from penicillin even when the tors suggested, with initial clinical success, using oral penicillin inten-
treatment began as long as 9 days after the start of throat symp- sively just 1 week each month.74 For most physicians, the continuous
toms.68 When long-acting benzathine penicillin became available, daily prophylaxis with either sulfadiazine or penicillin was the safest
the Fort Francis Warren group demonstrated that a single injection recommendation for children who survived one bout of RF.75
eliminated streptococci from the throats of nearly 100% of sufferers. Long-acting penicillin, benzathine penicillin or “bicillin,”
Lesson learnt: Importance of Primary prevention. “prevention is changed the calculus of prophylaxis. Gene H Stollerman, who began
better than cure”. a career devoted to streptococcal illness and RF at Irvington House,
Once the streptococci were gone, the threat of RF vanished.69 So found in 1952 that a single monthly injection provided sufficient
successful was long-acting penicillin that the navy began administer- penicillin to prevent streptococcal infection. Its advantage, imme-
ing a single shot to all recruits in 1957.70 Cementing the supremacy diately appreciated by workers in the field, was that nurses, doctors
of penicillin over the more familiar sulfonamides, such as sulfadia- and parents could make certain that children received an adequate
zine, which doctors continued to use successfully in prophylaxis of dose of the drug. Its disadvantage, also immediately appreciated by
recurrences, physicians at Fort Warren demonstrated once again child recipients, was that the volume of penicillin required was siz-
that these drugs were unsuccessful in eliminating streptococci from able and its intramuscular injection painful.76 Children balked so
throats and, as such, had no role in the treatment of the preceding often that some physicians, including May Wilson, who was now
streptococcal infection.71 working with a younger colleague, Wan Ngo Lim, at New York Hos-
pital, offered oral penicillin coupled with frequent reminders from
Long-acting Injections of Penicillin the office. Most doctors argued that monthly shots provided the most
efficient means of prophylaxis.77 In 1955, Stollerman formulated the
for the Prevention of RF
general principles of prophylaxis: antibiotic for at least 5 years after
The people with the most at stake were those recovering from RF. the initial bout of RF, preferably penicillin, in monthly injections
Until now, the only measure of safety against relapse was the daily because it eliminated the difficulties of multiple daily dosing.78 The
dosage of sulfonamide carried out for years. Would treatment with recommendation extended even to children who did not suffer car-
penicillin of subsequent streptococcal infections, instead of continu- ditis as a major manifestation of RF, out of concern that a second or
ous prophylaxis, serve this population? At the House of the Good third bout might attack the heart.79 Just how long to continue proph-
Samaritan, Benedict Massell too had a ready group of patients to ylaxis was a debated point. Clearly the risk of recurrence declined
study. Massell had taken over direction of much of the research at with time, especially after 20 years of age, but it never went away.80
“Good Sam” after Duckett Jones became the medical director at the Despite this observation and the marked decline in RF, the AHA in
Helen Hay Whitney Foundation, which sponsored research in RF. 1965 recommended prophylaxis for life.81 Continuous penicillin
posed theoretical problems. Would it lead to resistance of the group received telephone notification of a positive culture with instruction
A beta-hemolytic streptococcus? Fortunately, that did not occur. Pen- for the child to seek medical attention. The following day, the school
icillin did result, however, in other resistant mouth flora, especially nurse once again called the parent to ask what action had been tak-
among nonhemolytic streptococci, that presented the worrisome en. Fool proof? Not at all. Despite these efforts, only half of the chil-
possibility of untreatable bacterial endocarditis, always a concern for dren received any penicillin; less than a third received a full course of
people with scarred heart valves.82,83 the drug.85 Community and state programs proliferated. In 1950, two
states offered free antibiotics to needy patients; in 1958 the number
grew to 29. These antibiotic programs joined the Crippled Children’s
Penicillin and Public Health Programs Program public sector efforts which had grown to include all but one
Prophylactic penicillin offered communities a cheap alternative to state in aiding “cardiac cripples”.86
long hospital stays for convalescent care. Newton, Massachusetts, Lessons learnt: Intensive educational campaign like public lec-
was among the first to act. After consulting with Duckett Jones and tures, radio shows, newspaper articles, physicians and nurses, school
Benedict Massell, public health officials set up a program to iden- teachers, principals, parents and children has Parent-Teacher Associa-
tify those children who needed prophylaxis. First, Jones and Massell tion programs to be done now in developing countries where RF is en-
joined community leaders in public forums to educate physicians demic.
regarding the need to provide penicillin. Next, Jones and Massell The moderating nature of RF and hormonal therapies that car-
asked Newton’s doctors to cull their files for cases. Then public health ried serious side effects prompted physicians to rethink Duckett
officials sent questionnaires home with all 14,000 of the community’s Jones’s criteria for diagnosis. Initially revised in 1955 and again in
schoolchildren asking parents whether their child had ever received 1965, the new guidelines called for more objective evidence before
the diagnosis of RF. Responses revealed that 379 children had. The reaching a diagnosis. Recommending a lifetime punctuated with
parents were directed to make an appointment with their physicians painful monthly injections placed an increased burden of proof upon
to confirm the memory and, if correct, to seek penicillin tablets for frontline physicians. At mid-century, the challenge for the physician
continuous prophylaxis. Newton’s doctors substantiated the parents’ was the diagnosis, prevention, and treatment of an increasingly rare
recollections for 214 of the children. If parents could not afford the disease.
price of penicillin, the Newton Health Department supplied it with-
out cost. The program enjoyed considerable success. The question- INADEQUACY OF PUBLIC
naire revealed that only 16% of children who needed prophylaxis had
HEALTH PROGRAMS
received the antibiotic before the start of the project. The program
raised this to 80%. Of note, despite intensive physician and parent The Biological Evolution of Rheumatic Fever and Physician Error
education that reached into every home and the availability of free Despite identification and treatment programs, children with RF still
penicillin, one-fifth of those in need did not receive the drug.84 found their way to doctors’ offices. Leaders in the field analyzed the
Lesson learnt is Penicillin altered rheumatic fever’s clinical land- reasons for these “preventable” cases. After talking with parents and
scape. Penicillin prophylaxis is the sheet anchor of prophylaxis. children, physicians at Irvington House discovered that over 40% of
Officials in Youngstown, Ohio, went further; they set out to pre- bouts of RF were preceded by totally asymptomatic streptococcal ill-
vent even first attacks of RF. Beginning in 1950, the same year that nesses, which had been detected only through rising antistreptoly-
the Fort Francis Warren physicians reported the efficacy of treating sin O titer in the blood.87,88 Two-thirds of patients arriving with RF
the preceding bout of streptococcal sore throat, Youngstown public at the House of the Good Samaritan had not consulted a doctor for
health officials went to work. A close look at their program illustrates the preceding illness, largely due to the mild nature of the symptoms.
the immensity of the project. It began with an intensive educational The third who had attended a doctor received either an incorrect
campaign public lectures, parent-teacher association programs, diagnosis or inadequate therapy.89 A different, but no less distress-
radio shows, and newspaper articles that targeted, separately, physi- ing, story came from doctors at La Rabida Sanitarium in Chicago.
cians and nurses, school teachers and principals, and parents and Only one-third of patients with sore throats received a throat culture.
children. The following year, officials put their program into gear. Any Even more disturbing, only one-third of blood agar plates had been
child with a sore throat was directed to report to the school nurse, interpreted correctly by the physician as demonstrating the presence
who obtained a throat culture. The parent of an absent child received of hemolytic streptococci.90 With these problems in mind, Benedict
a phone call to determine whether the absence was due to tonsil- Massell advised parents and physicians: mothers should take a sick
litis. If so, the parent was urged to obtain a throat culture either at child’s temperature four times a day. If the fever ever reached 101°,
school or at a physician’s office. Through both routes, nearly 900 she should consult a physician. Unless the cause of the fever was
cultures were obtained in 1951. Six percent of the cultures grew clearly identified, a physician should obtain a throat culture. The
hemolytic streptococci. Both the parent and the child’s physician appearance of any beta-hemolytic colonies on the bacterial plate
should dictate penicillin. Even these stringent guidelines, of course, the rigors of enforced bed rest. The patients were randomly assigned
did not detect totally asymptomatic cases or prevent physician to one of three drug regimens: aspirin (at a dose somewhat lower
error.89 than Coburn’s suggested schedule), cortisone, or ACTH. The dura-
Programs for prophylaxis of recurrences fared no better. Two- tion of all three drugs was 6 weeks. Patients were kept in the hospital
thirds of children discharged from Herrick House, a convalescent under observation during this period and for 3 weeks after stopping
hospital 30 miles west of Chicago, were no longer taking penicillin at the drugs. Patients returned for clinic appointments monthly for
a follow-up visit. About half of the parents gave as a reason that they 6 months and then every other month. The protocol thus seemed
had stopped bringing their children to a doctor. The prescription had nearly perfect: the best investigators and institutions, rigorous diag-
simply run out. As woeful, the other half selected doctors who did nostic criteria, uniform administration of drugs, in-hospital obser-
not understand the need for continuous prophylaxis. Some of these vation, close follow-up, and conclusions subjected to demanding
physicians stopped the penicillin because there was no evidence of statistical tests. “Nearly” perfect in that detractors pointed out that
heart disease, a sign, of course, of the measure’s success and the need there was not a group receiving no drug at all.
for its continuance.90 A survey conducted by the US Public Health Sulfonamide and later penicillin brought similar enthusiasm.
Service and the American College Health Association of over 500,000 Shortly after Coburn singled out infection with the streptococcus as
first-year students entering 137 colleges during a 5-year period in the triggering event in RF (Coburn’s Phase I), sulfonamide became
the late 1950s revealed the immensity of the problem. Only half of available for treating bacterial infections, raising expectations that it
the adolescents in need of prophylaxis had ever been enrolled in a was just the drug to combat the disease. Here RF’s unusual nature
program; merely 12% arrived at college taking penicillin.91 A similar confounded early therapeutic attempts. Despite Coburn’s well-
poll of military recruits in 1960 revealed that only 7% of those in need articulated consensus that RF was not a widely disseminated infec-
received antibiotics.92 One interpretation of this neglect was that RF tion, early studies treated symptomatic RF (Coburn’s Phase III) with
had disappeared from the public mind as a health menace. sulfonamide. The drug had no effect on heart, brain or joint symp-
Lesson learnt: Stringent RF control Public Health Programs are toms, and serious side effects actually worsened the patient’s experi-
very important. ence.98 When physicians correctly targeted the triggering sore throat
for treatment, sulfonamide also came up short. It could not prevent
SORTING OUT THERAPY Phase I from progressing to Phase II and III.99 The first success with
sulfonamide came in preventing relapses with daily doses of the drug
The British Medical Research Council and the AHA took up the administered throughout the year: in other words, not permitting
responsibility of sorting out the appropriate therapy issue. The infection to occur in the first place.100 Newer sulfonamides produced
paucity of patients and the flush of excitement accompanying the fewer side effects, and prevention was so attractive to the United
dramatic first usage of cortisone were just two of the impediments States military that hundreds of thousands of seamen received daily
to assessing the true worth of steroid hormones.93 After the first sulfonamide starting in 1944. Within months of this massive and very
enthusiasm for hormone waned, the need plainly emerged to es- successful program, biological disaster struck: the streptococcus be-
tablish its worth compared with aspirin, the flawed, but nonetheless came resistant to sulfonamide and diseases caused by resistant strep-
accepted treatment. Complicating matters still further was the ques- tococci infected sailors. The US Navy had fewer cases of RF, but in the
tion whether it made a therapeutic difference which hormone was process it altered the germ.101
used, ACTH or cortisone. Early studies comparing hormones and Lessons learnt are sulphonamide had no effect on heart, brain,
aspirin could establish no obvious superiority, but these inves- or joint symptoms, but had serious side effects actually worsened the
tigations, carried out in single hospitals, also suffered from lack of patient’s experience. Still worse streptococcus became resistant to sul-
sufficient numbers of patients.94,95 Even Benedict Massell, hormo- phonamide.
nal advocate, conceded in 1953 that the relative merit of competing The first mention of RHD in India was in 1910. There was a low
drugs was an unresolved issue.96 prevalence as indicated by British Physicians working in this country.
In the hope of settling these therapeutic perplexities, the Medi- But after 1935–40, there were many reports of the high prevalence of
cal Research Council of Great Britain and the AHA collaborated in RF/RHD, (Table 37.1) though this was a percentage of cardiac cases
a carefully constructed, 12-hospital study. Its coordinators included in government hospitals (some 30–50%). So grave was the problem
many of the major leaders and institutions most closely involved that several research programs funded by WHO and the ICMR were
with RF.97 Each of the over 500 patients had to meet Jones’s criteria set up to investigate it. RHD was made into a program of the 4th and
for diagnosis, modified only to make it more rigorous by requiring 5th five year plan (1966), but not subsequently. A Streptococcal Ref-
observable swelling and limitation of motion of joints or arthritis, in erence Lab was set up in 1974 in Delhi and Vellore. These labs used
place of Jones’s original inclusion of simple joint pain or arthralgia. to hold annual conferences for the filed workers.
All patients received penicillin treatment for current streptococcal In 1959, Wilson103 clearly demonstrated striking capsules formed
infection and were placed on penicillin prophylaxis. All endured in 3–6 h serum enriched broth cultures of GAS strains isolated from
TABLE 37.1 Prevalence of RHD in India in Indian school surveys molecular makeup of the streptococcus and thus a chance to alter its
Source Year Prevalence per 1,000 history.
The abrupt termination of an epidemic by such treatment
ICMR 1972–1987 0.8–11
was associated with the prompt disappearance of RF and, simul-
Padmavati et al. 1978 6–11
taneously, of the highly encapsulated strains belonging to the
Patel et al. 1986 2.03 epidemic M Types 1, 3, 5, 14, 19 and 24. After mass prophylaxis in
Avasthi et al. 1987 1.3 military recruits resulted in the elimination of epidemic RF, per-
Jose et al. 2001–02 0.68 sistent GAS carriage and sporadic pharyngitis were noted to occur
ICMR 2002–2005 0.43–1.47 relatively frequently without the reappearance of RF.106,107 At about
this time, two highly encapsulated strains that clearly caused RF
Misra et al. 2003–2006 0.5
(an M3 and an M5) were isolated by Alan Siegel from Chicago in
Periwal et al. 2006 0.67
two school children during their antecedent episodes of pharyngi-
Abbreviations: ICMR: Indian Council of Medical Research; RHD: Rheumatic tis.108 These virulent strains became the source of many subsequent
heart disease studies of their virulence properties and of their potential for
Source: Table adapted from reference 102 development of M protein vaccines. While studying these strains,
Stollerman and Ekstedt109 reported that encapsulation significant-
ly shortened the chain length of GAS units, whereas, with loss of
patients with virulent human infection. On properly prepared and encapsulation or with growth in the presence of type specific anti M
preserved blood agar plates, the heavily encapsulated strains formed antibody, their chain length was greatly elongated.
large, domed “mucoid” colonies and the size was measured by light
microscopy using India ink preparations. Furthermore, the “matte” VARIATION OF VIRULENCE OF
strains previously described by Ward and Lyons50 and by Todd
STRAINS IN A SINGLE M TYPE
and Lancefield104 were demonstrated to be initially “mucoid”, but
upon drying, they developed a roughened, “matte,” collapsed (flat) Four variants of a single M14 strain (M+ Capsule+, M+ Capsule–,
surface. With use of phase contrast microscopy, Wilson had also M-capsule+ and M-capsule–) identified by Armine Wilson were
demonstrated virtually total resistance to phagocytosis of heavily used to study the innate host defense of germ-free mice110 and
encapsulated strains. In subsequent studies, resistance to “surface of colostrum deprived piglets.111 Maximal virulence was demon-
phagocytosis” of GAS strains by mouse and rat leukocytes was cor- strated only in strains that were both M protein rich and heavily
related with the degree of encapsulation or M protein content.105 encapsulated.112 Rothbard and Watson demonstrated that during
This is not to argue that the history of RF can be reduced convalescence from pharyngitis there is progressive loss of GAS
simply to an alteration of molecules. Rather, these molecular shifts strain virulence.113,114
set into motion biological and epidemiological changes that con- By the 1960s, it became more evident that the high attack rate of
fronted patients and doctors with an ever-changing health problem RF noted in military epidemics did not apply to endemic GAS phar-
that demanded attention. To be sure, technologies, such as the au- yngitis in schoolchildren.115 GAS strains were more often cultured
topsy, the stethoscope and electrocardiogram, the progression of from clinically mild pharyngitides, as well from convalescent or
medical thinking (individual case histories, large hospital-based asymptomatic carriers.116 Though 20% of school children had posi-
studies, Cheadle’s “typical” series, Coburn’s “phases,” and Jones’s tive throat cultures for GAS, the prevalence of RF abruptly declined.
“major/minor” criteria), the organization of medical care into There was a difference in the virulence of GAS strains isolated from
hospitals, and various research strategies all helped to define and sporadic infections in schoolchildren from Chicago with that of the
illuminate RF. If molecular biologists are correct in their singling out strains isolated from military epidemics.117,118 Thus it was proposed
of M proteins as the ultimate culprit, the very nature of the disease in 1969 that only certain heavily encapsulated strains were notori-
lay beyond truly “curative” therapy until the cusp of the 21st century. ous for causing RF (“rheumatogenic”).119 Further review of the exist-
This observation underscores the dilemma that patients and doctors ing literature120,121 confirmed the limited M-type association. After
have often faced in history: combating disease with the knowledge the standardization of an M-typing system based on the nucleotide
and tools at hand at a given moment, knowing full well that their sequence encoding the N-terminus of the mature M protein, GAS
efforts are not wholly adequate. reference laboratories widely adopted this sensitive method of M
The complex bond between molecules, disease, epidemiology, typing,122 but identification of colony morphology as a marker of
and history continues. Insights about the M proteins suggested to strain virulence was rarely noted.
Stollerman an additional means for physicians to attack RF: a vac- Lesson learnt: “rheumatogenic”encapsulated strains of GAS were
cine against M proteins, signaling an effort for humans to alter the notorious for causing rheumatic fever.
ened hearts worn out a decade before routine heart transplantation.

THE RETURN OF RHEUMATIC FEVER
Surviving RF meant that many victims could expect to lead fuller
AND INVASIVE GAS DISEASE lives. Women of childbearing years were clear beneficiaries. By 1970
In the 1980s, focal epidemics of RF occurred in cohorts of children many women with the reluctant blessing of their obstetricians con-
in several US states and Pennsylvania123-126 and in some US military ceived and survived pregnancy.
installations.127,128 The M types of the strains causing these epidem- In 1970 RF accounted for only 256 deaths in the United States,
ics were eventually to be the same as the notorious rheumatogenic a startling decline from nearly 40,000 deaths in 1940.145 Physicians
strains of the earlier World War II military epidemics.129 The state who had trained at Boston’s House of the God Samaritan, a hospital
of encapsulation of these strains was not reported originally, and that specialized in the care of the sickest sufferers of RF and where
systematic studies of their virulence were not made.130 Later, retro- many of the innovations of the 30s and 40s first saw light, remem-
spective analysis of outbreaks of invasive GAS infection that followed bered that some of the hospital’s beds went empty during their train-
revealed that mucoid colonies were often identified in some isolates ing in the 50s.146 Some of these same physicians remembered with
from affected cohorts—notably, M types 3 and 18.131 persistent excitement their investigations into RF a decade earlier
Finally, a retrospective study of the colonial morphology of the during World War II, because the disease, long in decline, briefly
GAS isolates recovered from patients with pharyngitis was made enjoyed an epidemiological encore in barrack147 and ship101 life that
during several years of recurrent waves of acute RF.130 For strains crowded recruits into tight living spaces. The stunning efficiency
that had been carefully preserved at –70°C, there was a clear correla- of sulfonamide and, a few years later, penicillin in driving the nails
tion between the outbreaks of acute RF and the prevalence of mu- into the coffin of a disease once so prevalent.66 Unfortunately same
coid strains.132 Identification of the genome of some of these strains decline is not seen in developing countries with poor socioeconomi-
revealed that a single virulent clone may have been responsible for cal condition and overcrowding.
the epidemics of RF reported from the Rocky Mountain States and Antibiotics played a role, especially in prevention, but they were
elsewhere133,134 and that a single genetically identified clone also only a small part of the story. In fact, RF had been in decline for a half
caused an outbreak of invasive streptococcal disease among school century before the discovery of penicillin.
children in Minnesota.135 In 1970, there were still vestiges of RF left visible for the
newcomer to medicine. On rare occasions, a child came to the
EXPERIMENTAL STUDIES OF THE pediatric clinic with complaints so unusual that the question of RF
arose. In such instances we would seek out of necessity the “gray-
CAPSULE’S RELATION TO ADHERENCE,
hairs,” because our regular teachers, pediatric house officers, had no
EPITHELIAL INTERNALIZATION, first-hand experience with the disease! The elders would enter the
COLONIZATION AND MUCOSAL INVASION examining room. If we had guessed correctly, great ceremony would
By the mid-1970s, the adherence of GAS to pharyngeal cells was be made in gathering together as many students and residents as
shown to be due to several fibronectin binding ligands, such as possible for a demonstration and discussion of this fascinating
lipoteichoic acid136,137 and the so-called F proteins,138 rather than disease! RHD brought laboratory scientists and clinicians together
to M protein alone. The hyaluronate capsule’s role was studied and intellectually and physically. This disease ignited controversy even
it was demonstrated that it attaches to a hyaluronic acid binding after its death in Western countries. Rheumatic fever fascinates,
protein, CD44, which is present on human epithelial cells139-142 and because it is a disease that abounds with change. Historians antici-
which induces cytoskeletal rearrangements, resulting in disrup- pate that medical and public health ideas about a particular illness
tion of intercellular junctions, thus allowing the microorganisms to and how to prevent or treat it will change considerably over time,
remain extracellular as they penetrate the epithelium. depending on the disease and on the social settings of patients and
More recently, strains of M types 3 and 18 that were strongly physicians. In this regard, RF does not disappoint.
associated with the reappearance of RF in the United States in the By 1970, RF had almost disappeared in developed countries. For
1980s were shown to avidly aggregate Type IV collagen.143 Such most families, the suffering it once produced took its place in the
aggregation was found to depend on the expression of both M memory of an afflicted parent or grandparent! Its diminished nature
protein and hyaluronate and was demonstrated in vivo (mouse skin), properly dictated its lowered status. Physicians and medical stu-
as well as in vitro. dents shifted interests elsewhere as well, for RF no longer produced
serious health consequences in the west. It lingered a while in
SURGERY FOR RHEUMATIC FEVER lectures, textbooks and clinical lore and then was largely forgotten.
Floyd Denny, who participated in the initial trials of penicillin
By 1970 surgically repairing or replacing heart valves had become after World War II, remarked in 1986, “I am impressed that we have
routine on the surgical service, more than 20 years after the “revival” raised an entire generation of young physicians who have never seen
of valvular surgery in the late 40s.144 These victims died, their weak- a case of acute RF.”148 Only in the continued exaggerated concern
over streptococcal sore throats, precautionary antibiotics before trips cal valvitis. These subclinical changes, detected only by ECHO, can
to dentists for those with suspicious heart murmurs, and repeated, persist and probably belong to a large group of patients who pre-
and largely unnecessary, heart examinations looking for newly sent later as RHD, without the past history of acute RF and prophy-
acquired heart disease during well-child visits did patients and laxis. These echocardiographic criterions, therefore, should now be
doctors still meet over the remnants of RF. included as one of the major criterions in the Jones’ system to permit
In 1980, echocardiography (ECHO) a modern tool was used to diagnosis of carditis in the setting of acute RF.150 ECO can change the
diagnose carditis. When ECHO is carried out in patients with acute epidemiological face of RF in the 21st century.
RF diagnosed strictly according to the Jones criterion, can avoid both
over diagnosis and under diagnosis of carditis. A high incidence of CONCLUSION
carditis or subclinical carditis, is detected by ECHO when performed
in patients with rheumatic chorea or arthralgia.149 When I gave grand Rheumatic fever is an illness of skin, brain, heart, connective
rounds at Fairview University, Minnessota and spoke on “Role of tissue, blood and serum, tonsils and joints, all bound intimately to
Echo in precise and early diagnosis of carditis in ARF” Liz Bruanlin a member of the streptococcus family of bacteria that causes several
said, “This may be the only lecture you may hear on rheumatic fever human diseases. Each component of the disease has its own history;
in the medical school that too from the person who sees poor patients together, as RF, they share a collective history. In addition, RF has
with rheumatic fever everyday”. I was surprised to see the enthusiasm been most responsive to the environment, especially living condi-
among all the senior persons like Ed Kaplan, Patricia Ferreri, Miller tions and physical setting.
et al. At the end of the lecture there was a hot discussion. Ed Kaplan Rheumatic fever’s researchers have also been its historians.
asked me “with the application of ECHO for the diagnosis of cardi- Understandably, the disease which challenged physicians at the
tis will there not be over diagnosis?’ In reply I asked him “If we over bedside, in the laboratory or in the making of health policy has also
diagnose, at the most we end up giving penicillin injection, which stimulated historical reflection. These medical leaders have dis-
is inexpensive. That is erring on the right side. If we do not use the cussed some of the early descriptions and changing symptoms of the
ECHO and miss the diagnosis and the patient ends up with RHD, disease, analyzed the perplexing relation of the streptococcus to RF,
needing expensive balloon valvuloplasty or valve repair or replace- detailed some of the social dimensions of RF, addressed the value
ment is expensive and carries high morbidity and mortality. That is of therapies and provided thoughtful appraisals of RF’s disappear-
erring on the wrong side. If you have a choice, would you err on the ance. The history of RF is of relevance to modern medicine because it
right side or the wrong side?” Ed Kaplan raised his arms and said has taught us much about the pathophysiology and epidemiology of
“You are disarming me”. In nut shell the disease is eradicated in US, autoimmune disease, and because RF is unique in the way that it has
but the problem is huge in many developing countries like India. changed repeatedly over time.
Hence early and precise diagnosis of carditis in acute RF, though dif- Lessons learnt from history are more important now in the
ficult, is very important in preventing serious consequences, mor- developing countries where disease is still a burning problem. It is
bidity and mortality in young. Echocardiographic criterions are now high time that the clinicians and policy makers in the developing
very important in providing precise diagnosis of carditis or subclini- countries learn the lessons from the history of RF and RHD.
REFERENCES
1. William Charles Wells. “On Rheumatism of the Heart,” Transactions of a society for the improvement of medical and chirurgical knowledge.
1812;3:373-424.
2. David Dundas. “An account of a peculiar disease of the heart,” medico-chirurgical transactions. 1809;1:37-46.
3. Matthew Baillie. The morbid anatomy of some of the most important parts of the human body, 2nd edition. London: J Johnson and G. Nicol; 1797.
pp. 44-6.
4. James Russell. “Case of rheumatism of the heart, successfully treated.” Edinburgh Medical and Surgical Journal. 1814;10:18-21.
5. Laennec RTH. A treatise on the diseases of the chest: In which they are described according to their anatomical characters, and their diagnosis
established on a new principle by means of acoustick instruments. London: T & G Underwood; 1821. p. 266.
6. Dewees WP. “A case of rheumatism with metastasis, producing carditis, pericarditis, peripneumonia, and pleuritis,” Am J Med Sci. 1828;2:473-5.
22.
7. Joseph-Irénée Itard. “Considérations sur le rhumatisme du coeur,” thèse présentée et soutenue à la faculté de médecine de Paris, le 13 juillet 1824,
pour obtenir le grade de docteur en médecine.
8. Audrey B. Davis. Medicine and its technology: An introduction to the history of medical instrumentation. Westport, Conn: Greenwood Press;
1981.
9. Jean-Baptiste Bouillaud. New Researches on acute articular rheumatism in general; and especially on the law of coincidence of pericarditis and
endocarditis with this disease, as well as on the efficacy of the method of treating it by repeated blood-letting at short intervals, trans. James
Kitchen. Philadelphia: Haswell, Barrington, and Haswell; 1837.
10. James B Herrick. “Jean-Baptiste Bouillaud and his contributions to cardiology,” Bulletin of the Society of Medical History of Chicago. 1940;5:230-
46.
11. Ackerknecht. Medicine at the Paris Hospital; Toby Gelfand, professionalizing modern medicine: Paris Surgeons and Medical Science and Institu-
tions in the 18th century. Westport, Conn: Greenwood Press; 1980.
12. Pamela Bright, Richard Bright. (London: Bodley Head, 1983); and Diana Freeman Berry and Campbell Mackenzie, Richard Bright (1789-1858):
Physician in an Age of Revolution and Reform (London: Royal Society of Medicine, 1992).
13. Bright R. “Cases of spasmodic disease accompanying affections of the pericardium,” medico-chirurgical transactions. Med Chir Trans. 1839;22:1-
19.
14. Andrew Cunningham. “Thomas Sydenham: Epidemics, experiment, and the ‘Good Old Cause,’” The medical revolution of the seventeenth cen-
tury, edition. Roger French and Andrew Wear. Cambridge: Cambridge University Press; 1989. pp. 164-90.
15. William Cullen, First Lines of the practice of physic, for the use of students in the university of edinburgh, 2nd editon. Philadelphia: Steiner and
Cist; 1781. p. 156.
16. Baron van Swieten, Commentaries upon Boerhaave’s Aphorisms concerning the knowledge and cure of diseases. Edinburgh: Charles Elliot; vol
31. 1776. p. 88.
17. William Balfour. “Observations on the pathology and cure of rheumatism,” Edinburgh Medical and Surgical Journal. 1815;11:168-87.
18. Edward J Seymour. “On the most effectual treatment of acute rheumatism I hospital practice in the last eight years,” Medico-Chirurgical Review
and Journal of Practical Medicine. 1838;29:657-60.
19. Haygarth J. A Clinical History of Diseases. 1. A clinical history of the acute rheumatism. 2. A clinical history of the nodosity of the Joints, 1805,
reprinted with an introduction by Lawrence A. May Oceanside, NY: Dabor Science Publications; 1977.
20. Alfred Stillé. “Case of rheumatism, endo-pericarditis, pleurisy, and double pneumonia , with autopsy.” Medical Examiner. 1840;3:21-5.
21. Saul Jarcho. “Pericarditis supervening on rheumatism (Roots, 1836).” Am J Cardiol. 1966;18:594-8.
22. Yonge. “Case of cerebral disturbance: Dependent upon disease of the pericardium.” Guy’s Hospital Reports. 1840;5:276-81.
23. Richard Bright. “Cases of spasmodic disease accompanying affections of the pericardium.” Med Chir Trans. 1839;22:1-19.
24. Thomas Sydenham. The works of Thomas Sydenham, trans. from the Latin edition of Dr Greenhill. Vol II. London: Sydenham Society; 1848. pp.
257-8.
25. Cheadle WB. “Harveian Lectures on the various manifestations of the rheumatic state: As exemplified in childhood and early Life,” Lancet. 1889;1
821-827. 871-877, 921-927.
26. Charles Clay. “Sulphur in rheumatic affections.” Lancet. 1839-40;2: 783-4.
27. De Roches JJ. “Two cases of acute rheumatism, treated with opium: And some observations on the comparative merits of that method, and of the
treatment which is founded on the principle of depletion,” Edinburgh Medical and Surgical Journal. 1805;1:154-9.
28. Samuel Fish. “Corroborative testimony in favor of large doses of opium in rheumatism.” Boston Medical and Surgical Journal. 1837;16:330-2.
29. John T Banks. “Acute rheumatism: Endocarditis followed by pericarditis and pleuropneumonia.” Dublin Hospital Gazette. 1854-55;1:53-5.
30. Corrigan DJ. “Observations on the treatment of acute rheumatism by opium,” Dublin Journal of the Medical Science. 1840;16:256-77.
31. Church WS. “An examination of nearly seven hundred cases of acute rheumatism: Chiefly with a view to determining the frequency of cardiac
affections, and especially pericarditis, at the present time.” St. Bartholomew’s Hospital Reports. 1887;23:269-87.
32. Bury GW. “A statistical account of four hundred cases of acute rheumatism admitted into the wards of the Middlesex Hospital during the Years
1853-59,” British and Foreign Medico-Chirurgical Review. 1861;28:194-8.
33. Pye-Smith PH. “Analysis of the cases of rheumatism, and other diseases of joints, which have occurred in the hospital during three consecutive
years: With remarks on the pathological alliances of rheumatic Fever.” Guy’s Hospital Reports. 1874;19:311-56.
34. Maclagan T. “The treatment of acute rheumatism by salicin.” Lancet. 1876;1:342-3. 2:601-4.
35. George E Murphy. “Salicylate and rheumatic activity: An objective clinical—histologic study of the effect of salicylate on rheumatic lesions, those
of joints and tendon sheaths in particular.” Bulletin of the Johns Hopkins Hospital.1945;77:1-42.
36. Helen B. Taussig. “Acute rheumatic fever: The significance and treatment of various manifestations.” Journal of Pediatrics. 1939;14:581-92.
37. Alvin F Coburn. “Salicylate therapy in rheumatic fever: A rational technique.” Bulletin of the Johns Hopkins Hospital. 1943;73:435-64.
38. Jager BV, Always R. “The treatment of acute rheumatic fever with large doses of sodium salicylate, with special reference to dose management and
toxic manifestations.” Am J Med Scie. 1946;211:273-85.
39. Katharine Smull, René Wégria, Jesica Leland. “The effect of sodium bicarbonate on the serum salicylate level: During salicylate therapy of patients
with acute rheumatic fever.” JAMA. 1944;125:1173-5.
40. Henry Z Sable. “Toxic reactions following salicylate therapy: A review of the literature and clinical reports.” Can Med Assoc J. 1945;52:153-9.
41. John D Keith, Alan Ross. “Observations on the salicylate therapy in rheumatic Fever.” Can Med Assoc J. 1945;52:554-9.
42. Harry A Warren, Higley CS, Coombs FS. “The effect of salicylates on acute rheumatic fever,” Am Heart J.1946;32:311-26.
43. Robert L Levy, Ross Golden. “Roentgen therapy of active rheumatic heart disease: A summary of eleven years’ experience.” Am J Med Sci.
1937;194:597-601.
44. Geo C Griffith, Halley EP. “The treatment of rheumatic fever by roentgen-ray Irradiation.” Annals of Internal Medicine. 1946;24:1039-42.
45. Sidney P Schwartz, Morris M Weiss. “Digitalis studies on children with heart disease: Effects of digitalis on the electrocardiograms of children with
rheumatic fever and chronic valvular disease.” Am J Dis Child. 1929;38:699-714.
46. Lucy Porter Sutton, John Wyckoff. “Digitalis: Its value in the treatment of children with rheumatic heart disease.” Am J Dis Child.1931;41:801-15.
47. Bernard J Walsh, Howard B Sprague. “The treatment of congestive failure in children with active rheumatic fever.” JAMA. 1941;116:560-62.
48. T. Duckett Jones. “The Diagnosis of Rheumatic Fever.” JAMA. 1944;126:481-4.
49. Taranta A, Markkowitz M. Rheumatic fever, Boston, London: MTP Press; 1981.
50. Ward H, Lyons C. Studies on the hemolytic streptococcus of human origin. I. Observations on the virulent, attenuated, and avirulent variants. J Exp
Med.1935;61:515–29.
51. Lancefield RC. Current knowledge of the type specific M antigens of group A streptococci. J Immunol. 1962;89:307-13.
52. Todd E, Lancefield R. Variants of hemolytic streptococci; their relation to type-specific substance, virulence, and toxin. J Exp Med. 1928;48:751–67.
53. Lancefield R, Todd E. Antigenic differences between matt hemolytic colonies and their glossy variants. J Exp Med. 1928;48:769-90.
54. Melvin H Kaplan, Mary Meyeserian. “An immunological cross-reaction between Group-A streptococcal cells and human heart tissue.” Lancet.
1962;1:706-10.
55. John Rodman Paul, The epidemiology of rheumatic fever: A preliminaryy report with special reference to environmental factors in rheumatic
heart disease and recommendations for future Investigation. New York: Metropolitan Life Insurance Co. 1930;30.
56. Philip S Hench. “Recent studies on arthritis and rheumatism in the United States.” Ann Rheum Dis.1941;2:172-92.
57. Carey F Coombs. “The diagnosis and treatment of rheumatic heart disease in its early Stages.” BMJ.1930;1:227-30.
58. Fred Hiss JG. “A Plan for rehabilitation for rheumatic subjects,” J Pediatr.1945;26:230-236.58.
59. Benedict F Massell, Joseph E Warren, George P Sturgis, et al. “The clinical response of rheumatic fever and acute carditis to ACTH.” New Engl J
Med.1950;242:641-7. 692-98.
60. Philip S Hench, Edward C Kendall, Charles H Slocumb, et al. “Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic
fever, and certain other conditions: A study in clinical physiology.” Archives of Internal Medicine.1950;85:545-666.
61. Arlie R Barnes, Harry L Smith, Charles H Slocumb, et al. “Effect of cortisone and corticotropin (ACTH), on the acute phase of rheumatic fever:
Further observations.” Am J Dis Child. 1951;82:397-425.
62. Arlie R Barnes, Harry L Smith, Charles Slocum, et al.” Acute rheumatic fever treated with cortisone and corticotropin,” Rheumatic Fever: A Sym-
posium, edition. Minneapolis: Lewis Thomas University of Minnesota Press; 1952. pp. 274-90.
63. Joseph J Bunim, Ann G Kuttner, Janet S Baldwin, et al. “Cortisone and Corticotropin in rheumatic fever and juvenile rheumatoid arthritis.” JAMA.
1952;150:1273-8.
64. David M Spain, Daniel Roth. “Effect of cortisone and ACTH on the histopathology of rheumatic carditis: Report of a necropsied case.” Am J Med.
1951;11:128-31.
65. Parascandola. “The Introduction of antibiotics into therapeutics.” History of Therapy In: Yosio Kawakita, Shizu Sakai, Yasuo Otsuka (Eds). Tokyo:
Ishiyaku EuroAmerica; 1990. pp. 261-81.
66. Floyd W Denny, Lewis W Wannamaker, William R Brink, et al. “Prevention of rheumatic fever: treatment of the preceding streptococcic infection,”
JAMA. 1950;143:151-3.
67. American Heart Association. “Prevention of rheumatic fever.” Lancet. 1953;1:285-6.
68. Frank J Catanzaro, Chandler A Stetson, Alton J Morris, et al. “The role of the strepococcus in the pathogenesis of rheumatic Fever.” Am J Med.
1954;17:749-56.
69. Robert Chamovitz, Francis J Catanzaro, Chandler A Stetson, et al. “Prevention of rheumatic fever by treatment of previous streptococcal infec-
tions: I. Evaluation of benzathine penicillin G,” New Engl J Med. 1954;251:466-71.
70. Paul F Frank, Gene H Stollerman, Lloyd F Miller. “Protection of a military population from rheumatic fever: Routine administration of benzathine
penicillin G to healthy individuals.” JAMA. 1965;193:775-83.
71. Alton J Morris, Robert Chamovitz, Frank J Catanzaro, et al. “Prevention of rheumatic fever by the treatment of previous streptococcic infections:
Effect of sulfadiazine.” JAMA. 1956;160:114-6.
72. Benedict F Massell, George P Sturgis, Joseph D Knobloch, et al. “Prevention of rheumatic fever by prompt penicillin therapy of hemolytic strepto-
coccic respiratory infections.” JAMA. 1951;146:1469-74.
73. Pitt Evans JA. “Oral penicillin in the prophylaxis of streptococcal infection and rheumatic relapse,” proceedings of the Royal Society of Medicine.
1950;43:206-8.
73a. Gale AH, Gillespie WA, Perry CB. “Oral penicillin in the prophylaxis of streptococcal infection in rheumatic children.” Lancet. 1952;2:61-3.
74. Kohn, Milzer, Maclean. “Prophylaxis of recurrences of rheumatic fever with penicillin given orally: Final report of a five year study.” JAMA.
1953;151:347-51.
75. Ella Roberts. “Use of sulfonamides and penicillin to prevent recurrence of rheumatic fever: A twelve year study.” Am J Dis Child. 1953;85:643-7.
76. Gene H Stollerman, Jerome H Rusoff. “Prophylaxis against Group A streptococcal infections in rheumatic fever patients: Use of new repository
penicillin preparation.” JAMA. 1952;150:1571-5.
77. Wan Ngo Lim, May G Wilson. “Comparison of the recurrence rate of rheumatic carditis among children receiving penicillin by mouth prophylacti-
cally or on indication: A six-year study,” New Engl J Med. 1960;262:321-5.
78. Gene H Stollerman. “The prevention of rheumatic fever by the use of antibiotics,” Bulletin of the New York Academy of Medicine. 1955;31:165-80.
79. Ann G Kuttner, Florence E Mayer. “Carditis during second attacks of rheumatic fever: Its incidence in patients without clinical evidence of cardiac
involvement in their initial rheumatic episode.” New Engl J Med. 1963;268:1259-61.
80. Eloise E Johnson, Gene H Stollerman, Burton J Grossman. “Rheumatic recurrences in patients not receiving continuous prophylaxis.” JAMA.
1964;190:407-13.
81. American Heart Association. “Prevention of Rheumatic Fever.” Circulation. 1965;31:948-52.
82. Joseph M Miller, Benedict F Massell. “Studies of bacterial throat flora during chemoprophylaxis of rheumatic fever,” New Engl J Med. 1956;254:149-
53.
83. Richard A Naimon, Gordon Barrow J. “Penicillin-resistant cacteria in the mouths and throats of children receiving continuous prophylaxis against
rheumatic fever.” Annals Intern Med. 1963;58:768-72.
84. Mary Alice Smith, Anton R Fried, Ernest M Morris, et al. “Rheumatic fever prophylaxis: A community program through the private physician.”
JAMA. 1952;149:636-9.
85. William H Bunn, Hugh N Bennett. “Community Control of Rheumatic Fever.” JAMA. 1955;157:986-9.
86. Aims C McGuinness. “The National Attack on Rheumatic Fever,” Public Health Reports. 1959;74:870-2.
87. Juanita G Zagala, Alvan R Feinstein. “The preceding illness of acute rheumatic fever.” JAMA. 1962;179: 863-6.
88. Feinstein, Mario Spagnuolo, Harrison F Wood, et al. “Rheumatic fever in children and adolescents: A long-term epidemiologic study of subse-
quent prophylaxis, streptococcal infections, and clinical sequelae: VI. Clinical Features of Streptococcal Infections and Rheumatic Occurrences.”
Annals Intern Med. 1964;60(suppl);5:68-86.
89. Gabor Czoniczer, Martin Lees, Benedict F Massell. “Streptococcal infection: The need for improved recognition and treatment for the prevention
of rheumatic fever.” New Engl J Med. 1961;265:951-2.
90. Burton J Grossman, Jeremiah Stamler. “Potential preventability of first attacks of acute rheumatic fever in children.” JAMA. 1963;183:985-8.
91. Carl J Marienfeld, Morton Robins, Roy P Sandige, et al. “Rheumatic fever and rheumatic heart disease among US College Freshmen, 1956-60.”
Public Health Reports. 1964;79:789-811.
92. Basil M RuDusky. “Heart murmurs in youths of military age: Evidence of inadequate rheumatic fever prophylaxis.” JAMA. 1963;185:1004-7.
93. Edward E Fischel, Charles W Frank, Charles Ragan. “Observations on the treatment of rheumatic fever with salicylate, ACTH, and Cortisone: I. Ap-
praisal of signs of systemic and local inflammatory reaction during treatment, the rebound period, and chronic activity.” Medicine. 1952;31:331-5.
94. Richard D Rowe, McKelvey AD, John D Keith. “The use of ACTH, cortisone, and salicylates in the treatment of acute rheumatic fever.” Can Med
Assoc J. 1953;68:15-20.
95. Holt, Illingworth, Lorber, et al. “Cortisone and salicylates in rheumatic fever.” Lancet. 1954;2:1144-8.
96. Benedict F Massell. “The medicinal treatment of acute rheumatic fever.” Med Clin North Am. 1953;37:1215-34.
97. Great Britain: James Spence, Royal Victoria Infirmary, Newcastle; EGL Bywaters, Canadian Red Cross Memorial Hospital, Taplow (England); Stan-
ley Graham, Royal Hospital for Sick Children, Glasgow; RS Illingworth, Children’s Hospital, Sheffield; BE Schlesinger, Hospital for Sick Children,
Great Ormond Street, London; AG Watkins, Llandongon Hospital, Cardiff; A. Bradford Hill, statistician. USA/Canada: David Rutstein, American
Heart Association; Albert Dorfman, La Rabida Jackson Park Sanatorium, Chicago; Edward Fischel, Columbia-Presbyterian Hospital, New York;
John Keith, Hospital for Sick Children, Toronto; John A. Lichty, University of Colorado; Benedict Massell, House of the Good Samaritan, Boston;
Currier McEwen, Bellevue Hospital, New York; Charles Rammelkamp, Jr., Ft. Francis E. Warren, Wyoming (contributed no patients to this study
that focused on treatment for children).
98. Homer F Swift, Johannes K Moen, George K Hirst. “The action of sulfanilamide in rheumatic fever.” JAMA. 1938;110:426-34.
99. Alvin F Coburn, Lucile V Moore. “The prophylactic use of sulfanilamide in streptococcal respiratory infections, with especial reference to rheu-
matic fever.” J Clini Invest. 1939;18:147-55.
100. Caroline Bedell Thomas, Richard France. “A preliminary report of the prophylactic use of sulfanilamide in patients susceptible to rheumatic fever.”
Bulletin of the Johns Hopkins Hospital. 1939;64:67-77.
101. Alvin Frederick Coburn, Donald Cook Young. The epidemiology of hemolytic streptococcus during World War II in the United States Navy. Balti-
more: Williams and Wilkins; 1949.
102. Ramakrishnan S, Kothari SS, Juneja R, et al. Prevalence of rheumatic heart disease: Has it declined in India? Natl Med J India. 2009;22(2):72-4.
103. Wilson AT. The relative importance of the capsule and the M antigen in determining colony form of group A streptococci. J Exp Med. 1959;109:257–
70.
104. Lancefield R, Todd E. Antigenic differences between matt hemolytic colonies and their glossy variants. J Exp Med. 1928;48:769-90.
105. Foley MJ, Wood WB. Studies on the pathogenicity of group A streptococci. II. The antiphagocytic effects of the M protein and the capsular gel. J Exp
Med. 1959;110:617-28.
106. Gray GC, Escamilla J, Hyams KC, et al. Hyperendemic Streptococcus pyogenes infection despite prophylaxis with penicillin G benzathine. N Engl J
Med. 1991;325:92-7.
107. Heggie AD, Jacobs MR, Linz PE, et al. Prevalence and characteristics of pharyngeal group A beta-hemolytic streptococci in US Navy recruits receiv-
ing benzathine penicillin prophylaxis. J Infect Dis. 1992;166:1006-13.
108. Siegel AC, Johnson EE, Stollerman GH. Controlled studies of Streptococcal pharyngitis in a pediatric population. 2. Behavior of the type specific
immune response. N Engl J Med. 1961;265:566-71.
109. Stollerman GH, Ekstedt R. Long chain formation by strains of Group A streptococci in the presence of homologous antiserum: a type-specific
reaction. J Exp Med. 1957;106:345-56.
110. Cohen IR, Stollerman GH. Non-type specific resistance to group A streptococci in germ free and conventional mice. Proc Soc Exp Biol Med.
1963;114:202–5.
111. Stollerman GH, Ekstedt RD, Cohen IR. Natural resistance of Germfree mice and colostrum-deprived piglets to group A streptococci. J Immunol.
1965;95:131-40.
112. Rothbard S, Watson R. Variation occurring in group A streptococci during human infections: Progressive loss of M substance correlated with in-
creasing susceptibility to bacteriostasis. J Exp Med. 1948;87:521-33.
113. Rothbard S. Protective effect of hyaluronidase and type-specific anti-M serum on experimental group A infections in mice. J Exp Med. 1948;88:325-
37.
114. Stollerman G. Factors determining the attack rate of rheumatic fever. JAMA. 1961;177:823-28.
115. Kaplan EL, Top FH, Dudding BA, et al. Diagnosis of streptococcal pharyngitis: differentiation of active infection from the carrier state in the symp-
tomatic child. J Infect Dis. 1971;123:490-501.
116. Stollerman GH, Siegel AC, Johnson EE. Variable epidemiology of Streptococcal disease and the changing pattern of rheumatic fever. Mod Con-
cepts Cardiovasc Dis. 1965;34:45-8.
117. Stollerman GH. Rheumatic fever and streptococcal infection. In: Grune, Stratton. (Eds). New York. 1975.
118. Stollerman GH. Nephritogenic and rheumatogenic group A streptococci. J Infect Dis. 1969;120:258-63.
119. Stollerman G. The relative rheumatogenicity of strains of group A streptococci. Mod Concepts Cardiovasc Dis. 1975;44:35-40.
120. Bisno AL. The concept of rheumatogenic and non rheumatogenic group A streptococci. In: Reed SE, Zabriskie JB, (Eds). Streptococcal diseases
and the immune response. New York: Academic Press; 1980. pp. 789-03.
121. Facklam RF, Martin DR, Lovgren M, et al. Extension of the Lancefield classification for group A streptococci by addition of 22 New M protein gene
sequence types from clinical isolates: emm103 to emm124. Clin Infect Dis. 2002;34:28-38.
122. Veasy LG, Wiedmeier SW, Orsmond GS, et al. Resurgence of acute rheumatic fever in the intermountain region of the United States. N Engl J Med.
1987;316:421-7.
123. Centers for Disease Control. Acute rheumatic fever—Utah. MMWR Morb Mortal Wkly Rep. 1987;36:108-10.
124. Congeni B, Rizzo C, Congeni J, Sreenivasan VV. Outbreak of acute rheumatic fever in northeast Ohio. J Pediatr. 1987;111:176-9.
125. Wald ER, Dashefsky B, Feidt C, et al. Acute Rheumatic fever in western Pennsylvania and the tristate area. Pediatrics. 1987;80:371-4.
126. Centers for Disease Control. Acute rheumatic fever at a Navy Training center—San Diego, California. MMWR Morb Mortal Wkly Rep. 1988;37:101-
4.
127. Centers for Disease Control. Acute rheumatic fever among Army Trainees - Fort Leonard Wood, Missouri, 1987–1988. MMWR Morb Mortal Wkly
Rep. 1988;37:519-22.
128. Kaplan EL, Johnson DR, Cleary PP. Group A streptococcal serotypes isolated from patients and sibling contacts during the resurgence of rheu-
matic fever in the United States in the mid-1980s. J Infect Dis. 1989;159:101-3.
129. Stollerman GH. Rheumatogenic group A streptococci and the return of rheumatic fever. Adv Intern Med. 1990;35:1-25.
130. Johnson DR, Stevens DL, Kaplan EL. Epidemiologic analysis of Group A streptococcal serotypes associated with severe systemic infections, rheu-
matic fever, or uncomplicated pharyngitis. J Infect Dis. 1992;166:374-82.
131. Veasy LG, Tani LY, Daly JA, et al. Temporal association of the Appearance of mucoid strains of Streptococcus pyogenes with a Continuing high
incidence of rheumatic fever in Utah. Pediatrics. 2004;113:168-72.
132. Smoot JC, Korgenski EK, Daly JA, et al. Molecular analysis of group A streptococcus type emm18 isolates temporally associated with acute rheu-
matic fever outbreaks in Salt Lake City, Utah. J Clin Microbiol. 2002;40:1805-10.
133. Smoot JC, Barbian KD, Van Gompel JJ, et al. Genome sequence And comparative microarray analysis of serotype M18 group A Streptococcus
strains associated with acute rheumatic fever outbreaks. Proc Natl Acad Sci USA. 2002;99:4668-73.
134. Cockerill FR, MacDonald KL, Thompson RL, et al. An outbreak of invasive group A streptococcal disease associated with high carriage rates of the
invasive clone among school-aged children. JAMA. 1997;277:38-43.
135. Beachey EH, Ofek I. Epithelial cell binding of group A streptococci by lipoteichoic acid on fimbriae denuded of M protein. J Exp Med. 1976;143:759-
71.
136. Ofek I, Beachey EH, Jefferson W, et al. Cell membrane-Binding properties of group A streptococcal lipoteichoic acid. J Exp Med. 1975;141:990-
1003.
137. Hanski E, Caparon M. Protein F, a fibronectin binding protein, is an adhesin of the group A streptococcus. Proc Natl Acad Sci USA. 1992;89:6172-6.
138. Schrager HM, Alberti S, Cywes C, et al. Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of
group A streptococcus to CD44 on human keratinocytes. J Clin Invest. 1998;101:1708-16.
139. Cywes C, Stamenkovic I, Wessels MR. CD44 as a receptor for Colonization of the pharynx by group A streptococcus. J Clin Invest. 2000;106:995-
1002.
140. Cywes C, Wessels MR. Group A Streptococcus tissue invasion by CD44- mediated cell signalling. Nature. 2001;414:648–52.
141. Wessels MR, Bronze MS. Critical role of the group A streptococcal capsule in pharyngeal colonization and infection in mice. Proc Natl Acad Sci
USA. 1994;91:12238-42.
142. Dinkla K, Rohde M, Jansen WT, et al. Rheumatic fever-associated Streptococcus pyogenes isolates Aggregate collagen. J Clin Invest. 2003;111:1905-
12.
143. Richard L Varco, Ivan D Baronofsky. “The surgical problem in rheumatic valvular heart disease,” in Rheumatic Fever: A Symposium, edition. Lewis
Thomas Minneapolis: University of Minnesota Press; 1952. pp. 249-64.
144. Richard F Gillum. “Trends in acute rheumatic fever and chronic rheumatic heart disease: A National Perspective,” Am J Heart. 1986;111:430-32.
145. Edward F Bland. “Rheumatic Fever: The Way It Was,” Circulation. 1987;76:1190-5.
146. Rantz. “Rheumatic Fever,” in Internal Medicine in World War II: Infectious Diseases. In: John Boyd Coates, (Ed.). Washington, DC: Office of the
Surgeon General. 1963;2:225-38.
147. Floyd W Denny. “T. Duckett Jones and Rheumatic Fever in 1986,” Circulation. 1987;76:963-70.
148. Vijayalakshmi IB, Mithravinda J, Prabhu Deva AN. ‘Role of echocardiography in diagnosing carditis in the setting of acute rheumatic fever’. Cardi-
ology in the Young. 2005;15:583-8.
149. B Vijayalakshmi IB, Vishnuprabhu OR, Chitra N, et al. The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic
fever. Cardiol Young. 2008;18:586-92.
History of Pediatric Cardiology:
38 From the “Untouchable” Heart
to the Brave New Era
Maheshwari S, Kiran VS
Philosophy of science without history of science is empty; history of

science without philosophy of science is blind.1
PREHISTORIC ERA—BABYLONIAN
“We do not remember our medical heroes, but, as everyone
CLAY TABLETS
knows, most of us mortals need to be reminded of most things most It is presumed that the prehistoric man was aware of the heart, its
of the time. Since medical history is at the bottom of the medical cur- position and possibly, its significance for a hunter. Some of the cave
riculum, there is no curiosity or incentive to find our medical roots, paintings, dating as old as 30,000 years, have suggested this.4 How-
and the young grow woefully unaware of those on whose shoulders ever, the earliest mention of congenital heart disease dates to around
they now stand…. Perhaps it should be the task of departments of BC 700. Babylonian clay tablets dating back to BC 4000 included a list
medical history across the country to remind the medical profession of sixty-two human malformations with their associated prophetic
of its forgotten or almost forgotten heroes so we can pay our respects implications. For example, ectopia cordis comes with a description,
on time!”2 “when a woman gives birth to an infant that has the heart open and
that has no skin over it, the country will suffer from calamities”. Till
LEGACY OF A YOUNG BRANCH now, these tablets are considered as the earliest written records of
congenital malformations.5
Pediatric cardiology is one of the youngest branches of the cardio-
vascular sciences. Paradoxically, the majority of children seen by a THE CONTRIBUTIONS FROM GREECE—
pediatric cardiologist would have congenital heart diseases, which
GALEN
is the oldest spectrum of anomalies humans have come across! At
the helm of this, paradox lie a few facts of reality. Congenital heart The intellectual enlightenment of the Greeks sought a logical ba-
diseases were considered as one of those “untouchables” of medi- sis for events, which helped in giving a scientific dimension to the
cine till the dawn of the 20th century. In his monumental work, “The field of medicine. One of the most noteworthy figures of this period
Surgery of the Chest” in AD 1896, the celebrated surgeon Stephen Pa- was Claudius Galenus (Fig. 38.1) (AD 129–201, popularly known as
get had opined that “Surgery of the heart has probably reached the Galen).
limits set by nature to all surgery. No method, no new discovery, can He is considered as the “genius of the era” by his contemporar-
overcome the natural difficulties that attend a wound of the heart”. In ies, he used several experiments to define some of the basic truths
the same year, the first textbook on pediatrics was published by Dr of heart structure and function. His pertinence to congenital heart
Thomas Morgan Roch, which spanned a phenomenal 1,100 pages. legacy is because he not only noticed, but also attempted to explain
However, the views of Sir Paget were clearly reflected here too as only the function of the arterial duct and the foramen ovale, probably for
7 pages out of the total 1,100 were devoted to congenital diseases of the first time in human history.6
the heart.3
From beginning of this magnitude, the field of pediatric cardiol- RENAISSANCE PERIOD—
ogy has grown to what it is today in a span of over 100 years. The views
LEONARDO DA VINCI
of Sir Paget are no longer valid and the lack of attention given by Dr
Roch has changed to a point where the pediatric cardiac sciences Congenital heart problems took a back seat for a few centuries. Not
carry an enviable reputation in the modern day medical system. This much work was documented until the 15th century, when another
transition from nowhere to powerful is the essence of our journey genius came into the picture. Born in AD 1452, this multifaceted per-
into the fascinating history of pediatric cardiology. son probably was ahead of his times even by Renaissance standards.
Chapter 38  History of Pediatric Cardiology: From the “Untouchable” Heart to the Brave ... 271
Figure 38.1: Claudius Galenus Figure 38.3: Niels Stensen
EUROPEAN CONTRIBUTION—
STENO AND TETRALOGY
The interest in anatomic defects of the heart started to develop in the

medical community of Europe in the late 17th century. Niels Stens-
en (Fig. 38.3) was an accomplished anatomist of Europe. He had
described the duct of the parotid salivary gland, which is eulogized
on him. In AD 1673, in a stillborn baby, he described the combi-
nation of bifid sternum, omphalocele, in addition to the modern
description of Fallot’s tetralogy (today’s pentalogy of Cantrell). As an
anatomist, his interest was primarily noncardiac. About the cardiac
abnormality he wrote, “As to the cause of this phenomenon, I have
nothing to say”. This appears to be the first description of tetralogy of
Fallot (TOF) in the history of pediatric cardiology.9
MASTERPIECE WORK—MORGAGNI
In AD 1761, a medical book titled “De sedibus et causis morborum
per anatomen indagatis” authored by Giovanni Morgagni (Fig. 38.4)
was published. The book vividly described ventricular septal defect
Figure 38.2: Leonardo da Vinci and single ventricle. Historically, it was the first time these lesions
were described authentically.10
In AD 1513, he described a case of atrial septal defect (ASD) with sets ACCOUNT OF A BLUE BOY—SANDIFORT
of brilliant drawings, accurate to present day standards. His name
was Leonardo da Vinci (Fig. 38.2). The credit for the first accurate In AD 1777, another European named Sandifort (Fig. 38.5),
description of any congenital heart disease should go to Leonardo described a “blue boy” with the anatomic findings of TOF, calling this
da Vinci.7,8 a “very rare disease of the heart”. In his observations, this baby was
Figure 38.4: Giovanni Morgagni Figure 38.6: William Hunter
CYANOTIC SPELLS—HUNTER
In 1785, one of the celebrated physicians of that time, William Hunter

(Fig. 38. 6) described a cyanotic spell as below: “… When the fit was
coming upon him … he grew oppressed at his heart, became weak or
faint, grew dark in his color, and at last almost black, fell down, and
seemed insensible … it was plain that, in the living body ... a very
small quantity only of blood (instead of the whole) passed through
the lungs to receive the benefit of respiration, and that with a small
force too.”
William Rashkind shows a great reverence to the observations
of Hunter. “Hunter’s comment on the small force of the pulmonary
blood flow was very prescient, preceding by 100 years the 1st cath-
eterization of the heart in animals, and by almost 200 years direct
measurement of intracardiac pressures in TOF.”12
THE DEBATE ON CYANOSIS—

19TH CENTURY EUROPE
Figure 38.5: Sandifort
By the beginning of the 19th century, clinical-pathological correla-
“a clever child” but had some blue color of the fingers. His descriptions had begun in the curious European minds. Also seen was a
tion of “sinking spells” in the child was commendable. He quoted lively debate (which used to run toxic if opposite parties met!) on
that the spells had begun after 1 year of age. The child passed away the origin of cyanosis—obstruction versus admixture. Obstruction to
during one of these spells and Sandifort observed the following the flow theory cited instances of cyanosis in the absence of septal
during necropsy: defects. The other group quoted patients of pulmonary stenosis who
“How great was the surprise … when we saw the point of the fin- had no cyanosis at all, thereby arguing in favor of admixture. None of
ger to stretch into the aorta, which is not at all accustomed to main- the early proponents of each theory survived to see the truth which
tain communications with the right ventricle.”11 was that they both were right, at least partially!13
WORKS OF A SEER—SIR THOMAS TETRALOGY DEFINED—FALLOT

BEVILL PEACOCK The publications of Dr Thomas Peacock and Dr Rokitansky aroused a
AD 1858 saw a monumental work “Malformations of the Human great deal of interest among physicians. Blue babies aroused interest
Heart”, authored by one of the luminaries of European physicians but no one kept a sustained interest, as no available treatment was
of that time, Sir Thomas Bevill Peacock (Fig. 38.7). The book con- effective. There were certain exceptions indeed. One among them
tained beautiful illustrations of various congenital heart malforma- was a big name then and a bigger name now! He was Etienne-Louis
tions, including ventricular septal defects, pulmonary stenosis and Arthur Fallot (Fig. 38.9).
transposition of great arteries, making it a pleasure to read. Even
Maude Abbott had exclaimed about Peacock’s book as “the first
comprehensive study covering the whole field (of pediatric cardiol-
ogy)”. Peacock was famous not just for his publications, but also for
his ability to accommodate to the new technology available in the
period. He noted a characteristic radiation of the murmur of pulmo-
nary stenosis using the new tool, the stethoscope, to correlate physical
findings with anatomy in congenitally malformed hearts. He thus be-
came a pioneer in the use of this device for the heart, others of the era
being more interested in lungs. He also observed the familial nature
of cardiac defects, presaged a long period of analysis of genetic and
familial aspects of heart malformations, a process that continues
using vastly more sophisticated tools to the present day.14
CARDIAC SEPTAL DEFECTS—ROKITANSKY

About 17 years after Peacock’s publication, another celebrated phy-
sician, Carl von Rokitansky (Fig. 38.8) published his monumental
work from Vienna, named “Defects of the Cardiac Septa”. Having
personally done some 30,000 autopsies, Rokitansky was probably
the best-suited person of 19th century to write anything related to
pathological anatomy. No wonder, he was later called as “Linnaeus
of pathological anatomy” by Rudolf Virchow.15 Figure 38.8: Carl von Rokitansky
Figure 38.7: Thomas Bevill Peacock Figure 38.9: Etienne-Louis Arthur Fallot
In AD 1888, Fallot coined the term “tetralogy”. He had no desire

for this lesion complex to be named after him; nor did he make any
statement about him ‘discovering’ this entity. Apart from three cases
seen by him, Fallot reviewed and summarized 68 other cases of blue
disease. Fallot referred to and summarized the first known case of
Stenson in AD 1673, the second known case of Sandifort in AD 1777,
the cases of Hunter in AD 1785 and many more.
In Fallot’s own words, “Blue disease had hardly been described
clinically when the cardiac alterations which caused it were simulta-
neously established. Knowledge of the symptoms and lesions have,
one might say, marched together. It is sufficient to go over the obser-
vations of Hunter and others, ... to find indicated here in a fashion
most clear ... our pathologic anatomic tetralogy: stenosis of the pul-
monary artery, interventricular communication, hypertrophy of the
right ventricle and deviation of the aorta to the right”.
Fallot wanted to call the tetralogy combination as “la maladie Figure 38.10: Maude Elizabeth Abbott
bleue”, i.e. the blue disease or morbus caeruleus (in Latin). Till his
death in AD 1911, the lesion complex did not bear his name. It is to
the credit of Maude E Abbott, who coined the diagnosis “TOF” in AD In bringing order to what had previously been a disorganized
1924.16-18 array of fascinating, but poorly understood, congenital malforma-
tions of the heart, she divided these patients into three groups: (1)
THE GODMOTHER ARRIVED Those with no abnormal communications, (2) Those with a left-to-
right shunt (acyanotic), including patients with shunt reversal later
By the end of 19th century, after much controversy and fighting, in life (cyanose tardive) and (3) Those with permanent right-to-left
McGill medical school took its first women candidate in to study shunt (Morbus coeruleus). For each she developed a diagram of the
medicine. When she applied for a position in the same medical circulation.
school, she was appointed as the assistant curator of the medical The impetus provided by this lady in understanding the etiolo-
museum in AD 1898, largely because nobody else wanted this job. gies of congenital heart disease have never been forgotten and she
The museum was a disorganized collection of a large number of has been called by various names such as “The beneficent Tornado”,
specimens collected over 75 years. The gutsy lady decided that the “The Saint”, “The big chief of Heart”, etc. but what probably best suits
chaos should end. She did an extraordinary cataloguing of the speci- her is the name: “God-Mother” of Congenital heart diseases. This
mens of museum, making it a place worth a visit for all the students lady was Dr Maude Elizabeth Abbott (Fig. 38.10).19-21
and faculty. In AD 1904, Sir Osler visited McGill and was spellbound
by the beauty with which it had metamorphosed in the hands of its MOTHER OF PEDIATRIC CARDIOLOGY
assistant curator. He told the Dean of McGill that the museum was
“the best that McGill had done to date … there was no collection in AD 1898 was the year Dr Maude Abbott joined her job in McGill.
North America or Britain that came close to it”. Impressed Sir Osler In the same year was born another person in Cambridge, Massa-
asked the young lady doctor to write a chapter for his Magnum Opus, chusetts—Dr Helen Brooke Taussig (Fig. 38.11). She became the
“Systems of Modern Medicine”. She was the only woman contribu- “Mother of Pediatric Cardiology”. Despite losing her mother by the
tor in the list of 104 authors. She did a job extraordinaire! In a 100- age of 11 years, suffering from dyslexia and hearing loss as a child
page chapter, she had evaluated 400 cases and correlated the clinical and rejected by school, she overcame all the difficulties in her
findings with the autopsy reports. Sir Osler wrote a thank you note personal life to earn a seat at Harvard’s School of Public Health and
to her, saying … “It is by far the best thing ever written on the subject got special permission to take courses at Harvard’s Medical School.
in English—possibly any language … For years it will be the stand- At that time, Harvard was yet to open the doors of its medical school
ard work on the subject…” She returned the compliments by naming to women. She later went to pursue her interest in cardiac research at
her McGill museum catalogue as ‘The Osler Catalogue’. Although her Johns Hopkins University in Baltimore.
biographers differ, this was possibly the moment of inspiration for By the time of graduation from Hopkins, she had lost her hear-
her monumental Atlas. ing almost completely and relied on lip-reading and hearing aids for
Her “Atlas of Congenital Cardiac Disease” was published by the rest of her career. Some of her innovations in pediatric cardiol-
the American Heart Association in 1936. The Atlas described 1,000 ogy have been attributed to her ability to distinguish the rhythms of
hearts with their pathophysiological and statistical analysis of the normal and damaged hearts by touch, rather than by sound. It was
clinical and anatomical abnormalities. always said that she auscultated from her fingertips.
Figure 38.11: Helen Brooke Taussig with her angels
Thanks to the mentorship of Johns Hopkins Chairman,

Dr Edwards Park, in AD 1930, she was appointed head of the SURGICAL VICTORY OVER THE ARTERIAL
Children’s Heart Clinic at the Johns Hopkins Hospital pediatric unit, the DUCT—ROBERT GROSS
Harriet Lane Home. He encouraged her to concentrate not only on
rheumatic fever, the big problem, but also to learn about congenital On March 6, 1937, Dr John Streider at the Massachusetts General
heart disease. Hospital had successfully interrupted a ductus for the first time in
Dr Taussig was extremely meticulous with her observations. She history. But his choice of patient selection was unfortunately not the
had the habit of recording her findings in each patient. She realized right one. His idea was to save a septic patient, but the patient died
that certain malformations repeated with characteristic and recog- on the fourth postoperative day. At autopsy, vegetations filled the
nizable patterns. The concept of “Pattern Recognition” in pediatric pulmonary artery down to the valve. This heroism went unsung by
cardiology was her contribution. She correlated her observations the medical fraternity and Dr Streider retired to his regular surgical
with the anatomy at postmortem examination. Soon she was able practice.
to make clinically an accurate anatomic and physiologic diagnosis, On 16th August, 1938, Dr Robert Gross (Fig. 38.12), a
using the tools of history taking, physical examination, electrocardio- dynamic young surgeon at Boston Children’s ligated 7-year-old
gram, fluoroscopy and X-ray. She paid particular attention to pulmo- Lorraine Sweeny’s patent arterial duct. The patient made an
nary vascular markings, whether increased or decreased. Despite all uneventful recovery and history was created. The case was report-
her efforts, she was always concerned about the fact that she could ed in JAMA in the year 1939 and created a sensation in the surgical
not help the children in prolonging their life or find ways to cure circles. Dr Gross became a big name.24,25
heart problems in them.
The 4th decade of the 20th century was a crucial one. It was see- NEW IDEAS, NEW DIRECTIONS
ing new waves in the front of cardiac treatment. The new age sur-
geons were bold enough to challenge the age-old concept of “better A few hours from Boston, Dr Taussig was active in Baltimore, discuss-
not to touch the heart”.22,23 ing the possible causes of cyanosis in blue babies. Her astute obser-
vation had taught her that blue children with continuous murmurs
TOMBSTONE OF PAGET’S VIEWS were less cyanotic than those with systolic or no murmurs. She had
correctly reasoned that the murmur was due to the continuous flow
In the year AD 1938, the world witnessed something to remember. It of blood from vessels that left the aorta and anastomosed with the
was time to change the views of Dr Paget permanently. pulmonary artery or its branches, thereby increasing pulmonary
Figure 38.12: Robert Gross with his first patient in her adulthood Figure 38.13: Alfred Blalock and Vivien Thomas
blood flow. This simply meant that any measure to increase the pul- hypertension. They were successful in about 200 such experiments
monary blood flow would make the blue babies better! When Dr on dogs.
Gross’s success was celebrated for technique and results, the brilliant After the success of patent ductus arteriosus (PDA) ligation, sur-
thinking of Dr Taussig went lateral. If a surgeon could tie off a patent gical repair of coarctation was being contemplated. At a conference
ductus, could he also create one? in AD 1942, in Johns Hopkins, Dr Blalock was discussing his ideas
This idea would not let her sleep! She traveled all the way to Bos- on coarctation repair with Dr George Duncun and Dr Edwards Park.
ton and met Dr Gross. She asked him if it was possible to create a duct They were talking about the practical difficulties of surgery in which
in a blue baby. Dr Gross is said to have told her curtly that he was in the coarctation segment was excised, left subclavian artery was
the business of closing a duct, not in creating one! divided, and the proximal end was turned down and anastomosed
Although Dr Taussig could not convince the surgeon in Boston, end-to-end to the descending thoracic aorta. Dr Park said, “Could
the opportunity came searching for her at her home, the Johns Hop- you not use the carotid artery as a bypass? It is a long, straight artery
kins, in the form of Dr Alfred Blalock and his phenomenally skilled and there are four vessels to the brain. Would not it be possible to
and gifted surgical assistant, Vivien Thomas in the year 1942. This turn the carotid artery down and anastomose it to the aorta below the
combination worked and changed the prognosis of blue babies for- coarctation”?
ever. Dr Taussig barged into their conversation at this moment. “If you
could put the carotid artery into the descending aorta, could not you
SUCCESS OF TEAMWORK—ALFRED put the subclavian artery into the pulmonary artery?” was her ques-
tion to the elite surgeons.
BLALOCK AND VIVIEN THOMAS
Thomas reminded Dr Blalock of their dog experiments to cre-
Dr Alfred Blalock (Fig. 38.13) was the ideal person to create the ate pulmonary hypertension. At that moment, impressed with the
first Blalock-Thomas-Taussig (BTT) shunt. Since the 3rd decade of honesty, concern and commitment of Dr Taussig toward the blue
the 20th century, Dr Blalock was working on experimental shock. babies, Dr Blalock agreed to take up the challenge of creating shunts.
In AD 1930, Vivien Thomas (Fig. 38.13) came to work at Vanderbilt Six-year-old Eileen Saxon qualified for the surgery. She was frail,
and became a laboratory technician for Dr Blalock. They formed a had many hypercyanotic spells and was deeply cyanosed. On 24th
professional relationship that lasted until Blalock’s death. Blalock’s of November, 1944, history was created in the operating theater of
incredibly productive laboratory work during the 1930s is largely Johns Hopkins, Baltimore when the first BTT shunt was created by
attributed to the hard work and meticulous record keeping of turning the subclavian artery to join the pulmonary artery. In the
Thomas. Everyone who visited the lab noticed his attention to detail. operating room that day Vivien Thomas stood behind Dr Blalock
Many of these visitors became great names in the field and always and Dr Taussig positioned herself at the head of the table. When the
applauded Dr Thomas and held him in high regard later. anastomosis was completed and the clamps released, Dr Taussig
The team of Dr Blalock and Dr Thomas had been working on exclaimed with delight that Eileen had a “lovely pink color”. Dr
pulmonary hypertension modules for a long time. For this, in dogs, Denton Cooley and Dr Mary Engle (both later became big names
they turned the subclavian artery and connected it to the ipsilateral in the field) stood as surgical assistants to witness the making of
pulmonary artery. This flooded the lungs and caused pulmonary history.
At the following Johns Hopkins Medical and Surgical Association miraculous change in the children themselves and in witnessing the
annual meeting, the auditorium was packed with faculty and stu- joy and relief of the parents when they see their children running
dents. Dr Blalock described the operation and Dr Taussig brought in about happily and without effort like other children’’.
the first five-surviving postoperative children with their smiling faces The Brock procedure was immediately adopted in the United
and normal pink color. She described how before the operation they States and in Europe for those patients with pulmonary stenosis and
could not walk across a room without stopping to squat down to rest an intact interventricular septum, following which the introduction
and catch their breath. of hypothermia and subsequently extracorporeal circulation in the
The world of pediatric cardiology changed with this success for mid 1950s enabled an open and, therefore, more precise operation
ever. However, Dr Blalock lost the race of coarctation repair to his on the abnormality to be performed.27
European counterparts. On October 10, 1944, about a month prior For the treatment of TOF, it was never established whether the
to Dr Blalock’s surgery on Eileen, Dr Crawford and Dr Nylin, at the direct operation (Brock procedure) was preferable to an indirect
Karolinska Hospital in Sweden, successfully repaired a coarctation anastomotic operation—as Lillehei (Minneapolis) introduced total
of the aorta. Dr Blalock would have probably won this race if he had correction of the abnormality by an open technique, first in 1955 by
pursued coarctation repair. But, what he eventually achieved was a controlled cross-circulation, and then in 1956 by heart-lung bypass.28
lot bigger.22,23,26
STRUCTURING PEDIATRIC CARDIOLOGY—
LATERAL THINKING—OTHER PATHS FOR FELLOWSHIP PROGRAMS
TETRALOGY OF FALLOT PALLIATION
The success of consecutive BTT shunts led to the publication of
The First World War had decimated the earliest efforts in the treat- the article, “The surgical treatment of malformations of the heart
ment of TOF. Further operations to relieve right ventricular outflow in which there is pulmonary stenosis or atresia” in the year 1945 in
tract obstruction were not undertaken until after World War II. JAMA by Dr Blalock and Dr Taussig. This led to the influx of cyanotic
It was Lord Russell Brock (Fig. 38.14) at London, who was the patients from all over the world to the team at Hopkins. The influx
main protagonist for the direct operation of pulmonary valvotomy. was too heavy for Dr Taussig to handle alone. The new set of patients
Lord Brock thought that ‘‘relief by direct attack must be our goal”. needing attention called for assistants. Hence, Dr Taussig devised a
In 1948, he designed a valvulotome to cut the stenosed valve, an novel way of dealing with the crisis by appointing interested young
expanding dilator to split the valve and an infundibular punch to re- doctors as fellows and thereby started the first training program in
sect the thickened infundibular muscle. He reported the successful pediatric cardiology.
use of these instruments in 1950 and wrote that ‘‘we are in large part The grace with which Dr Taussig and Dr Blalock divided respon-
recompensed for the long and difficult hours by seeing the almost sibilities between their teams was the inspiration for the concept of
the current eras pediatric cardiac teams. Her team would diagnose
and recommend surgery; both the teams would meet at a joint con-
ference to finalize; his team would perform the operation, both teams
would do the postoperative care in the hospital, and her team was
responsible for the long-term follow-up. Both teams willingly gave
their time for talks at medical and surgical meetings and they accom-
modated the many doctors who came to observe the coordination of
pediatric cardiac and surgical care. Dr Taussig analyzed not only the
many successes of the operation but also the failures. This module is
the recipe for successful pediatric cardiac services even today.23
NEW ANGLES TO DIAGNOSIS—

CATHETERIZATION TECHNIQUES
The catheterization techniques developed in the subsequent decade
changed the morphology of pediatric cardiology. Dr Taussig devel-
oped the concept of angled views in radiography for better deline-
ation of individual parts of the heart and thereby, better anatomical
delineation of cardiac structures. Improved catheterization tech-
niques led the bravehearts of cardiology to explore into the fascinat-
Figure 38.14: Lord Russell Brock ing world of pediatric catheter interventions.29
CONQUERING VALVULAR LESIONS— DEVISING THE DEVICES—

PERCUTANEOUS TECHNIQUES THE AMPLATZER ERA
As early as 1953, the team of Rubio-Alvarez in Mexico described cath- Different modifications of devices were attempted, some success-
eter techniques of relieving pulmonic stenosis. It became practical fully and some which fell by history’s wayside. However, the arrival
with the team of Semb performing a balloon valvulotomy of pulmo- of Amplatzer devices changed the scenario of device closure of con-
nic valve. Very soon, in 1982, Kan et al. reported a superior method genital heart lesions in a revolutionary manner. Amplatzer devices
called percutaneous balloon valvuloplasty, which still remains the were invented by Dr Kurt Amplatz (Fig. 38.16). With the turn of the
treatment of choice.30 millennium, Amplatzer devices found a place in almost every ma-
The true impetus for pediatric cardiac interventions came in jor cardiac center across the world. Today, the scope of interven-
1966, when Rashkind (Fig. 38.15) and Miller, showed the world tional pediatric cardiology is phenomenal and seems endless in the
something called a “balloon atrial septostomy” in d-TGA to promote future.31,32
atrial level mixing. No procedure in the history of pediatric cardiol-
ogy had a faster appreciation and incorporation into the practice! As FROM NO ONE’S CHILD TO A WORLD CLASS
soon as more cardiologists started practicing the technique, newer
ENTITY—PROGRESS TO WORLD CONGRESS
indications were discovered.
Although Porstmann had envisioned the idea of percutaneous Wider recognition led to the development of the first subspecialty
closure of the arterial duct in 1967, it did not take off well. Similarly section of American Academy of Pediatrics in 1957, that of Pediatric
mortality with the percutaneous closure of ASD by King and Mills in Cardiology. Four years later, in 1961, came the board examination for
1974 was higher than the conventional surgical repair. But innova- certification and the establishment of training programs in this field
tions of the 1980s changed the scenario. There was an explosive spirit with high standards. On similar grounds, International development
in the pediatric interventional cath lab. Balloon dilatations extended of Pediatric Cardiology specialty began in 1964 when the Association
to aortic stenosis, coarctations, postsurgical baffle stenoses, branch of European Pediatric Cardiologists was established, which had 57
pulmonary arteries and so on. Catheter-based closure of arterial members from Europe and 17 from the United States. Thereafter, the
duct by devices and coils superseded their surgical numbers. And by first World Congress of Pediatric Cardiology was held in London in
the 1990s, use of radiofrequency energy to perforate the atretic pul- 1980 with Dr Jane Somerville in charge of the planning committee.
monic valve in intact ventricular septum was conceived along with The academic story continues to date.29
endovascular stents which appeared to strengthen the balloon
dilated vessels. DREAMS OF CORRECTION—
EVOLUTION OF DEFINITIVE SURGERY
The success of coarctation repair and BTT shunt prompted the sur-
geons across the Atlantic to explore the possibilities of treating dif-
ferent congenital heart lesions. While low Qp was at one end of the
spectrum and was dealt with a BTT shunt, high Qp, on the other end,
required protection to the pulmonary circulation from developing
Figure 38.15: William Rashkind Figure 38.16: Kurt Amplatz

irreversible pulmonary vascular obstructive disease. Hence, Muller The pessimism was all prevailing except in Minnesota. A daring
and Dammann in 1952 ventured into pulmonary artery banding with attempt on controlled cross ventilation with the mother of the patient
credible success rates. being the “heart-lung machine” was achieved by the team of Walton
Once these palliative measures got established, the attention of Lillehei (Fig. 38.18). They succeeded in repairing lesions as complex
surgeons shifted to total correction when they realized that intra- as TOF and complete atrioventricular (AV) canal defect in 1955. The
cardiac repairs were a more permanent solution to congenital heart success story led to the development of the bubble oxygenator by
problems. But, practical difficulties were numerous. Richard DeWall (Fig. 38.19) and reduced the risk of involving a live
Canine experiments in 1907 had shown that the cerebral circu- oxygenator. This led to the phenomenal success of Minnesota in car-
lation could not withstand hypoxia of more than 3 minutes. Hence, diac surgeries in that decade.36,37
breaking the “3 minutes cut off” became the “mantra” of surgeons Once the heart could be opened safely, surgery of congenital
trying out the intracardiac surgeries. Experiments with hypother- heart defects appeared feasible to many centers across the globe.
mia began in Amsterdam, Toronto and Minnesota. The last team Open heart surgery became synonymous with correction of congeni-
succeeded in prolonging the critical time to 10 minutes at 28°C core tal heart defects. Slowly, palliative measures gave way to corrective
temperature. The team of John Lewis succeeded in closing a secun- ones by the early seventies. The Japanese were the first to attempt the
dum ASD within the 10 minutes cut off. The success was replicated in primary repair of complex heart surgeries in infants, soon to be fol-
Europe.33,34 lowed by a team in New Zealand. Their success prompted the teams
from USA to take up this issue seriously and thereby, the concept
HEART-LUNG MACHINE—SAGA OF GIBBON of arterial switch in neonates for transposition of the great arteries
began. Castaneda (Fig. 38.20) and his team in Boston heralded the
The unfortunate death of a young girl by pulmonary embolism in new era.38
1933 had set a young surgical assistant John Gibbon (Fig. 38.17) at
Massachusetts General Hospital in Boston thinking. He felt the need STORY OF A SINGLE PUMP—
for a machine that could bypass the circulation, so that the cardio-
GLENN AND FONTAN
pulmonary system could be tackled by surgery. The dream fortified
in the next 20 years. But the initial failure of surgeries leading to 5 The concept of bypassing the pumping chamber to the pulmonary
deaths depressed him.35 circulation was a revolutionary one. The first canine experiments
Figure 38.17: John Gibbon with the heart-lung machine Figure 38.18: Walton Lillehei
Figure 38.19: Richard DeWall Figure 38.21: William Glenn
ian, Harris Shumacker and Evgenii Meshalkin, which led to the im-
plementation of the technique to humans. Today, what we refer to as
the Glenn shunt is named after the Yale surgeon, William Glenn (Fig.
38.21). He reported neither the concept, nor the first experimental
study, nor the first clinically successful operation. But, an extensive
study undertaken by the Yale University group and prolific writing of
Glenn published in the most-read surgical journals helped in con-
vincing the world about the utility of the surgery.39
The success of the Glenn shunt brought about new possibilities
of total cavopulmonary anastomosis. It was the quest for bypassing
the right heart in totem. The initial procedures met with failure and
the surgeons at one point had concluded that any effort of connect-
ing the inferior vena cava to pulmonary artery would cause splanch-
nic congestion and would be incompatible with life. However, some
out of the box thinking and daring experiments by teams of Haller
and deLeval disproved this fact, paving the way for the future. The ge-
nius of Francis Fontan (Fig. 38.22) developed a new, more complete
operation based on the principle of low-pressure pulmonary flow
and right ventricular bypass, which today is known as the Fontan
Figure 38.20: Aldo Castaneda procedure. Even today, the criteria for successful Fontan procedure
and selection of patients are evolving continuously.40
were done in Chicago, but were near perfected by a group of sur- CHANGING HEARTS—QUEST FOR
geons led by Carlon at Padua, Itlay. Their experiments of bypassing
PEDIATRIC HEART TRANSPLANTS
the right ventricle by an anastamosis between the azygous vein and
right pulmonary artery went unsung for more than a decade. It was Pediatric heart transplants did not follow the adult trend imme-
followed by some remarkable pioneering contributions of many oth- diately. Lots of questions on donor, management, outcome and
er surgeons like Francis Robicsek, Nikolai Galankin, Tigran Darbin- surgical techniques had put the pediatric heart transplants on a
Figure 38.22: Francis Fontan Figure 38.23: Denton Cooley
backfoot. However, history was made on 1st November 1984, when enlightened generations in the nosology of congenital cardiology.
the team of surgeons led by Denton Cooley (Fig. 38.23) from Texas Every single medicine used in heart diseases of children—from
Children’s Hospital, performed an orthotopic heart transplantation digoxin to sildenafil—has fantastic historical details to offer. These
in an 8-month-old infant. The girl diagnosed as endocardial fibroe- are to be sacrificed for the space constraints. Readers interested in
lastosis with end-stage cardiac disease had a heart donation from a these can look into the references.42-48
2-year-old brain-dead girl. Despite a stormy postoperative course,
the girl eventually led a healthy life for another 13 years. Pediatric THE FUTURE: DARE TO TRY—
cardiac transplant received a deserving boost with this.41
NO STAR IS TOO HIGH!
OTHER CORRELATIONS—GENETICS, We have come all the way—from discarding the subject of congenital
cardiology from a nonentity to percutaneous solutions in the tough-
THERAPEUTICS, NOSOLOGY AND
est of scenarios. The journey seems to have just taken off! The chal-
EPIDEMIOLOGY lenges are high but so are the spirits. The hybrid labs are waiting, the
Any discussion on the history of pediatric cardiology is probably percutaneous valve replacements are strengthening, diagnostic mo-
incomplete without mentioning the contributions by the epidemio- dalities are getting better every day, genetic and molecular diagnoses
logical studies. Fabulous work has been done by Mitchell, Hoffmann, are shedding new lights, better medications are awaiting us and so
Freedom, Christiansen, Kaplan and others to make the science what on. More than all this, committed minds are at work. Young blood
it stands for today. Similarly, phenomenal work in the field of genet- is putting its sweat and energies to better the present. Devotion to
ics was done by Noonan, Nora, Gleb, Benson, Strauss and others. science continues. What more can anyone seek? It is time to fly and
The enchanting discussions of Dr Van Praagh and Dr Anderson have conquer the stars. Welcome to the exciting world of possibilities!
REFERENCES
1. Lakatos I. History of science and rational reconstructions. In: Buck RC, Cohen RS (Eds). Essays in Memory of Imre Lakatos. Dordrecht: Reidel;
1976. pp. 359-69.
2. Chiong MA. Dr. Maude Abbott deserves better. CMAJ. 1990;143:995.
3. Acierno LJ. The History of Cardiology. London: Parthenon; 1994. pp. 159-75.
4. Brodsky I. Congenital abnormalities, teratology and embryology: some evidence of primitive man’s knowledge as expressed in art and lore in
Oceania. Med J Australia. 1943;1:417.
5. Pollak K, Underwood EA. The Healers: The Doctor, Then and Now. London: Nelson; 1968.
6. Osler W. The Evolution of Modern Medicine. New Haven: Yale University Press; 1921.
7. Thiene G. The discovery of circulation and the origin of modern medicine during the Italian Renaissance. Cardiol Young. 1996;6:109-19.
8. Da Vinci L. Disegni anatomici della Biblioteca Reale di Windsor. Casa Editrice Giunti. Firenze: Barbiera; 1979.
9. Warburg E. Niels Stensen’s description of first published case of tetralogy of Fallot. Nord Med. 1942;16:3550-1.
10. Morgagni GB. De Sedibus ei Causis Morborum per Anatomen Indagates, Venetia: Remondiniana; 1761.
11. Nadas A, Bing RJ. Congenital heart disease. In: Bing RJ (Ed). Cardiology: The Evolution of the Science and the Art. Philadelphia: Harwood Aca-
demic; 1992. pp. 87-107.
12. Rashkind WJ. Congenital Heart Disease: Benchmark Papers in Human Physiology/16. Stroudsburg, PA: Hutchinson Ross; 1982.
13. Gintrac E. Observations and Researches on Cyanosis or Blue Disease. Paris: lmprime et Fonderie de J Pinard; 1824.
14. Peacock TB. On Malformations of the Human Heart. London: John Churchill; 1858.
15. Rokitansky: Defects of the Cardiac Septa. Vienna; 1875.
16. Fallot A. Contribution à l’anatomie pathologique de la maladie bleue. Marseille-Médical. 1888;25:77-93, 138-58, 207-23, 270-86, 341-54, 403-20 (in
6 parts).
17. Abbott ME, Dawson WT. The clinical classification of congenital cardiac disease, with remarks upon its pathological anatomy, diagnosis and treat-
ment. Int Clin. 1924;4:156-88.
18. Allwork SP. Tetralogy of Fallot: the centenary of the name, a new translation of the first of Fallot’s papers. Eur J Cardiothorac Surg. 1988;2:386-92.
19. Abbott ME. Atlas of Congenital Heart Disease. New York, NY: American Heart Association; 1936.
20. MacDermot HE. Maude Abbott: A Memoir. Toronto: Macmillan; 1941.
21. Wiglesworth FW. Maude E. Abbott. Perspect Pediatr Pathol. 1984;8:291-4.
22. Neill CA, Clark EB. The Paediatric Cardiology Hall of Fame: Helen Brooke Taussig MD. May 24, 1898 to May 21, 1986. Cardiol Young. 1999;9:104-8.
23. Engle MA. Dr. Helen Brooke Taussig, living legend in cardiology. Clin Cardiol. 1985;8:372-4.
24. Graybiel A, Strieder JW, Boyer NH. An attempt to obliterate the patent ductus in a patient with subacute endarteritis. Am Heart J. 1938;15:621-4.
25. Gross RE, Hubbard JP. Landmark article Feb 25, 1939. Surgical ligation of a patent ductus arteriosus. Report of first successful case. JAMA.
1984;251:1201-2.
26. Friedman M. Helen Brooke Taussig, M.D.: the original pediatric cardiologist. Md Med J. 1997;46:445-7.
27. Campbell M, Deuchar DC, Brock R. Results of pulmonary valvotomy and infundibular resection in 100 cases of Fallot’s tetralogy. Br Med J.
1954;17:111-22.
28. Hurt R. The History of Cardiothoracic Surgery from Early Times. London: Parthenon; 1996. pp. 432-6.
29. Engle MA. Growth and development of pediatric cardiology: a personal odyssey. Trans Am Clin Climatol Assoc. 2005;116:1-12.
30. Mullins CE. History of pediatric interventional catheterization: pediatric therapeutic cardiac catheterizations. Pediatr Cardiol. 1998;19:3-7.
31. Rashkind WJ, Wagner HR, Tait MA. Historical aspects of interventional cardiology: past, present and future. Tex Heart Inst J. 1986;13:363-7.
32. Holzer R, Hijazi ZM. Interventional approach to congenital heart disease. Curr Opin Cardiol. 2004;19:84-90.
33. Boerema I, Wildschut A, Schmidt WJ, et al. Experimental research into hypothermia as an aid in the surgery of the heart. Arch Chir Neerl. 1951;3:25-
34.
34. Lewis FJ, Taufic M. Closure of atrial septal defect with the aid of hypothermia: experimental accomplishments and the report of the one successful
case. Surgery. 1953;33:52-9.
35. Gibbon JH. Application of a mechanical heart-lung apparatus to cardiac surgery. Minn Med. 1954;37:171.
36. Lillehei CW, Cohen M, Warden HE, et al. The direct-vision intracardiac correction of congenital anomalies by controlled cross circulation: result
in thirty-two patients with ventricular septal defects, tetralogy of Fallot, and atrioventricularis communis defects. Surgery. 1955;38:11-29.
37. Lillehei CW, DeWall RA. Design and clinical application of the helix reservoir pump-oxygenator system for extracorporeal circulation. Postgrad
Med. 1958;23:561-73.
38. Castaneda AR, Lamberti J, Sade RM, et al. Open-heart surgery during the first three months of life. J Thorac Cardiovasc Surg. 1974;68:719-31.
39. Robicsek F. The history of right heart bypass before Fontan. Herz. 1992;17:199-212.
40. Castaneda AR. From Glenn to Fontan. A continuing evolution. Circulation.1992;86:1180-4.
41. Cooley DA. Session I: pediatric heart transplantation in historical perspective. J Heart Lung Transplant. 1991;10:787-90.
42. Nora JJ, Nora AH. Maternal transmission of congenital heart diseases: New recurrence risk figures and the questions of cytoplasmic inheritance
and vulnerability to teratogens. Am J Cardiol. 1987;59:459-63.
43. Gelb BD. Recent advances in the understanding of genetic causes of congenital heart defects. Front Biosci. 2000;5:D321-33.
44. Benson DW, Basson CT, MacRae CA. New understandings in the genetics of congenital heart disease. Curr Opin Pediatr. 1996;8:505-11.
45. Strauss AW, Johnson MC. The genetic basis of pediatric cardiovascular disease. Semin Perinatol. 1996;20:564-76.
46. Van Praagh R. Terminology of congenital heart disease. Glossary and commentary. Circulation. 1977;56:139-43.
47. Shinebourne EA, Macartney FJ, Anderson RH. Sequential chamber localization: logical approach to diagnosis in congenital heart disease. Br
Heart J. 1976;38:327-40.
48. Narayanapediatric cardiology. Blog posts from 2009 and 2010. [online] Available from wbsite www.narayanapediatriccardiology.blogspot.com;
[Accessed july, 2012].
39 History of Pulmonary Embolism
Pathak LA, Pravin P, Parikh A
the patients were found to have DVT in fibrinogen uptake study,

INTRODUCTION which was later confirmed by venography. Nine patients were found
Deep venous thrombosis (DVT) and pulmonary embolism (PE) are to have extension of thrombi into the popliteal or femoral veins and
two phases of the same disease, which can be termed as venous four of them later suffered from PE.
thromboembolism (VTE). A thrombus formed in the deep veins of It is now well recognized that without treatment, half of the
lower limbs in hours, days or weeks later can get dislodged, travel patients with proximal DVT develop PE and 50% of patients with
through the right ventricle (RV) and obstruct the pulmonary vascu- diagnosed PE have right ventricular dysfunction on echocardiogra-
lature giving rise to various clinical presentations of PE.1,2 phy, which is associated with high short-term mortality.8 Eleven per-
Many advances have occurred in this area of medicine since Ru- cent of the patients with acute PE die within 1 hour, and therefore,
dolf Virchow, a pathologist of 19th century, discovered the phenom- they do not receive therapy. In the last two decades, although the
enon of VTE.3 This article reviews the major historical milestones in mortality rate due to PE has reduced from 8% to 5%, 90% mortality
the diagnostics, therapeutics and prophylaxis of VTE/PE. to PE is seen in patients who are not treated, because the diagnosis
is not made and less than 10% deaths occur in patients in whom the
PATHOGENESIS OF PULMONARY EMBOLISM treatment for PE is initiated.3,9
William Harvey in early 1600s confirmed the direction of blood flow DIAGNOSIS OF DEEP VENOUS THROMBOSIS
through the pulmonary circulation for the first time. After another
AND PULMONARY EMBOLISM
200 years in early 18th century, Giovanni Battista Morgagni first
noted the presence of large clots in pulmonary circulation, but he had Till today, diagnosis of DVT and PE is one of the most difficult
no explanation regarding its origin. In 1819, Laennec first described problems faced by clinicians working in emergency settings. This
the pathological features of hemorrhagic pulmonary infarction. At is because of the varied clinical presentation of PE including chest
around the same time, a French pathologist, Jean Cruveilhier hypoth- pain, dyspnea, hemoptysis and many a times, asymptomatic.
esized that the cause of this disease was phlebitis of pulmonary ves-
sels. Rudolf Virchow, in late 19th century for the first time, pointed Clinical Assessment of Pulmonary Embolism
out that the clots arose from deep veins of periphery. He realized that
a venous thrombus can break loose from its origin, travel through the Following clinical findings were more significantly associated with
blood stream and involve vessels of other organs. He further observed confirmed PE than in patients without PE:10
the presence of two types of thrombi in PE. One, which arises from
systemic veins and lodges into pulmonary circulation, and second,
which arises distal to this embolus as a result of stagnant blood flow.4 TABLE 39.1 Risk factors for development of venous thromboembolism5
He described the three main factors associated with DVT, now known
Virchow’s Triad Risk Factors
as Virchow’s triad, i.e. stasis, hypercoagulability of blood and injury to
Stasis Major surgery, cancer, prolonged immobilization,
the vessel wall.5 All the risk factors associated with PE revolve around
fracture (hip or leg), pregnancy, myocardial
these factors, which are described in Table 39.1.
infarction, congestive heart failure, burns
Amongst the Virchow’s triad, hypercoagulability is now found to
Hypercoagulability Previous venous thromboembolism, cancer,
be associated with more than 25% of patients with VTE.6
pregnancy, estrogen therapy
In 1969, Kakkar et al.7 confirmed the pathogenesis of VTE in
patients undergoing surgery without prophylaxis. Thirty percent of Injury to vessel wall Trauma, major surgery, fracture (hip or leg)
• Hemoptysis Due to the nonspecific signs and symptoms of PE and frequent

• Tachypnea absence of symptoms of DVT, the diagnosis of VTE, today, relies
• Fourth heart sound (S4), loud second pulmonary heart sound mainly on the objective tests.
(P2) and inspiratory crackles on chest auscultation.
Although the clinical assessment of PE is not sufficient for diag- Tests for Diagnosis of Deep
nosis, it has been used for categorization of patients into mild, mod-
Venous Thrombosis
erate and severe risk categories, the prognosis varying according to
the level of risk.11 In 1972, Rabinov and Paulin described a technique for venography,
The inaccuracy of the clinical diagnosis of PE is due to the fact which was later accepted as the gold standard for diagnosis of DVT.
that PE can present as three different syndromes: (1) pulmonary In venography, a thrombus can be recognized by the presence of con-
infarction and hemorrhage, (2) acute cor pulmonale and (3) acute stant filling defects, abrupt cut-offs, nonfilling of the entire deep sys-
unexplained dyspnea.3,12 tem, or portions thereof and/or demonstration of collateral flow.13,14
However, this technique was invasive, required expertise and was not
Pulmonary Infarction and Hemorrhage (50–60%) available at all hospitals. The search for easier and noninvasive meth-
ods resulted in few more techniques for diagnosis of DVT, which were
Pulmonary embolism always does not result into pulmonary compared with the standard technique of venography.
infarction. Karsner and Ash in 1912 demonstrated that embolism of a Of these, Iodine-125 fibrinogen scanning and impedance ple-
healthy lung does not cause “true” infarction. Hampton and Castle- thysmography showed 94% sensitivity (positive in 94% of the patients
man in their postpartum study on 400 patients reported that intra- who had positive venogram findings).
alveolar hemorrhage without necrosis of the alveolar walls is the Doppler ultrasound was a revolution in the diagnosis of DVT,
most common finding in the first 2 days of infarction. After 2 days, which was reported to have a sensitivity of 95.2% and a specificity of
necrosis of the alveolar walls begin leading to true pulmonary infarc- 98.6% in the detection of DVT.15 Today, the diagnosis of DVT is most
tion. Patients with pulmonary infarction more commonly present effectively accomplished noninvasively, by using color and duplex
with hemoptysis, pleuritic chest pain, a pleural friction rub, whereas ultrasonography.
those with PE present with intensive dyspnea and intrathoracic dis- In patients with suspected PEs in whom lung scan findings have
tress. been inconclusive, the determination of the presence or absence of
DVT helps to determine, which patients require therapy.3
Acute Cor Pulmonale (10–15%)
Tests for Diagnosis of Pulmonary Embolism
McGinn and White (1935) were the first to describe acute cor pulmo-
nale in the cases of massive PE. These patients typically had shock, Chest X-ray
collapse, dilatation of neck veins as direct evidence of increased
venous pressure and dilatation of the pulmonary artery and the right Westermark, in 1938, differentiated the radiographic findings in
heart chambers (as confirmed on postmortem or by pulmonary patients with or without pulmonary infarction. Pulmonary infarction
embolectomy). The term “acute cor pulmonale” was used to distin- was typically associated with a wedge shaped shadow. The shadow
guish it from chronic cor pulmonale secondary to various pulmonary or density is always in contact with one or more pleural surfaces. The
diseases. cardiac margin of the consolidation was noted to be sharp in out-
line and convex or hump-shaped. However, in patients with PE, but
Acute Unexplained Dyspnea without pulmonary infarction, he described the areas of decreased
pulmonary vascularity which has been termed as Westermark sign.
These patients have submassive PE that is insufficient to cause acute Patients without having pulmonary infarction also have non-
cor pulmonale, but is sufficient to cause dyspnea. They present with specific findings, including pleural effusion, pleural-based opacity,
tachypnea and severe dyspnea, and on investigation have an evi- elevated hemidiaphragm, atelectasis and consolidation.13
dence of DVT and PE.
Deep venous thrombosis is now known to be the most important Partial Pressure of Oxygen in Arterial Blood
risk factor associated with PE. About 70% patients with symptomatic
PE have DVT. However, less than 25% of patients with symptomatic Although normal partial pressure of oxygen in arterial blood (PaO2)
PE have clinical evidence of DVT in the form of calf tenderness and cannot rule out PE, it helps to indicate the hemodynamic severity of
unilateral leg edema.7,9 PE in patients with confirmed diagnosis.16
Chapter 39  History of Pulmonary Embolism 285
Pulmonary Angiography Echocardiography
Pulmonary angiography first done successfully by Aitchison and The first report of the echocardiographic findings in a patient with
McKay in 1956 became the gold standard for diagnosis of PE.17 acute PE was given by Steckley et al. in 1978.3 Right ventricular dila-
However, it suffered from the disadvantage of invasiveness and is tation, RV hypokinesis and dilatation of the right pulmonary artery
not available at all hospitals. Further, it is an expensive technique, on echocardiography are frequent findings, although, not diagnostic
requires expertise and is associated with some morbidity (0.3%).11 in PE. Transesophageal echocardiography detection of emboli in the
Hence, easier and less invasive tests were developed for diagno- central pulmonary circulation may prove to be highly specific for the
sis, and were validated by comparing with the standard diagnostic PE.20
technique.
Computed Tomography Scan
Lung Perfusion Scans
It has sensitivity and specificity, ranging from 86% to 92% from
It was first introduced by Wagner and colleagues at Johns Hopkins several studies. It is a noninvasive technique that directly identifies
in 1964. The findings of perfusion scans were compared with pulmo- the pulmonary embolus as an intraluminal filling defect within a
nary angiography in several studies. As a conclusion, normal lung pulmonary artery. It can also help to rule out other conditions that
scan finding essentially excludes the presence of acute PE. An abnor- may have symptoms and signs, which are suggestive of PE. Chest
mal perfusion scan finding is not specific for PE.3 computed tomography (CT) scanning is of utmost utility in diagnos-
ing PE in critically ill patients with shock and/or signs of acute cor
Ventilation/Perfusion Scans pulmonale. With the technological advances, a combination of CT
with pulmonary angiography is now taken as the gold standard for
The very high sensitivity of ventilation/perfusion (V/Q) scans was diagnosis of PE.3,21,22
confirmed in prospective investigation of pulmonary embolism
diagnosis (PIOPED) study in 1990, during which nearly all MANAGEMENT OF PULMONARY EMBOLISM
patients with PE (98%) had abnormal V/Q scan findings. Till
today, V/Q scan remains to be an important diagnostic modal- Pulmonary Embolectomy
ity for detecting pulmonary thromboembolism available to the
clinician. It was the first definitive therapy for the treatment of PE, introduced
High-probability scans were defined as two or more moder- by Trendelenburg, a noted German surgeon.23 Observing the sud-
ate or large segmental perfusion defects without corresponding den mortality associated with nine patients of PE at the hospital in
ventilation or roentgenographic abnormalities. The PIOPED study Leipzig in 1987, he experimented a surgical procedure of pulmonary
concluded that “high-probability scan is nearly specific (88%) for embolectomy through left parasternal thoracotomy. However, the
acute PE. In the circumstances of indeterminate or low-probabil- two patients that he treated did not survive longer than 37 hours.
ity scans, the diagnosis of acute PE can be neither confirmed nor Kirschner, a formal pupil of Trendelenburg, performed the first
excluded.”10 successful pulmonary embolectomy in 1924. Approximately, 300
operations were performed over the next decade led to less than 10
Fibrin Split Products/D-dimer survivors. Finally, in 1944, this surgery was labeled of an historical
interest by Ochsner, while addressing the American Surgical Associa-
Wilson et al. in 1971 reported the elevated levels of fibrin split prod- tion. He reflected that it would be more beneficial to prevent PE by
ucts (FSPs) in patients with PE, and the findings were confirmed dur- ligating veins on the cardiac side of the thrombus.
ing angiographic studies in 1973.18 The negative predictive value of In 1932, John Gibbon, surgical resident from Philadelphia
a normal D-dimer test result is greater in patients with a low clinical observed an unsuccessful attempt at pulmonary embolectomy by
probability of VTE. his mentor, Edward Churchill, who said that the patient might have
The early tests for FSPs were not specific for fibrin derivatives, been saved; if there had been mechanism to take over her respiration
but newer tests, like latex agglutination test and enzyme linked and cardiac function. This prompted Gibbon to work on an extracor-
immunosorbent assay (ELISA) use monoclonal antibodies to poreal circulation. He first performed an open heart surgery in 1953,
specifically measure cross-linked fibrin derivatives in plasma. The using an extracorporeal circulation machine. This led to the begin-
sensitivity of newly developed rapid ELISA tests ranges from 90% ning of a new era in cardiothoracic surgery. In 1961, Denton Cooley
to 95%, are now looked as important in order to avoid unnecessary first performed pulmonary embolectomy using an extracorporeal
workup in patients with low clinical probability of VTE.19 circulation device.4
Now, with the advent of pulmonary angiography and cardiopul- subcutaneous LMW heparin or adjusted-dose IV unfractionated
monary bypass, the procedure became more feasible.23 In later years, heparin followed by oral anticoagulants for 12 weeks. There was no
techniques for transfemoral or transjugular catheterization reduced significant difference in recurrence of VTE, major bleeding and mor-
the need of thoracotomy for pulmonary embolectomy. Still, there tality rate amongst both the groups.28
is about 30% mortality associated with pulmonary embolectomy. Recent guidelines by the American College of Physicians and
Hence, today, it can only be considered in patients with massive PE the American Academy of Family Physicians recommend the use of
complicated by shock.23,24 LMW heparin over unfractionated in the initial treatment of DVT and
either of them for the treatment of PE.29
Venous Ligation and Inferior Vena Cava Filters

Ochsner and DeBakey in 1932, advocated inferior vena caval (IVC) Oral Anticoagulants
ligation for prevention of PE. However, 2 years later, Homans actually The first placebo-controlled clinical trial to demonstrate the efficacy
performed proximal femoral vein ligation. of oral anticoagulants in preventing VTE was reported by Sevitt and
Vena caval interruption by surgical ligation or clip placation was Gallagher in 1959.23
the initial method that was replaced by intraluminal occlusive device Two large randomized studies clearly showed the benefits of
such as Mobin-Uddin umbrella device.4 However, these were asso- long-term oral anticoagulant therapy.30,31 However, benefits of
ciated with complications, like device migration, embolization and decreasing the incidence of recurrent VTE have to be weighed
perforation of IVC. In order to avoid the morbidity of IVC ligation, against the increased risk of bleeding in each case.
IVC filters were invented that required direct approach to IVC under The combined use of heparin along with oral anticoagulants has
general anesthesia.25 The first clinical trial on IVC filters conducted been shown to offer significant benefit, and is now accepted as the
in 400 patients showed that it reduced the incidence of PE in early standard treatment for VTE.32
course of time, however, it failed to provide a long-term protection It is recommended that anticoagulation should be maintained
(2 years) against PE.26 for 3–6 months for VTE secondary to transient risk factors and for
Today, IVC filters have significant role in patients with active more than 12 months for recurrent VTE.29
bleeding or other contraindications to anticoagulants and with
recurrent PE despite anticoagulant therapy.23 Thrombolytic Therapy
Heparin Streptokinase, Urokinase and recombinant tissue plasminogen

activator (rt-PA) are the Food and Drug Administration (FDA)
In 1916, heparin was discovered by McLean, a medical student approved agents for the treatment of acute PE. From a randomized
while experimenting on thromboplastins. It was purified from bo- controlled trial done on urokinase [urokinase pulmonary embolism
vine lungs and intestines, and it was available for use in 1932.4 Use of trial (UPET)] and four randomized trials on rt-PA, it was evident that
intravenous heparin for prevention of postoperative DVT led to great thrombolytic therapy only led to early resolution of PE in lung scans
success and it reduced the incidence of postoperative DVT to less as compared with heparin and anticoagulant therapy. However,
than 1%. The use of heparin for treatment of thrombophlebitis and within 2 weeks the percentage improvement in scans was not dif-
PE in clinical settings also gave spectacular results with improvement ferent than the comparator. In fact, rt-PA for PE was associated with
in symptoms within few hours.23 8.4% incidence of major hemorrhage and 2.2% incidence of fatal
hemorrhage.33
Low-Molecular-Weight Heparin Recently, Tenecteplase, a new fibrinolytic with high fibrin speci-
ficity was tried in six patients of acute and subacute PE as a weight
It has the very significant advantage over unfractionated heparin in optimized intravenous bolus dose. The patients presented with
that it can be administered in fixed doses, and it does not require shortness of breathe and syncope. The diagnosis of PE was con-
laboratory monitoring. The use of unfractionated heparin for DVT firmed, based on echocardiography and pulmonary CT angiography.
was compared with low-molecular-weight (LMW) heparin in several There was significant improvement in breathlessness, reduction
clinical studies. The meta-analysis of the important studies indicates in heart rate, improvement in hemodynamics and regression of RV
that LMW heparin is associated with significantly higher success rate pressure by echocardiography without any major bleeding compli-
and less incidence of hemorrhagic events as compared to unfrac- cations. There was no mortality at the end of 30 days.34 Thus, fibrin-
tionated heparin.27 specific fibrinolytics, like tenecteplase may prove to be a safe and
In a large randomized study with 1,021 patients of symptomatic effective salvage therapy in patients with acute PE, which remains to
PE, the Columbus investigators compared the effects of fixed-dose, be tested in larger studies.
Chapter 39  History of Pulmonary Embolism 287
Prophylaxis for Deep Venous Thrombosis proximal DVT and continuing for a minimum of 1 year after diag-
nosis.23,35
Low dose of subcutaneous heparin is sufficient to prevent coagu- Calnan et al. in 1970 first reported the use of external pneumatic
lation in postsurgical prophylaxis of DVT. About eight randomized compression, which intermittently compresses the calf and thigh
studies confirm the benefit of LMW heparin treatment in prophylaxis accelerates deep venous flow, thereby decreasing venous stasis.
of DVT. Low-molecular-weight heparin and low-dose unfractionat- Intermittent pneumatic compression was found to be clinically and
ed heparin surgery have largely replaced oral anticoagulants except statistically significant, which reduce the frequency of both proximal
for hip fractures, total hip replacement and total knee replacement vein and calf vein thrombosis.36 Pneumatic compression is now indi-
because of the very high incidence of VTE, where LMW heparin cated primarily in patients, undergoing neurosurgical and urological
failed to show clear benefit.23 surgery in adjunct to anticoagulants because of the increased risk, if
Wilkins et al. in 1952 reported that the use of elastic stock- bleeding occurs.23
ings had reduced the incidence of postoperative PE based on Thus, from the historical perspective, we have achieved a great
the clinical or postmortem diagnosis of PE. There is a sufficient excellence in the diagnosis and management of VTE. We owe a great
evidence to recommend the use of elastic compression stockings deal of gratitude to the pioneers in the history who have contributed
from several studies and are now recommended to prevent post- much to our understanding and treatment of a commonly lethal con-
thrombotic syndrome, beginning within 1 month of diagnosis of dition, like pulmonary thromboembolism.
REFERENCES
1. Mason RJ, Broaddus VC, Murray JF, et al. Natural history: Pulmonary embolism. In: Mason RJ, Broaddus VC, Murray JF, Nadel JA (Eds). Mason:
Murray and Nadel’s Textbook of Respiratory Medicine, 4th edition. Philadelphia: Saunders; 2005.
2. Marx J, Hockberger R, Walls R. Pulmonary embolism. In: Marx J, Hockberger R, Walls R, (Eds). Marx: Rosen’s Emergency Medicine – Concepts and
Clinical Practice, 7th edition. Philadelphia: Mosby; 2009.
3. Dalen JE. Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest. 2002;122(4);1440-
56.
4. McFadden PM, Ochsner JL. A history of the diagnosis and treatment of venous thrombosis and pulmonary embolism. Ochsner Journal. 2002;4:9-
13.
5. Kroegel C, Reissig A. Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogen-
esis. Respiration. 2003;70(1):7-30.
6. Greengard JS, Eichinger S, Griffin JH, et al. Brief report: variability of thrombosis among homozygous siblings with resistance to activated protein
C due to an Arg→Gln mutation in the gene for factor V. N Engl J Med. 1994;331(23):1559-62.
7. Kakkar VV, Howe CT, Flanc C, et al. Natural history of postoperative deep-vein thrombosis. Lancet. 1969;2(7614):230-2.
8. Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107(23 suppl 1):122-30.
9. Douketis JD, Kearon C, Bates S, et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279(6):458-
62.
10. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis
(PIOPED). The PIOPED Investigators. JAMA. 1990;263(20):2753-9.
11. Rodger M, Wells PS. Diagnosis of Pulmonary Embolism. Thromb Res. 2001;103(6):V225-38.
12. Wicki J, Perneger TV, Junod AF, et al. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern
Med. 2001;161(1):92-7.
13. Rabinov K, Paulin, S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 1972;104(2):134-44.
14. Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary
embolism and no pre-existing cardiac or pulmonary disease. Chest. 1991;100(3):598-603.
15. Chan-Wilde C, Lim WE. Diagnosis of deep venous thrombosis by Duplex Doppler ultrasound imaging at the Singapore General Hospital. Singa-
pore Med J. 1995;36(1):56-9.
16. Stein PD, Goldhaber SZ, Henry JW. Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism. Chest. 1995;107(1):139-43.
17. Aitchison JD, McKay JM. Pulmonary artery occlusion demonstrated by angiography. Br J Radiol. 1956;29(343):398-9.
18. Rickman FD, Handin R, Howe JP, et al. Fibrin split products in acute pulmonary embolism. Ann Intern Med. 1973;79(5):664-8.
19. Indik JH, Alpert JS. Detection of pulmonary embolism by D-dimer assay, spiral computed tomography, and magnetic resonance imaging. Prog
Cardiovasc Dis. 2000;42(4):261-72.
20. Krivec B, Voga G, Zuran I, et al. Diagnosis and treatment of shock due to massive pulmonary embolism: approach with transesophageal echocar-
diography and intrapulmonary thrombolysis. Chest. 1997;112(5):1310-6.
21. Rathbun SW, Raskob GE, Whitsett TL. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a
systematic review. Ann Intern Med. 2000;132(3):227-32.
22. Mullins MD, Becker DM, Hagspiel KD, et al. The role of spiral volumetric computed tomography in the diagnosis of pulmonary embolism. Arch
Intern Med. 2000;160(3):293-8.
23. Dalen JE. Pulmonary embolism: what have we learned since Virchow?: treatment and prevention. Chest. 2002;122(5):1801-17.
24. Cooley DA, Beall AC Jr, Alexander JK. Acute massive pulmonary embolism. Successful surgical treatment using temporary cardiopulmonary by-
pass. JAMA. 1961;177:283-6.
25. Mobin-Uddin K, McLean R, Bolooki H, et al. Caval interruption for prevention of pulmonary embolism. Long-term results of a new method. Arch
Surg. 1969;99(6):711-5.
26. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal
deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-15.
27. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous
thromboembolism: results of a meta-analysis. Am J Med. 1996;100(3):269-77.
28. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. The Columbus Investigators. N Engl J Med.
1997;337(10):657-62.
29. Snow V, Qaseem A, Barry P, et al. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians
and the American Academy of Family Physicians. Ann Intern Med. 2007;146(3):204-10. Epub 2007.
30. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous
thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med. 1995;332(25):1661-5.
31. Schulman S, Granqvist S, Holmström M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The
Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997;336(6):393-8.
32. Douketis JD, Kearon C, Bates S, et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279(6):458-
62.
33. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med.
1997;157(22):2550-6.
34. Abstract of the 60th Annual Conference of the Cardiological Society of India. December 4-7, 2008. Chennai, India. Indian Heart J. 2008;60(5):381-
495.
35. Wells PS, Lensing AW, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis.
Arch Intern Med. 1994;154(1):67-72.
36. Hull RD, Raskob GE, Gent M, et al. Effectiveness of intermittent pneumatic leg compression for preventing deep vein thrombosis after total hip
replacement. JAMA. 1990;263(17):2313-7.
40 History of Stroke in Cardiac
Patients
Patel A, Bharani A
closely inspired by Aretaeus but was more close to modern medicine

INTRODUCTION
and postulated several causes of apoplexy. The first cause described
Stroke (origin somewhere in 1250–1300 from stracian; to stroke and was inability of blood to deliver spirits to the brain (spiritus inter-
Greek word streich; akin to strike) acquires its morbid meaning sim- ception-stoppage of spirits). In modern medicine, spirits would be
ply from the context.1 Other terms for describing similar situation considered equivalent to oxygen, which was discovered in 1772, well
are apoplexy (from LG Apoptexia, G Apoptessein; to strike down after era of Hermann Boerhaave. Next cause described was anemia,
and incapacitate; to cripple with stroke) and Sideratio, which means through blood loss from any site of trauma. He also postulated me-
disease caused by a constellation, suggests both a disease caused by chanical causes interfering with cerebral circulation, such as compres-
celestial force and an affliction of the mind.2 sion of the vessels in the neck either by tumor or by ligation. The most
Conditions similar to stroke were known to ancient Egyptian as impressive factor enumerated was “Stenochoria in chondrogonia
early as 3000–2500 BC as evident from the Edwin Smith Surgical Pa- arteriae”—narrowing of the artery due to cartilaginous changes with-
pyrus. Probably first use of word “Brain” appeared in this papyrus in it, this correlate well with carotid stenosis due to atherosclerosis/
including neurological sequelae of head injury as residual paresis of arteriosclerosis.11
arm and leg with nails in the middle of the palm.3,4 Giovanni Ballista Morgagni published nearly 3000 case studies
Hippocrates (400 BC) described the detailed account of apoplexy with autopsies in 1679. Morgagni followed Celesus and Theophile
with observation of paralysis or convulsions following brain injury, Bonet and eventually favored pathological classification of apoplexy.
appearing on the opposite side of the body to the head wound.4-6 He described apoplexy as either sanguineous—analogous to the
However, Hippocrates and his contemporary were concerned mainly intracerebral hemorrhage or serous.7,12 Morgagni’s second apo-
with prognosis and primitive treatment of apoplexy, sharing a pes- plexy—the serous, did not find firm ground in medical fraternity
simistic view expressed adequately in aphorism “It is impossible to for around next 60 years, since for most physicians, apoplexy had
cure a severe attack and difficult to cure a mild one”.5
Aelius Galenus (Galen), Aretaeus of Cappadocia and Soranus
of Ephesus were contemporary physicians in Roman and Greek
empire (100–200 AD). They were probably not much concerned
about pathogenesis of the stroke. Aretaeus identified two groups
(physical and mental) as causes for strokes. The physical causes for
stroke included a wound, a blow, cold exposure, indigestion, intoxi-
cation and venereal. The mental factors included are astonishment,
fear, dejection, fright, unexpected joy and unrestrained laughter.7,8
An almost similar list can be found in “On Acute Disease And On
Chronic Diseases” by Soranus of Ephesus which is translated later on
by Caelius Aurelianus into Latin.7,9,10 King Alfred of Britain (871–900
AD) wrote in his book, that later was translated by Cockayne (1864)
as “Medical Remedies, Herbals And Astrology” and described hemi-
plegia “the half dead disease” is caused by thick viscid humor and it
could be treated by removing such thick humor by bleeding, drinks
or leechdom.4
Herman Boerhaave (1668–1738) (Fig. 40.1), a Dutch physician,
famous to demonstrate the relation of symptoms to lesions, who was Figure 40.1: Hermann Boerhaave
become associated with hemorrhage and still remain so today. In be thrown towards the extremities as well as brain in a great num-
1820, Leon Rostan revived the concept of serous stroke by estimat- ber of cases and again noted that there fragments are impossible to
ing softening to be the most frequent cerebral lesion in contrast to prove and hard to distinguish from the obliterating arteritis—the end
apoplexy (now hemorrhagic stroke).13 result.16
Although cartilaginous changes in cranial arteries were previ- Nearly at the same time, Rokitansky in Vienna published a four-
ously described by Hermann Boerhaave and even earlier by Willis, volume manual of Pathological Anatomy in 1840. He closely relat-
they did not firmly establish its causative relationship with occur- ed apoplexy (hemorrhagic variant) with heart diseases. According
rence of stroke. Similarly, Johann Georg Christian Friedrich Martin to him, many apoplexies were due to left ventricular hypertrophy
Lobstein described the arterial thickening with yellow puree like, and thus an increased impulse carried out to the blood vessels.17
uneven, knobby matter, neither phlogistic nor inflammatory but was Rokitansky was probably concerned with high blood pressure in
unable to give whether it was its cause or its effect.7 arteries but at that time it was neither a significant disease entity
Mathew Baillie in 1825 (Fig. 40.2) described hardening of arter- nor any method was available to measure it. (Idea of blood pres-
ies associated with cerebral hemorrhage. He described deposition of sure measurement started in 1733 by Stephen Hales in animal ex-
earthy matter deposited in the coat of internal carotid arteries and perimentation but actual measurement was possible only after 1855
frequently extending into smaller branches. Similar findings were when first noninvasive sphygmomanometer was discovered by Vi-
also described in basilar arteries and he concluded that without such erordt).18 Another novel concept related to cardiac contribution in
alteration in arteries, effusion of blood would probably be much causing apoplexy was its relationship with congestion or dilatation of
more rare.14 With Baillie’s description of atherosclerosis, the notion right ventricle. Rokitansky also added another dimension to Baillie’s
began to take shape that stroke is primarily a result of mechanical finding by considering hardened arteries contributing to hemor-
alteration of vascular structure in contrast to blood mediated or rhage either alone or in combination with the above-mentioned
inflammatory process. factors.14,18 Most of his presentation of softening of brain closely
In 1838, Robert Carswell in his authoritative book “Pathologi- corresponds to the current description of hemorrhagic infarct and
cal Anatomy” described “gangrene senilis”, equivalent to ischemic ischemic infarct (yellow softening). The most common variety he de-
stroke of modern medicine, as not due to inflammation of arteries scribed was yellow softening and declared it to be definitively nonin-
but due to obstructive lesions, such as fibrous, fibrocartilaginous, flammatory but could not find any cause for it. He was not fascinated
osseous tissue formation.15 Carswell by placing strings in the lumen by theories of vascular occlusion.
of blood vessels proved that yellow softening of the brain follows In 1847, Virchow (Fig. 40.4) came into forefront with strong
arterial obliteration and that it was noninflammatory in nature. At denial to theory of inflammation leading to stroke. He agreed with
the same time, Cruveilhier (Fig. 40.3), an anatomist in Paris, con- the Carswell’s concept of obstructive, noninflammatory origin of the
tinued to support the traditional view that stroke generally had an yellow softening of brain but added another dimension to it by sug-
inflammatory origin but he also forwarded a novel view that brought gesting that in thrombosis, inflammation is a secondary event, pos-
core cardiology and neurology on the same platform. He suggested sibly related to chemical changes in the thrombus itself. Carswell’s
about blood clot formation in the heart and that its fragment could idea that blood clot can form in the heart and break away to more
Figure 40.2: Matthew Baillie Figure 40.3: Cruveilhier

Chapter 40  History of Stroke in Cardiac Patients 291
peripherally in arterial system found its firm ground in Virchow’s ing to patient and physician alike, which is reflected in Osler’s advice
observation. He described another kind of clot in which there was no to discontinue all treatment and let the pressure rise.21,22 By 1930s,
change in the vessel wall and its surrounding. He thought that these malignant hypertension and associated acute mortality prompted
clots did not form in situ but formed at a distance, subsequently vigorous search for effective antihypertensive treatment. In 1939,
torn off and carried along the blood stream, until they lodge some- joint statement by British Cardiac Society and the American Heart
where in smaller arteries. These observations led to clear distinction Association on standardized method of blood pressure measure-
between thrombosis and embolism as two separate entities.7,19 ment helped in adoption of sphygmomanometry in routine clinical
Virchow’s concept regarding thrombosis and embolism were practice.23
further advanced by his student Julius Cohnheim to a new dimen-
sion which is essentially similar to our current concept of “cerebral MYOCARDIAL INFARCTION AND STROKE
infarct”. He produced experimental stroke by arterial embolization
with wax globules and produced two kinds of lesion which came Soviet physicians VP Obraztsov and ND Strazhesko described an
to be recognized as ischemic necrosis and hemorrhagic infarct. accurate account of myocardial infarction in 1910.24 Subsequently,
Ischemic necrosis was the straightforward outcome of sudden ces- stroke has been recognized as an important complication related
sation of blood supply in his experiments. New observations that he to myocardial infarction as described by Levine in 1929.25 Thomp-
made include retrograde filling of the vessel distal to embolic ob- son and Robinson correlated size of myocardial infarction to stroke
struction and subsequent seepage of blood from vessel walls without frequency based on kinase as surrogate marker for myocardial
any actual break in the integrity of vessels. Cohnhim also described damage.26 These observations led others to adopt anticoagulation
paradoxical embolism through patent foramen ovale into a cerebral in early post-MI period to reduce the risk of stroke. Nakashima and
artery.20,21 For many years, heart ailment, increased blood pressure associates described occurrence of myocardial infarction in a 9-year-
and thrombosed vein, in case of paradoxical embolization were con- old boy with congenital coronary artery fistula originating from the
sidered as the only source of embolization and atherosclerotic arter- left coronary artery and emptying into the right atrium. The boy
ies to give rise to thrombosis in situ with subsequent brain infarction. developed mural thrombi and subsequent cerebrovascular accident
(CVA).27 In most cases of myocardial infarction, stroke is ischemic in
HYPERTENSION AND STROKE origin, usually due to development of mural left ventricular throm-
bus in akinetic region. The risk of embolization and subsequent
Stephen Hales carried out initial experiments in horses to measure stroke is highest within the first few days after myocardial infarction
blood pressure in 1727.18 Significance of increased blood pressure and then declines exponentially.
was not appreciated at that time and sphygmomanometry was con-
sidered special investigation of uncertain clinical relevance. By 1912, HEART FAILURE AND STROKE
high blood pressure was recognized widely for its association with
stroke, but reluctance to measure blood pressure persisted as there John Chyne, a physician in Dublin, described a 60-year-old patient
was no effective treatment available and its knowledge was alarm- of heart failure and irregular pulse, ultimately that patient died of
“apoplexy”. His autopsy finding described heart in which much of
the muscle replaced by fat. In the same patient, Chyne described
irregular breathing pattern during terminal part of life which we
know today as Chyne—stokes breathing.21,28 Similar case was de-
scribed by Robert Adams in 1827 in whom antemortem finding was
frequent apoplectic attacks.21,29 Subsequently, fatty degeneration
of heart became a common diagnosis, mainly because of extensive
work done by Richard Quain.30 It was described in two forms. In one
form, fat grows over surface of heart and gradually encroaches in
between the muscular fibers and another form in which fat globules
fill the sheath of what were previously muscle fibers. Fatty degenera-
tion was considered to interfere with the action of heart and cause
shortness of breath. It was thought to result from action of alcohol
or insufficient blood supply to heart because of diseased coronaries.
MITRAL STENOSIS AND STROKE

John Mayow (1640–1679) gave description of constriction of mitral
Figure 40.4: Rudolf Virchow orifice in a young man in 1668.31 Nearly 150 years passed, when the
description of thrombus in the left auricle in a 15-year-old girl with observed that in dying animal heart, ventricles stop beating before
mitral stenosis was given by William Wood in 1814.32,33 An article auricles and right auricle continues to beat when other parts of heart
published in 1950 by Jordon and associates describes some early become inactive. Eventually, right auricle also stops beating and
studies on co-association of mitral stenosis and thromboembolism. then an undulating obscure movement continues in the right auric-
Nearly one-third of patients with severe disease were found to have ular blood.51 These observations were probably the very first direct
evidence of intracardiac thrombi.34-36 Welch considered auricular observation on AF, made long before invention of electrocardiogram
appendages to be the most common site hosting the blood clots and (ECG). However, chaotic irregularity of the pulse was considered on
only rarely other parts of heart are involved, in patients with mitral ominous clinical sign even by most ancient physicians.52 Invention
stenosis.37 As left atrial appendage became recognized as a frequent of stethoscope by Laennec made it easy for Robert Adams in 1827
source of embolism, a natural thought evolved to reduce the con- to describe the common association between the irregular pulse
sequences of recurrent episodes of thromboembolism by surgical (AF, then described as delirium cordis pulse irregularis and ataxia of
removal of left atrial appendage.38-40 the pulse) with mitral stenosis.53,54 Soon it was considered diagnos-
tic of mitral stenosis. Another concurrent significant advancement
PROSTHETIC HEART VALVE AND STROKE was development of electrocardiography by Eienthoven in 1990.
Eienthoven published first ECG tracing from a case of pulses irregu-
With the recognition of mitral stenosis and its frequent association laris (now AF) in 1906 that was further characterized by Lewis, Roth-
with atrial fibrillation (AF), heart failure and stroke, early effort to enberger and Winterberg in 1909.52,54-56 The association between
treat it surgically started in 1920s.41 Elliot Culter and Samuel Levine stroke and AF in patients with rheumatic heart disease (RHD) was
performed the first human mitral commissurotomy in 1923 in Bos- widely recognized in 1950.
ton.42 Effort to treat AF dates back to 1918 when Frey described qui-
Soon it was recognized that these techniques were not appro- nidine sulphate as effective therapy in at least some patients.57
priate for all patients, particularly those with severely deformed and Virchow’s concept of thrombosis also influenced the treatment
calcific valves and also for patients with regurgitant lesions. Initial approach towards use of anticoagulant therapy to arrest the recur-
attempts to use mechanical prosthesis in place of mitral valve were rent embolism due to AF in patients with mitral stenosis.58,59 Nonval-
made by Ellis and Bulbulian, and by Braunwald NS in 1950s.43,44 All vular AF as a cause of embolic stroke was established as an important
of them faced the problem of thrombosis, particularly at the junction cause by the Framingham Study. This study established that nonval-
between the myocardium and prosthetic valve, followed by embo- vular AF results in greater than 5-fold increase in stroke incidence
lism in next 3–4 week in the animal experiments as well as problems while AF in association with RHD leads to 17-fold increase in risk.60
of postoperative anticoagulation and subsequent hemorrhages lead-
ing to many deaths.45 INFECTIVE ENDOCARDITIS AND STROKE
Starr and Edward plagued with problem of thrombus formation,
covered the area of ball valve with a silastic shield where thrombus Intracardiac masses resembling vegetation of infective endocarditis
had been forming.46 This method slowed down the thrombus forma- were described by Lazarus Riverius in 1646, by Giovanni Lancisi in
tion and achieved 80% survival rate in animal experiments. However, “De Subitaneis Mortibus” in 1709 and by Morgagni in “The Seats and
they selected nonshielded valve for placement in humans because Causes of Diseases” in 1969.12,61 However, the relationship between
of ease and speed of insertion with minimal surgical trauma.46,47 intracardiac masses and inflammation to our modern status were
First successful prosthetic valve model was thus Starr Edward valve. brought to the attention by Jean Baptiste Bouillaud, who was the first
First recipient of Starr Edward valve was a 30-year-old lady, who died person to define endocardium and its inflammation as “gangrenous
10 hours after procedure because of cerebral air embolism, thought endocarditis.62 William Senhouse Kirkes described cardioembolic
to arise secondary to air trapped in pulmonary veins. Subsequent stroke in patient with diseased mitral valve and warty excrescences
procedures were successful and patients received postoperative an- in 1852 in his famous paper.63 Later on, Samuel Wilks made a dif-
ticoagulation started on seventh postoperative day and to be contin- ferentiation between arterial and venous pyemia. Initially infective
ued lifelong.48-50 Addition of aspirin as adjuvant therapy to antico- endocarditis was recognized in its acute form as a febrile illness with
agulation is a recent development only. embolism as a prominent feature, which invariably culminated into
death.64,65 William Osler (Fig. 40.5) was able to recognize chronic
ATRIAL FIBRILLATION AND STROKE form of infective endocarditis, as a prolonged illness of insidious
onset with fever and few cardiac symptoms and valvular vegetations
William Harvey (1578–1657) had made many interesting observa- at postmortem.66 He also reinforced the views of Sir James Paget
tions in his book “De Motu Cordis” (On The Motion Of The Heart And (1844) and Ormered (1851) about common association of infective
Blood) and established heart as generator of pulse in 1628. He also endocarditis with pre-existing RHD.67,68
Figure 40.5: Sir William Osler Figure 40.6: Claude Galien
embolic occlusion in territories of spleenic, renal and iliac arteries

PARADOXICAL EMBOLISM AND STROKE
and a branched thrombus lying in patent foramen ovale. However,
Although term paradoxical embolism was coined around year that case also had multiple small thrombi adherent to it ventricu-
1885, pathological description closely resembling this entity were lar wall, casting a doubt on probable source of emboli. This case
first described by Julius Cohnheim, a professor of pathology and attested the possibility of transforamen passage of emboli for the
pathological anatomy at the university of Leipzig.69,70 Cohnheim first time. Later on, many reports appeared that described embolus
in his “Lectures On General Pathology” described autopsy finding lying across foramen ovale and no evidence of thrombus in situ on
in a 35-year-old woman who had stroke and a large thrombus in a left-sided heart, an excellent review of which was written by John-
femoral vein and finding of a large foramen ovale and he attributed son.69
stroke to paradoxical embolization. Subsequently, more cases of
systemic embolization through the patent foramen ovale were de- ACKNOWLEDGMENT
scribed. Definitive evidence of paradoxical embolism was provided
by Zahn in 1981 by describing autopsy findings in a postpartum All images included with this work are taken from the Wikimedia
female with thrombus lying in iliac and uterine veins, evidence of Commons, a freely licensed media file repository.
REFERENCES
1. Dictionary.com Unabridged. Random House, Inc. Apoplexy. [Online] Available from http://dictionary.reference.com/browse/apoplexy. [Ac-
cessed August 2010].
2. Online Etymology Dictionary. Apoplexy. [Online] Available from http://www.etymonline.com/index.php?term=apoplexy. [Accessed August
2010].
3. Wilkins RH. Neurosurgical Classic-XVII. Edwin Smith Surgical Papyrus. J Neurosurg. 1964;240-4. Cybermuseum of Neurosurgery. [Online] Avail-
able from http://www.neurosurgery.org/cybermuseum/pre20th/epapyrus.html. [Accessed August 2010].
4. Adams GF. History and the half-dead disease. Campbell oration 1972. Ulster Med J. 1972;41:89-107. [Online] Available from http://www.ncbi.nlm.
nih.gov/pmc/articles/PMC2385369/. [Accessed June 2010].
5. Clarke E. Apoplexy in the hippocratic writings. Bull Hist Med. 1963;37:301-14.
6. Karenberg A, Hort I. Medieval descriptions and doctrines of stroke: preliminary analysis of select sources. Part I: The struggle for terms and theo-
ries—late antiquity and early Middle Ages. J Hist Neurosci. 1998;7:162-73.
7. Schiller F. Concepts of stroke before and after Virchow. Med Hist. 1970;14:115-31.
8. Aretaeus. De causis et signis acutorum morborum (lib. 2). In: Francis Adams LLD (Ed) (trans). On Paralysis. Of aretaeus, The Cappadocian, on the
cause and symptoms of chronic disease. [Online] Available from http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.01.02
54%3Atext%3DSD%3Abook%3D1%3Achapter%3D7. [Accessed June 2010].
9. Caelius Aurelianus. On Acute Diseases and On Chronic Diseases. In: Drabkin IE (Ed) (trans). Chicago: University Press; 1950.
10. Phillips ED. Aspects of Greek medicine. Philadelphia: Charles Press Publishers; 1987.
11. Boerhaave H. Praelectiones de Morbis Nervorum. In: Jacobus VE (Ed). Lugduni Batavorum: Petrum vander Eyk et Cornelium de Pecker; 1761.
[Online] Available from http://www.archive.org/details/praelectionesaca02boer [Accessed June 2010].
12. Morgagni GB. The Seats and Causes of Diseases investigated by Anatomy. Benjamin A (trans). [Online] Available from http://www.archive.org/
details/seatscausesofdis02morg. [Accessed June 2010].
13. Rostan L. Recherches sur le ramollissement du cerveau (Researches on cerebral softening), 2nd edition. Paris: Bechet; 1820.
14. Baillie M. The morbid anatomy of some of the most important parts of the human body, 3rd edition. Philadelphia; 1820. pp. 260-1.
15. Carswell R. Pathological anatomy, illustrations of the elementary forms of disease. London: Longman; 1838.
16. Cruveilhier J. Traite d’Anatomie pathologique generale. —Paris: Bailliere; 1862.
17. Rokitansky C. A manual of pathological anatomy. London: Sydenham Society; 1856. pp. 399-419.
18. Booth J. A short history of blood pressure measurement. Proc R Soc Med. 1977;70:793-9.
19. Warlow CP, Dennis MS, Gijn JV, et al. Stroke: a practical guide to management. Wiley-Blackwell; 2001.
20. Cohnheim J. Lectures on general pathology. McNee AB (trans). London: New Sydenhem Society; 1884.
21. Fleming PR. A short history of cardiology. Amsterdam-Atlanta, GA: Rodopi; 1977.
22. Osler W. An address on high blood pressure: its associations, advantages, and disadvantages: Delivered at the Glasgow Southern Medical Society.
Br Med J. 1912;2:1173-7.
23. Standardization of methods of measuring the arterial blood pressure: a joint report of the committees appointed by the cardiac society of Great
Britain and Ireland and the American Heart Association. Br Heart J. 1939;1:261-7.
24. Muller JE. Diagnosis of myocardial infarction: historical notes from the Soviet Union and the United States. Am J Cardiol. 1977;40:269-71.
25. Levine SA, Brown CL. Coronoary thrombosis: its various clinical features. Medicine. 1929;8:245-418.
26. Thompson PL, Robinson JS. Stroke after acute myocardial infarction: relation to infarct size. Br Med J. 1978;2:457-9.
27. Nakashima M, Takashima S, Hashimoto K, et al. Association of stroke and myocardial infarction in children. Neuropediatrics. 1982;13:47-9.
28. Cheyne J. A case of apoplexy, in which the fleshy part of the heart was converted into fat. Dublin Hosp Rep Commun Med Surg. 1818;2:216-23.
29. Adams R. Cases of diseases of the heart accompanied with pathological observations. Dublin Hosp Rep. 1827.
30. Quain R. On fatty diseases of the Heart. Med Chir Trans. 1850;33:121-96.
31. Rolleston H. The history of mitral stenosis. Br Heart J. 1941;3:1-12.
32. Wood W. Letter enclosing the history and dissection of a case in which a foreign body was found within the heart. Edinburgh Med Surg J.
1814;10:50-4.
33. Hobbs ML, Harley JB. Tricuspid occlusion due to mass thrombus of the right auricle. Ann Intern Med. 1957;46:990-6.
34. Irving G, Berger AR, Bunim JJ, et al. Auricular thrombosis in rheumatic heart disease. Arch Path. 1937;24:344.
35. Harvey EA, Levine SA. A study of uninfected mural thrombi of the heart. Am J M Sc. 1930;180:365-71.
36. Jordan RA, Scheifley CH, Edwards JE. Mural thrombosis and arterial embolism in mitral stenosis; a clinico-pathologic study of fifty-one cases.
Circulation. 1951;3:363-7.
37. Welch WH. Thrombosis. In: Allbutt, Clifford, Rolleston HD (Eds). A System of Medicine, 2nd edition. London: Macmillan and Co Limited; 1909.
pp. 691-762.
38. Garvin CF. Mural thrombi in heart. Am Heart J. 1941;21:713.
39. Hellerstein HK, Sinaiko E, Dolgin M. Amputation of the canine atrial appendages. Surgery. 1948;24:719-23.
40. Burdette WJ. Removal of the auricular appendage in the dog. Surg Gynec Obst. 1949;89:623-8.
41. Matthews AM. The development of the Starr-Edwards heart valve. Tex Heart Inst J. 1998;25:282-93.
42. Cutler EC, Levine SA. Cardiotomy and valvulotomy for mitral stenosis: experimental observations and clinical notes concerning an operated case
with recovery. Boston Med Surg J. 1923;188:1023-7.
43. Ellis FH, Bulbulian AH. Prosthetic replacement of the mitral valve. I. Preliminary experimental observations. Mayo Clin Proc. 1958;33:532-4.
44. Braunwald NS, Cooper T, Morrow AG. Complete replacement of the mitral valve: successful clinical application of a flexible polyurethane pros-
thesis. J Thorac Cardiovasc Surg. 1960;40:1-11.
45. Starr A. Total mitral valve replacement: fixation and thrombosis. Surg Forum. 1960:11:258-60.
46. Starr A, Edwards ML. Mitral replacement: the shielded ball valve prosthesis. J Thorac Cardiovasc Surg. 1961;42:673-82.
47. Lefrak EA, Starr A. Starr-Edwards ball valve. Cardiac valve prostheses. New York: Appleton-Century-Crofts; 1979. pp. 67-117.
48. Starr A, Edwards ML. Mitral replacement: clinical experience with a ball-valve prosthesis. Ann Surg. 1961;154:726-40.
49. Starr A, Edwards ML. Mitral replacement: late results with a ball valve prosthesis. J Cardiovasc Surg. 1963;4:435-47.
50. Starr A, Herr RH, Wood JA. Mitral replacement. Review of six years’ experience. J Thorac Cardiovasc Surg. 1967;54:333-58.
51. McMichael J. History of atrial fibrillation 1628-1819 Harvey-de Senac-Laennec. Br Heart J. 1982;48:193-7.
52. Lip GY, Beevers DG, Singh SP, et al. ABC of atrial fibrillation. Aetiology, pathophysiology, and clinical features. BMJ. 1995;311:1425-8.
53. Milliken JA. Atrial fibrillation and embolism. Can Med Assoc J. 1983;128:1370-2.
54. Flegel KM. From delirium cordis to atrial fibrillation: historical development of a disease concept. Ann Intern Med. 1995;122:867-73.
55. Lewis T. Auricular fibrillation: a common clinical condition. Br Med J. 1909;2:1528.
56. Auricular fibrillation. Cal State J Med. 1911;9:356-7.
57. Hewlett AW. Indications for the administration of quinidine in auricular fibrillation. Cal State J Med. 1922;20:395-8.
58. Lackay H, Housel EL. The arrest of recurrent embolism due to auricular fibrillation with mitral stenosis by quinidine-anticoagulant therapy. Ann
Intern Med. 1951;35:1143-9.
59. Askey JM, Cherry CB. Thromboembolism associated with auricular fibrillation; continuous anticoagulant therapy. J Am Med Assoc. 1950;144:
97-100.
60. Wolf PA, Dawber TR, Thomas HE, et al. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurol-
ogy. 1978;28:973-7.
61. Levy DM. Centenary of William Osler’s 1885 Gulstonian lectures and their place in the history of bacterial endocarditis. J R Soc Med. 1985;78:
1039-46.
62. Bouiliaud JB. Traite clinique des maladies du Coeur, 2nd edition. Paris: JB Balliere; 1841.
63. William SK. On some of the principal effects resulting from the detachment of fibrinous deposits from the interior of the heart, and their mixture
with the circulating blood. Med Chir Trans. 1852;35:281-324.
64. Wilks S, Gull WW, Bright JM. Report of a case of pyæmia from valvular disease of the heart: death. Br Med J. 1868;1:221.
65. Wilks S. Abstract of a clinical lecture on pyæmia as a result of endocarditis. Br Med J. 1868;1:297-8.
66. Osler W. Gulstonian Lectures “On Malignant Endocarditis,” Royal College of Physicians, London. Br Med J. 1885;1:467-70.
67. Paget J. Transactions of the Royal Medical-Chirurgical Society. 1844;27:162-88.
68. Ormerod EL. London Medical Gazette 47 (N.S. 12), pp. 503-12.
69. Johnson BI. Paradoxical embolism. J Clin Pathol. 1951;4:316-32.
70. Lippmann H, Rafferty T. Patent foramen ovale and paradoxical embolization: a historical perspective. Yale J Biol Med. 1993;66:11-7.
41 Tobacco and Heart:
A Historical Perspective
Mathur MR, Prabhakaran D
Tobacco related morbidity and mortality continue to escalate, par-

INTRODUCTION
ticularly among the low and middle income countries (LMIC) of the
Tobacco use is a growing worldwide epidemic.1 It is the single most world.4 By 2030, the death toll due to tobacco use is expected to rise
important preventable cause of death in the world today (Fig. 41.1).2 up to 8.3 million annually out of which more than 80% of tobacco
Based on recent estimates, tobacco would kill more than 5 million deaths will be in LMIC.3 Consumption of tobacco is one of the most
people this year, which is more than the combined deaths due to important preventable risk factor of cardiovascular diseases (CVD).
tuberculosis (TB), human immunodeficiency virus (HIV) acquired It has been estimated that in the year 2000, 1.62 billion deaths (ac-
immunodeficiency syndrome (AIDS) and malaria.3 According to the counting for more than one in every ten cardiovascular deaths) in the
MPOWER report of World Health Organization (WHO) on the global world were due to smoking tobacco in any form and it is projected
tobacco epidemic, if effective measures are not urgently taken, to- that by the year 2015, 29% of deaths due to tobacco will be attributed
bacco could kill more than one billion people during this century.2 to CVDs (Fig. 41.2).4
Figure 41.1: Tobacco use is a risk factor of six of eight leading causes of death in world2
Source: WHO Report on Global Tobacco Epidemic, 2008
Chapter 41  Tobacco and Heart: A Historical Perspective 297
Figure 41.2: Deaths due to tobacco; 2015 projection.

Source: Adapted from the tobacco atlas 2009
In India, tobacco consumption represents an emerging, signifi-

cant and growing threat to health of people. An estimated 5,500 peo-
ple try tobacco in any form for the first time in India everyday.5 The
World Health Organization predicts that during the first two decades
Figure 41.3: Columbus discovers tobacco in 1492. Source: http://
of the 21st century, India will experience the fastest rate of rise in logicophilosophicus.org/cigar_news/cigar_news_2006_10_22.htm
deaths attributable to tobacco worldwide, from 1% of all deaths in
1990 to over 13% in 2020.1 Overall, tobacco currently causes about
800,000 deaths in India each year, primarily due to vascular and (Fig. 41.3).8 Columbus in his journal reported smoking by native
respiratory diseases.1 Most deaths occur at a younger age in India Americans by stating that “The Spanish upon their journey met with
(e.g. among men in their 30s, 40s and early 50s), compared to other great multitudes of people, men and women with firebrands in their
countries of the world.1 The three major tobacco related diseases in hands and herbs to smoke after their custom”.9
India (cancer, coronary artery disease and chronic obstructive air- The tobacco plant was botanically named by Swedish botanist
way disease) also poses a huge economic burden on people who Carolus Linnaeus in 1753. He described two species of tobacco plant
suffer from these diseases and the nation’s health care system. Nicotiana rustica and Nicotiana tabacum. He named tobacco plant
In 1999, the cost of treating these three diseases in India was esti- after French Diplomat Jean Nicot who introduced tobacco in France
mated at 6.5 billion USD.6 The future prospects of improvement in from Portugal.8
this scenario are also very grim. It has been estimated that by 2015, In the 16th century, tobacco was introduced to various other
30–45% of tobacco related deaths will be due to cardiovascular ef- parts of the world. In early 1500s, Egyptians introduced tobacco in
fects of smoking.7 We believe understanding the historical perspec- Middle East. Between 1530 and 1600, tobacco was introduced in
tive of tobacco use and anti-tobacco movements will enthuse as well China via Japan or Philippines and it was the Japanese army which
as provide important insights for future tobacco control policies and introduced tobacco in Korea between 1592 and 1598. The Portuguese
activism. In this regard, we briefly review the history of tobacco and and Spanish traders brought tobacco with them to Africa during their
its relationship with CVDs. voyages in the latter part of 16th century.10
The ways in which tobacco had been used has changed from
HISTORICAL OVERVIEW OF JOURNEY OF time to time and from one region to other. In 16th century, Euro-
pean doctors used to recommend tobacco as a cure for headache,
TOBACCO ACROSS THE WORLD
toothache, falling fingernails, lock jaw, halitosis, worms and cancer.11
The story of tobacco goes back for more centuries then most real- The most common form in which tobacco was consumed in the lat-
ize. The tobacco plant is mostly indigenous to Americas and the ter half of 16th century was pipe smoking which was popularized by
native population started cultivation of tobacco in the year 6000 Thomas Harriot, (on his return from Virginia where he was sent to
BCE. Tobacco was mainly used by native Americans for ceremonial explore opportunities in the newly acquired colony) and his friend
purposes. They used tobacco for smoking, ingesting orally as syrup Sir Walter Raleight (an English aristocrat, who developed the art of
and chewing. They even consumed tobacco through rectal enemas curing tobacco leaves in a way which popularized smoking among
as a spiritual ritual. Tobacco was introduced in Europe in 1492, when British courtiers). In the beginning of 17th century, pipe smoking
Christopher Columbus and his crew returned from their first voyage became popular in Netherlands and later in 18th and 19th century, it
of the Americas and brought with them tobacco leaves and seeds spread across Europe and to the East Asian countries.11
Use of tobacco in form of snuff, taken either orally or nasally was popular because growing tobacco in the agricultural fields fetched
most common in 18th century which was later on replaced by cigars higher returns than any other cash crop. The tobacco cultivation
a century later. It was during the Crimean War that use of cigarettes and its processing for various types of uses provided employment to
started becoming popular. Consumption of cigarettes increased several people in the rural areas. After India became independent in
exponentially during World War I and by the end of World War II, cig- 1947, tobacco continued to play an important role in the economy
arette smoking was the most common form of tobacco consumption of the country. Andhra Pradesh, Karnataka and Tamil Nadu are the
in the developed countries of the world. Cigarette smoking became largest growers of tobacco in India. Tobacco is also cultivated in
deeply ingrained in Western society, post World War II. Almost 80% Gujarat, Maharashtra, Orissa, Bihar and UP. Thus, India has be-
of British men in their middle ages were smokers. Even some doctors come the second largest producer of tobacco in the world and the
prescribed cigarettes to their patients to allay pain and anxiety.11 export of tobacco from India is fetching revenue to the tune of ` 8,834
millions.1
History of Tobacco in India
ANTI-TOBACCO MOVEMENTS AND
Tobacco was unknown in India till 1600 AD. It was first brought to
SENTIMENTS—A HISTORICAL SNAPSHOT
India by the Portuguese traders who exchanged tobacco leaves for
Indian spices.12 The presumed medicinal and stimulant properties Peeping into history also reveals the fact that during the time when
of tobacco made it popular in the Mughal courts where smoking tobacco consumption was gaining popularity and was spreading all
of tobacco was extremely popular among the nobility. In order to across the world, anti-tobacco activities were also surfacing across
overcome the purported ill effects of smoking, hookah was devised the globe.
wherein the tobacco smoke was filtered through water. Thus, the In the year 1604, King James I of England wrote “A Counterblaste
Hookah became a status symbol and was popularly used by Nobles to Tobacco” in which he said, “Smoking is a custom loathsome to the
and Elites of those days.12 Though smoking of Tobacco was a taboo eye, hateful to the nose, harmful to the brain, dangerous to the lungs,
even in those days and women shunned it, still some old paintings and in the black, stinking fume thereof nearest resembling the horrible
reveal that some women from the royal families developed the habit Stygian smoke of the pit that is bottomless”.11
of smoking Hookah. Sharing a Hookah while sitting in a gathering be- During the same period, famous Chinese philosopher Fang Yizhi
came a symbol of equality, brotherhood, fellowship and solidarity.12 commented that long years of smoking “scorches one’s lungs”.10 In
By 1670, Cigars were brought to India from Europe. The use of the 17th and early 18th century, smoking was banned in countries
Tobacco gradually spread in India so much so that even a poor man like Japan, France, Korea, Greece and Russia, though the ban lasted
living in the village became addicted to tobacco and would not leave only for a short period of time. Qing dynasty in China and the regime
the use of tobacco because it is considered to be a drug to avert hun- in Turkey at that time imposed death penalty on persons who were
ger during travel and sustain long hours of work. As the Hookah was caught smoking.14 Many anti-tobacco societies were established
a bit cumbersome, the cigar was locally modified by the labor class during the early parts of the 20th century in the western world. These
in Andhra Pradesh and they named it as Chutta. Later on this was societies were partly successful in UK but had more impact in USA
further modified to take the shape of Bidi, i.e. tobacco wrapped in where they succeeded to get sale of tobacco products banned in 12
tendu leaves to suit the pocket and convenience of the working men states.15
and women. Cigarettes were introduced in India, when the first ciga- One of the most successful anti-tobacco campaigns took place
rette industry was established in India in 1906 in Bihar. Cheroot was in Germany which was led by the Association against Tobacco for
another tobacco smoking instrument which was extensively used by the Protection of Non Smokers (Deutscher Tabakgegnerverein zum
Indian men and women in South India.13 Schutze fur Nichtraucher) which was formed in 1904 and rose to
Chewing of tobacco picked up during the medieval period. strength with the National Socialist Party of Germany coming to
Tobacco flakes of different flavors were served along with Pan. Chew- power in 1930s. Hitler was strongly against the use of tobacco and
ing of Pan became very popular among women during medieval made education warning about harmful effects of tobacco compul-
period, because in those days, there were no lipsticks and the women sory in junior schools. The government printed pamphlets warning
use to color their lips and mouth red by chewing tobacco and Pan. people against harms of tobacco and doctors organized mass meet-
Sniffing of tobacco through nasal passage also provided stimula- ings to raise public awareness. Smoking by uniformed police officers,
tion and was widely accepted by the consumers of tobacco. Thus the persons under 18 years of age, and in buses and trains was banned.
import of tobacco into India started increasing manifold.1 However, this campaign against tobacco was short lived and had a
During the preindependence period, cultivation of tobacco was very little impact on the per capita consumption of cigarettes which
introduced in India by the “East India Company”. This soon became rose year after year.16
nian longshoremen31 also showed higher incidence of CHD in male

A HISTORICAL SYNOPSIS OF smokers than nonsmokers.
ESTABLISHMENT OF RELATIONSHIP A large cohort study of British physicians was analyzed by Sir
BETWEEN TOBACCO CONSUMPTION AND Richard Doll and Prof Austin Bradford Hill in the year 1964. Their
CARDIOVASCULAR DISEASE seminal study reported that male cigarette smoking doctors have the
highest risk of death from coronary thrombosis and also that mor-
One of the first evidence from modern literature trying to present the tality ratio was highest for the relatively younger age group between
relationship between tobacco consumption and heart diseases was 35 years and 54 years (ratio of death rate for male smokers in com-
authored by Huchard,17 in his article on diseases of heart and blood parison to lifelong nonsmokers under 70 years of age was 2:1 and for
vessels in late 19th century. He wrote: “The (unfavourable) influences men over 70 years was 5:1).32 One of the most important cohort stud-
of nicotinism on the development of arterioscelerosis appear to have ies that has become a global standard of CVD epidemiology is the
been demonstrated. And this is not surprising since nicotine produces Framingham Heart Study founded in 1948, to identify causal factors
most often arterial hypertension by vasoconstriction”.17 of CVDs. In the year 1960, Framingham study found that cigarette
Erb in his research on arterioscelerosis published in 1904 found smoking increased the risk of heart disease and in the year 1988, the
that almost 60% of patients with intermittent claudication were same cohort provided conclusive evidence that smoking is one of the
heavy smokers.18 Buerger in 1908 reported that a rare form of periph- most important factors to cause Stroke.33
eral vascular disease which leads to progressive inflammation and
thrombosis of small and medium arteries and veins of hand and feet Landmark Studies from Modern Era
rarely occurred in nonsmokers.19 This disease was later on named
Establishing Tobacco and Heart Relationship
after him as “Buerger’s disease” (Thromboangiitis Obliterans). His
findings were supported subsequently by Weber (1916),20 Brown In the following paragraphs, the authors have summarized some of
and Allen (1928),21 Allen et al. (1948)22 and Silbert (1935).23 Hoffman the landmark studies that have established links between tobacco
who was among the first ones to statistically analyze heart diseases consumption and various ailments of cardiovascular system.
showed the correlation between smoking and coronary thrombo-
sis.24 In 1924, Reader’s Digest published an article on “Does Tobacco Coronary Heart Disease
Injure Human Body” to sensitize readers about the harms of smok-
ing.10 The evidence around the effect of tobacco use on CHD has been
English et al. in their article on tobacco and coronary disease in elaborated in various editions of Surgeon General’s Report from
1940 showed a possible association of CVD with habit of smoking by 1965 to 2004. The latest US Surgeon General’s report concluded that
comparing 1,000 smokers matched with 1,000 nonsmokers.25 They there is now sufficient evidence to infer a causal association be-
concluded by saying: “A more profound effect on younger individu- tween smoking and CHD.34 Benowitz, in his article on pathophysi-
als owing to the existence of relatively normal cardiovascular systems, ology of smoking and CVDs stated that smoke has a greater impact
influencing perhaps the earlier development of coronary disease”.25 In on acute, typically thrombotic events than on atherogenesis.35 The
a further write up discussing the same paper, they wrote: “Physicians INTERHEART study, a large international case control study (52
are not yet ready to agree on this important subject”.25 countries and 262 participating centers, involving 15,152 cases of in-
In the year 1964, the first US Surgeon General’s Report on Smok- cident acute myocardial infection (AMI) and 14,820 normal controls
ing and Health announced that male cigarette smokers have higher matched by age) found that smokers have a threefold higher odds
death rates from coronary artery diseases than nonsmoking males.26 of developing nonfatal AMI than nonsmokers.36 Teo et al. analyzed
The evidence was elaborated further in US Surgeon General’s Report the data from the same INTERHEART study and compared 12,133
of 1971.27 This report extended the evidence from 1964’s report and cases of first MI with nearly 14,000 age- and sex-matched controls.
stated that smoking is associated with increased mortality in male They found that the impact of current smoking on AMI was signifi-
smokers due to coronary thrombosis, coronary arterioscelerosis and cantly higher in younger [odds ratio (OR) 3.53, 95% confidence in-
aortic aneurysms. The 1971 report also stated that cigarette smoking terval (CI) 3.23–3.86] than older study population (OR 2.55, 95% CI
not only operates as an independent risk factor, but also combine 2.35–2.76).37 Smoking has also been identified as a major predispos-
with other risk factors to affect cardiovascular health.27 Hammond ing factor for CHD in women less than 50 years of age. There is also
(1966) in his study on approximately 1 million persons showed that a dose-response relationship that has been found in women, with
men and women who smoke cigarettes have relatively higher death increasing number of cigarettes smoked leading to higher chances of
rates from coronary heart disease (CHD) than nonsmokers. He also AMI.38-40 Dunn et al. through a case control study of women less than
showed that for each sex and each age group, the mortality rates 44 years of age found that women smoking 1–5 cigarettes per day had
for CHD increased with increasing intensity of cigarette smoking.28 a 2.47 times higher odds for AMI than nonsmoking women. The odds
Similar studies on US veterans,29 Canadian pensioners30 and Califor- were as high as 74.6 (95% CI 33–169) for women smoking more than
40 cigarettes per day as compared to nonsmokers.40 Similar relation- and found that smoking along with male sex and hypertension was
ships have been found in other studies conducted in various regions one of the strongest risk factor for the development of AAA.61
of the world.41-43
A huge volume of literature has also addressed the question of Stroke
whether low tar cigarettes lower the risk of CHD due to smoking.
Tang et al. studied four waves of cohorts of British men and found Smoking has been found to be causally associated with hemorrhagic
that the risk of CHD was slightly lower [relative risk (RR) 0.76, 95% stroke, ischemic stroke and subarachnoid hemorrhage.62 Colditz
CI 0.56–1.03] among men who smoked filter tipped cigarettes than et al. analyzed data from the cohort of Nurses’ Health study which fol-
those who consumed plain cigarettes.44 This study showed that lowed more than 100,000 women for close to 8 years. They found that
though processed cigarettes have slightly lower risk of causing CHD, current smokers had a higher rate (RR 2.2, 95% CI 1.5–3.3 for women
the risk is still very high as compared to nonsmokers. Other studies who smoked 1–14 cigarettes per day and RR 3.7, 95% CI 2.7–5.1 for
have also given an inconclusive whether low tar; processed cigarettes women who smoked more than 25 cigarettes per day as compared
are less harmful than normal high-tar cigarettes.45-47 to nonsmoking women) of stroke than nonsmokers and the rate of
Hasdai et al. studied 5,437 patients who had successful percu- stroke increased with the increasing pack of cigarettes smoked.63
taneous coronary artery revascularization by following them for 4.5 Kelly and colleagues studied a cohort of 170,000 Chinese people and
years. Persistent smokers were found to be at a higher risk of AMI and found that current smokers had a higher rate of stroke mortality.64
death than nonsmokers.48 Wanameethee et al. studied risk factors
for sudden cardiac death in middle aged British men by following Second Hand Smoke and
7,735 British men, 40–59 years of age for almost 8 years. They con-
Cardiovascular Diseases
cluded that smokers have double the risk of sudden cardiac death
than nonsmokers.49 A recent analysis of Cancer Prevention Study It is not only the mainstream smoke which is inhaled by the person
(CPS II), conducted on more than 900,000 adults looked at the effect who himself is smoking but also the side stream smoke which is
of smoking on CHD after adjusting for various confounders like use inhaled by nonsmokers in close proximity to a smoker that is harmful
of aspirin, alcohol consumption, body mass index (BMI), physical to health. He et al. in their comprehensive systematic review found
activity and dietary fat consumption. The study found that even after that second hand smoke increases the chance of CHD by 25%.65
adjusting for all other factors, smoking was a significant predisposing Law et al. in their extensive review of literature on second hand
factor for development of CHD (RR for male smokers was 1.9, 95% CI smoke exposure and cardiovascular health found that there is a 30%
1.8–2.1 and for female smokers was 2.1, 95% CI 2.0–2.3).50 increased risk of ischemic heart disease and acute myocardial infarc-
tion in people exposed to second hand smoke.66 Teo et al. in their
Peripheral Vascular Disease analysis of data from INTERHEART study found out that second
hand smoke has an incremental risk of acute myocardial infarction
Price et al. in a follow-up study of 1592 men and women, 55–74 on nonsmokers.37 In individuals who were least exposed to tobacco
years of age in Scotland found out that cigarette smoking increases smoke (1–7 hours per week) the odds of suffering from AMI was 1.24
the risk of peripheral vascular disease sevenfold.51 The amputation (95% CI 1.17–1.32) whereas in nonsmokers who were most exposed
rate of smokers suffering from peripheral vascular disease was found (> 21 hours per week) to tobacco smoke, the odds were 1.62 (95% CI
to be twice that of nonsmokers in a study conducted by Bender- 1.45–1.81).37
macher et al.52 A number of studies have shown an increasing risk
of developing claudication with increase in the number of cigarettes Smokeless Tobacco as a Risk Factor
smoked.53-57
of Cardiovascular Disease
Abdominal Aortic Aneurysm Unlike smoking forms of tobacco, relatively lesser number of stud-
ies have looked at a relationship between smokeless tobacco and
Witterman58 and Brady59 in their respective studies have shown that CVDs. Critchley and Unal undertook a systematic review of epide-
smoking is the most important modifiable risk factor which can lead miological studies looking at a relationship between smokeless to-
to abdominal aortic aneurysm (AAA). Kaiser Multiphasic Health bacco and CVD. They were able to identify very few studies and there
Checkup cohort study was one of the largest cohort study in which was one cohort study which they elaborated that showed a modest
more than 100,000 people were followed till the development of dis- association between use of Swedish snuff (a type of smokeless tobac-
ease. Irribaren et al. analyzed the study and found that smoking more co which is placed in buccal or labial mucosa and chewed or sucked
than three packs of cigarette a day was the most important risk factor over extended periods of time) and CVD (RR 1.4, 95% CI 1.2–1.6).67
for developing AAA (RR 6.6).60 Vardulaki et al. studied the prevalence A recent review by lee looked at the effect of smokeless tobacco
of AAA in a sample of 5,356 British men and women aged 65–79 years on the onset of circulatory diseases in Western populations. They
summarized the evidence from the western world or the high income country of the world to adopt comprehensive smoking ban in in-
countries and found that smokeless tobacco use in nonsmokers was door workplaces including bars, pubs and restaurants.71 This ban
associated with an increased risk of heart disease (RR 1.12, 95% CI was strengthened by overwhelming public support and was seen as
0.99–1.27) and stroke (RR 1.42, 95% CI 1.29–1.57).68 Boffetta and a societal revolution in a country known for its smoke filled pubs and
Straif conducted a meta-analysis of observational studies from USA restaurants. New Zealand followed the Irish model of smoking ban
and Sweden to find out the association between use of smokeless and became smoke free in 2005.70 Soon after a number of European
tobacco and its association with the risk of MI. They meta-analysed countries like Scotland, England, France and Italy placed adopted
11 studies and found that RR for ever use of smokeless tobacco the legislation of smoke-free indoor areas. The smoking bans were
products on myocardial infarction was 1.13 (95% CI 1.06 to 1.21).69 not confined to European nations only and recently Canada and
Although the evidence shows that smokeless tobacco has a compara- Australia have also put into effect legislations banning smoking in
tively lesser association with CVDs still it is an important risk factor indoor areas.10
for the diseases related to circulatory system. This is well highlight- India has also been one of the world leaders in tobacco control.
ed in the results from the data generated from INTERHEART study On October 2nd 2008, Indian government put into effect, Cigarette
which showed that using smokeless tobacco alone increased the and Other Tobacco Products Act (COTPA) which banned smoking
odds of suffering from AMI by 2.23 times (95% CI 1.41–3.52).37 any form of tobacco in public places. The law also prohibited sell-
ing of any tobacco product to children less than 18 years of age and
ANTI-TOBACCO POLICIES— within 100 yards of any educational institution. Cigarette and Other
Tobacco Products Act has been considered as the biggest tobac-
A HISTORICAL SYNOPSIS
co control legislation that has been brought into effect across the
During the time when tobacco consumption was gaining popular- world.72
ity across the world, the health, societal and economic harms of Given the importance of tobacco control in reducing CVD bur-
tobacco were also being highlighted by various scientists, think- den, the WHO proposed one of the most rapidly embraced treaties
ers and philosophers. The first recorded legislation against tobacco of all time known as Framework Convention of Tobacco Control
use dates back to 1575, when Roman Catholic Church passed a law (FCTC) which came into effect on February 27, 2005 (Table 41.1).
prohibiting smoking in any place of worship throughout the Spanish Till date 170 of the 192 members of WHO have signed and ratified
colonies.11 In the year 1624, Pope Urban VIII issued a worldwide ban this treaty.10 The treaty has been immensely successful in mobiliz-
on using or carrying tobacco products in any place of worship. He ing resources; rallied hundreds of non-governmental organizations
also issued a warning to excommunicate those who violated this law. (NGOs), encouraged government action, led to political maturation
The law was however was abolished by Pope Benedict XIII who was
a tobacco user himself.11
From the 17th century onwards, different rulers and religious
leaders all across the world have imposed some form of tobacco TABLE 41.1 Main provisions of WHO framework convention of tobacco
ban in their regimes or amongst their followers. Sultan Murad IV of control
Ottoman Empire and Czar Michael of Russia issued smoking bans Regulation of:
with violators being treated as criminals and issued death penalty.8 • Contents, packaging and labeling of tobacco products
In 1891, Iranians lead by the Grand Ayatollah Haji Mirza Hasan Shi- • Sales to and by minors
razi banned the trading of any tobacco products.8 Cigarette trading
• Illicit trade in tobacco products
was also banned for about 26 years in North Dakota, USA.10 Adolf
• Smoking at work and public places
Hitler in order to curb the spread of tobacco epidemic imposed heavy
taxation on tobacco products.8 Tobacco companies in 20th century Reduction in consumer demand by:
became so powerful financially that they started providing financial • Price and tax measures
assistance to the governments and so all the existing smoking bans • Comprehensive ban on tobacco advertising, promotion and
were either made very weak or were taken back.10 sponsorship
Different countries all over the world are now trying to put in • Education, training, raising public awareness and assistance with
place comprehensive legislations in order to reduce tobacco con- quitting
sumption, as well as to prevent people who are not smokers from Protection of environment and health of tobacco workers:
second hand smoke. California was the first US state to pass legisla-
• Support for economically viable alternative activities
tion against smoking in public places including bars and restaurants,
• Research, surveillance and exchange of information
in the year 1998.70 This was followed by South Africa, where a law
was passed making public places smoke free but this law exempted • Support for legislative action to deal with liability
bars and restaurants from being smoke free.70 Ireland was the first Source: Adapted from ‘The Tobacco Atlas’ - 2009
of health ministers and raised tobacco control awareness. In a further nificantly from changes in the external control community even after
addition to its tobacco control efforts, WHO published the MPOWER adjustment for seasonal trends (P < 0.001).74 In a similar study, Juster
report on global tobacco epidemic in 2008. The MPOWER report et al. compared the differences in hospital admissions for AMI before
elaborates six strategies, recommended by WHO as an entry point and after a statewide antismoking ban was enacted. They found out
to implementation of the WHO FCTC73 (Table 41.2). The report is that there were 3,813 fewer admissions in New York hospitals for AMI
evidence-based and is shown to reduce the burden of NCDs in coun- after the ban was put in place which denoted an 8% reduction after
tries that have successfully implemented them. The MPOWER report controlling for potential mediating and confounding factors. This
serves as a guiding document especially for LMICs to help them plan reduction in admissions also led to a direct savings of 56 million
effective tobacco control strategies. USD.75 A matched case control study comparing the hospital admis-
sions for AMI in Monroe County where a public smoking ban was
Evidence for Effectiveness of Smoke-free implemented with Delaware County where no such ban was in place
was carried out by Seo and Torabi. There was a significant decrease
Policies on Cardiovascular Events
in the number of admissions for AMI of nonsmoking residents of
Smoke-free bans have been found out to have a positive impact on Monroe County as compared to Delaware County showing the effec-
cardiovascular health of both smokers and nonsmokers. tiveness of smoking ban in reducing second hand smoke. No signifi-
Sargent et al. analyzed effect of antismoking law, on hospital cant difference was found however in the admission rate of smoking
admission for myocardial infarction, by comparing admissions dur- patients between both counties.76 Barone-Adesi et al. analyzed the
ing the time when law was in effect with admissions before the en- hospital discharge rates in Piedmont Region (Northern Italy) to
actment of law and after the law was repealed, in the small township assess whether a national antismoking law has any effect on hospital
of Helena, Montana, USA. A smoking ban in public and workplaces admissions for AMI. They calculated that the number of admissions
was enacted in Helena on 5th June 2002 which was later suspended for AMI decreased significantly after the introduction of the ban:
on December 3rd 2002, when the opponents of this law won a court from 922 cases in February–June 2004 to 832 cases in February–June
order. Sargent et al. reviewed records of patient admissions for acute 2005 (sex- and age-adjusted rate ratio, 0.89; 95% CI, 0.81–0.98), the
MI. There was a significant drop in number of admissions for acute time period for which the ban was in effect.77
myocardial infarction (24 admissions) in Helena during the months Pell, et al. conducted a prospective study to look at the effect of
when law was in effect in comparison to number of admissions 6 Scotland’s antismoking law in indoor areas on cardiovascular health
months, before and after law (40 admissions). This was the first study of both smokers and nonsmokers. They collected data on patients
of its kind to show association between implementation of a smoke with acute coronary syndrome admitted to nine selected hospitals
free law and drop in admissions for acute myocardial infarction.73 in Scotland for 10 months before and 10 months after the enactment
Bartechhi et al. in order to assess the impact of a smoke-free of legislation. Acute coronary syndrome was defined as a detectable
ordinance, analyzed the number of hospital admissions in an level of cardiac troponin after an emergency admission of chest pain.
isolated community, Pueblo, Colo, USA for a 3-year period (1.5 There was a 17% reduction in hospital admissions for acute coronary
year before the ordinance and 1.5 years after the ordinance was syndrome (3,235 prelegislation to 2,684 postlegislation). There was
passed). They also compared the number of hospital admissions for a reduction of 14% in the number of admissions of smokers, 19%
AMI in Pueblo city after the law was enacted with another isolated among former smokers and 21% nonsmokers. This was the first pro-
community and with hospital admissions outside the city limits. A spective study to analyze the effect of smoking ban and also includ-
reduction in AMI hospitalizations was observed in the period after ed the exposure to second hand smoke as a variable which was not
the ordinance among Pueblo city limit residents (RR 0.73, 95% CI included in previous studies.78 Similar studies conducted in differ-
0.63–0.85).74 The reduction in AMI rate within Pueblo differed sig- ent regions of the world analyzing the impact of a smoking ban on
number of admissions for CHD or acute coronary events have also
shown a reduction in number of hospital admissions after the legis-
lation was put into effect.79,80
TABLE 41.2 WHO MPOWER strategy All the above studies provide substantial evidence for formulat-
• Monitor tobacco use and prevention policies ing and effectively implementing antismoking policies to promote
• Protect people from tobacco smoke cardiovascular health and prevent premature losses of lives and dis-
ability due to CVDs.
• Offer help to quit tobacco use
• Warn about the dangers of tobacco
CONCLUSION
• Enforce bans on tobacco advertising, promotion and sponsorship
• Raise taxes on tobacco Cardiovascular diseases are the major cause of mortality and mor-
Source: Adapted from ‘The MPOWER Package’, WHO - 2009 bidity in the world especially in the LMICs. Tobacco consumption
forms a major risk factor for CVDs and is one of the most important only be successful if this situation is tackled at multiple levels. The
preventable causes of CVD globally. Smoking also acts synergisti- social norms supporting tobacco use has to be changed but the pro-
cally with other risk factors of CVDs and exacerbates the risk of cess to achieve this is slow and is multidimensional depending not
AMI, sudden cardiac death, stroke, peripheral vascular disease and only on government support and financing but also on strong and
aortic aneurysm. The pathophysiological mechanism by which sustainable efforts at the grass root level. Global health governance of
tobacco uses enhances the risk of CVD has been well-delineated. this issue can play a major role in tackling this problem as it is a trans-
There is also a large body of evidence showing the benefits of smok- border health threat and is affected by multinational marketing, trade
ing cessation in reduction of cardiovascular events and the effective- agreements and information asymmetry that supports tobacco use.
ness of smoking ban in reducing hospital admissions for various The Framework Convention on Tobacco Control is one such initiative
cardiovascular ailments. in this direction. Physicians also can play a very crucial role in curb-
A concerted action is required at international, national and ing both the epidemics (tobacco and CVDs) as they can act as advo-
societal level is needed in order to curb the epidemic of tobacco, cates ensuring every smoker under their care and who are at high-risk
which in turn will immensely help in reducing the burden of CVDs. of CVD, receives appropriate cessation treatment and support. They
The tobacco industry has worked for years in order to embed to- should actively support smoke free hospitals and clinics, and other
bacco use in culture, national economies, political structures both at workplaces and advocate for effective tobacco control policies benefi-
national and local level and personal behaviors. Tobacco control can cial for both an individual and to the population as a whole.
REFERENCES
1. Reddy KS, Gupta PC. Tobacco Control in India. New Delhi: Government of India, Ministry of Health and Family Welfare; 2004.
2. WHO Report on the Global Tobacco Epidemic, 2008: The MPOWER Package. Geneva: World Health Organisation; 2008.
3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442.
4. Ezzati M, Lopez AD. Regional, disease specific patterns of smoking-attributable mortality in 2000. Tob Control. 2004;13(4):388-95.
5. Patel DR. Smoking and children. Indian J Pediatr. 1999;66(6):817-24.
6. Shimkhada R, Peabody JW. Tobacco control in India. Bull World Health Organ. 2003;81:48-52.
HEART study): case-control study. Lancet. 2004;364(9438):937-52.
8. Borio G (N.d.). Tobacco timeline. [Online]. Available from http://www.tobacco.org/History/Tobacco_History.html. [Accessed August, 2010].
9. Athena Review Vol.1 (3). [Online]. Available from http://www.athenapub.com/coluvoy1.htm. [Accessed August, 2010].
10. Shafey O, Eriksen M, Ross H, et al. The Tobacco Atlas, 3rd edition. Atlanta: American Cancer Society; 2009.
11. Corti E. A History of Smoking. England P, trans. London: George Harrap; 1931.
12. Sanghvi LD. Challenges in tobacco control in India: A historical perspective. In: Gupta PC, Hamner JE, Murti PR (Eds). Control of tobacco-related
cancers and other diseases. International Symposium, 1990. Mumbai: Oxford University Press; 1992. pp. 47-55.
13. Bhonsle RB, Murti PR, Gupta PC. Tobacco habits in India. In: Gupta PC, Hamner JE, Murti PR (Eds). Control of tobacco-related cancers and other
diseases. International Symposium 1990. Bombay: Oxford University Press; 1992. pp. 25-45.
14. Korbler J. Thomas Harriot (1560-1621) fumeur de pipe, victime de cancer. Gesnerus. 1952;9:52-4.
15. Doll R. Tobacco: a medical history. J Urban Health. 1999;76:289-313.
16. Proctor RN. The Nazi war on tobacco: ideology, evidence, and possible cancer consequences. Bull Hist Med. 1997;71:435-88.
17. Huchard H. Traitd Clinique des Maladies du Coeur et des Vaisseaux, 2nd edition. Paris: Doin; 1893. pp. 125-6.
18. Erb W. Ueber dysbasia angiosclerotica (“intermittierendes Hinken”). Münch Med Wochenschr. 1904;51:905-8.
19. Buerger L. Thrombo-angiitis obliterans: a study of the vascular lesions leading to presenile spontaneous gangrene. Am J Med Sci. 1908;136:567-80.
20. Weber JB. Thrombo-angiitis obliterans. Q J Med. 1916;5:289-300.
21. Brown GE, Allen EV. Thrombo-angiitis Obliterans. Philadelphia: WB Saunders; 1928. pp. 141.
22. Allen EV, Barker NW, Hines EA. Peripheral Vascular Disease. Philadelphia: WB Saunders; 1946. pp. 390.
23. Silbert S. Thrombo-angiitis obliterans (Buerger): treatment of 524 cases by repeated intravenous injections of hypertonic salt solution: experience
of 10 years. Surg Gynecol Obstet. 1935;51:214-22.
24. Hoffman FL. Recent statistics of heart disease with special reference to its increasing incidence. JAMA. 1926;74:1364-71.
25. English JP, Willius FA, Berkson J. Tobacco and coronary disease. JAMA. 1940;115:1327-9.
26. Advisory Committee to the Surgeon General of the US Public Health Service. Smoking and Health. Washington DC: US Government Printing Of-
fice; 1964. Public Health Service Publication no. 1103.
27. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington DC: US Department of
Health, Education and Welfare; 1971.
28. Hammond EC. Smoking in relation to the death rates of 1 million men and women. In: Haenssel W (Ed). Epidemiological Approaches to the Study
of Cancer and Other Diseases. Bethesda, US Public Health Service, National Cancer Institute monograph No. 19, January lQ38. pp. 127-204.
29. Kahn HA. The Dom study of smoking and mortality among US veterans: report on 8.5 Years of observation. In: Haensel W (Ed). Epidemiological
Approaches to the Study of Cancer and Other Diseases. Bethesda, BS Public Health Service, National Cancer Institute monograph No. 19; 1968.
pp. l-125.
30. Best EWRA. A Canadian study of smoking and health. Ottawa, Department of National Health and Welfare; 1966. pp. 13.
31. Borhani No, Hechter HH, Breslow R. Report of a l.5 year follow-up study of the San Francisco longshoremen. Mortality from coronary heart dis-
ease and from all causes. Journal of Chronic Diseases (St. Louis). 1963;16:1251-66.
32. Doll R, Hill AB. Mortality in relation to smoking: 10 years’ observations of British doctors. (Part 1.) Br Med J (London). 1964;l(5395):1399-410.
33. Dawber TR, Kannel WB, Revotskie N, et al. Some factors associated with the development of coronary heart disease; six years’ follow-up experi-
ence in the Framingham Study. Am J Public Health. 1959;49:1349-56.
34. The Health Consequences of Smoking: A Report of the Surgeon General; Office of the Surgeon General; US Department of Health and Human
Services; 2004. [Online]. Available from http://www.surgeongeneral.gov/library/smokingconsequences/accessed on August 2nd 2010.
35. Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003;46(1):91-
111.
36. Burns DM. Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Dis. 2003;46(1):11-29.
37. Teo KK, Ounpuu S, Hawken S, et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study.
Lancet. 2006;368(9536):647-58.
38. Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral con-
traception study [letter]. Br Med J. 1989;298(6667):165-8.
39. Rosenberg L, Palmer JR, Rao RS, et al. Risk factors for coronary heart disease in African American women. Am J Epidemiol. 1999;150(9):904-9.
40. Dunn NR, Faragher B, Thorogood M, et al. Risk of myocardial infarction in young female smokers. Heart. 1999;82(5):581-3.
41. Liao Y, McGee DL, Cooper RS. Prediction of coronary heart disease mortality in blacks and whites: pooled data from two national cohorts. Am J
Cardiol. 1999;84(1):31-6.
42. Prescott E, Hippe M, Schnohr P, et al. Smoking and risk of myocardial infarction in women and men: longitudinal population study. Br Med J.
1998;316(7137):1043-7.
43. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med.
2000;343(1):16-22.
44. Tang JL, Morris JK, Wald NJ, et al. Mortality in relation to tar yield of cigarettes: a prospective study of four cohorts. Br Med J. 1995;311(7019):1530-
3.
45. Kaufman DW, Helmrich SP, Rosenberg L, et al. Nicotine and carbon monoxide content of cigarette smoke and the risk of myocardial infarction in
young men. N Engl J Med. 1983;308(8):409-13.
46. Negri E, Franzosi MG, La Vecchia C, et al. Tar yield of cigarettes and risk of acute myocardial infarction: GISSI-EFRIM Investigators. Br Med J.
1993;306(6892):1567-70.
47. Palmer JR, Rosenberg L, Shapiro S. “Low yield” cigarettes and the risk of nonfatal myocardial infarction in women. N Engl J Med. 1989;320(24):1569-
73.
48. Hasdai D, Garratt KN, Grill DE, et al. Effect of smoking status on the long-term outcome after successful percutaneous coronary revascularization.
N Engl J Med. 1997;336(11):755-61.
49. Wannamethee G, Shaper AG, Macfarlane PW, et al. Risk factors for sudden cardiac death in middle-aged British men. Circulation. 1995;91(6):1749-
56.
50. Thun MJ, Apicella LF, Henley SJ. Smoking vs other risk factors as the cause of smoking-attributable deaths: confounding in the courtroom. JAMA.
2000;284(6):706-12.
51. Price JF, Mowbray PI, Lee AJ, et al. Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease
and coronary artery disease: Edinburgh Artery Study. Eur Heart J. 1999;20(5):344-53.
52. Bendermacher BLW, Willigendael EM, Teijink JAW, et al. Medical management of peripheral arterial disease. J Thromb Haemost. 2005;3(8):1628-
37.
53. Kannel WB, Shurtleff D. The Framingham Study. Cigarettes and the development of intermittent claudication. Geriatrics. 1973;28(2):61-8.
54. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA. 2006;295(5):547-53.
55. Hooi JD, Kester AD, Stoffers HE, et al. Incidence of and risk factors for asymptomatic peripheral arterial occlusive disease: a longitudinal study.
Am J Epidemiol. 2001;153(7):666-72.
56. Hooi JD, Stoffers HE, Knottnerus JA, et al. The prognosis of non-critical limb ischaemia: a systematic review of population-based evidence. Br J
Gen Pract. 1999;49(438):49-55.
57. Hooi JD, Stoffers HE, Kester AD, et al. Risk factors and cardiovascular diseases associated with asymptomatic peripheral arterial occlusive disease.
The Limburg PAOD Study. Peripheral Arterial Occlusive Disease. Scand J Prim Health Care. 1998;16(3):177-82.
58. Witteman JC, Grobbee DE, Valkenburg HA, et al. Cigarette smoking and the development and progression of aortic atherosclerosis. A 9-year
population-based follow-up study in women. Circulation. 1993;88(5 Pt 1):2156-62.
59. Brady AR, Thompson SG, Fowkes FGR, et al. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. Circulation.
2004;110(1):16-21.
60. Iribarren C, Darbinian JA, Go AS, et al. Traditional and novel risk factors for clinically diagnosed abdominal aortic aneurysm: The Kaiser Mul-
tiphasic Health Checkup Cohort Study. Ann Epidemiol. 2007;17:669-78.
61. Vardulaki KA, Walker NM, Day NE, et al. Quantifying the risks of hypertension, age, sex and smoking in patients with abdominal aortic aneurysm.
Br J Surg. 2000;87(2):195-200.
62. Kurth T, Kase CS, Berger K, et al. Smoking and risk of hemorrhagic stroke in women. Stroke. 2003;34(12):2792-5.
63. Colditz GA, Bonita R, Stampfer MJ, et al. Cigarette smoking and risk of stroke in middle-aged women. N Engl J Med. 1988;318(15):937-41.
64. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American
Stroke Association Stroke Council. Stroke. 2006;37(6):1583-633.
65. He J, Vupputuri S, Allen K, et al. Passive smoking and the risk of coronary heart disease: a meta-analysis of epidemiologic studies. N Engl J Med.
1999;340(12):920-6.
66. Bonita R, Duncan J, Truelsen T, et al. Passive smoking as well as active smoking increases the risk of acute stroke. Tob Control. 1999;8(2):156-60.
67. Critchley JA, Unal B. Is smokeless tobacco a risk factor for coronary heart disease? A systematic review of epidemiological studies. Eur J Cardiovasc
Prev Rehabil. 2004;11:101-12.
68. Lee PN. Circulatory disease and smokeless tobacco in Western populations: a review of the evidence. Int J Epidemiol. 2007;36:789-804.
69. Boffetta P, Straif K. Use of smokeless tobacco and risk of myocardial infarction and stroke: systematic review with meta-analysis. BMJ.
2009;339:b3060.
70. Koh HK, Joossens LX, Connolly GN. Making smoking history worldwide. N Engl J Med. 2007;356:1496-8.
71. Fong GT, Hyland A, Borland R, et al. Reductions in tobacco smoke pollution and increases in support for smoke-free public places following the
implementation of comprehensive smoke-free workplace legislation in the Republic of Ireland: findings from the ITC Ireland/UK Survey. Tob
Control. 2006;15:Suppl 3:iii51-8.
72. FCTC vs. COTPA; WHO India Office. [Online]. Available from http://www.whoindia.org/LinkFiles/Tobacco_Free_Initiative_FCTC_Vs_COTPA.
pdf. [Accessed August 2010].
73. Sargent RP, Shepard RM, Glantz SA. Reduced incidence of admissions for myocardial infarction associated with public smoking ban: before and
after study. BMJ. 2004;328:977-80.
74. Bartecchi C, Alsever RN, Nevin-Woods C, et al. Reduction in the incidence of acute myocardial infarction associated with a citywide smoking
ordinance. Circulation. 2006;114:1490-6.
75. Juster HR, Loomis BR, Hinman TM, et al. Declines in hospital admissions for acute myocardial infarction in New York State after implementation
of a comprehensive smoking ban. Am J Public Health. 2007;97:2035-9.
76. Seo DC, Torabi MR. Reduced admissions for acute myocardial infarction associated with a public smoking ban: matched controlled study. J Drug
Educ. 2007;37:217-26.
77. Barone-Adesi F, Vizzini L, Merletti F, et al. Short-term effects of Italian smoking regulation on rates of hospital admission for acute myocardial
infarction. Eur Heart J. 2006;27:2468-72.
78. Pell J, Haw S, Cobbe S, et al. Smoke-free legislation and hospitalizations for acute coronary syndrome. N Engl J Med. 2008;359:482-91.
79. Khuder SA, Milz S, Jordan T, et al. The impact of a smoking ban on hospital admissions for coronary heart disease. Prev Med. 2007;45:3-8.
80. Cesaroni G, Forastiere F, Agabiti N, et al. Effect of Italian smoking ban on population rates of acute coronary events. Circulation. 2008;117:1183-8.
42 History of Stress and Heart
Disease Relationship
Bhat KSS, Vikranth V, Veeranna V
Sushrutha, a famous surgeon in the ancient India, while de-

INTRODUCTION
scribing many diseases comments on what he calls Hritshoola, liter-
Cardiovascular diseases are the largest causes of death worldwide. ally heart pain in his famous treatise Sushrutha Samhita. His vivid
Cardiovascular diseases are amongst the most intensely studied of account of angina is marvelous. It includes all the essential compo-
the health hazards. They have also attracted significant attention of nents of present day definition of angina, i.e. site, nature, aggravating
behavioral scientists. The many ways in which these diseases are and relieving factors. According to him, angina is chest pain, which
affected by environmental, social and behavioral factors have pro- is precordial, temporary, exertional, emotional, burning like and
vided a fertile ground for study by many disciplines. Thus, many relieved by rest. It is remarkable that Sushrutha described this
cardiovascular diseases are considered as prototype psychosomatic condition some 150 years before Hippocrates.1
diseases (also called neurovisceral diseases). Beginning 18th century anecdotal accounts with focus on emo-
Historically, the heart is referred as the spiritual, emotional, tion, with particular emphasis on hostility and anger in existing clini-
moral and intellectual core of human being. The heart was once cal symptoms or precipitating sudden death were reported. The most
considered to be the center of human thinking and action. Many well known amongst them was of John Hunter. John Hunter (1729–
philosophers including Aristotle and Galen considered heart as the 1793), a great pioneer Scottish surgeon, was known for his violent
seat of thought, reason and emotion, often rejecting the role of brain. and fiery temper. He suffered from emotion-related bouts of angina
Hippocrates (460–377 BC), the ancient Greek philosopher and physi- and had stated, “My life is at the mercy of any rascal who chooses
cian famous for systematic study of medicine, was the first person to to put me in a passion”. Hunter died shortly after participating in a
reject superstition and divine forces in the causation of diseases. He vociferous and heated faculty meeting at the Royal College of Physi-
argued that disease was not a punishment by gods as believed dur- cians, Glasgow, Scotland. As Sir William Osler (1849–1919), a great
ing his times, but rather a product of environmental factors, diet and physician and an early historian of medicine later described it “In a
living habits. He thus tried to separate medicine from religion. Dur- silent rage and in next room gave a deep groan and fell down dead”.2
ing many centuries that followed Hippocrates, the physicians per-
suaded by spurious Hippocratic aphorism “COR AEGROTARI NON THE BRAIN HEART CONNECTION
POTEST”, believed the heart is immune to disease. Hence, the subject
matter of cardiology did not exist. Emotional feeling has been traditionally seen as distinct from rational
The Mahabharata (estimatedly composed between 300 BC to thought. The brain locked away in its bony case, was conceived as
300 AD) is one of the excellent ancient epics and contains Gita or responsible for rational thought and for ideas that direct behavioral
Bhagavadgita. The philosophy, practical guidelines on health, wor- interactions with the external environment. Emotions, visceral rather
ship, duties, rights and wrongs, responsibilities and entitlements are than rational, were linked with the function of internal organs. We
universal and exemplary. have “Gut feelings, the heart is the seat of love, we vent our spleen
To quote: etc”. Bichat (1771–1802), French anatomist and physiologist divided
life into two distinct forms, one (relational life) governed by brain
“Yuktaharaviharasya yuktachestsya karmasu and the other (organic, vegetative life) by abdominal ganglia. Claude
Yukktswapnavabodhasya yogah bhavati dukhaha” Bernard (1813–1878), a French physiologist first described Milieu
(Bhagavadgita, shloka 17, Ch 6) interior or the internal environment. In any acute insult, survival
depends on maintaining the milieu interior. The constancy of inter-
If one is appropriate in diet and exercise, his duties, thoughts in nal environment is the condition for a free and independent life.3
sleep as well as wakefulness, yoga will keep such a person free from Walter B Cannon (1871–1945), an American physiologist, profes-
sorrow and illness. sor and chairman of department of physiology at Harvard Medical
Chapter 42  History of Stress and Heart Disease Relationship 307
School further extended the concept of Milieu interior put forth by diovascular disease and, in particular, on its relationship to the phe-
Claude Bernard. He called this “homeostasis”. He recognized the nomenon of sudden unexplained deaths.
importance of integrated brain control of all bodily functions. He Selye further said, “Stress is ‘stressful’ whether one receives good
proposed that the brain activates sympathetic nervous system dif- or bad news, whether the impulse is positive or negative”. He called
fusely and nonspecifically during bodily emergencies. He named it negative stress “distress” and positive stress “eustress”. Thus, a soldier
the “Fight or flight reaction”.4 John Newport Langley (1852–1925), who sustained wounds in the battle, the mother who worries about
a British physiologist who later became the vice president of the her soldier son, the gambler who watches the races, the horse and
Royal Society coined the term “autonomic nervous system”. He fur- the jockey he bet on, all are under stress. A beggar who suffers from
ther characterized afferent, efferent and the central connections of hunger and the glutton who overeats, the little shopkeeper with his
the system. Based on the connections and actions, he classified it as constant fear of bankruptcy and the rich merchant struggling for yet
sympathetic nervous system and parasympathetic nervous system. another million are also under stress. A painful blow and a passion-
He also demonstrated the pathways and the amount of central nerv- ate kiss can be equally stressful. All living beings are constantly under
ous system control over it.5 Much of the present days’ understanding stress and anything pleasant or unpleasant that speeds up the inten-
of the autonomic nervous system has not changed since the descrip- sity of life causes a temporary increase in stress, the wear and tear
tion of Langley. exerted upon the body. Thus, stress is the rate at which we live at any
The term “Stress” was first used in biological context by Hans moment.
Selye (1907–1982).
Hans Selye was born in Vienna and studied in Prague, Paris and Behavioral Pattern, Stress and
Rome, and finally obtained his DSc at McGill University in Montreal
Cardiovascular Diseases
where he served from 1945 till death as professor, endocrinologist
and Director of the Institute of Experimental Medicine and Surgery Emotional outbursts, hostility and anger in exciting clinical symp-
at the University of Montreal. He established the International Insti- toms or precipitation of sudden death was well known. However, in
tute of Stress in 1976 and served as the founder president. describing individuals prone to cardiovascular disease, the German
The word “stress” is derived from distresse (old English), which physician Theodor von Dusch (1824–1890) included not only emo-
itself is derived from Latin stringere, which means to draw tight. Selye tions, but also other behavioral attributes, such as vigorous voice
further did research, which led to the understanding of the hypothal- stylics and hard driving job involvement. Similarly, William Osler
amus-pituitary-adrenal axis (HPA axis). He also identified the role felt “The high pressure at which men live and the habit of working
of adrenal hormones especially cortisol and its role in the physiol- the machine to its maximum capacity”. He described his typical
ogy, disease and during stress. In a classic article published in 1936, coronary patient as “Not a delicate neurotic person, but a robust,
Selye based on experiments with rats, which on exposure to various the vigorous in mind and body, the keen and ambitious man, the
nonspecific nocuous agents such as exposure to cold, surgical injury, indicator of whose engine is always at full speed ahead”. Similar ob-
variety of drugs in sublethal doses produced typical symptoms, servations were made by others—Meningers (1936); patients with
which were independent of the nature of the damaging agent or the strong aggressive attributes, Kemple 1943; chronically performing
type of drug. He also found loss of cortical lipoids and chromaffin in a tough minded manner in the interest of achieving power and
substances from the adrenals. This he concluded as “general alarm prestige while being insensitive to nuances in environment, and
reaction”. Since the syndrome as a whole represents a generalized Arlow 1945; compulsively engaging in a never ending struggle for
effort of the organism to adapt itself to new conditions, it was termed mastery.7
general adaptation syndrome (GAS). The symptoms of the alarm Despite the wealth of clinical impressions regarding the relation-
reaction are very similar to histamine toxicosis or of surgical ana- ship between behavioral characteristics and coronary heart disease,
phylactic shock. Selye therefore concluded “It is not unlikely that an systematic research in the area was not launched until the 1950s. Two
essential part in the initiation of the syndrome is the liberation of pioneering American cardiologists Meyer Freidman (1910–2001)
large quantities of histamine or some similar substance.6 Since and Ray Rosenman shared a cardiology practice in San Francisco in
Selye’s original work, similar experiments have been repeated in the 1950s. They began to question the conventional thinking about
many different types of laboratory animals with comparable results. major risk factors in heart disease. They felt that classic risk factors,
Although the administration of exogenous steroids facilitates the such as diet and cholesterol could not explain the epidemic of coro-
production of cardiac lesions, it is clear that stress alone can result in nary artery disease (CAD). Thus, began orderly analysis of coronary
the production of morphologically identical lesions. prone behavior.
Whether a similar pathophysiology could ever be repeated in hu- The research led to a:
man beings is, of course, of great interest. Many investigators have 1. Conceptual definition of coronary prone behavior pattern
speculated on the role of stress in the pathogenesis of human car- 2. Means to assess the pattern
3. Further studies to investigate the validity of coronary prone studies in cardiovascular patients have shown that Type D personal-
behavior ity is an independent predictor of negative health outcomes, such as
The work of Freidman and Rosenman opened up a new field poor health status, recurrent myocardial infarctions and increased
of inquiry into mind-heart relationship, which is still debated and mortality.11
investigated today. The conceptual definition they evolved and to Type D personality also predicts poor outcome after percutane-
which they applied the label of Type A personality pattern, con- ous coronary interventions. Patients with Type D personality are at
sidered as coronary prone behavior as an action-emotion complex increased risk of adverse events after angioplasty, including stent
consisting of high levels of achievement concerns, hard driving job thrombosis. Poor compliance with medications is also one of the
involvement, competitiveness, aggressiveness, hostility, time ur- contributory factors for stent thrombosis. The risk is higher even
gency and impatience. The action-emotion complex was seen as after adjustment for clinical markers of severity, and the associ-
emerging most often in response to environmental challenges or ated risk was similar to that of traditional cardiovascular risk fac-
provocations common in western industrial existence, e.g. traffic tors.12 The neuroendocrine and immunological pathways to explain
jam, standing in a queue, etc. Initial prevalence studies revealed that Type D personality links it to increased cortisol, increased oxidative
Type A pattern was substantially more characteristic of coronary stress, immune dysfunction and decreased number of bone marrow
patients than others. Evidence linking Type A pattern with clinical derived endothelial progenitor cells.13
CAD was derived from prospective Western Collaborative Group
Study (WCGS).8 Over 3,000 middle-aged male patients of CAD were Depression and Heart Disease
followed for 8.5 years. Type A was twice as likely as Type B (the milder
and calm group) to manifest CAD. Independent of other risk factors, The association between depression and adverse cardiovascular out-
Type A behavior has been linked to: comes is substantially proven in literature. More than 100 studies have
1. Increased incidence and prevalence of CAD (both in males and been done over the past century trying to ascertain this association.
females) Nearly 20% of all patients diagnosed with heart disease have
2. Recurrent clinical events evidence of depression. In the systematic reviews by Wulsin et al.
3. Angiographically severe CAD and Ruguile, depressed individuals had an increased risk [1.64 (95%
4. Progression of atherosclerosis confidence interval (CI) = 1.41–1.90] and 1.64 (95% CI = 1.29–2.08,
5. Rupture of plaque. p < 0.001 respectively) of developing heart disease, in an apparently
Jenkins et al. (1978) developed a questionnaire (Jenkins Activ- healthy population free of prior heart disease.14 Further, the presence
ity Survey), which made identification of Type A personality easy. He of depression portends a poor prognosis in patients with heart dis-
argued for the establishment of Type A pattern as an independent ease, elevated health care costs and greatly reduced quality of life in
risk factor for CAD, similar to age, serum cholesterol, blood pressure patients who have pre-existing heart disease. Despite the presence
and cigarette smoking.9 The National Heart, Lung and Blood Insti- of overwhelming evidence for this association, depression is seldom
tute (NHLBI) review panel report based on the evidence accepted addressed during routine cardiovascular care.
this recommendation. “The review panel accepts the available body Although the specific pathophysiologic mechanism for this asso-
of scientific evidence as demonstrating that Type A behavior is ciation between depression and cardiac disease has not been eluci-
associated with an increased risk of clinically apparent coronary dated, various biological and behavioral mechanisms have been put
artery disease in employed middle-aged US citizens. This risk is forth. Autonomic imbalance characterized by increased sympathetic
over and above that imposed by age, systolic blood pressure, serum tone and reduced parasympathetic activity, increased inflamma-
cholesterol, smoking and appears to be of the same order of magni- tion, endothelial dysfunction, impaired cortisol activity are seen in
tude as the relative risk associated with any of the factors. Further patients with depression, which have been implicated in devel-
studies have found that not all attributes of Type A personality pre- opment and progression of cardiac disease. Furthermore, these
dict future CAD. Anger and hostility were more often associated with patients have poor lifestyle habits, including increased prevalence
increased risk of CAD.10 of cigarette smoking, reduced physical activity and nonadherence to
medications, which further potentiate the cardiac risk.
Type D Pattern and Heart Disease The current scientific advisory from the American Heart Associa-
tion in 2008 addresses the importance of identifying and treating the
Type D personality is described as the tendency to experience a high presence of depression and depressive symptoms. Various validated
occurrence of negative affectivity (often feel unhappy) and social screening tools are available for screening patients for the presence
inhibition (is a closed person). A short and easy to use DS14 ques- of depression or depressive symptoms. Beck Depression Inven-
tionnaire is used to identify Type D personality. In the past few years tory I and II, Center for Epidemiological Studies Depression Scale,
studies on the effect of Type D (depressed) personality trait on clini- Hospital Anxiety and Depression Scale, Geriatric Depression Scale,
cal and psychological outcomes has been studied. Majority of the Patient Health Questionnaire-2 and Patient Health Questionnaire-9
are some of the frequently used screening tools with varying sensiti myocardial infarction (AMI) and 14,820 controls matched by age more
vity (39–100%) and specificity (58–94%) for depression.15 or less than 5 years and sex but with no history of heart disease were
Pharmacotherapy, cognitive behavioral therapy and physical recruited. Globally, nine risk factors were significantly associated with
exercise have been recommended for patients who are diagnosed AMI. In the order of decreasing risk, they are ApoB1/ApoA1, current
with depression and have heart disease. Selective serotonin reup- smoking, diabetes, hypertension, abdominal obesity, psychosocial,
take inhibitors have been used safely in this subgroup of patients. lack of daily consumption of fruit and vegetables, lack of exercise and
Although currently recommended, using any therapy alone or a alcohol consumption. These risks were consistent in all regions, ethnic
combination of these has not shown any benefit in the reduction of groups, and in men and women worldwide (Table 42.1).
adverse cardiovascular outcomes. However, a significant improve-
ment in the quality of life has been seen. Psychosocial Factors in INTERHEART
Mental Stress-induced Ischemia Psychosocial risk factors were assessed by a simple questionnaire:
• Stress at home or work
A significant percentage of patients with CAD experience myocardial • Financial stress
ischemia in response to mental stress and in a small proportion of • Major life events in past 1 year
patients, mental stress-induced ischemia may occur in the absence • Depression.
of exercise or adenosine-induced ischemia on myocardial perfusion The results indicated that psychosocial factors contribute to sub-
studies. Mental stress-induced ischemia is an independent predic- stantial proportion of the risk of AMI. The global effect was less than
tor of poor prognosis in CAD patients.16 Based on all these results in that of smoking but comparable with hypertension and abdominal
2003, behavioral and psychological factors were introduced for the obesity.
first time in the official European guidelines on cardiovascular dis-
ease prevention.17 Intervention Studies in Stress and Heart Disease
One of the largest and most important cardiology studies ever
conducted the INTERHEART, a global case control study was pub- Multiple studies have assessed pharmacological and other treatment
lished in 2004.18 Since most studies on risk factors were conducted modalities for depression in cardiac disease in the last few years. The
in western population, INTERHEART was conducted to identify risk Myocardial Infarction and Depression Intervention Trial (MIND-IT)
factors on a global basis. INTERHEART was a standardized case con- evaluated the effects of mirtazipine, a nontricyclic antidepressant on
trol study that screened all patients admitted to coronary care unit or adverse clinical events and long-term depression postmyocardial
equivalent ward for a first myocardial infarction at 262 participating infarction.19 Mirtazipine was found to be safe in cardiac patients and
centers in 52 countries throughout Africa, Asia, Australia, Europe, and had no effect on recurrent cardiac events in patients assigned to drug
North and South America. A total of 15,152 incident cases of acute when compared to the placebo group. Similar results were found in
TABLE 42.1 Risk of acute myocardial infarction (AMI) associated with risk factors in the overall population
Risk Factors Controls (%) Cases (%) OR (99% CI) Adjusted for OR (99% CI) Adjusted for all
Age, Sex and Smoking Other Risk Factors
ApoB/apoA1 (5 vs 1)* 20.0 33.5 3.87 (3.39–4.42) 3.25 (2.82–3.76)
Current smoking 26.8 45.2 2.95 (2.72–3.20) 2.87 (2.58–3.19)
Diabetes 7.5 18.5 3.08 (2.77–3.42) 2.37 (2.07–2.71)
Hypertension 21.9 39.0 2.48 (2.30–2.68) 1.91 (1.74–2.10)
Abdominal obesity (3 vs 1)† 33.3 46.3 2.22 (2.03–2.42) 1.62 (1.45–1.80)
Psychosocial - - 2.51 (2.15–2.93) 2.67 (2.21–3.22)
Daily consumption of vegetables and fruit 42.2 35.8 0.70 (0.64–0.77) 0.70 (0.62–0.79)
Exercise 19.3 14.3 0.72 (0.65–0.79) 0.86 (0.76–0.97)
Alcohol intake 24.5 24.0 0.79 (0.73–0.86) 0.91 (0.82–1.02)
All combined - - 129.2 129.2
All combined (extremes) 333.7 333.7
*Fifth quintile vs lowest quintile
†Top two quintiles vs lowest quintile
two trials, which used selective serotonin receptor uptake inhibitors an important clue to understanding the phenomenon of sudden
(SADHART and CREATE). death in modern society as well as providing a window into the world
of neurovisceral disease (also known as psychosomatic illness).
George Engel collected 160 accounts from the lay press of sud-
Stress and Sudden Death den death that was attributed to disruptive life events. He found that
William Harvey from whom we date the modern era of cardiology such events could be divided into eight categories:
had commented on the association of stress and sudden death. He 1. The impact of the collapse or death of a close person
wrote “Every passion of the mind, which troubles men’s spirits, 2. During acute grief
either with grief, joy, hope or anxiety and gets access to the heart, 3. On threat of loss of a close person
there makes it to change from its natural constitution by distempar- 4. During mourning or on an anniversary
ment, pulsation and the rest …..”. Sudden death is most often due to 5. On loss of status or self-esteem
ventricular tachyarrhythmia (ventricular tachycardia and fibrilla- 6. Personal danger or threat of injury
tion) occurring in the setting of CAD. Nearly 80% of all sudden car- 7. After the danger is over
diac death is due to ischemic heart disease. 8. Reunion, triumph or happy ending.
Epidemiological studies suggest that psychosocial risk factors Common to all is that they involve events impossible for the vic-
exist for the development of both CAD and sudden cardiac death. tim to ignore and to which the response is overwhelming excitation,
While it is likely that both conditions share the same standard, and giving up or both.22
some behavioral and environmental risk factors, the sudden on- The most common underlying cause of sudden death is CAD.
set of ventricular fibrillation in a heart that has been long diseased Other causes include structural heart disease, such as hypertrophic
requires additional risk factors. Gairdner who is cited by McWilliam cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right
observed a century ago that “It is plainly out of question to suppose ventricular dysplasia, severe aortic valvular stenosis, abnormal
that a chronic and by its very nature, gradually advancing lesion like coronary origins and other congenital heart diseases. Ventricular
fatty degeneration or disease of the coronary vessels is the direct and tachyarrhythmias also occur in structurally normal hearts, such as
immediate cause of death, which occurs in a moment.” McWilliam idiopathic ventricular tachyarrhythmias, long QT syndromes and
also suggested that sudden death was due to ventricular fibrillation Brugada syndrome. Drugs are also known to alter QT interval and
and advanced a view that sympathetic discharge may be an impor- cause sudden death. With the understanding of the genetic basis of
tant factor in inciting this fatal arrhythmia. Since early 20th century, many tachyarrhythmias, many cases earlier classified as idiopathic
several experimental and clinical studies have attempted to demon- could be now reclassified as one of the above syndromes. Inspite
strate that the activity of the central nervous system contributes to of these findings and numerous population-based studies showing
the onset of ventricular tachyarrhythmia and sudden cardiac death.20 strong relationship between risk factors for CAD and sudden cardiac
In 1942, at the culmination of his distinguished career as the death, no study has identified risk factors, which would predict sud-
Professor of Physiology at Harvard Medical School, Walter B Cannon den cardiac death.23
published a remarkable paper entitled “Voodoo Death”, in which Beta blockers are beneficial in most of the above conditions,
he recounted anecdotal experiences, largely from the anthropology which suggest that sympathetic nervous system has a role in genesis
literature, of death from fright.21 These often remote events, drawn of tachyarrhythmias. There are many reports linking stress particu-
from widely disparate parts of the world, had several features in com- larly emotional stress to sudden cardiac death. Patients experiencing
mon. They were all induced by an absolute belief that an external intense anger tend to have higher rates of implantable cardioverter-
force, such as a wizard or medicine man, could, at will, cause demise defibrillator discharge and an estimated seven times greater relative
and that the victim himself had no power to alter this course. This risk of appropriate discharge during mental and physical stress.24
perceived lack of control over a powerful external force is the sine qua
non for all the cases recounted by Cannon, who postulated that death Major Environmental Stress and Sudden Death
was caused “by a lasting and intense action of the sympathoadrenal
system”. Cannon believed that this phenomenon was limited to so- When an entire population simultaneously experiences a major
cieties in which the people were “so superstitious, so ignorant that environmental stress, there is an increase in death. The acute effects
they felt themselves bewildered strangers in a hostile world. Instead of earthquake-related psychological stress on total and cardiac mor-
of knowledge, they have fertile and unrestricted imaginations, which tality were investigated using mortality data from the city of Thessa-
fill their environment with all manner of evil spirits capable of affect- loniki in Greece. The city was hit on June 19–20, 1978 by two strong
ing their lives disastrously”. Over the years since Cannon’s observa- earthquakes. During the 3-day period of June 19–21, mortality from
tions, evidence has accumulated to support his concept that “voo- cardiac and all other pathological causes increased. The estimated
doo” death is, in fact, a real phenomenon but, far from being limited risks were 3.0 for CAD and 1.6 for all other causes. Stress-related car-
to ancient people, may be a basic biological principle that provides diac deaths were common when atherosclerotic heart disease was
the underlying condition.25 Similar conclusions were drawn from the TABLE 42.2 Morphological left ventricular (LV) variants of stress
study of Northridge earthquake in California. There was an increase cardiomyopathy31
in death due to CAD but not due to other cardiac causes followed • Apical and midventricular LV dysfunction (the classical description
by a decrease that overcompensates for excess deaths. The overcom- of Takotsubo cardiomyopathy)
pensation may represent a residual population that is more resistant • Isolated midventricular and basal LV dysfunction/isolated
to stress or a possible preconditioning effect of stress or both. This midventricular LV dysfunction (apical-sparing Takotsubo
study supports the concept that cardiovascular events within an cardiomyopathy)
entire population can be triggered by a shared stress.26 • Isolated basal LV dysfunction
Admissions for AMI increased by 25% on June 30, 1998, the day
• Global LV hypokinesis
England lost to Argentina in a penalty shoot out in football match
• Other noncoronary distribution wall motion abnormalities
and the following two days. The increase in admissions suggest that
myocardial infarction can be triggered by emotional upset, such as
watching your football team lose an important match.27
features.30 Takotsubo is a pot with a round bottom and narrow neck
Stress-induced Cardiac Dysfunction used for trapping octopuses in Japan. More recently, the condition
has been called transient LV apical ballooning syndrome or ampulla
In 1928 while still a medical student Hans Selye found that prepa- cardiomyopathy in relation to the balloon-like wall-motion abnor-
ration of synthetic Vitamin D, given to tuberculous guinea pig pro- malities involving the LV apex (Table 42.2).
duced calcinosis of soft tissues. Later, it was discovered that cardio- The onset of the transient LV apical ballooning syndrome is
vascular calcification produced by Vitamin D could be enhanced by often preceded by emotional or physical stress (stress cardiomyopa-
giving sodium phosphate, calcium chloride or by stressors, such as thy). In a meta-analysis of Takotsubo cardiomyopathy, an emotional
cold, heat, trauma and starvation while none of these produced such stressor, such as unexpected death of a relative or friend, domestic
lesions themselves. This led to the concept of pluricausal cardiopa- abuse, confrontational arguments, a catastrophic medical diagnosis,
thies. Selye called this as metabolic cardiopathies [endocrine steroid devastating business or gambling losses, was identified in 68 of 254
cardiopathy with necrosis (ESCN)]. Selye in September 1959 at the patients (26.8%, 95% CI: 21.7–32.5%; range: 10–100%) and a physical
International Symposium on Arteriosclerosis and Coronary Disease stressor, such as exhausting work, asthma attack, gastric endoscopy
in New Mexico presented in his lecture infarct-like cardiac necrosis and exacerbated systemic disorders in 96 of 254 patients (37.8%, 95%
produced without vascular obstruction, e.g. by combined treatment CI: 32.1–43.9%; range: 14–70%), in whom the presence or the absence
with corticosteroids and electrolytes, or corticosteroids and stress.28 of a stressor was reported. However, in 87 of 212 patients (34.3%, 95%
Catecholamines given in high concentration produce myocar- CI: 28.7–40.3%; range: 0–100%), there was no preceding emotional
dial damage in several mammalian species. The histological changes or physical stressful event identified.32 Several pathophysiological
are similar to those found in patients given large amounts of pressor mechanisms have been proposed to explain the unusual features of
agents and in those who develop pheochromocytoma. This consists this syndrome, such as multivessel coronary vasospasm, abnormali-
of myofibrillar necrosis, myofibrillar degeneration and mononuclear ties in coronary microvascular function and catecholamine-mediated
cell infiltration. Cardiac function is significantly impaired (catecho- cardiotoxicity. However, the precise etiology and pathophysiology of
laminergic cardiomyopathy). Endogenous release of catecholamines this syndrome remain unknown.
also produces myocardial injury in rabbits.29 The true prevalence of the apical ballooning syndrome remains
uncertain. In the last few years, the number of published reports of
Takotsubo Cardiomyopathy (Stress patients presenting with this syndrome is constantly increasing. In a
recent study from the USA, Bybee et al.33 reported that the apical bal-
Cardiomyopathy, Broken Heart Syndrome)
looning syndrome accounted for ~ 2.2% of the ST segment elevation
Some people who are subjected to an extreme stress may develop acute coronary syndrome presenting to the investigators’ institution
an acute cardiomyopathy that presents with chest pain and/or in the years 2002 and 2003. All the studies showed a marked gender
symptoms of heart failure. This process is most commonly seen in discrepancy, with much more common involvement of women. Two
older women, whose echocardiograms and ventriculograms show a hundred and fifty-four of 286 patients (88.8%) were women (95% CI:
typical pattern of left ventricular (LV) apical ballooning, which was 84.6–92.0%) Patients’ age ranged from 10 years to 89 years and mean
named Takotsubo-like cardiomyopathy. This transient LV apical bal- age in the studies ranged from 58 years to 77 years. Among these, only
looning syndrome is characterized by transient LV dysfunction, elec- 5 of 185 evaluated patients were younger than 50 years. Other risk
trocardiographic changes that can mimic AMI and minimal release factors included hypertension in 43% of patients (108/247), diabetes
of myocardial enzymes in the absence of obstructive CAD. This syn- in 11% (26/237), dyslipidemia in 25.45% (53/217) and current or past
drome was first described in 1991 in Japan and named Takotsubo- smoking in 23%. The most common abnormalities were ST segment
like LV dysfunction in reference to the associated LV morphological elevation and T wave inversion, usually observed during the acute
and subacute phases. ST elevation was detected in 208 of 255 evalu- 1. Management of coronary risk factors (CRFs) by Yoga (Bhat KS,
ated patients. Cardiac biomarker levels were usually only slightly el- 1987)34 and
evated. Plasma levels of catecholamines and their metabolites were 2. Nonpharmacological management of hypertension (Bhat KS,
measured in few studies, which found elevated norepinephrine con- 1987)35
centrations in 26 of 35 evaluated patients. It was considered that Yoga and meditation acted through the
Myocardial perfusion using single photon emission computed autonomic nervous system, which otherwise was beyond voluntary
tomography (SPECT) in patients with Takotsubo cardiomyopathy control.
showed moderate or severe myocardial ischemia. Thus, Abe et al. Pranayama breathing exercises influenced and regulated auto-
reported that 11 of 13 patients (85%), in whom resting technetium- nomic nervous system, brought about a significant reduction of CRFs
99m tetrofosmin tomographic myocardial imaging was performed and was found to be safe and effective. Since then there has been a lot
during the acute phase, had decreased radioisotope uptake at the of worldwide attention on this subject.
LV apex. Ito et al. reported that myocardial perfusion assessed by the The effects of cognitive behavioral therapy (CBT) and interper-
SPECT imaging was impaired immediately after hospital admission, sonal psychotherapy has been studied in two behavioral interven-
but improved considerably at 3–5 days. They interpreted the nuclear tional studies on depression. (ENRICHED and CREATE trials). The
imaging findings of decreased myocardial perfusion in the absence results of these trials are mixed at best.
of obstructive coronary lesions as direct evidence for impaired coro- Interventional trials in anxiety have primarily focused on
nary microcirculation as a causative mechanism of this syndrome. employing either CBT, telephonic support and cardiac rehabilitation
with positive outcomes.
Biomarkers of Stress Stress management uses specific cognitive behavioral strategies
like relaxation training, cognitive techniques and cognitive chal-
“Everything that can be counted does not necessarily count; every- lenge, and consideration of specific coping strategies to be used at
thing that counts cannot necessarily be counted” times of stress. Relaxation techniques, such as Yoga and Pranayama
—Albert Einstein have found beneficial in reducing psychological stress. Meta-analysis
Since stress affects central nervous system, the autonomic nerv- of studies on relaxation techniques has shown that if an intervention
ous system, other organs and tissues, and metabolism, multiple bio- is successful in reducing psychological stress, the 2-year mortality is
chemical markers are affected by stress. Although the biomarkers do reduced by 28%.36
not quantitate or diagnose stress, they are indirect markers of stress. Biofeedback is increasingly used in addition to stress manage-
Serum cortisol, adrenaline, noradrenaline, serum dihydroepian- ment programs in management of patients. Thus, management of
drosterone sulphate (DHEA-S), insulin-like growth factor 1, IL-6, IgA psychological factors, which adversely affects the outcome depends
and testosterone have all been used as markers of stress in studies. on early evaluation, a comprehensive cardiac rehabilitation pro-
The role of cortisol has been elegantly shown in an experimental gram, which stresses on balanced diet, limiting alcohol and quitting
study by Bradley AJM, 2005. They studied healthy volunteers were smoking, relaxation techniques (regular exercise, Yoga and medi-
subjected to stress by asked to defend themselves in police station tation), biofeedback, cognitive behavioral therapy and the role of
after being falsely implicated. In those pretreated with metyrapone, social support groups: family, colleagues, friends and society.
there was normal baroreceptor reflex and flow-mediated vasodilata-
tion. These were significantly impaired in those given only placebo, CONCLUSION
who also had higher cortisol levels.
Cardiovascular epidemic causes one of the highest mortality and
Behavioral Interventions morbidity all over the world, especially so in developing societies.
Atherovascular diseases are polygenic and the causation, progres-
A number of clinical trials have examined whether behavioral treat- sion and onset of acute coronary syndrome is only partially under-
ment of psychological factors would lead to an improvement in car- stood.
diac prognosis. In the last century, the focus was on individual risk factors rath-
er than holistic approach. In the last few decades, there is a better
Beneficial Role of Yoga and Meditation in understanding of mind-body relation, integration of the individual
with family, society and local culture.
Reduction of Coronary Risk Factors and
Stress affects the physiological functions of the brain and heart.
Management of Hypertension Increase in sympathoadrenal stimulation leads to increased risk of
The ancient and highly respected Indian system of Yoga has received sudden cardiac death, arrhythmias, angina and myocardial infarc-
great attention in the last few decades. Two papers focused on these tion. Acute stress also causes stress cardiomyopathy. Behavioral
issues: and psychosocial factors are now accepted as risk factors for CAD.
Certain behavioral traits, such as anger and hostility are markers for tions Behavioral and psychological factors modification is now in the
increased risk of heart disease. Type D behavior pattern is associated official cardiovascular prevention strategies. Thus, behavioral cardi-
with increased risk of heart disease and poor outcome after interven- ology is now an emerging branch of future cardiology.
REFERENCES
1. Dwivedi G, Dwivedi S. Sushrutha—the clinician-teacher par excellence. Indian J Chest Dis Allied Sci. 2007;49:243-44.
2. DeBakey M, Gotto A. The living heart. New York: Charter Books; 1977.
3. Bernard C. An Introduction to the Study of Experimental Medicine. New York: Dover Publishers; 1957.
4. Cannon WB. Bodily changes in pain, fear, hunger and rage. Washington: McGrath Publishers; 1929.
5. Langley JN. The Autonomic nervous system. Cambridge: Cambridge University press; 1921.
6. Selye H. A syndrome produced by diverse nocuous agents. Nature, vol. 138, July 4, 1936, p. 32.
7. David SK, Andrew B, Jerome ES. Cardiovascular disorders and behavior. Handbook of Psychology and Health; Vol. 3. New Jersy, London: Law-
rence Elbaum Publishers; 1983. p. 12-32.
8. Rosenman RH, Friedman M, Straus R, et al. A predictive study of coronary heart disease. Western Collaborative Group Study (WCGS). JAMA.
1964;189:15-22.
9. Jenkins CD. Behavioral risk factors in coronary artery disease. Annu Rev Med. 1978;29:543-62.
10. Chida Y, Steptoe A. The association of anger and hostility with future coronary heart disease: a meta-analytic review of prospective evidence. J Am
Coll Cardiol. 2009:53:936-46.
11. Denollet J, Sys SU, Stroobant N. Personality as independent predictor of long-term mortality in patients with coronary heart disease. Lancet.
1996:347:417-21.
12. Pederson SS, Lemos PA, van Vooren PR. Type D personality predicts death or myocardial infarction after bare metal stent or sirolimus-eluting
stent implantation: a Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry substudy. J Am Coll Cariol.
2004;44(5):997-1001.
13. Sher L. Type D personality: the heart, stress, and cortisol. QJM. 2005;98(5):323-9.
14. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom
Med. 2003;65(2):201-10.
15. Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med. 2002;23(1):51-61.
16. Strike PC, Steptoe A. Systematic review of mental stress-induced myocardial ischemia. Eur Heart J. 2003;24:690-703.
17. De Backer G, Ambrosioni E, Borch-Johnson k, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task
Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003;24:1601-10.
18. Yusuf S, Hawken S, Ounpuu S, et al. On behalf of INTERHEART study investigators. Effect of potentially modifiable risk factors associated with
myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-63.
19. Denollet J, de Jonge P, Kuyper A, et al. Depression and Type D personality represent different forms of distress in the Myocardial Infarction and
Depression-Intervention Trial (MIND-IT). Psychol.Med. 2009;39:749-56.
20. DeSilva RA. Central nervous system risk factors for sudden cardiac death. Ann N Y Acad Sci. 1982;382:143-61.
21. Cannon WB. “Voodoo” death. American Anthropologist, 1942;44(new series):169-181. Same article republished in Am J Public Health.
2002;92:1593-6.
22. Engel GL. Sudden and rapid death during psychological stress. Folklore or folk wisdom? Ann Intern Med.1971;74:771-82.
23. Kannel WB, Thomas HE Jr. Sudden coronary death: the Framingham Study. Ann N Y Acad Sci.1982;382:3-21.
24. Frier R, Konig J, Schafers HJ, et al. Triggering effect of physical and mental stress on spontaneous ventricular tachyarrhythmias in patients with
implantable cardioverter-defibrillators. Clin Cardiol. 2002;25(10):474-8.
25. Katsouyanni K, Kogevinas M, Trichopoulus D. Earthquake-related stress and cardiac mortality. Int J Epidemiol. 1986;15(3):326-30.
26. Leor J, Poole WK, Kloner RA. Sudden cardiac death triggered by an earthquake. N Engl J Med. 1996;334:413-9.
27. Caroll D, Ebrahim S, Tilling K, et al. Admissions for myocardial infarction and World Cup football: database survey. BMJ. 2002;325:1439-42.
28. Selye H. The pluricausal cardiopathies. The Beaumont Lecture. JAMA. 1962;181(11);1015.
29. Jiang. JP, Downing SE. Catecholamine cardiomyopathy: review and analysis of pathogenetic mechanisms. Yale J Biol Med. 1990;63(6):581-91.
30. Dote K, Sato H, Tateishi H, et al. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol. 1991;21:
203-14.
31. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation. 2008;118:397-409.
32. Dentali F, Grandi AM, Sumner G, et al. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J. 2006;27(13):
1523-9.
33. Bybee KA, Prasad A, Barsness GW, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient
left ventricular apical ballooning syndrome. Am J Cardiol. 2004;94:343-6.
34. Bhat KS, et al. Non-pharmacological management of hypertension. Indian J Cardiol: Abstract issue of the National Conference; 1987.
35. Bhat KS, et al. Modification of coronary risk factors by Yoga and naturopathy. Indian J Cardiol: Abstract issue of the National Conference; 1987.
36. van Dixhoorn J, White A. Relaxation therapy for rehabilitation and prevention in ischaemic heart disease: a systematic review and meta-analysis.
Eur J Cardiovasc Prev Rehabil. 2005;12:193-202.
43 History of Cardiorenal Connectors
Hotchandani R, Khaira A
INTRODUCTION used the clamping technique of Goldbatt to produce experimental

hypertension, and demonstrated renal secretion of a pressor agent
It is not rare to see a patient with concomitant heart failure and renal similar to renin. Both teams subsequently described the presence of
insufficiency and the twin diseases have gained epidemic propor- a new compound in the renal vein blood of ischemic kidneys. The
tions. Cardiovascular disease is the leading cause of death (43.6%) agent was found to have short pressor effect and was finally extracted
in patients with end-stage renal disease (ESRD). Heart and kidney from blood with 70% acetone. It was then concluded that renin acted
act in synchronization to regulate blood pressure, vascular tone, diu- enzymatically on a plasma protein to produce the new substance.
resis, natriuresis, intravascular volume, homeostasis, peripheral tis- The new agent was called hypertensin in Buenos Aires and angio-
sue perfusion and oxygenation. They have endocrine functions with tensin in the United States. In 1958, Eduardo Braun-Menéndez from
interdependent physiological hormonal actions regulated by arterial Argentina and Irving H Page from the United States agreed to name
natriuretic peptide (ANP) and renin-angiotensin aldosterone system it angiotensin.
(RAAS). Changes in the RAAS, the imbalance between nitric oxide
(NO) and reactive oxygen species (ROS), the sympathetic nervous HISTORY OF CARDIORENAL CONNECTORS
system and inflammation are the cardiorenal connectors (Fig. 43.1).
These connectors together decrease the sensitivity of erythropoi- In 1836, Richard Bright in his seminal paper first described his
etin and are responsible for renal anemia that also aggravates car- observation linking renal disease to left ventricular hypertrophy. He
diac failure. Tigerstedt and Bergman, in 1898, reported the pressor related hypertrophy to an increased resistance to blood flow in the
effect of renal extracts; and they named the renal substance renin small vessels due to altered condition of the blood. Left ventricu-
based on its origin. Harry Goldblatt in 1934, for the first time induced lar hypertrophy was then attributed to occur due to hyaline-fibroid
experimental hypertension in dogs by clamping a renal artery. In alterations in the renal vessels due to an impure condition of the
the next few years, two independent group of researchers worked blood in 1868 by George Johnson in patients with nephritis. Using a
simultaneously at the Medical School of the University of Buenos primitive sphygmograph, F A Mahomed, for the first time, described
Aires, Argentina, and in the Eli-Lilly Laboratories in Indianapolis and high blood pressure in 1872. He also linked left ventricular hyper
Figure 43.1: Cardiorenal connectors

Chapter 43  History of Cardiorenal Connectors 315
trophy to hypertension due to nephritis and reported the presence of with important vascular lesions, mostly in the kidney, pale skin and
high blood pressure in patients without renal disease. Finally, Riva- cerebral damage (malignant hypertension) as white.
Rocci, in 1896, described the first indirect sphygmomanometer to Toward the end of the 19th century, Tigerstedt, a Finnish profes-
measure arterial pressure in humans, and in 1905, Korotkoff defined sor of physiology working at the Karolinska Institute and his assistant
the sounds that are named after him. Bergman analyzed the effect of renal extracts of rabbit kidney on ar-
Richard Bright (September 28, 1789–December 16, 1858) was an terial pressure. They named the pressor compound renin. The com-
English physician and early pioneer in the research of kidney disease. pound was found to be not dialyzable and stable at 56°C, and could
He was born in Bristol, Gloucestershire, the third son of Sarah and be extracted with glycerin; however, it was destroyed by boiling. They
Richard Bright Sr, a wealthy merchant and banker. Bright Sr shared also went on to demonstrate an increase in the blood pressure of ne-
his interest in science with his son, encouraging him to consider it as phrectomized animals when injected with renal vein blood extract.
a career. In 1808, Bright Jr joined the University of Edinburgh to study They also detected the potentiation and protraction of the pressor
philosophy, economics and mathematics, but switched to medicine response to renin in the nephrectomized recipient. It was thus pos-
the following year. In 1810, he accompanied Sir George Mackenzie tulated that renal disease was linked to cardiac hypertrophy due to
on a summer expedition to Iceland where he conducted naturalist the release of a vasoactive substance that had the ability to induce
studies. Bright then continued his medical studies at Guy’s Hospi- contraction of the blood vessels through a direct action.
tal in London and in September 1813 returned to Edinburgh to be The clinician, Franz Volhard, and the pathologist, Theodor Fahr,
granted his medical doctorate. His thesis was De erysipelate conta- worked closely together in Mannheim from 1909 until 1915 and
gioso (On contagious erysipelas). During the 1820s and 1830s, Bright introduced a novel classification of renal diseases. In the monograph
again worked at Guy’s Hospital, teaching, practicing and researching entitled Die Bright’sche Nierenkrankheit, Klinik, Pathologie und At-
medicine. There he worked alongside two other celebrated medical las, 1914, they differentiated between degenerative (nephroses), in-
pioneers, Thomas Addison and Thomas Hodgkin. His research into flammatory (nephritides) and arteriosclerotic (scleroses) diseases.
the causes and symptoms of kidney disease led to his identifying Nephrosclerosis was divided into the benign and malignant form, of
what became known as Bright’s disease. For this, he is considered as which the latter stood the test of time as a new disease entity. Fahr
the “Father of Nephrology”. further divided benign nephrosclerosis into the compensated and
Frederick Akbar Mahomed, who worked at Guy’s Hospital in decompensated form, depending on the presence or absence of
London, made substantial contributions to the study of high blood glomerular injury. In the pathogenesis of malignant nephrosclerosis,
pressure during his short professional career from 1872 to 1884, Volhard stressed the decisive role of severe blood pressure elevation,
when he died at the age of 35. Michael F O’Rourke summarizes the while Fahr postulated an inflammatory mechanism, a concept later
contributions of Frederick Akbar Mahomed as follows: confirmed by Adalbert Bohle for at least a minority of patients. A very
In detailed clinical studies, he separated chronic nephritis with far reaching concept of Franz Volhard was his idea that pale (renal)
secondary hypertension from what we know the term “essential hypertension results from a pressor substance released from ischem-
hypertension”. He described the constitutional basis and natural ic kidney(s) contributing via a vicious circle to a further rise in blood
history of essential hypertension and pointed out that this disease pressure with subsequent renovascular injury and aggravation of hy-
could terminate with nephrosclerosis and renal failure. His clini- pertension. This hypothesis was supported in 1930 by initial experi-
cal studies were done without the benefit of a sphygmomanometer, ments of his collaborator, Hartwich (demonstrating in dogs a mild
but with the aid of a quantitative sphygmogram that he had initially rise in blood pressure after ligation of branches of the renal artery)
developed while a medical student. He described characteristic and definitively proven by Goldblatt in 1934 in dogs by induction
features of the pressure pulse in patients with high blood pressure of severe and persistent hypertension after clamping of both renal
and in persons with arteriosclerosis consequent on aging. These arteries. The consequent detection of the renin-angiotensin system
pressure wave changes have recently been verified and explained. was the final confirmation of Volhard’s postulated renal pressor sub-
He contributed to a number of other advances in medical care, stance. In the pathogenesis of red (essential) hypertension, Volhard
including blood transfusion and appendectomy for appendicitis. He stressed the role of hereditary factors, age, obesity and potentially of
initiated the collective investigation record for the British Medical severe alcoholism. He emphasized a premature reduction of vascu-
Association; this organization collected data from physicians prac- lar distensibility (due to elastosis of the prearterioles), a high cardiac
ticing outside the hospital setting and was the precursor of modern output as well as a dampening of baroceptor function. Additionally,
collaborative clinical trials. Volhard made crucial advances in cardiology and pneumology.
The relationship between pathological alterations in the kid- Franz Volhard (May 2, 1872–May 24, 1950) was a German
ney and the development of systemic arterial hypertension was internist who was born in Munich. He studied Medicine in Bonn,
postulated by Franz Volhard. He suggested the existence of a circu- Strasbourg and Halle. His instructors included Eduard Friedrich
lating vasopressor substance and went on to classify the hyperten- Wilhelm Pflüger (1829–1910), Bernhard Naunyn (1839–1925), Oswald
sive patients: those with slight vascular damage as reds, and those Schmiedeberg (1838–1921) and Joseph von Mering (1849–1908), and
from 1897 to 1905, he worked at the University Medical Clinic at Gies- main renal arteries, from the beginning, resulted in great elevation
sen under Franz Riegel (1843–1904). In 1905, he became head of the of systolic blood pressure, which was accompanied by severe dis-
medical department at the City Hospital in Dortmund, and in 1908, turbance of renal function and uremia. This resembled the type of
director of the Krankenanstalt in Mannheim. Afterwards, he was a hypertension, which is associated with so called malignant nephro-
professor at Halle an der Saale (from 1918) and Frankfurt am Main sclerosis. In several of the animals with persistent elevation of systolic
(from 1927). blood pressure, anatomical changes were observed in the glomeruli,
Volhard made several important contributions in the fields of vessels and parenchyma of the kidneys, which were most probably
cardiology and nephrology. He is especially remembered for his col- directly referable to the ischemia. Their results were confirmed by
laboration with pathologist Karl Theodor Fahr (1877–1945) in Man- several groups, and the search for the mechanisms involved for the
nheim concerning research of kidney diseases. The two physicians increase in blood pressure began. The section of the sympathetic
created a classification system of renal disorders, in which they made nervous system that regulates the vasomotor mechanisms did not
the differentiation between degenerative (nephroses), inflammatory prevent or abolish the development of hypertension.
(nephritides) and arteriosclerotic (scleroses) diseases. With Fahr, Two research groups, working independently, simultane-
he published a classic monograph on Bright’s disease called Die ously reached similar conclusions on this matter. One of them was
Bright’sche Nierenkrankheit, Klinik, Pathologie und Atlas. investigating at the University of Buenos Aires, Argentina, under the
Volhard recognized that constrictive pericarditis was a treat- leadership of Dr Bernardo Houssay at the Physiology Institute of the
able condition, and as a result of his research with Viktor Schmieden School of Medicine. The other group pursued their studies at the Eli-
(1874–1945), it led to the first pericardectomy for constrictive peri- Lilly Research Laboratories in Indianapolis, under the leadership of
carditis. Volhard also performed extensive studies involving reno- Dr Irvine H Page. His work on the purification of renin began again
vascular hypertension and uremia. Regarding uremia, he divided in 1937, with Helmer doing the fractionation, Corcoran studying the
associated symptoms into two criteria called “true uremia” and renal hemodynamic effects, and Kohlstaedt measuring the vasocon-
“pseudouremia”. Pseudouremia was described as having symptoms striction in dog’s tail perfused with Ringer’s solution, a method that
of independent origin, such as cases involving elevated arterial blood was compared with the perfused isolated rabbit’s ear vessels by a
pressure. technician. The samples were tested in intact dogs and cats and also
In 1903, Volhard was credited with the discovery of lipase in the after various organs had been removed and subsequently led to the
heart and kidney. He also developed a method of preserving cardiac discovery of angiotensin.
specimens via a process of dehydration and the application of hot Bernardo Alberto Houssay (April 10, 1887–September 21, 1971)
paraffin. In 1917, he joined the German Fatherland Party. In Berlin, was an Argentine physiologist who, in 1947, received one half Nobel
the Franz-Volhard-Klinik is named in his honor. Prize for Physiology or Medicine for his discovery of the role played
In the light of the results of these experiments, many attempts by pituitary hormones in regulating the amount of blood sugar (glu-
were performed to develop an experimental model of arterial hyper- cose) in animals. He was the first Argentine and Latin American No-
tension by manipulation of the renal function. Reduction of the renal bel laureate in the sciences. He shared the prize with Carl Ferdinand
mass, X irradiation of the kidney, renal artery occlusion, renal vein Cori and Gerty Cori, who won for their discoveries regarding the
constriction, and wrapping of the kidney with a membrane were all role of glucose in carbohydrate metabolism. He was born in Buenos
tested; however, due to inappropriate techniques and/or inadequate Aires, to émigrés from France, Albert and Clara Houssay. A preco-
methods to measure blood pressure, the results were at variance and cious youngster, he was admitted to the Pharmacy School at the
unreliable. The first successful experiment was performed by Gold- University of Buenos Aires at 14 years of age and subsequently to the
blatt et al. in 1934, and their technique led to the discovery of the Medical School of the same university from 1904 to 1910, beginning
active polypeptide. They induced experimental hypertension in the when he was only 17 years old. While a third year medical student,
dog by partial constriction of the renal artery using a silver clip. Their Houssay took up a post as a research and teaching assistant in the
experiments indicated that in dogs at least, ischemia localized to the Chair of Physiology. In 1919, Houssay was appointed to the chair of
kidneys was a sufficient condition for the production of persistently physiology at the University of Buenos Aires Medicine School, and,
elevated systolic blood pressure. When the constriction of both main until 1943, he transformed and directed it into a highly respected re-
renal arteries was made only moderately severe in the beginning, the search department in experimental physiology and medicine of in-
elevation of systolic blood pressure was unaccompanied by signs of ternational class. In that year, however, the military dictatorship de-
clinically significant decreased renal function. This was comparable prived him of his university posts due to his liberal political ideas and
to benign nephrosclerosis in man. On further increasing, the con- he was forced to re-establish his research lines and staff at a privately
striction of the main renal arteries, they did not find significant dam- funded Instituto de Biología y Medicina Experimental. This situation
age of renal function, probably because of adequate development of reinforced by a second dismissal by the Peronista Government in
accessory circulation. Whereas almost complete constriction of both 1945, was prolonged until 1955, when Peron was ousted from power
and Houssay was reinstated in the University of Buenos Aires, where Experimental results had demonstrated that in the acute period,
he remained till he died. After this, he was also the director of the Na- the ischemic kidney of the hypertensive dog released a vasoconstric-
tional Scientific and Technical Research Council from 1957 onwards. tor agent. It became necessary to establish the nature of this com-
The discovery of the renin-angiotensin system in Buenos Aires pound and to characterize, purify and isolate it to identify its chemi-
began with the arrival of Dr Juan C Fasciolo, a young physician, at cal structure.
the institute chaired by Dr Houssay. The interest of Dr Houssay in In 1938, Taquini went to the United States with a 2-year fellow-
this problem was related to the fact that one of his young disciples, ship. And, at the same time, Eduardo Braun-Menéndez returned
32-year-old, Dr J Guglielmetti, had recently died of malignant hyper- from his stay in England, where he had studied the metabolism of
tension. Houssay and Fasciolo in 1937 grafted ischemic kidneys of the heart with Dr Lovatt Evans. He planned to continue his work
dogs with chronic renal hypertension onto the vessels of normal and on this subject after returning to Buenos Aires. However, when he
nephrectomized dogs. An immediate large increase in arterial pres- returned, he had to replace Taquini as head of research. He learned
sure occurred, while little change was produced by grafted normal of the promising experiments that were being developed in the field
kidneys. Houssay and Taquini in 1938 collected venous blood from of arterial hypertension. He decided to lead a team that also includ-
normal and ischemic kidneys, diluted it with citrate and Ringer’s ed Drs Juan C Fasciolo, Luis F Leloir and Juan M Muñoz. Leloir and
solution, and assayed it. Vasoconstriction occurred only in blood Muñoz were already involved in studies related to the chemical
from the ischemic kidney. Grimson in 1939 confirmed this finding. nature of physiological enzymatic processes.
Braun-Menéndez et al. in 1939 and Munoz et al. in 1939 found that Eduardo Braun-Menéndez (January 16, 1903–January 1959) was
renin acts on blood protein to produce a substance with the same a noted Chilean-Argentine physiologist. Born in Punta Arenas, Chile,
properties as those of the substance in blood from ischemic kidneys. he was, however, nationalized Argentine and developed his entire
Based on these findings, an experiment was designed to life in this country. He studied Medicine at the Faculty of Medical
search for the presence of a pressor agent in the venous blood of the Sciences at the University of Buenos Aires, choosing Cardiovascular
ischemic kidney. Grafting of an ischemic kidney into the neck of a Medicine and Physiology as his specialties. His doctoral thesis was
recently nephrectomized dog was chosen. Blood pressure of the dog developed at the Institute of Physiology under the supervision of
began to rise shortly after the grafting, and it remained elevated even Nobel award winner Dr Bernardo Houssay, in 1934, about the
after the graft was eliminated, supporting the presence of a true pres- relationship between the pituitary gland, diencephalon and blood
sor secretion. Moreover, grafting a kidney from a normal dog did not pressure. After receiving his doctoral degree, he went to England to
show a pressor action. Further support for the release of a pressor study at the University College of London, where he investigated the
substance was afforded by the experiments of Dr Alberto C Taquini, metabolism of the heart. On his return from England, he joined the
the head of research at the Physiology Institute. He added strong prestigious team at the Institute of Physiology with Luis Federico
evidence supporting the secretion of a vasoactive agent from the Leloir, Juan Fasciolo, Juan Muñoz and Alberto Tarquini to work for
ischemic kidney. Indeed, plasma obtained from the renal vein a few years on the mechanism of nephrogenic hypertension. In this
blood of the ischemic kidney, diluted with saline and injected in research, he made the most important of his discovery, that of angio-
the well-known preparation of Lawen-Trendelenburg, produced a tensin. At the institute, Braun-Menéndez became a research leader
strong constrictor effect on the isolated vascular bed of the hind leg in cardiovascular physiology in 1935 and served as a senior lectur-
of the toad. The venous plasma from numerous ischemic kidneys of er and teaching assistant in the same area until 1946. He directed
hypertensive dogs always induced a significant and immediate the Institute of Experimental Biology and Medicine until 1946 and
vasoconstrictor effect. To the contrary, venous plasma from normal was also the head of electrocardiography and physiotherapy at the
kidneys had little or no pressor action. Municipal Institute of Radiology and Physiotherapy of Buenos Aires.
The Instituto de Investigaciones Cardiológicas (ININCA) was In 1955, he returned to the Chair of Houssay at the Institute of Physi-
founded by Alberto C Taquini in 1944 and directed by him during ology as a Professor. In addition, he was part of the National Academy
more than 50 years, until his death in 1998. From the very beginning, of Medicine and was honored with the title of Doctor Honoris Causa
research was centered on hypertension, hypoxia and hemodynamic by the University of California and the University of Brazil. In addi-
adaptations, renal physiology and electrolytes, arterial wall, cardiac tion, he was the vice president of the Argentine Society of Biology
metabolism, myocardial pharmacology and regulation of the circu- and secretary of the Argentine Association for the Advancement of
lation by the central nervous system. Taquini also played an impor- Sciences. He received the National Award for Science twice.
tant role in promoting science at national levels including his role as Braun-Menéndez also helped to create the important scientific
the first secretary of Science and Technology from 1968 to 1971. He journal Ciencia y Investigación, which published its first issue in 1945
believed that scientific research is something more than planning and was directed by him until 1959, when he died. Another of his
and producing, that it also involves creating knowledge. As such, he initiatives was the Acta Physiologica Latinoamericana, a publication
made many contributions to science, formed many disciples and written in multiple languages for the publication of the work of Latin
directed an institute, which is demonstrating its continuity. American physiologists.
Luis F Leloir was born in Paris of Argentine parents on September plasma to release hypertensin as the final product of the enzymatic
6, 1906 and lived in Buenos Aires since he was 2 years old. He gradu- reaction.
ated as a Medical Doctor in the University of Buenos Aires in 1932 Through subsequent experiments, these researchers dem-
and started his scientific career at the Institute of Physiology working onstrated that renin was secreted by the kidney, and hypertensin
with Professor Bernardo A Houssay on the role of the adrenalin car- was formed in the plasma from a proteic substrate that was named
bohydrate metabolism. In 1936, he worked at the Biochemical Labo- hypertensinogen because it was the actual origin of the active prin-
ratory of Cambridge, England, which was directed by Sir Frederick ciple. Blood, as well as kidney, was able to inactivate hypertensin
Gowland Hopkins. There he collaborated with Malcom Dixon, N L through the action of other enzymes that were called hyperten
Edson and D E Green. On returning to Buenos Aires, he worked with sinases. Inactivation of hypertensin was avoided by purifying prepa-
J M Muñoz on the oxidation of fatty acids in liver, and also together rations containing either renin or hypertensinogen.
with E Braun-Menéndez, J C Fasciolo and A C Taquini on the forma- The fact that bilateral nephrectomy increased considerably the
tion of angiotensin. In 1944, he was the research assistant in Dr Carl plasma concentration of hypertensinogen was also demonstrated. At
F Cori’s laboratory in St. Louis, United States and thereafter worked the same time, the specificity of the enzymatic system was described.
with D E Green in the College of Physicians and Surgeons, Columbia Hog renin could not release hypertensin from the human plasma
University, New York. substrate, whereas human renin was able to hydrolyze hog and cow
A significant increase in arterial blood pressure few minutes after hypertensinogen.
inducing renal ischemia in the dog had been described previously. The hepatic origin of renin substrate was suggested by Page et al.
It was imperative, thus to perfuse dog kidneys after a short period of However, conclusive experiments were performed later by Leloir et
ischemia. Braun-Menéndez and Fasciolo demonstrated that in acute al. in nephrectomized dogs with and without hepatectomy.
ischemia, the blood coming from the renal vein induced a strong Kohlstaedt, Helmer and Page showed that renin itself is not phys-
pressor effect when injected in the circulation of nephrectomized iologically active but requires the presence of proteins in order to be
dogs. The pharmacological characteristics of this pressor agent effective as a pressor agent. They suggested that it is enzyme-like. At
indicated that its effect was not modified by the action of atropine, first, serum was used as substrate but a pseudoglobulin fraction pre-
cocaine or sympatholytic agents and that it was potentiated after pared from serum was found to be even more effective. This fraction
bilateral nephrectomy of the recipient animal. has been temporarily called “renin activator” because the nature of
The following goal now was to isolate the active substance from the reaction was not fully understood. The mechanism of the inter-
the blood. Extraction of the active principle was accomplished with action of renin and renin activator was more critically analyzed and
acetone 70%. This compound with a quick pressor action of very its enzymatic nature was kinetically demonstrated (first order reac-
short duration was thermostable and soluble in acetone, and was tion). It was seen that the percentage of renin activator decomposed
not detected in the venous blood of an intact kidney. It had a strong per unit time was proportional to the renin concentration; therefore
vasoconstrictor action on the vascular bed of the toad and thus was renin was the enzyme and renin activator the substrate. The final
completely different from renin. The chemical and pharmacological product, a pressor substance formed through the interaction of
characteristics of this new compound were different from those of renin and its activator, was named angiotonin and was, probably, the
all the known substances at that time. And since the new compound actual effector of the renin pressor action.
had been isolated from the blood coming from the ischemic kidney, Irvine Heinly Page (January 7, 1901–June 10, 1991) was born in
it was named hypertensin. Indianapolis, Indiana and was an American physiologist who played
Renin, the pressor principle obtained from renal extracts by an important part in the field of hypertension for almost 60 years.
Tigerstedt and Bergman in 1898, was thermolabile and had a pro- His first contributions were published in the early 1930s and his most
longed pressor effect. This action was recorded when studying renal recent, “Hypertension Research: A Memoir: 1920–1960” in 1988.
grafts from hypertensive dogs and also when injecting blood com- He is perhaps best known for the co-discovery of serotonin in 1948,
ing from acute ischemic kidneys. Previous observations, therefore, although his pre-eminence is a matter of record in four other areas:
linked renin with the newly discovered agent. However, the nature of the renin-angiotensin system, the mosaic theory of hypertension,
the relationship between the two compounds remained unknown. treatment of hypertension, and public and professional advocacy of
The Argentine group was finally able to isolate a vasoconstrictor the recognition of this condition and its effects in daily life. In earlier
substance similar to hypertensin. The compound was soluble in 75% work, he published on the neurochemistry of the brain.
acetone and in glacial acetic acid, was insoluble in ether and amyl Page received many honors for his work. He was the president
alcohol, and was resistant to acid hydrolysis and dialyzable. These of the American Heart Association (1956–57); he received 10 honor-
characteristics were different from those of renin, epinephrine, ary degrees and a number of prestigious awards—the Ida B Gould
tyramine, vasopressin and urohipertensin. Based on these results, Memorial Award of the American Association for the Advancement
the group described, for the first time, renin as an enzyme similar of Science in 1957; Albert Lasker Award in 1958; Gairdner Founda-
to papain (protease), which could act on a protein present in the tion Award in 1963; Distinguished Award of the American Medical
TABLE 43.1 Five different subtypes of CRS

Type Name Mechanism and Clinical Conditions Markers
Type I Acute CRS Acute kidney injury in the setting of acute cardiogenic shock and acute ET-1, troponins, CPK-MB
decompensated CHF
Type II Chronic CRS Chronic and potentially permanent kidney injury in CHF ET-1, BNP
Type III Acute renocardiac syndrome Abrupt kidney disease causing acute cardiac disorder, i.e. acute TNF-α, IL-1, IL-6, IL-8
glomerulonephritis with CHF
Type IV Chronic renocardiac syndrome CKD leading to decline in cardiac function PTH, CPP, Cystatin C
Type V Secondary CRS Systemic conditions causing both cardiac and kidney dysfunction, i.e.
diabetes, sepsis
Abbreviations: CRS: Cardiorenal syndrome; CHF: Congestive heart failure; CKD: Chronic kidney disease; CPK-MB: Creatine phosphokinase muscle type B;
ET-1: Endothelin-1; BNP: Brain natriuretic peptide; TNF-α: Tumor necrosis factor-α; IL: Interleukin; PTH: Parathyroid hormone; CPP: Calcium phosphate
product
Association in 1964; Oscar B Hunter Award in 1966; Passano Foun- hypertrophy and atherosclerosis, is well established. However,
dation Award in 1967 and the Stouffer Prize (now the Novartis Ronco C, for the first time, described in detail the cardiorenal
Award) for hypertension research in 1970. He was elected to the syndrome (CRS). Since many details regarding this peculiar syn-
National Academy of Sciences in 1971 and published his memoirs drome still elude us, no single comprehensive definition completely
in 1988. describes it. The simple view of CRS is that a relatively normal kidney
The American Heart Association Irvine H Page Young Inves- is dysfunctional because of a diseased heart with the assumption that
tigator Research Award and the Irvine Page-Alva Bradley Lifetime in the presence of a healthy heart, the same kidney would perform
Achievement Award are named in his honor. normally. This concept has been recently challenged, and a more
Synthesis of the octapeptide was successfully accomplished, for articulated definition of the CRS has been advocated. Thus, CRS in-
the first time, by the group led by Dr Page, then in Cleveland, and cludes a variety of acute or chronic conditions, where the primary
by Dr Schwyzer in Basil, Switzerland. The Basil group, working at the failing organ can be either the heart or the kidney. Direct and indirect
CIBA laboratories, marketed the octapeptide under the name hyper- effects of each organ that is dysfunctional can initiate and perpetuate
tensin. the combined disorder of the two organs through a complex com-
Even though there was already a marketed name of hypertensin, bination of neurohormonal feedback mechanisms. For this reason,
Braun-Menéndez agreed to name the active final compound angio- a subdivision of CRS into five different subtypes seems to provide a
tensin, taking half of each original name. Similarly, the renin sub- more concise and logically correct approach (Table 43.1).
strate was named angiotensinogen, and the enzymes that metabolize In spite of the fact that more than 50 years have elapsed, the role
the peptide were termed angiotensinases. of full implications of the renin-angiotensin system on the develop-
A few years were needed for the general acceptance of the new ment of renal arterial hypertension has not been completely eluci-
nomenclature. The leading groups in the United States, like those of dated. Not withstanding, there are no doubts about the beneficial
Goldblatt and Skeggs, and in Europe continued using the Argentine effect of inhibition of the enzymatic system in a group of essential
name. In 1959, Braun-Menéndez died, and in 1961, Taquini et al. hypertensive patients. In this sense, drugs that are able to block the
insisted on the necessity of using the unified nomenclature. effect of angiotensin II have contributed to modify the evolution of
We have come a long way since then and the role of the RAAS arterial hypertension and to increase the lifespan of the hypertensive
in many cardiovascular disorders, including hypertension, cardiac patients.
BIBLIOGRAPHY
1. Bouckaert JJ, Grimson KS, Heymans C. Increase of blood pressure by perfusion of the ischemic kidneys of hypertensive dogs. J Physiol. 1939;96:44-
8.
2. Braun-Menéndez E, Fasciolo JC, Leloir LF, et al. Hipertensión Arterial Nefrógena. Buenos Aires, Argentina: El Ateneo; 1943.
3. Braun-Menéndez E, Fasciolo JC, Leloir LF, et al. La sustancia hipertensora de la sangre del riñón isquemiado. Rev Soc Arg Biol. 1939;15:420-5.
4. Braun-Menéndez E, Fasciolo JC. Mecanismo de la acción hipertensora de la sangre venosa del riñón en isquemia incompleta aguda. Rev Soc Arg
Biol. 1939;15:401-10.
5. Braun-Menéndez E, Fasciolo JC. Acción vasoconstrictora e hipertensora de la sangre venosa del riñón en isquemia incompleta aguda. Rev Soc Arg
Biol. 1939;15:161-72.
6. Braun-Menéndez E, Page IH. Suggested revision of nomenclature: angiotensin. Science. 1958;127:242.
7. Braun-Menéndez E, Paladini AC. Pressor polypeptides formed in vivo and in vitro as mediators of renal hypertension. Circulation. 1958;27:668-71.
8. Braun-Menendez E, Fasciolo JC, Leloir LF, et al. The substance causing renal hypertension. J Physiol. 1940;98:283-98.
9. Bright R. Tubular view of the morbid appearances in 100 cases connected with albuminous urine: with observations. Guy’s Hosp Rep. 1836;1:380-
400.
10. Fasciolo JC, Houssay BA, Taquini AC. The blood pressure-raising secretion of the ischemic kidney. J Physiol. 1938;94:281-93.
11. Fasciolo JC, Leloir LF, Muñoz JM, et al. On the specificity of renin. Science. 1940;92:554-5.
12. Fasciolo JC. Hipertensión arterial nefrógena: estudio experimental. Tesis Doct Med Ferrari, Hnos, Buenos Aires, 1939.
13. Freeman NE, Page IH. Hypertension produced by constriction of the renal artery in sympathectomized dogs. Am Heart J. 1937;14:405-14.
14. Goldblatt H, Lynch J, Hanzal RF, et al. Studies on experimental hypertension, I: the production of persistent elevation of systolic blood pressure by
means of renal ischemia. J Exp Med. 1934;59:347-79.
15. Goldblatt H. Studies on experimental hypertension, V: the pathogenesis of experimental hypertension due to renal ischemia. Ann Intern Med.
1937;11:69-103.
16. Grimson KS. The onset of renal ischemia hypertension induced by readily adjustable renal artery clamps. J Physiol. 1939;95:P45.
17. Harrison TR, Blalock A, Mason MF, et al. Relation of kidneys to blood pressure: effects of extracts of kidneys of normal dogs and of dogs with renal
hypertension on blood pressure of rats. Arch Intern Med. 1937;60:1058-68.
18. Harrison TR, Blalock A, Mason MF. Effect on blood pressure of injection of kidney extracts of dogs with renal hypertension. Proc Soc Exp Biol.
1937;35:38-40.
19. Heymans C, Bouckaert JJ. Vasoconstrictor properties in blood of hypertensive dogs. Proc Soc Exp Biol. 1938;39:94-5.
20. Houssay BA, Fasciolo JC. Demostración del mecanismo humoral de la hipertensión nefrógena. Bol Acad Nac Med. 1937;18:342-4.
21. Houssay BA, Fasciolo JC. Secreción hipertensora del riñón isquemiado. Rev Soc Arg Biol. 1937;13:284-7.
22. Houssay BA, Taquini AC. Acción vasoconstrictora de la sangre venosa del riñón isquemiado. Rev Soc Arg Biol. 1938;14:5-14.
23. Houssay BA, Braun-Menendez E. Renin in experimental hypertension. Br Med J. 1942;2(4258):179-81.
24. Johnson GI. On certain points in the anatomy and pathology of Bright’s diseases of the kidney, II: on the influence of the minute blood vessels
upon the circulation. Med Chir Trans. 1868;51:57-80.
25. Kohlstaedt KG, Helmer OM, Page IH. Activation of renin by blood colloids. Proc Soc Exp Biol Med. 1938;39:214-5.
26. Korotkoff NS. On methods of studying blood pressure. Izv Voennomed Akad. 1905;11:365-70.
27. Leloir LF, Muñoz JM, Braun-Menéndez E, et al. La secreción de la renina y la formación de hipertensina. Rev Soc Arg Biol. 1940;16:75-80.
28. Leloir LF, Muñoz JM, Taquini AC, et al. La formación del angiotensinógeno. Rev Argent Cardiol. 1942;9:269-78.
29. Mahomed FA. Chronic Bright’s disease without albuminuria. Guy’s Hosp Rep. 1881;25:295-416.
30. Mahomed FA. On the sphygmographic evidence of arterio-capillary fibrosis. Trans Path Soc. 1877;28:394-7.
31. Mahomed FA. The physiology and clinical use of the sphygmograph. Med Times Gaz. 1872;1:62-4.
32. Menendez EB, Fasciolo JC, Houssay BA, et al. Angiotonin or hypertensin. Science. 1943;98(2553):495.
33. Page IH, Helmer OM, Plentl AA, et al. Suggested change in designation of “renin-activator” (hypertensinogen) to “renin-substrate (agr globulin)”.
Science. 1943;98:153-4.
34. Page IH, Helmer OM. A crystalline pressor substance (angiotonin) resulting from the reaction between renin and renin-activator. J Exp Med.
1940;71:29-42.
35. Page IH, Helmer OM. A crystalline pressor substance: angiotonin. Proc Center Soc Clin Invest. 1939;12:17.
36. Page IH, McCubbin JW. Renal hypertension. Chicago: Year Book Medical Publishers; 1968.
37. Page IH, McSwain B, Knapp GM, et al. The origin of renin activator. Amer J Physiol. 1941;135:214-22.
38. Page IH. On the nature of the pressor action of renin. J Exp Med. 1939;70:521-542.
39. Page IH. Vasopressor action of extracts of plasma of normal dogs and dogs with experimentally produced hypertension. Proc Soc Exp Biol.
1937;35:112-6.
40. Prinzmetal M, Friedman B, Oppenheimer ET. Failure to demonstrate pressor properties in extracts of blood from hypertensives. Proc Soc Exp Biol.
1938;38:493-4.
41. Prinzmetal M, Friedman B. Pressor effects of kidney extracts from patients and dogs with hypertension. Proc Soc Exp Biol. 1937;35:122-4.
42. Rittel W, Iselin B, Kappeler H, et al. Synthese eines hochwirksamen hypertensin II-amids. Helv Chim Acta. 1957;40:614-6.
43. Riva-Rocci S. Un nuovo sfigmomanometro. Gazz Med Torino. 1896;47:981-1001.
44. Ronco C, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527-39.
45. Schwarz H, Bumpus FM, Page IH. Synthesis of a biologically active octapeptide similar to natural isoleucine angiotonin octapeptide. J Am Chem
Soc. 1957;5697-703.
46. Schwyzer R, Iselin B, Kappeler H, et al. Synthese von hypertensin-peptiden: über die partielle hydrolyse von hypertensin-asp-ß-amiden zu den
entsprechenden dicarbonsäuren: hypertensin II-analogue. Chimia. 1957;11:335-8.
47. Solandt DJ, Massin R, Cowan CR. Hypertensive effect of blood from hypertensive dogs. Lancet. 1940;1:873-4.
48. Taquini AC, Blaquier P, Taquini AC Jr. Studies on the renal humoral mechanism of chronic experimental hypertension. Circulation. 1958;27:672-5.
49. Taquini AC, Braun-Menéndez E. Liberación de substancia vaso-constrictora en el riñón completamente isquemiado. Rev Soc Arg Biol.
1938;14:422-9.
50. Taquini AC Jr, Taquini AC. The renin-angiotensin system in hypertension. Am Heart J. 1961;62:558-64.[Medline] [Order article via Infotrieve]
51. Taquini AC. Producción de sustancia vasoconstrictora renal en diversas circunstancias. Rev Soc Arg Biol. 1938;14:456-60.
52. Tigerstedt R, Bergman PG. Niere und Kreislauf. Skand Arch Physiol. 1898;8:223-71.
53. Verney EB, Vogt M. An experimental investigation into hypertension of renal origin, with some observations on convulsive “uraemia”. Q J Exp
Physiol. 1938;28:253-9.
54. Volhard F. Nieren und ableitende Harnwege. In: Bergmann G, Staehelin R (Eds). Handbuch der Inneren Medizin, vol 6. Berlin: Springer Verlag;
1931. pp. 1-1023.
44 History of Oxidative Stress and
Cardiovascular Disease Protection
Prakash A, Agarwal SK
air. Davies et al. (1982) using electron paramagnetic resonance spec-

INTRODUCTION
troscopy proved that strenuous exercise induces oxidative stress
The stress purported by the various reactive oxygen species (ROS) as measured by oxidative damage of lipids, proteins and even the
which threaten to oxidize biological moieties involved in various genetic material.3 The cells in the human body do harbor defenses
organ systems and thus inducing damage is called “Oxidative Stress”. against ROS generated by external and endogenous environmen-
Under normal circumstances, biological systems are capable of tal factors. This antioxidant defense has two components, e.g.
detoxifying the various reactive intermediates and repair such dam- enzymes and low-molecular-weight antioxidants component. Various
age. In essence, oxidative stress represents an imbalance between enzymes which serve to scavenge ROS include superoxide dismutase,
the production of ROS and a biological system’s ability to readily catalase, glutathione peroxidase and peroxiredoxins. Other anti-
detoxify or repair the resulting damage. oxidants include a-lipoic acid, mixed carotenoids, coenzyme Q10,
Reactive oxygen species are basically the “free radicals”. The bioflavonoids, minerals (copper, zinc, manganese and selenium)
term “free radicals” was initially used to describe intermediate com- and vitamins (folic acid, vitamins B1, B2, B6, and B12), which work
pounds in organic and inorganic chemistry and has been known against free radicals. Vitamin E suppresses propagation of lipid per-
since the beginning of the 20th century. Daniel Gilbert and Rebecca oxidation; vitamin C and vitamin E inhibit hydroperoxide formation
Gersham (1954), suggested that these radicals are important play- and vitamins A and E scavenge free radicals,4 when the produc-
ers in biological environments and were responsible for deleterious tion of ROS exceeds the body’s natural antioxidant defense mecha-
processes in the cell. Herman Denham (1956) suggested that the free nisms. Oxidative stress has the potential to be harmful to the human
radical species might play a role in physiological events and particu- body and its cells, by damaging lipids (peroxidation of unsaturated
larly in the ageing process. He hypothesized the free-radical theory fatty acids), proteins (denaturation), ribonucleic acid (RNA) and
of ageing, particularly the oxygen-derived and other non oxygen- deoxyribonucleic acid (DNA), etc. In fact, it is believed that it is the
derived, radical reactive species.1 The ROS are highly active chemical cumulative damage over a period of time, which contributes to the
moieties, which contain oxygen and are unstable. Of the ROS, hydro- process of ageing. Apart from ageing, oxidative stress is associated
gen peroxide (H2O2) and superoxide (O2–) are produced in a number with a number of diseases including cancer, cardiovascular diseases
of cellular reactions by various enzymes, such as lipoxygenases, per- (CVD), diabetes, etc. Glucose is oxidized in a transition-metal-de-
oxidises, nicotinamide adenine dinucleotide phosphate (NADPH) pendent reaction to an enediol radical anion that is converted into
oxidase and xanthine oxidase as a result of energy production from reactive ketoaldehydes and to superoxide anion radicals, undergoing
mitochondria. They carry out highly sophisticated intra, inter and dismutation to H2O2, which leads to production of reactive hydroxyl
extracellular signaling roles, which are essential for normal radicals. This process is exaggerated in diabetics wherein oxidative
biochemical functioning. It is important to realize that ROS are also stress-linked damage results in diabetic complications.
generated by the human body in times of stress, as well as detoxifica-
tion reactions carried out by the cytochrome P-450 system. However, HISTORY
during environmental stress, there can be excessive production of
ROS and such high levels have the potential to damage cell structures Oxidative stress and CVD protection has generated a lot of interest
in which scenario it is known as “oxidative stress”. and the work has largely been performed in the last half century
Excessive generation of ROS is an integral part of many stress with major advances being made in the last two decades itself. In-
situations; including hypoxia,2 exercise, etc. which increases free terestingly, the first published article relating to oxidative stress to
radical production and overwhelms defenses, resulting in oxidative the cardiovascular system dates back to 1968.5 The authors studied
insult. Dillard et al. (1978) showed that moderate exercise increased oxidative and phosphorylative activities in mitochondria isolated
the content of pentane, a lipid peroxidation by-product, in expired from the right and left ventricles of normal and chronically stressed
dog hearts. The authors reported that there were no differences contributes significantly to the development of atherosclerosis.19
between mitochondria from normal and stressed hearts with regard Elevated indices of lipid peroxidation were reportedly associated
to the efficiency of oxidative phosphorylation or the amount of mi- with the pathogenesis of atherosclerosis and vitamin E supplemen-
tochondria. However, the mitochondria isolated from the stressed tation suppressed indices of lipid peroxidation in smokers and non-
hearts had abnormally high values for oxidative activity under cer- smokers.20 Vitamin E supplementation was shown to protect LDL
tain conditions. An inference can thus be drawn that there does exist against copper-induced and macrophage-mediated oxidation, in-
an element of oxidative stress in the stressed dog hearts. hibit oxidation-dependent accumulation of LDL in macrophages and
The vascular endothelium is extremely sensitive to oxidative prevent stimulation of cholesteryl ester formation in macrophages.
damage mediated by reactive oxygen metabolites, which play a role Further, intracellular enrichment with vitamin E prevented oxidative
in the pathogenesis of atherosclerosis and is postulated to contribute modification of LDL by macrophages.21
to the aging process.6,7 Soon thereafter, another study indicated that In 1995, a new perspective was presented regarding hyperten-
acute smoking exerts an oxidative stress on plasma lipoproteins and sion and atherosclerosis vis-à-vis role of oxidative stress. Increases
that higher plasma levels of natural antioxidants, such as vitamins in blood pressure cause continuing adaptive responses in the blood
C and E have a protective role.8 The next year, oxygen free radicals vessels, be it larger arteries or the microvasculature. The increased
were implicated in ischemia-reperfusion injury to endothelium growth response of vascular smooth muscle is one of the charac-
of heart, lung and other vital organs and contributing to develop- teristics of atherosclerosis in large arteries. This increased vascular
ment of atherosclerosis and pulmonary toxicity. Endothelial cell smooth muscle cell growth is a common feature in the pathogenesis
injury due to oxidative stress was believed to be the result of calcium of both atherosclerosis and hypertension; and the endothelium plays
influx and resultant activation of calcium-dependent proteases.9 By an important role in this process. The normal endothelium exhibits
the end of 1991, oxidative stress was strongly implicated in a num- an inhibitory influence on the vascular smooth muscle cell growth,
ber of diseases including atherosclerosis.10 Oxidative stress, when which when becomes dysfunctional, contributes to vascular smooth
associated with electrocardiographic aspects of coronary artery dis- muscle growth and the resultant narrowing of the lumen, so very
ease (CAD) indicates an accelerated course of atherosclerosis in the characteristic of the atherosclerotic process. There was mounting
onset phase and an additional thrombogenic risk in the ischemic evidence that hypertension, like hyperlipidemia, induces oxidative
disease phase; and when associated with chronic cardiac failure, it stress in the arterial wall to trigger the development of hyperten-
indicates a progressive form with replacement fibrosis. In fact, it was sion, presumably by inactivating endothelium-derived nitric oxide
suggested that therapies that reduce oxidative stress can slow down and thus mitigating this important vasodilator mechanism. Nota-
the pathophysiologic process and clinically improve the patients’ bly, one mechanism of blood pressure elevation was the destruction
condition and prognosis.11 Oxidative stress indicators were found of nitric oxide by excessive production of oxygen free radicals. Re-
to be abnormal in unstable angina as well. Free radicals and toxic cently, a number of models of hypertension support the notion that
oxygen species were proven experimentally to bear adverse effects oxygen free radicals contribute to the causes and consequences of
on myocardial contractile function, myocardial electrical stabil- hypertension. Presence of hypertension along with hyperlipidemia
ity, endothelial mediated vasodilatation and coagulation.12 In 1993, exerts a more potent stimulus, suggesting that through a common
vitamin C was demonstrated to protect low-density lipoprotein mechanism both conditions enhance the oxidative stress on the
(LDL) against atherogenic modification by free radical scavenging.13 arterial wall. In fact, hypertension sustained coronary artery plaque
Epidemiological work and the evidence from studies suggested that progression despite the return of cholesterol levels towards normal
oxidative damage does indeed make an important contribution to with dietary manipulation. One reason that hypertension facilitates
plaque development.14 Even the role of a molecular linkage between the development and progression of atherosclerosis may be that it
an antioxidant sensitive transcriptional regulatory mechanism and oxidatively stresses or injures the endothelium which resulting in
VCAM-1 gene expression expanding on the notion of oxidative stress activation of redox-sensitive mechanisms that recruit mononuclear
as an important regulatory signal has been implicated in the patho- leukocytes in to the arterial wall. The article22 concluded that hyper-
genesis of atherosclerosis.15,16 With interest in oxidative stress and it tension increases oxidative stress and may activate genes involved
is being implicated in genesis of atherosclerosis, researchers started in generating an inflammatory response that, in the presence of
dwelling in to the prevention aspect of oxidative stress and in the hyperlipidemia, leads to formation of atherosclerotic plaque. A lot of
mid-1990s role of antioxidants was evaluated in various researches interest has been generated in use of antioxidants in the treatment of
to prevent oxidative stress.17,18 atherosclerosis.
In fact, it was starting to be believed that antioxidants are the Low-density lipoprotein cholesterol must undergo oxidative
magic wands of medicine and will be able to control not only athero- modification by means of oxygen free radical processes before it
sclerosis, but also other associated diseases where oxidative stress becomes atherogenic. Patients with high levels of oxidative stress
was implicated. Several studies reported that lipid peroxidation include those with risk factor clustering or insulin resistance or both.
Chapter 44  History of Oxidative Stress and Cardiovascular Disease Protection 323
Such patients are characterized by hypertension, truncal obesity, showed improvement in endothelial dysfunction, oxidative stress
hypertriglyceridemia, depressed high-density lipoprotein (HDL) and glycemic control in microalbuminuria in diabetics.28-30 In fact,
cholesterol levels, and increased insulin levels. They also have different sulfonylureas have also been implicated to have differing
increased levels of triglyceride-rich remnant lipoproteins and LDL roles in ameliorating oxidative stress among diabetics.31 With oxida-
particles that are characterized by their small dense nature and pro- tive stress and endothelial dysfunction firmly in the saddle as con-
nounced predisposition to oxidative modification. Biologic antioxi- tributors in the pathophysiology of atherosclerosis and CVD, the end
dants seem to be a promising therapy for the prevention of athero- of the 20th century and the dawn of the 21st century saw a search for
genesis. Although long-term prospective data were not available in a number of antioxidants, which could reverse or halt the progres-
1995, vitamin E had been shown to be effective in both animal and sion of atherosclerosis and offer protection to human beings against
human models in preventing LDL oxidation and it was believed to CVD.
have a useful role in the prevention of CAD. A healthy diet of fresh Prospective clinical trials with vitamins, hormone replace-
fruits, vegetables and whole grains is beneficial because it improves ment therapy have not fulfilled the expectations, although there
the lipid levels and provides high levels of natural antioxidants. is still continuing interest in other dietary supplements. Beta-
The atherogenic potential of hydrogenated polyunsaturated fats is carotene had been investigated for many years, but lycopene, in
approximately equivalent to that of saturated fats. Monounsaturated tomato attracted a lot of interest. Lycopene has unique structural
fat is inherently resistant to oxidation and may be protective against and chemical features which contribute to its biological properties.
CAD. Niacin may be effective in patients with clustered risk factors. It is chemically quite resistant to heat and cooking and because
It has been found to convert the easily oxidized small dense LDL of its high number of conjugated double bonds, lycopene exhib-
pattern to the large buoyant oxidation-resistant particles. Hydroxym- its higher singlet oxygen quenching ability compared with a- or
ethylglutaryl-coenzyme A reductase inhibitors (HMG-coA inhibitors b-carotene. The oxidation-protecting effect of lycopene has been
or commonly called statins) are well tolerated and highly effective shown to result in a reduction in the risk of CAD and atherosclerotic
in decreasing LDL cholesterol, but they are expensive. Estrogen has progression. Circulating high levels of lycopene, plays a role in the
multiple potentially beneficial effects relative to CVD. Persons with early stages of atherogenesis and may have a clinical and public
or at high risk for CAD should be identified early and aggressively health relevance.28,29,32-34 In 2002 itself, patients with mild essen-
treated with a program that involves lifestyle changes, alterations tial hypertension reportedly had reduced endothelium-depend-
in dietary intake and pharmacologic therapy.23 The possible role of ent vasodilation, lower levels of ascorbate, urate, b-carotene and
combined therapy with antioxidant vitamins C, E and carotene and lycopene in plasma as compared to normotensive subjects.35
a diet rich in antioxidants could independently inhibit free radical Benfotiamine is a synthetic S-acyl derivative of thiamine (vitamin
generation and the development of atherosclerosis.24 B1) and has recently evinced interest because of its antioxidant
In 2000, Dhalla NS reported that the existing evidence supported effect for which it is being used as “anti-AGE” (advanced glycation
the view that oxidative stress may play a crucial role in cardiac and end-product) supplement in diabetics.
vascular abnormalities in different types of CVD and that the antioxi- Superoxide dismutase mimetics, thiols, xanthine oxidase and
dant therapy may prove beneficial in combating these problems.25 NAD(P)H oxidase inhibitors are currently receiving much interest,
The Heart Outcomes Prevention Evaluation (HOPE) study was a while animal studies using gene therapy show promise, although are
landmark study in cardiovascular protection. The HOPE study was still at an early stage.36 Angiotensin converting enzyme inhibitors,
a 19-country, prospective randomized trial in which the angiotensin AT1 (angiotensin II type I) receptor blockers and statins have been
converting enzyme (ACE) inhibitor ramipril, but not vitamin E sig- proven to have definite beneficial effects on oxidative stress apart
nificantly reduced the risk of future cardiovascular events in a high- from their usual antihypertensive and lipid-lowering properties,
risk population of men and women, including many with diabetes.26 respectively.
Although the HOPE study was initially planned for 4 years, the The journey of antioxidant role in prevention of CVD is far from
vitamin E arm was further extended, but did not show any benefit over. The role of oxidative stress and endothelial dysfunction has been
despite the long follow-up. However, recently vitamin E has been established in the pathophysiology of CVD; however, the role of anti-
shown to reduce CVD in individuals with diabetes mellitus and the oxidants in prevention of CVD and atherosclerosis is still debatable.
haptoglobin 2-2 genotype. As the antioxidant function of the Hp Antioxidants have shown benefit in experimental studies, but definite
2-2 protein is impaired, antioxidant vitamin E supplementation did evidence of benefit in humans is yet to be established. Antioxidant
prove to be beneficial in preventing CVD.27 Like ramipril (an ACE role in CVD has dawned on the horizon late, and hopefully the scene
inhibitor), angiotensin receptor antagonists viz losartan have also will be much clearer as further studies unfold in the years to come.
REFERENCES
1. Kohen R, Nyska A. Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantifica-
tion. Toxicol Pathol. 2002;30:620-50.
2. Blokhina O, Virolainen E, Fagerstedt KV. Antioxidants, oxidative damage and oxygen deprivation stress: a review. Ann Bot. 2003;91:179-94.
3. Atalay M, Laaksonen DE. Diabetes, oxidative stress and physical exercise. J Sports Sci Med. 2002;1:1-14.
4. Maritim AC, Sanders RA, Watkins JB. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003;17:24-38
5. Stoner CD, Ressallat MM, Sirak HD. Oxidative phosphorylation in mitochondria isolated from chronically stressed dog hearts. Circ Res. 1968;23:87-
97.
6. Whorton AR, Montgomery ME, Kent RS. Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic
endothelial cells. J Clin Invest. 1985;76:295-302.
7. Hennig B, Boissonneault GA, Wang Y. Protective effects of vitamin E in age-related endothelial cell injury. Int J Vitam Nutr Res. 1989;59:273-9.
8. Harats D, Ben-Naim M, Dabch Y, et al. Effect of vitamin C and E supplementation on susceptibility of plasma lipoproteins to peroxidation induced
by acute smoking. Atherosclerosis. 1990;85:47-54.
9. Geeraerts MD, Ronveaux-Dupal MF, Lemasters JJ, et al. Cytosloic free calcium and proteolysis in lethal oxidative injury in endothelial cells. Am J
Physiol. 1991;261:c889-96.
10. Farr SB, Kogoma T. Oxidative stress responses in Escherichia coli and Salmonella typhimurium. Microbiol Rev. 1991;55:561-85.
11. Popovici D, Olinescu R, Hertoghe J. The negative impact of oxidative stress in chronic cardiac failure and coronary heart disease calls for a new
pathophysiologic and therapeutic approach. Rom J Endocrinol. 1992;30:87-101.
12. McMurray J, Chopra M, Abdullah I, et al. Evidence for oxidative stress in unstable angina. Br Heart J. 1992;68:454-7.
13. Retsky KL, Freeman MW, Frei B. Ascorbic acid oxidation products protect human low density lipoprotein against atherogenic modification. J Biol
Chem. 1993;268:1304-9.
14. Halliwell B. The role of oxygen radicals in human disease, with particular reference to the vascular system. Haemostasis. 1993;23 (suppl1):118-26.
15. Marui N, Offermann MK, Swerlick R, et al. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through
an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993;92:1866-74.
16. Offermann MK, Medford RM. Antioxidants and atherosclerosis: a molecular perspective. Heart Dis Stroke. 1994;3:52-7.
17. Artur Y, Cals MJ, Clerc M, et al. Updating of relative data on tocopherols in clinical biochemistry. Ann Biol Clin. 1994;52:9-31.
18. Henriksen T, Endresen M. Oxidative stress and antioxidants. Tidsskr Nor Laegeforen. 1994; 114:328-30.
19. Halliwell B. Free radicals and antioxidants: a personal view. Nutr Rev. 1994;52:253-65.
20. Brown KM, Morrice PC, Duthie GG. Vitamin E supplementation suppresses indexes of lipid peroxidation and platelet counts in blood of smokers
and non-smokers but plasma lipoprotein concentrations remain unchanged. Am J Clin Nutr. 1994;60:383-7.
21. Suzukawa M, Abbey M, Clifton P, et al. Effects of supplementing with vitamin E on the uptake of low density lipoprotein and the stimulation of
cholesteryl ester formation in macrophages. Atherosclerosis. 1994;110:77-86.
22. Alexander RW. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new
perspective. Hypertension. 1995;25:155-61.
23. O’Keefe JH, Lavie CJ, McCallister BD. Insights into the pathogenesis and prevention of coronary artery disease. Mayo Clin Proc. 1995;70:69-79.
24. Singh RB, Niaz AM, Ghosh S, et al. Randomized controlled trial of antioxidant vitamins and cardioprotetive diet on hyperlipidemia, oxida-
tive stress, and development of experimental atherosclerosis: the diet and antioxidant trial on atherosclerosis (DATA). Cardiovasc Drugs Ther.
1995;9:763-71.
25. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000;18:655-73.
26. McQueen MJ, Lonn E, Gerstein HC, et al. The HOPE (Heart Outcomes Prevention Evaluation) Study and its consequences. Scand J Clin Lab Invest
Suppl. 2005;240:143-56.
27. Blum S, Vardi M, Brown JB, et al. Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.
Pharmacogenomics. 2010;11:675-84.
28. Pathania A, Agarwal SK, Agarwal S, et al. Effect of Angiotensin receptor blocker, Losarton and raw tomato on endothelial function, lipid peroxida-
tion and urine albumin excretion rate in normotensive type 2 diabetes with microalbuminuria. JAPI. 2002;50:1469.
29. Sikdar S, Agarwal SK, Prakash A, et al. Lycopene supplementation in Losartan treated normotensive type 2 Diabetes Mellitus patients with micro-
albuminuria and its effect on endothelial function markers. JAPI. 2003;51:1163. Abstract 51, 2003.
30. Sikdar S, Anuradha S, Singh NP, et al. Serum lycopene in type 2 diabetes mellitus with microalbuminuria and its correlation with endothetial
dysfunction. Ind Heart J 2003;55:561-70.
31. Agarwal SK. Oxidative stress and type 2 diabetes mellitus: Role of different sulfonylureas as antioxidant. JIMSA. 2003;16:184-8.
32. Suganuma H, Inakuma T. Protective effect of dietary tomato against endothelial dysfunction in hypercholesterolemic mice. Biosci Biotechnol
Biochem. 1999;63:78-82.
33. Rissanen T, Voutilainen S, Nyyssonen K, et al. Lycopene, atherosclerosis, and coronary heart disease. Exp Biol Med. 2002;227:900-7.
34. Rissanen TH, Voutilainen S, Nyyssonen K, et al. Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease
Risk Factor Study. Am H Clin Nutr 2003;77:133-8.
35. Moriel P, Sevabian A, Ajzen S, et al. Nitric oxide, cholesterol oxides and endothelium-dependent vasodilation in plasma of patients with essential
hypertension. Braz J Med Biol Res. 2002;35:1301-9.
36. Hamilton CA, Miller WH, Al-Benna S, et al. Strategies to reduce oxidative stress in cardiovascular disease. Clin Sci. 2004;106:219-34.
45 History of Hormone Replacement
Therapy and the Heart
Nath RK
INTRODUCTION MENOPAUSAL SYMPTOMS

Hormone replacement therapy (HRT) is the way of replacing or sup- Experiences of menopausal symptoms vary widely and are found to
plementing the declining amount of female sex hormones, namely be related to a wide range of factors like socioeconomic class, eth-
estrogen and progesterone for (1) treatment of postmenopausal nicity, culture, etc. Before the starting of true menopause or perma-
symptoms and (2) prevention of chronic diseases like coronary heart nent cessation of menstruation cycles there is a period during which
disease (CHD) or osteoporosis during and after menopause, which the menstruation cycles of a woman become irregular in respect of
are attributed to the declining levels of female sex hormones. Meno- intercycle duration or the duration of the menstrual flow. The men-
pause is the time in every woman’s life when her menstrual period strual flow may become scanty in some women. After a period of
stops. Meno is derived from the Greek word for month and pause is such changes, duration of which may vary from woman to woman,
derived from the Greek word pauses or halt. Menopause is a nor- the permanent cessation of the cycle occurs and once it lasts for 12
mal physiological phenomenon in the aging process of a woman. continuous cycles then a woman is leveled as attaining menopause.
Although all women experience menopause, not all of them experi- Even after attaining menopause some women may experience inter-
ence the symptoms resulting from the reduced production of their mittent break-through bleeding without any definite cyclical pattern
sex hormones. All these symptoms may not be related to the reduced for some time. All these changes occur due to the gradual reduction
hormone levels, as some of them may be related to the normal aging in amount of hormone secretion by the ovaries, mainly the estrogen
process of a woman, but there is a great degree of diversity in attribut- and progesterone. Part of the reduced secretion is due to the ever
ing the symptoms of menopause to the levels of hormones.1 decreasing number of the follicle in the ovaries and partly due to the
Hormone replacement therapy is one such area in the medical age-related changes occurring in the hypothalamic control over the
history, where the pharmaceutical product was widely prescribed hormone synthesis. The following are the commonly encountered
and used for prolong period before proving their effectiveness and menopausal symptoms that are attributed to the reduced levels of
knowing the side effect profile comprehensively. This was because of sex hormones in women:1
the publicity that the drug would keep the women forever young and • Changes in the menstrual cycle like difference in the interval
would work as an antiaging wonder drug. The publicity was so dis- between periods and difference in the flow level
proportionate to the clinical evidence available during that time that • Hot flashes that includes getting warm in the face, neck and
even after showing its causal association with endometrial cancer the chest
in 1975–76, this drug was the most commonly prescribed and easily • Night sweats
available medicine across the United States of America and the other • Vaginal changes that includes vulvar and vaginal atrophy;
parts of the developed countries.1,2 Though, a substantial reduction dryness, itching, burning or thinning of the vagina
in its use was seen after the publication of these trials showing its • Painful intercourse due to the vaginal changes.
association with cancer, some data showing its benefit in reducing Some of the symptoms that appear during the perimenopausal
cardiovascular disease (CVD) led to the second peak in its use.1 After and menopausal period of a woman may be attributed to the meno-
multiple large scale trials showing that there is a significant increased pausal hormonal changes; others may be related to the aging process
risk of CHD and other cardiovascular disorders with its long-term of a woman. These include a variety of symptoms like:
use, the HRT is no more a commonly prescribed therapeutic inter- • Depression
vention. • Irritability
• Sleeplessness product Progynon from the pregnant women urine and was mar-
• Increased body fat keted in Germany for treatment of hot flashes and night sweats of
• Weight gain, salt and fluid retention menopause. Subsequently, they also used the pregnant mare’s
• Headache, migraines urine product named Progynon2 as the availability and collection
• Low sex drive of the pregnant women’s urine in a large scale was not feasible. In
• Incontinence 1938, Schering scientist Hans Inhoffen and Walter Hohlweg first
• Osteoporosis synthesized ethinyl estradiol, which subsequently became the most
• Blood clotting commonly used estrogen for birth control.2
• High blood pressure A team of English Chemists including Charles Dodds, developed
• Memory problems and forgetfulness. synthetic, nonsteroidal estrogen and published the formula in the
British magazine Nature on February 5, 1938. This estrogen, diethyl-
DISCOVERY OF ESTROGEN stilbestrol, had the same effect as estrogens derived from natural
sources, but was three times more powerful and was easy to manu-
Biologist, Edgar Allen and the biochemist, Edward Doisy are credited facture by anyone. From the starting Dodds was suspicious about the
to the discovery of the female sex hormone, estrogen. After complet- cancer-causing potential of diethylstilbestrol, as well as any harm-
ing their assignment with the US Army as part of World War I, both of ful effects of using a foreign substance into the female reproductive
them accepted positions at Washington University School of Medi- physiology. Other scientists started working on these suspicions and
cine in 1919. Edgar Allen had studied the estrous cycle of the mouse in December 1939, the JAMA published editorials urging a thorough
as his doctoral dissertation, which described the cellular changes investigation of diethylstilbestrol prior to approval by the Food and
in the animal’s reproductive organs during its reproductive cycle. Drug Administration (FDA) of USA.1
During the period of 1922–23, Edward Doisy was involved in the
purification of insulin to treat young diabetic patients as the hormone, PROGESTERONE
though discovered, was not easily available for treating patients.
While discussing their projects and the way pancreatic hormone Progesterone or progestins are added to estrogen in HRT to protect
insulin works in the cellular uptake of glucose, Allen could draw against the risk of hyperplasia and adenocarcinoma of the endome-
a relationship between the ripening of the follicular cells of the trium as studies have shown that the exogenous estrogens adminis-
ovaries and the development of the reproductive organs like uterus tered alone to non-hysterectomized women significantly increases
and vagina. He postulated the relationship to the possible effect of a the risk of endometrial hyperplasia and carcinoma. Addition of pro-
hormone.2 gesterone at adequate dosage reduces that risk. But this combination
To test the hypothesis, Allen injected the liquid extracted from of progestins to estrogen may lead to an increased risk of breast can-
the follicles of sow ovaries into the female mice and rats whose ova- cer in women on HRT. Progesterone in its naturally occurring form is
ries had been removed. The injections caused the vaginas of the mice not suitable for use in HRT, as it is rapidly metabolized in the gut and
and rats to become estrous and the cellular changes were clearly vis- liver after oral ingestion. The high dose of oral progesterone required
ible under the microscope. Allen subsequently injected the follicu- to achieve therapeutic plasma level produces sedation. Natural pro-
lar extract into baby mice and rats, which resulted in rapid matura- gesterone creams never give the required therapeutic level for its
tion of the uteruses and vaginas of those animals into adult size. The action. Several synthetic progesterones or progestins are available,
results proved the existence of some “estrogenic hormone” (so called which does not undergo rapid metabolic degradation. Progestins
because it stimulated estrous growth in the sex organs). Doisy tried can be given sequentially with estrogen, for 10–14 days in the second
to purify the active substance in the follicular fluid. He took the help half of the cycle and bleeding occurs towards the end of this phase or
of the urine of the pregnant women where the estrogenic hormone when the progesterone is withdrawn.3
was said to be present in large quantities by Selmar Ascheim and
Bernhard Zondek in 1927 from Berlin. On July 13, 1929, Doisy iso- HORMONE REPLACEMENT THERAPY
lated the first sample of pure crystalline estrogen.2 Subsequently they
described its effect and also identified all other female hormones As the name suggests the therapy constitutes replenishment of some
and their inter-relations in female reproductive physiology. of the hormones the ovaries have stopped producing. The formula
Biochemist Dr James Bertrand Collip in association with Ayerst is mostly a combination of estrogen and progestin (a synthetic form
Laboratory produced the first commercial product in 1930. Ayerst of progesterone), which can be used in the form of pills, patches,
Lab named the product as Premarin (PREgnant MARes’ urINe) as the gels or implants and at different dosages according to the need of
estrogen was extracted from the urine of the pregnant mares. Dur- the individual woman. The common reason for taking HRT is to re-
ing the same period scientist Adolph Butenandt in association with duce the symptoms of menopausal symptoms. Studies comparing
German pharmaceutical company Schering came out with the HRT with placebo show strong evidence that HRT is effective in al-
Chapter 45  History of Hormone Replacement Therapy and the Heart 327
leviating such symptoms when it is taken for a short-term ranging major concern with these pills. After the HRT was started in the treat-
from 6 months to 5 years. On September 19, 1941, the FDA officially ment of menopausal symptoms, there was the indiscriminate use of
approved diethylstilbestrol for use in four types of illnesses:1,2 these drugs for lot other reasons including to remain young forever.
• Menopausal symptoms Part of this indiscriminate use was due to the publicity by pharma-
• Senile vaginitis ceutical companies and partly due to the enthusiasm of the Gynecol-
• Gonorrheal vaginitis ogists. This began to change the estrogen therapy into a long-term
• To prevent lactation in women who had recently given birth. treatment for chronic illnesses of aging. Gynecologist Robert Wil-
In 1947, the US FDA officially approved diethylstilbestrol for use son wrote the 1966 best seller “Feminine Forever” where he argued
in preventing miscarriages. Known side effects of the drug include that menopause was not a natural age-related condition; but it was
breast tenderness, fluid retention, nausea and headache. Women a chronic illness like diabetes or renal failure and can be treated by
taking combined pills of estrogen and progestin may witness with- estrogen to replace the hormones that a woman’s ovaries secreted
drawal bleeding. Some women may gain weight after taking HRT in ever diminishing amounts.8 Subsequently, estrogen became one
for a period due to the increased body fat, as well as fluid and water of the most extensively prescribed and popular drug treatment in
retention in the body. the America and other parts of the world. By mid-1990s, the Ameri-
Over the period, the use of HRT therapy has shown some can Heart Association, the American College of Physicians and the
benefits and risks. The proven roles for prescribing HRT are to get American College of Obstetricians and Gynecologists had all con-
relief from menopausal symptoms, and prevention and treatment of cluded that HRT could be recommended to older women for preven-
osteoporosis. There is some evidence in its role in prevention of CVD, tion of heart disease and osteoporosis as their beneficial effects were
colorectal carcinoma and Alzheimer’s disease. However, HRT seems sufficiently well established.8
to be associated with an increased risk of breast cancer, myocardial In 1985, the Nurses’ Health Study from the Harvard Medical
infarction, stroke, thrombotic disease and cholecystitis.4 School and the Harvard School of Public Health had reported that
as compared to the risk in women who never used postmenopausal
THE PROTECTIVE EFFECTS OF ESTROGEN hormones, the age-adjusted relative risk of coronary disease in those
women who used them were significantly lower.9 The 10-year follow-
ON THE CARDIOVASCULAR SYSTEM
up from the Nurses’ Health Study reported that the postmenopau-
There is a significant difference in the incidence of CVD between sal estrogen use was associated with a reduction in the incidence of
men and women. Part of it is because of the difference in the risk CHD, as well as in mortality from CVD, but it was not associated with
factor profiles and the difference in the hormones.5 The incidence any change in the risk of stroke.10 These and multiple other small tri-
of atherosclerotic diseases is significantly low in the premenopausal als supported the hypothesis that the postmenopausal use of estro-
women, rises in postmenopausal women and is again reduced to gen reduces the risk of CHD. This further confirmed the belief that
premenopausal levels in postmenopausal women who receive estro- estrogen protected the women from heart attacks until menopause
gen therapy. Part of the benefit is due to the hormone’s effects on and hence the protection by taking the HRT after menopause.
serum lipid concentration. Estrogen also alters the coagulation and
fibrinolytic systems, antioxidant systems and production of other HORMONE REPLACEMENT THERAPY AND
vasoactive molecules like nitric oxide and prostaglandins. All these
HEART DISEASE
alterations can influence the development of atherosclerotic vascu-
lar disease. Direct actions of estrogen on blood vessels contribute In 1998, the result of the Heart and Estrogen/progestin Replacement
substantially to the cardiovascular protective effects of estrogen.6 The Study (HERS) Research Group was published. The objective of the
Women Health Initiative Investigators and Women Health Initiative trial was to determine if HRT alters the risk for CHD events in post-
Coronary Artery Calcium Study was published in 2007, where they menopausal women with established coronary disease in a rand-
examined the relationship between estrogen therapy and coronary omized, blinded, placebo-controlled trial in a total of 2,763 women
artery calcium levels, as the calcified plaque in the coronary arter- in 20 US clinical centers. For the first time it showed that HRT therapy
ies is a marker for atheromatous plaque burden and is predictive of did not reduce the overall CHD events; instead it increased the rate
future risk of cardiovascular events. It was found that among women of thromboembolic events and gallbladder disease and likelihood
50–59 years old at enrolment, the calcified-plaque burden in the cor- of suffering a heart attack by a woman who already had heart dis-
onary arteries after trial completion was lower in women assigned to ease.11 In August 2003, the Women’s Health Initiative (WHI) investi-
estrogen than in those assigned to placebo.7 gators published the result of their randomized, placebo controlled
If the HRT is taken for reasons other than menopausal symptoms primary prevention trial of HRT on 16,608 postmenopausal women
like prevention of osteoporosis and heart disease, it needs to be taken of 50–79 years age group. It was reported that HRT does not confer
for a longer duration. Their use for prolong period is associated with protection from CHD and may increase the risk of CHD among gen-
substantial increase in the risk for side effects and that remains the erally healthy postmenopausal women. Though HRT might protect
them against osteoporosis and colorectal cancer, there is substantial ment therapy is partially reduced by addition of progesterone to
increased risk of heart disease, stroke, thrombosis, breast cancer and the regime. But the protection of progesterone decreases with
perhaps dementia.12 In 2007, Rossouw et al. evaluated the timing of long-term use of the pills and the risk significantly increases after
initiation of hormone therapy which may influence its effect on CVD. 5 years of continuous use.
The objective was to explore whether the effects of hormone therapy A serious concern for prescribing HRT to postmenopausal
on risk of CVD vary by age or years since menopause began. They women for long duration is the reported increased risk of breast
found that women who initiated hormone therapy closer to meno- cancer. Epidemiological studies have shown that the risk of breast
pause tended to have reduced CHD risk compared with the increase cancer is higher with estrogen and progesterone combined pills than
in CHD risk among women more distant from menopause.13 After with estrogen alone. In a large meta-analysis of data from 51 observa-
these trials and lot other observational trials it is clear that HRT in tional studies of 52,705 women with breast cancer and 108,411 wom-
postmenopausal women should not be used for reducing risk of en without breast cancer reported that the risk of breast cancer in-
CHD. creased by 2.3% for every year of use of HRT. This increased risk does
not become significant unless HRT is taken for more than 5 years,
HORMONE REPLACEMENT THERAPY when the relative risk is 1.35. The cumulative incidence of breast can-
cer in women aged 50–70 years who have never used HRT is about 45
AND STROKE
cases per 1,000 women. The increased risk in women taking the HRT
Hormone replacement therapy has been shown to be associated translates to two extra cases per 1,000 women in those exposed to the
with an increased incidence of stroke, specially the ischemic stroke. pills for 5 years, 6 extra cases per 1,000 women exposed for 10 years,
Meta-analysis of 28 randomized controlled trials with 39,769 subjects and 12 extra cases per 1,000 women exposed for 15 years.18 The risk of
were analyzed for rate of cerebrovascular events and was found that breast cancer falls after stopping the therapy and returns to baseline
HRT was associated with significant increases in total stroke, nonfa- risk within 5 years. The WHI also showed the increased risk of breast
tal stroke, stroke leading to death or disability. It was not associated cancer with HRT although it could not estimate the risk of death from
with hemorrhagic stroke.14 It is clear from this large meta-analysis breast cancer due to the early termination of the trial. There was a
that HRT cannot be recommended for the primary or secondary 15% increased risk of invasive breast cancer in women taking com-
prevention of stroke. bined estrogen and progesterone pills for less than 5 years and a 53%
increased risk in those taking pills for more than 5 years. The study
HORMONE REPLACEMENT THERAPY concluded that there would be eight more cases of invasive breast
cancer a year for every 10,000 women taking the combined pills.12
AND CANCER
Although there is a concern of association of ovarian cancer with
As early as 1940, in an article published in the JAMA, Allen warned HRT, studies are yet to show a consistent increase in risk. In a study of
that excessive use of estrogen might lead to more incidences of 44,241 women taking HRT were looked for the increased risk of ovar-
cancers among older women. A few months later in the same jour- ian cancer in 29 US clinical centers. It was found that women who
nal, Doisy wrote “The increased incidence of malignant change used estrogen-only replacement therapy for 10 or more years were at
following administration of estrogens to cancer susceptible significantly increased risk of ovarian cancer (relative risk for 10–19
strains of animals serves as a definite warning”.2 Subsequently, years and 20 or more years were 1.8 and 3.2 respectively; p < 0.001).
the risk of cancer after prolong use of HRT was definitely in the Women who used short-term estrogen-progestin-only replacement
minds of the scientists, but was not shown in a treated cohort. In therapy were not at increased risk.19
1975, Smith et al. had shown that the risk of endometrial cancer Observational studies have shown that HRT reduces the risk of
was 4.5 times greater among women exposed to estrogen thera- colorectal cancer. The WHI study for the first time reported six fewer
py in comparison to those who were not exposed.15 In another colorectal cancers each year for every 10,000 women taking HRT
investigation, Ziel et al. reported that conjugated estrogens use was compared with the placebo group.12 The mechanisms behind this
recorded for 57% of 94 patients with endometrial carcinoma and reduction are not clear.
for 15% of controls. The risk-ratio estimate increased with dura-
tion of exposure: from 5.6 for 1–4.9 years of exposure to 13.9 for HORMONE REPLACEMENT THERAPY AND
7 or more years. These data suggest that conjugated estrogens
THROMBOEMBOLIC DISEASE
have an etiologic role in endometrial carcinoma.16 Mack et al.
also reported the same type of finding from their investigation in There are multiple studies showing an increased risk of deep vein
a community with the increased incidence of endometrial car- thrombosis and pulmonary embolism in women taking HRT.
cinoma among the users of estrogen and conjugated estrogen.17 The absolute risk of 16–23 cases per 100,000 women a year for all
This increased incidence of endometrial hyperplasia and endo- venous thromboembolism and 6 per 10,000 women a year for
metrial carcinoma associated with unopposed estrogen replace- pulmonary embolism. Current users of HRT have twice the risk of
Chapter 45  History of Hormone Replacement Therapy and the Heart 329
venous thromboembolism compared with women who never used

CONCLUSION
it. The increased risk for thromboembolism is greater in the initial
year of use. The odds ratio of 4.6 (95% confidence interval 2.5–8.4) Hormone replacement therapy is an established therapeutic modal-
during the first 6 months of use of HRT. Hormone replacement ther- ity for the short-term treatment of menopausal symptoms and in
apy may precipitate thromboembolism in women with underlying menopausal women with osteoporosis not responding to the usual
conditions that predisposes venous thromboembolism. Chance is care. Prolonged use of this therapeutic modality is associated with
high in women with existing predisposing factors like family history a serious concern for disabling or dangerous side effects, including
of thromboembolic disease, presence of varicose vein, obesity, pro- CHD, stroke and cancer. With the available evidence till date, HRT
longs bed rest, post-trauma, postsurgery and advanced age.4 cannot be prescribed for prevention of CHD in menopausal women.
REFERENCES
1. Carla J Rothenberg. The rise and fall of estrogen therapy: the history of HRT. Harvard Law School. 2005.
2. Elizabeth Siegel Watkins. The estrogen elixir: a history of hormone replacement therapy in America. USA: The Johns Hopkins University Press;
2007.
3. David W Sturdee. The facts of hormone therapy for menopausal women. The Parthenon Publishing Group. 2004.
4. Rymer J, Wilson R, Ballard K. Making decisions about hormone replacement therapy. BMJ 2003;326:322-6.
5. Barrett-Connor E. Sex differences in coronary heart disease: why are women so superior? The 1995 Ancel Keys Lecture. Circulation. 1997;95:252-
64.
6. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999;340:1801-11.
7. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591-602.
8. Gary Taubes. Do we really know what makes us healthy? The New York Times Magazine. September 16, 2007.
9. Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J
Med.1985;313:1044-9.
10. Stampfer MJ, Willett WC, Colditz GA, et al. Ten-Year follow-up from the Nurses’ Health Study. N Engl J Med. 1991;325:756-62.
11. Stephen Hulley, Deborah Grady, Trudy Bush, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart dis-
ease in postmenopausal women. JAMA. 1998;280(7):605-13.
12. JoAnn E Manson, Judith Hsia, Karen C Johnson et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-34.
13. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since meno-
pause. JAMA. 2007;297:1465-77.
14. Philip MW Bath, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. [online] Available from BMJ
website http://www.bmj.com/content/330/7487/342 (Accessed July 2012).
15. Smith DC, Prentice R, Thompson DJ, et al. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med. 1975;293:1164-67.
16. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med.1975;293:1167-70.
17. Mack TM, Pike MC, Henderson BE, et al. Estrogens and endometrial cancer in a retirement community. N Engl J Med. 1976;294:1262-67.
18. Beral V, Bull D, Doll R, et al. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of
52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet.
1997;350:1047-59.
19. Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002;288:334-41.
46 Tuberculosis and Heart
Kumar S, Sindhe P
discovery in March 1882 that TB was due to an infectious agent. The

INTRODUCTION
dawn of 20th century witnessed the first International Conference
Tuberculosis (TB) is a known entity to human being for thousands of of TB at Berlin in 1902, followed 4 years later by development of the
years although it has been known by several names through the ages. BCG vaccine in 1906 by Calmette and Guerin. Treatment of TB had a
Such names include phthisis, Pott’s disease, scrofula, white plaque, major breakthrough in 1944 when Streptomycin was developed. The
yaksma and so on. Signs of the disease were described in Egyptian second half of the 20th century witnessed rapid advances in diagno-
mummies between 3000 BC and 2400 BC. Thereafter, a mention of sis and management of TB.
the disease by the name Phthisis can be traced in the Greek literature
around 460 BC and similar description can be found in the works TUBERCULOSIS OF HEART
of Hippocrates. Galen described phthisis as an ulceration of lung
accompanied by cough and fever and consumption of the body by
Tuberculosis and Pericardium
pus. First reference of TB in Asian civilization is found in Vedas as
yaksma. In Atharvaveda, reference to the disease by the name of Tubercular pericarditis is not a common disease, but nevertheless is
scrofula has been found. In South America, evidence of the disease an important one. The credit of first description goes to Carl Rokitan-
can be found in Arawak culture around 1050 BC. sky in 1852. However, it was the work of William Osler which estab-
Following these initial descriptions, no important descriptions lished tubercular pericarditis as an entity. Osler wrote in 1893, “TB
regarding the disease can be traced between Galen and 17th Century pericarditis is due in majority of cases to infection of membrane by
AD. In 1679, Franciscus Sylvius came forward with description of caseous mediastinal lymph node”. Osler detected TB in 215 of 1,000
various forms of TB. Ten years later in 1689, Richard Morton empha- cases of autopsy and further reported that 3% of these 215 cases had
sized on the fact that the tubercle is a key pathological finding of the pericardial involvement. Apart from contiguous or direct extension,
disease. First clinical description of tubercular meningitis was given pericardium can also be infected either via bloodstream or via lym-
by Robert Whytt in 1768 and in 1779, Percivall Pott described Pott’s phatics. In 1929, Burrel Hare and Ross reported that chronic TB of
spine. After Jean Antoine Vilemin demonstrated that the disease was serous sac produces serositis usually polyserositis and such serous
contagious, Robert Koch (Fig. 46.1) came out with the landmark involvement can produce obstruction to heart. Few years later, Han-
neson in 1941 proposed lymphatic spread as the most likely mecha-
nism of tubercular pericarditis. Few years later in 1944, Rich and
others reported that tuberculous effusion can develop following dis-
charge into serous cavity of tuberculoprotein or dead bacilli. A year
later in 1945, Graham, Singer and Ballon opined that TB is the most
common cause of pericarditis. While steady strides were being made
in the understanding of the pathogenesis of tuberculous pericardi-
tis, clinical findings were also being described by some stalwarts in
the field of medicine. Corrigan described pericardial knock in 1842
and Kussmaul described the Kussmaul sign and pulsus paradoxus in
1873.
Although it was progressively being accepted that TB was the
most common infective cause of chronic constrictive pericardi-
tis, it was also being acknowledged that the diagnosis was difficult
to prove despite presence of presumptive evidence. White and
Figure 46.1: Robert Koch Churchill1 proved TB to be the agent in only 5 of 37 cases, whereas
Chapter 46  Tuberculosis and Heart 331
Blalock and Burwell2 found 21 tuberculous cases among 28, Har- value because of high prevalence of primary TB, mass BCG immuni-
rington3 reviewed 24 cases and proved TB in only 5. Holman4 re- zation, and the likelihood of cross-sensitization from mycobacteria
ported from proved cases among nine and McKusick5 considered 8 present in the environment.
of 20 cases to be proved or probable. It was commented by Deterling
et al.6 that all the case-series mentioned had “idiopathic” cases; it Indirect Methods
was appearing certain that additional cases of tuberculous pericardi-
tis would be recognized with greater performance of autopsy. In view of the fact that high mortality rates are associated with
Fowler7 reported that tuberculous pericarditis, causes by My- untreated tuberculous pericarditis and direct methods mentioned
cobacterium tuberculosis, was found in approximately 1% of all au- above are time-consuming and have low yield, indirect diagnostic
topsied cases of TB and 1–2% of instances of pulmonary TB. Mayosi methods have assumed importance. Elevated pericardial adenosine
et al.8 reported that TB was the most common cause of pericarditis in deaminase (ADA) activity has been demonstrated by recent studies
Africa and other countries in which TB remains a major public health to be suggestive of tuberculous pericarditis.16,17 Different cut-off lev-
problem. In recent times, Reuter et al.9 reported that tuberculous els of ADA activity, ranging from 30 U/L to 60 U/L, have been sug-
pericarditis accounted for 69.5% of cases referred for diagnostic peri- gested as being indicative of disease. In a recent study conducted
cardiocentesis. In contrast, tuberculous pericarditis was reported to in South Africa, pericardial ADA levels more than or equal to 35
account for only 4% of cases in developed countries.10 The human U/L was shown to have a sensitivity and specificity of 90% and 74%
immunodeficiency virus (HIV) epidemic in Sub-Saharan Africa is respectively for diagnosis of tuberculous pericarditis.17 Usefulness of
closely linked to increasing incidence of tuberculous pericarditis and ADA as a diagnostic tool has been demonstrated in both HIV-positive
this trend is likely to appear in other parts of the world where spread and HIV-negative patients; however, lower ADA levels are observed
of HIV is leading to resurgence of TB.11 In the Western cape of Africa in HIV-positive patients with severe CD4 lymphocyte depletion. The
too, one half of the patients presenting with large tuberculous peri- measurement of interferon-g (IFN-g) levels in pericardial fluid may
cardial effusion were reported to be infected with HIV.9 offer another means of early diagnosis. A study of 30 consecutive
Amidst this scenario of probable resurgence of tuberculous patients with diverse causes of pericardial effusion demonstrated
pericarditis in the world, definitive diagnosis of tuberculous peri- sensitivity and a specificity of 100%, using a cut-off level of more
carditis has remained a challenge over the years. Clinicians often than 200 pg/L of IFN-g for diagnosis of tuberculous pericarditis.18 In
have had to rely heavily on the clinical features of pericardial TB to a larger study of 233 consecutive patients with pericardial effusion,
initiate therapy; however, in view of the potential for toxic effects Reuter et al.18 demonstrated that pericardial fluid IFN-g ≥ 50 pg/
and duration of anti-tuberculous chemotherapy, it is important to ml concentration had 92% sensitivity, 100% specificity and a posi-
identify which clinical and basic laboratory features should be used. tive predictive value (PPV) of 100% for the diagnosis of tuberculous
There are both direct and indirect methods for diagnosis of tubercu- pericarditis. They further reported that pericardial fluid ADA more
lous pericarditis. than or equal to 40 IU/l had 87% sensitivity and 89% specificity.
They concluded that a diagnostic model including pericardial ADA,
Direct Methods lymphocyte/neutrophil ratio, peripheral leukocyte count and HIV
status had 96% sensitivity and 97% specificity; substituting pericar-
Tuberculous pericardial effusions have been found to be typically dial IFN-g for ADA yielded 98% sensitivity and 100% specificity.
exudative and characterized by a high protein content and in-
creased leukocyte count with a predominance of lymphocytes and Treatment
monocytes. Light’s criteria12 for diagnosing pleural exudates are also
applicable to pericardial exudates.13 The variability in the detection In areas with a high prevalence of TB, a pericardial effusion is of-
of tubercle bacilli in the direct smear examination of pericardial ten considered to be tuberculous in origin unless an alternative
fluid is well documented and ranges from 0% to 42%.10 Pericardial pathogenesis is obvious. Emperical antituberculosis chemothera-
biopsy is invasive, requires technical skills and diagnostic sensitivity py is recommended for exudative pericardial effusion in endemic
been found to range from 10% to 64%.14 Hence, a normal pericardial areas before a bacteriological diagnosis is established provided other
biopsy specimen does not exclude tuberculous pericarditis because causes, such as malignancy, uremia and trauma have been excluded.
in some patients, examination of the pericardium removed at peri- In approximately, two-thirds of the cases treated for tuberculous
cardiectomy or autopsy is required to demonstrate clear-cut evidence pericarditis, diagnosis is based on bacteriology, histology or analy-
of TB. The polymerase chain reaction (PCR) has also been suggested sis of the pericardial fluid. In the remaining patients, an adequate
for detecting Mycobacterium tuberculosis DNA in pericardial fluid.15 response to antituberculous chemotherapy serves as support for
However, currently the technique is less sensitive than established diagnosis. In contrast, in nonendemic areas, if systematic investiga-
methods and is prone to contamination and false-positive results.15 tion fails to yield a diagnosis of tuberculous pericarditis, there is no
In countries where TB is endemic, tuberculin skin testing is of little justification for starting antituberculosis treatment empirically.
Antituberculosis chemotherapy has dramatically improved sur-

TUBERCULOSIS AND MYOCARDIUM
vival in tuberculous pericarditis. According to a report by Harvey
et al. 1937, mortality was 80–90% in the preantibiotic era.19 Currently, Tuberculosis has been mostly described as a cause of pericardial dis-
it ranges from 8% to 17% in HIV-negative patients20 and 17–34% in ease; myocardial involvement, though known, is often not diagnosed
HIV-positive individuals.21 A regimen consisting of rifampicin, iso- during life. Definite diagnosis of tubercular myocarditis can only be
niazid, pyrazinamide and ethambutol for at least 2 months, followed established by tissue studies or on autopsy. Prevalence of isolated
by isoniazid and rifampicin (total of 6 months of therapy) has been myocardial TB has been reported as 0.14%, 0.2% and 2% in various
shown to be highly effective in patients with extrapulmonary TB.22 series.27-29
Treatment for 9 months or longer gives no better results and has the The first case of isolated tubercular myocarditis was reported by
disadvantages of increased cost and poor compliance.22 This shorter Maurocadat in 1664 and second case in 1761 by Morgagni after a gap
course is also effective in HIV-infected patients suffering from TB. of 97 years.27 The rarity of myocardial TB has been linked to constant
Use of corticosteroids in tuberculous pericarditis has been movement of myocardium which may not be conducive to lodgment
another controversial use. No significant benefit of steroids has been of tubercle bacilli; however, Raviart has proposed that lactic acid
demonstrated on the reaccumulation of pericardial effusion or pro- produced by muscular activity may be protective against lodgment
gression of constrictive pericarditis.23 A randomized trial from India of the tubercle bacilli. The various routes of spread of tubercle bacilli
failed to show that antituberculosis treatment prevents development to myocardium that have been suggested include: (1) hematogenous
of constructive pericarditis or alter the clinical course in patients route, (2) direct extension from pericardium, (3) retrograde lympha
with large chronic pericardial effusion of undetermined pathogen- tic spread from bronchial lymph nodes due to endobronchial TB.
esis in patients living in a TB endemic area.24 Despite this report, em- Horn and Saphir30 have described three histological types of
pirical antituberculosis treatment retains its place in a TB endemic myocardial TB: (1) nodular tubercles (tuberculomas) of the myo-
area as mentioned earlier. cardium, varying from pea to egg size, with central caseation,
Constrictive pericarditis occurs in 30–60% of patients suffering (2) miliary TB of the myocardium as part of generalized miliary
from tuberculous pericarditis despite prompt antituberculosis treat- disease, (3) diffuse infiltration of the myocardium by granulation
ment and use of corticosteroids.10 TB is said to be the most frequent tissue containing giant cells, endothelial cells and lymphocytes.
cause of constrictive pericarditis in Africa and Asia.8 Cardiac tuberculomas have been reported postmortem in fewer
In a double-bind, randomized, controlled trial in South than 0.3% of all TB patients.31 Single or multiple cardiac tuber
Africa,25 constriction resolved remarkably on antituberculosis culomas are most often observed in the right heart chambers,
chemotherapy within 6 months in most patients out of total 114 particularly in the wall of the right atrium. These tuberculomas are
and only 29 (25%) required pericardiectomy for persistent or wors- usually well-circumscribed and sharply demarcated from surrounding
ening constriction during follow-up of 2 years. The benefits were parenchyma. Ulcers may form if tuberculomas erode into underlying
maintained up to 10 years. Pericardiectomy is therefore recom- myocardium and such ulcers form the nidus of thrombus formation
mended if the patient’s condition is static hemodynamically or and subsequent embolism. This process may also result in hematog-
deteriorates after 4–8 weeks of antituberculosis therapy. Surgery enous seeding and subsequent embolism. Right atrial tuberculomas
should be undertaken earlier in patients with markers of chronic have been described by several persons starting from Townsend in
disease like pericardial calcification. Risk of death after pericar- 1832 to Krishnaswami.32
diectomy for tuberculous constrictive pericarditis ranges from Myocardial TB is generally asymptomatic and is rarely diag-
3% to 16%.26 Effusive-constrictive pericarditis is a difficult entity nosed during life. Only four case reports are available in the litera-
to treat since pericardiocentesis does not relieve impaired filling ture of presentation of myocardial TB as congestive heart failure.33-35
of heart in the face of loculated effusion and surgical removal of Other uncommon disturbances reported include tachyarrhythmias
fibrinous exudate coating the visceral pericardium is not possible. (supraventricular and ventricular) and atrioventricular block.36-39
Antituberculosis drugs remain the major option and serial echo Superior vena caval obstrucftion38 right ventricular outflow obstruc-
should be performed to detect development of pericardial skin tion,39 aortic insufficiency40 have also been reported.
that is amenable to surgical stripping. Place of corticosteroids is Calcified myocardial tuberculoma may be seen as an echogenic
unknown in this situation.8 immobile mass in the ventricular myocardium by echocardiography.
Despite global prevalence of tuberculous pericarditis, several In recent times, cardiac magnetic resonance imaging (MRI) has been
unresolved issues remain. Some of these are role of diagnostic found to show characteristic T2 shortening in tuberculous involve-
pericardiocentesis versus open drainage and biopsy, use of ad- ment of myocardium similar to that seen in intracranial tuberculo-
junctive corticosteroids (especially in HIV-infected patients) and mas.41 Characteristic appearance of T2W images includes a central
timing of pericardiectomy. Better description of the entity in HIV- isointense core, corresponding to central caseation, a hypointense
infected patients in terms of clinical presentation and outcome is rim, which represents the fibrous capsule and a thin hyperintense
also needed. line, which correlates with an inflammatory cellular infiltrate.42,43
With timely diagnosis of myocardial TB, almost all patients can Apart from the indirect evidence of association between TB
be successfully treated with standard antitubercular therapy.32,44,45 and atherosclerosis, some more irrefutable evidence is avail-
In cases where diagnosis is still doubtful, surgical resection with able from animal experiments. Xu had found in experimentation
biopsy may be required.43,45,46 with rabbits with normal cholesterol that injecting tuberculopro-
teins resulted in atherosclerotic changes.58 Similar findings were
TUBERCULOSIS AND ATHEROSCLEROSIS replicated by Afek in mice following injection of high dose of
tuberculoproteins despite administration of a low-fat diet.59 As
William Osler, arguably the greatest physician since Hippocrates an interesting counterpart in human beings, Mukherjee and De
made a clear statement in 1908 that arteriosclerosis was frequently Benedictis showed that an increase in antibodies against such
associated with TB.45 Twenty-five year later in 1933, MacCallum, in tubercular proteins were associated with restenosis or future
his study based on 101 cases of autopsy in advanced TB, observed stenosis of coronary vessels.60
that of all the infections causes of heart disease, only one, TB, caused Despite such overwhelming evidence, many ridicule the possi-
arteriosclerosis.46 American Heart Association (AHA) was actually bility that microbes might be the agents of arteriosclerosis. It should
an offshoot of the National Tuberculosis Association, without whose not be forgotten that there were many who had jeered the possibility
money and help it would never have survived. AHA reported a long that syphilis in its later stages had a special preference for the arter-
list of the similarities between TB and heart disease in 192747 and ies. The linkage of TB to acute myocardial infarction and resulting
this exact view was supported by Ellis in The New England Journal of heart attacks is nothing new;61,62 however, serious clinical trials have
Medicine 50 years later.48 never undertaken. With the resurgence of TB and the ongoing near-
Mycobacterial disease has interesting links with cardiac dis- epidemic of cardiovascular diseases, such trials will really not be out
ease. M. tuberculosis is the only microorganism which depends of place.
on cholesterol for its pathogenesis. The Centers for Disease
Control and Prevention (CDC) maps for the total cardiovascular TUBERCULOSIS IN HEART TRANSPLANT
disease and death rates across USA49 bore a conspicuous similarity
RECIPIENTS
to state and regional incidence for CDC TB case rates maps in the
USA.50 When macrophages are depleted of cholesterol by statin ther- In a review of case records of 716 patients who underwent 727
apy, mycobacteria like TB cannot enter macrophages that mycobac- orthotopic heart transplantations in Germany, TB was proved in
teria like to house in, thrive in and depend upon.51 The large Heart seven (1%) patients. None of them had primary history of TB and
Protection Study (HPS) demonstrated that even lowering “normal” TB developed from 2.5 months to 41 months after transplanta-
cholesterol levels lowered cardiovascular event rate.52 Although the tion.63 In another report, during a 5-year period (1989–1993), active
principal investigator of HPS, Collins explained this by stating that extrapulmonary TB was diagnosed in 3 of 144 patients who sur-
even so called “normal” cholesterol levels are too high, this finding vived heart transplantation resulting in an incidence of 1.35 cases
may well be explained by the fact that with lower blood cholesterol per 100 heart transplant years (> 20 fold the national average in
levels, there is lower likelihood of chronic mycobacterial infection. Spain).64 Prevalence of TB in heart transplant recipients was higher
In recent times, an elevated C-reactive protein (CRP) has been than that in the general population. It is recommended that a high
touted as an excellent marker for risk of cardiovascular diseases. degree of clinical suspicion is maintained for TB in heart transplant
However, CRP and elevated sedimentation rate have long been recipients with meticulous follow-up. Since rifampicin decreases
excellent markers of active TB too. Indeed, CRP is a sensitive indica- cyclosporine levels, treatment of TB in transplant patients needs to
tor of activity of TB.53 Elevated homocysteine is a modest independ- be meticulous too.
ent predictor of ischemic heart disease (IHD) in healthy popula-
tions.54 Vitamin B12 and “folate” are often low in tubercular infection CONCLUSION
leading to elevated homocysteine levels.55
Nieto in his extensive review in 1998 has concluded that intro- Although TB can affect any organ in the body, respiratory tract is the
duction of antibiotic therapies in the 1940s and 1950s may have con- organ most commonly affected. Tuberculosis of the heart is rela-
tributed to decline of heart disease and heart attacks in the last few tively uncommon and pericarditis is its commonest expression. In
decades.56 Although it was hypothesized that such decline was the contrast, myocardial TB is rare, but must be suspected in a patient
effect of tetracycline and macrolides against Chlamydia pneumoni- with TB if congestive heart failure or arrhythmias or valve dysfunc-
ae, many of the atypical mycobacteria were also sensitive to erythro- tion supervenes, TB has an interesting link with atherosclerosis, but
mycin and tetracycline doxycycline.57 Also, the antibiotic time-curve more scientific work is needed to examine the plausibility of this link.
that Nieto cites, excludes the actual introduction of antitubercular Growing incidence of HIV and increasing heart transplants have
antibiotics. contributed to resurgence of TB.
REFERENCES
1. White PD, Churchill ED. Relief of obstruction to circulation in case of chronic constrictive pericarditis (concretio cordis). NEJM.1930;202:165.
2. Blalock A, Burwell CS. Chronic pericardial disease. Report of 28 cases of constrictive pericarditis. Surg Gynec Obst. 1941;73:43.
3. Harrington SW. Chronic constrictive pericarditis: Partial pericardiectomy and epicardiolysis in 24 cases. Ann Surg. 1944;120;468-85.
4. Holman E. The recognition and correction of constrictive pericarditis. J Thoracic Surg.1949;18:643-51.
5. McKusick VA. Chronic constrictive pericarditis: I. Some clinical and laboratory observations. Bull Johns Hopkins Hosp.1952;90:3-26.
6. Deterling RA, Humphreys GH. Factors in the etiology of constrictive pericarditis. Circulation. 1955;12:30-43.
7. Fowler NO. Tuberculous pericarditis. JAMA. 1991;266:99-103.
8. Mayosi BM, Volmink JA, Commerford PJ. Pericardial disease: an evidence-based approach to diagnosis and treatment. In: Yusuf S Cairns JA,
Camm AJ, Fallon BJ, (Eds). Evidence-Based Cardiology, 2nd edition. London: BMJ Books; 2003. pp. 735-48.
9. Reuter H, Burgess LJ, Doubell AF. Epidemiology of pericardial effusions at a large academic hospital in South Africa. Epidemiol Infect. 2005;133:
393-9.
10. Sagristà-Sauleda J, Permanyer-Miralda G, Soler-Soler J. Tuberculous pericarditis ten-year experience with a prospective protocol for diagnosis and
treatment. J Am Coll Cardiol. 1988;11:724-8.
11. Cegielski JP, Ramaya K, Lallinger GJ et al. Pericardial disease and human immunodeficiency virus in Dar es Salaam, Tanzania. Lancet. 1990;335:
209-12.
12. Light RW. Pleural effusions. Med Clin North Am. 1977;61:1339-52.
13. Burgess LJ, Reuter H, Carstens ME, et al. Cytokine production in patients with tuberculous pericarditis. Int J Tuberc Lung Dis. 2002;6:439-46.
14. Barr JF. The use of pericardial biopsy in establishing etiologic diagnosis in acute pericarditis. Arch Interm Med. 1955;96:693-6.
15. Ng TTC, Strang JIG, Wilkins EGL. Serodiagnosis of pericardial tuberculosis. QJ Med. 1995;88:317-20.
16. Komsouglu B, Goldeli O, Kulan K, et al. The diagnostic and prognostic value of adenosine deaminase in tuberculous pericarditis. Eur Heart J.
1995;16:1126-30.
17. Burgess LJ, Reuter H, Carstens ME, et al. The use of adenosine deaminase and interferon-gamma as diagnostic tools for tuberculous pericarditis.
Chest. 2002;122:900-5.
18. Reuter H, Burgess L, van Vuuren W, et al. Diagnosing tuberculous pericarditis. QJ Med. 2006;99:827-39.
19. Harvey AM, Whitehill MR. Tuberculous pericarditis Medicine. 1937;16:45-94.
20. Bhan GL. Tuberculous pericarditis. J Infect. 1980;2:310-64.
21. Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomized placebo controlled trial of adjunctive prednisolone in the treatment of effusive
tuberculous pericarditis in HIV seropositive patients. Heart. 2000;84:183-88.
22. Combs DL, O’Brien RJ, Getter LJ. USPHS Tuberculosis short-course chemotherapy Trials 21: effectiveness, toxicity and acceptability: the report of
final results. Ann Intern Med. 1990;112:397-406.
23. Ntsekhe M, Wiysonage C, Volmink JA, et al. Adjuvant corticosteroids for tuberculous pericarditis: promising but not proven. QJ Med. 2003;96:
593-9.
24. Dwivendi SK, Rastogi P, Saran RK, et al. Antituberculous treatment does not prevent constriction in chronic pericardial effusion of undetermined
aetiology. Indian Heart J. 1997;49:411-4.
25. Strang JJG, Kakaza HHS, Gibson DG, et al. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in
Transkei. Lancet. 1987;2:1418-22.
26. Fennell WMP. Surgical treatment of constrictive tuberculous pericarditis. S Afr Med J. 1982;62:353-5.
27. Alan G Rose. Cardiac tuberculosis. Archieves of Pathology Laboratory Medicine. 1987;111:422.
28. Auerbach A, Geggentuim A. Tuberculosis of the myocardium: A review of literature and report of six new cases. Quarterly bulletin of Sea View
Hospital 1937;2:264.
29. Kairlej CK, Ryan M, Wall PG, et al. The organism reported to cause infective myocarditis and pericarditis in England and Wales. Journal Infect.
1996;32(3):223-5.
30. Horn H, Saphir O. The involvement of myocardium in tuberculosis: a review of the literature and report of three cases. Am Rev Tuberc. 1935,32:492.
31. Gaultier Y, Alou A, Cenae A, et al. Tuberculoma of the heart. Contribution of echography. Apropos of a case. Arch Mal Coeur Vaiss. 1987;80(9);
1413-6.
32. Krishnaswami H, Cherian G. Right atrial tuberculoma: report of a case with complete recovery. Thorax. 1984;39(7):550-1.
33. Wilbur EL. Myocardial tuberculosis: a case of congestive cardiac failure. Am Rev Tuberc. 1938;38:769.
34. Agarwal MP, Avasthi R. Miliary tuberculosis presenting as myhocarditis. Ind J Tub. 1994:41:171.
35. Agarwal N, Sharma SK. Concomitant endobronchial tuberculosis, myocarditis and congestive heart failure. Ind J Tub. 2000;47:169.
36. Behr G, Palin HC, Temperly JM. Myocardial tuberculosis. Br. Med J. 1977;1:951.
37. Schnitzer R. Myocardial tuberculosis with paroxysmal ventricular tachycardia. Br Heart J. 1947;9:213-9.
38. Kinare S, Deshmukh M. Complete atrioventricular block due to myocardial tuberculosis. Arch Pathol. 1969,88:684-7.
39. Rawls WJ, Shuford WH, Logan WD, et al. Right ventricular outflow tract obstructrion produced by a myocardial abscess in a patient with tubercu-
losis. Am J Cardiol. 1968;21:738-45.
40. Soyer R, Brunet A, Chevallier B, et al. Tuberculous aortic insufficiency: report of a case with successful surgical treatment. J Thorac Cardiovasc
Surg. 1981;82:254-6.
41. El Saleeby C, Lynn WA, Jayanthi M. Probable intracardial tuberculoma in an HIV positive woman. Heart. 1999;81:181.
42. Kim TK, Chang KH, Kin CJ, et al. Intracranial tuberculoma: Comparison of MR with pathologic findings. AJNR Am J Neuroradiol. 1995;16:1903-8.
43. Rodriguez E, Soler R, Jaffe A, et al. CT and MR findings in calcified myocardial tuberculoma of the left ventricle. J Comput Assist Tomogr.
2001;25:577-9.
44. O’Neill PG, Rokey R, Greenberg S, et al. Resolution of ventricular tachycardia and endocardial tuberculoma following antituberculosis therapy.
Chest. 1991;100:1467-7.
45. Osler W. Diseases of the arteries. In: Osler W, MacCraeT, (Eds). Modern Medicine. Its therapy and practice in original contributions by Americans
and foreign authors, vol.4. Philadelphia, PA: Lea & Fabiger; 1908. pp. 426-47.
46. MacCallum WG. Acute and chronic infections as etiological factors in arteriosclerosis. In: Cowdry EV, (Ed.). Arteriosclerosis. A survey of the prob-
lem. New York: MacMillan Co; 1933, p.355-62.
47. AHA. Similarity of tuberculosis and heart disease. Bull Am Heat Assoc. 1927;2(5):22.
48. Ellis TG. Plaque tuberculosis and plaqueatherosclerosis. N Eng J Med. 1977;296(12):695.
49. CDC Map total cardiovascular disease 1995 death rate, Atlanta Georgia: US Department of Health, Education and Welfare CDC; 2001.
50. CDC Map: TB case rates, United States, 2001. Atlanta Georgia: US Department of Health, Education and Welfare CDC. 2001.
51. Gatfield J, Pieters J. Essential role for cholesterol in entry of mycobacteria in macrophages. Science. 2000;288:1647-50.
52. Collins R, Armitage J. MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized pla-
cebo controlled trial. Lancet. 2003;361(9374):2005-16.
53. Bajaj G, Rattan A, Ahmad P. Prognostic value of ‘C’ reactive protein in tuberculosis. Indian Pediatr. 1989;26(10):101-03.
54. Wilson PW. Homocysteine and coronary heart disease: how great is the hazard ? JAMA. 2002;288(16):204-23.
55. Markkansen T, Levanto A. Folic acid and vitamin B12 in tuberculosis. Scand J Haemat. 1967;4:283-91.
56. Nieto FJ. Infections and atherosclerosis : new clues from an old hypothesis. Am J Epidemiol.1998;148(10):937-48.
57. Molavi A, Weinstein L. In vitro activity of erythromycin against atypical mycobacteria. J. Infect Dis. 1971;123:216-9.
58. Xu Q. Dietrich Induction of arteriosclerosis in normocholesterolemic mice and rabbits by immunization with heat shock protein 65. Arterial
Thromb. 1992;12:789-99.
59. Afek A, George J. Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65(HSP-65) promotes early
atherosclerosis. J. Autoimmun. 2000;14(2):115-21.
60. Mukherjee M, De Benedictis. Association of antibiotics to heat-shock protein-65 with percutaneous transluminal coronary angioplasty and sub-
sequent restenosis. Thromb Haemost. 1996;75(2):258-60.
61. Ferrari-Sacco A, Ferraro U. Myocardial Infarct and Pulmonary Tuberculosis. Discussion of 2 cases of mycocardio-coronary disease appearing dur-
ing hospitalization in a sanatorium. Minerva Cardiological. 1966;14(8):465-75.
62. Tarakanova KN, Terent’eva GM. Myocardial infarct in patients with pulmonary tuberculosis. Probl Tuberk. 1972;50(4):90-1.
63. Komer MM, Hirata N, Tenderich G, et al. Tuberculosis in heart transplant recipients. Chest. 1997;111;365-9.
64. Muñoz P, Palomo J, Muñoz R, et al. Tuberculosis in heart transplant recipients. Clin Infect Dis. 1995;21:398-402.
47 History of Cardiac Syncope
Das MK
The present attempt is to unravel the truth behind the mystical find-
ABSTRACT
ing of sudden loss of consciousness of human being, many a time
Syncope as defined today is transient loss of consciousness (TLOC) attributed in the past to weird abnormality causing lot of inhuman
accompanied by postural loss of tone caused by cerebral hypoperfu- torture.
sion. Syncope derived from Latin Syncopa was known as fainting fit
and was thought to be God’s curse or weird and used to be treated by
HISTORICAL LANDMARKS
people knowing witchcraft. Thanks to the human effort of unraveling
the mystery and establish the scientific truth, syncope is now a clinical The association of slow heart rate and syncope was known to ancient
entity and well researched subject. The importance of knowing history physicians. Imhotep in 2980 BC and Hippocrates in 460 BC noticed
of Science gets enhanced by knowing the history of syncope. This is a fainting fits in their patients. Galen in 131 AD mentioned syncope as
symptom and not a disease per se. This is not only common, disabling, a complication of fever. Caelius Aurelinus described it under morbus
but at times dangerous to health and difficult to diagnose and treat. cardiacus and Aretacus (81 AD to 138 AD) used the term syncope and
Pursuit of knowing the truth started way back in 2980 BC, when the recommended venesection as a therapy.1
first association between slow heart rate and syncope was thought of. Marcus Garbezius of Nuremburg (1658–1718 AD) in 1692 AD first
Later on, various investigators went on searching various anatomical reported cardiac arrest or slow heart rate associated with syncope.1
structures of the heart associated with cardiac impulse generation and Giovanni Batista Morgagni (1682–1771 AD) at Padua published two
conduction, clinical conditions and diseases related to syncope and cases of syncope in 1761 AD as “epilepsy with slow pulse”.1 Thomas
the best therapy for each clinical set up. History is quite long. Many Spencer was the first British physician to publish “History of a Case in
references being quite old are mostly anecdotal either being quoted Which There Took Place a Remarkable Slowness of the Pulse”, a paper
from books and monograms or my own Thesis works. Various bodies of on syncope in 1793 AD. Robert Adams in 1827 AD described a “clean
physicians classified syncope for easy reckoning, which can be found case of syncopal attack with heart block”. William Stokes in 1846 AD
out from books and journals. The present article will attempt only to first gave account of syndrome to the alteration of cardiac function
highlight important milestones. along with bradycardia. This syndrome later came to literature as
Morgagni-Adams-Stokes or simply Stokes-Adams syndrome.1
KEYWORDS: Syncope, Sick Sinus Syndrome, Heart Block, Arrhyth- Though Holbrook Gaskel in 1883 AD coined the term Heart
mias. Block1, it was Galabin who in 1875 AD reported first case of complete
heart block (Bellet).2
INTRODUCTION Congenital complete heart block was first described by Morquio
in 1901 AD.2
Cardiac passion was an ancient Greek expression for syncope Meckenzie in 1902 AD mentioned first about the sino-atrial
(Latin Syncopa).1 Today it is defined as TLOC accompanied by pos- block and in 1908 AD Rihi described the pathophysiological analy-
tural loss of tone caused by cerebral hypoperfusion is a conclusion sis clearly. Laslett in 1909 AD reported the syncope associated with
derived from many observations, many postulations, experimen- sinus bradycardia. Paul Maurice Zoll in 1952 AD first applied external
tations spanning over many years. The historical journey to know cardiac pacing in ventricular stand still.1-4
the truth of this clinical entity is quite interesting, intriguing and Levine in 1967 AD first coined the term “Sick Sinus Syndrome” or
enigmatic. It gathered immense importance as a health hazard be- SSS to indicate diseased sinus node. Haw and Erant in 1970 AD used
cause: (1) it is common, (2) can be dangerous, (3) disabling and (4) the term “Lazy Sinus syndrome”.5
difficult to diagnose at times and last but not the least (5) causes After the clinical association was established, search went on to
lot of expenditure while performing evaluation and management. find the anatomical location of the malady.
Chapter 47  History of Cardiac Syncope 337
The study of specialized conducting tissues of the heart began in heart disease or renal disease may develop the symptoms and signs
1845 AD with the demonstration of terminal element of the conduct- acutely. The cardiac output progressively increases as the heart rate
ing system, namely the Purkinje fibers in the sheep heart (Purkinje, increases up to 160 BPM and then starts decreasing. Malfunction of
1845 AD).6 the atria can affect the cardiac output because the atrial “kick” con-
The existence of a conducting system composed of specialized tributes to 10–20% of the total output. During atrial tachycardia, atrial
muscled fibers joining atria and ventricles was first demonstrated by flutter and fibrillation with rapid ventricular rate, there is an average
Gaskell in frog and tortoise in 1882 AD.1 reduction of cerebral perfusion by 23% and may be as high as 40–
Kent (1893 AD) and His (1893 AD) discovered the conducting 75% (Corday et al. 1961 AD).14 Similarly, the average coronary flow
channels and described the histological findings. Kent dissected becomes less than 60% during a bout of ventricular tachycardia and
the atrioventricular node and demonstrated that propagation of very low during episode of ventricular flutter (Corday et al. 1959 AD).
impulse from auricle to ventricle is accomplished “by strands of He described that there could be a range of symptoms from dizzi-
altered muscular tissue“. This tissue later on appeared in the litera- ness to weakness, syncope, visual disturbance, psychosis to regional
ture as Bundle of His.7 paresis or paralysis. Rasmussen in 1971 AD found evidence of con-
Interestingly, Gaskel in 1884 AD demonstrated suppression of duction tissue disease in 21 cases of “chronic sinoatrial block” and
pacemaker of heart by titanic stimuli and this epoch making finding used the term “panconductional disease”. Schnieder et al. in 1978 AD
marked the onset of electrophysiological study of heart for evalua- reported a family with heart block with sinus bradycardia in adults and
tion of syncope or alike symptoms.1 commented that mixed conduction system disease is prevalent in
Tawara in 1906 AD first delineated the complete structure and familial heart block. Barooah and Das et al. in 1985 AD published
anatomical continuity AV node, Bundle of His, bundle branches and similar pan-conduction disease in population across Eastern part of
Purkinje fibres.8 India.15
Keith and Flack in 1907 AD identified the aggregation of cells Hypersensitive carotid sinus syndrome presenting with synco-
at the sinoatrial location, between anterolateral junction of supe- pe was first described by Roskam in 1930 AD. Later on, many other
rior vena cava and base of the right atrial appendage, exactly where workers, Weiss and Baker in 1933 AD, Lown and Levine in Chughtai
McWillium had predicted that the master pacemaker resided. They in 1977 AD, Kar et al. in 1983 AD and Barooah and Das et al. in 1985
called it the “primum mobile”.9 AD described similar cases in their series of patients with syncope.
Wybouw and Lewis et al. (1910 AD) described the electrophysi- Weiss and Baker divided this condition into three types: (1) cardio-
ological property of sinus node as pacemaker.2 inhibitory type with bradycardia or asystole for more than 3 seconds
The conducting tracts between the sinus node and AV node are with or without hypotension, (2) Vaso-depressor type associated
the last major structure to be identified by Wenckebach (1910 AD) with fall of blood pressure more than 55 mm Hg without fall in heart
and Thorel (1910 AD) and Bachman (1916 AD).10 rate, (3) primary cerebral type not associated with asystole or hypo-
Lewis in 1914 AD; however, challenged the role of these struc- tension. It was labeled as controversial. Later on the third type was
tures in impulse transmission and demonstrated that impulse con- attributed to combination of Type I and Type II of hypersensitive
duction from sinus (SA) node to atrioventricular (AV) node occurred carotid sinus disease.16
through atrial musculature. Later on, James in 1963 AD demon- Defrancis in 1968 AD first used the technique of suppression of
strated three specific intermodal tracts between the SA node and AV pacemaker activity clinically. Thereby, the journey of electrophysi-
node, now known as James’ fibers. ology as a therapeutic tool started. Thereafter, there were surge of
Atlantis, Gonzalez and Lopez in 1958 AD recorded first the His various modes of electrical therapies including pacemakers for brad-
Bundle electrocardiogram in canine heart and same in man by ycardia-induced diseases, anti-tachycardia devices in the form of
Schlerlag (1969 AD) and Damato et al. (1969 AD).5 internal cardioverter defibrillators (ICD), biventricular devices with
Mobitz in 1924 AD classified heart block according to precise or without ICD support, ablation therapy for various types tachycar-
criteria. Katz in 1941 AD reported the clinical correlation with vari- dia. Diagnostic tools like Holter monitoring, external loop recorder
ous types of heart blocks viz, First degree AV Block, Second degree (ELR) and implantable loop recorder (ILR) eased the detection of the
AV block comprising Mobitz Type I and Type II AV block and Third disease and furthered the various therapeutic options. The list is long
degree AV block. and the history of each of them is fascinating, but beyond the scope
Lenegre and Lev in 1963 did intense anatomical studies that led of present article. Nevertheless they not only changed the scenario
to the concept of intraventricular conduction defect. Rosenbaum in of management of syncope, but definitely altered the life style and
1970 AD offered the logical classification of block within the fascicles longevity of the population suffering from morbid syncope. Shukla
of His-Purkenje system.11-13 and Zimetbaum have aptly highlighted that ICDs are now default
Normal resting subjects will have little disturbance of circulatory option for management of malignant arrhythmias as compared to
hemodynamics unless heart rate drops below 40 beats per minute 2 decades ago, when antitachyarrhythmic drugs were the standard
or exceeds 160 beats per minute (BPM). Patients with structural therapy.17
Orthostatic hypotension (OH) as a cause of syncope gathered Basso C et al. in 1996 AD reported a unique condition named as
attention only since early eighties. It is defined as a decline of 20 mm arrhythmogenic right ventricular dysplasia (AVRD). It is caused by
Hg in systolic blood pressure after standing. This is apparent within massive or partial replacement of myocardium by fibro-fatty tissue
2 minutes of standing up right in the classical cases and can be diag- mostly affecting the right ventricle. The current concept is that there
nosed by lying-to-standing test. The second category requiring pro- is progressive cell death or apoptosis initiated by cardiac injury like
longed standing with decrease of blood pressure below or equal to myocarditis, toxic agents or genetic alteration. So far, there has been
90 mm Hg causing impending syncope and below or equal to 60 mm detection of 10 types: AVRD-1 to AVRD-10. The infiltration provides
Hg causing syncope. Head-up tilt test or tilt-table test with or without substrate for electrical instability and thus genesis of arrhythmias
provocation was thus added to the diagnostic armamentarium for causing syncope and other symptoms including sudden cardiac
syncope. Orthostatic hypotension was implicated in 8% of patients death.21
(range 4–12%) of syncope; however, only 31% may show positive for Brugada Syndrome named after Brugada et al. who published
orthostasis as reported by Kapoor et al. in 1983 AD.18 a similar condition with intractable ventricular arrhythmias arising
Tachycardia, supra-ventricular or ventricular as cause of syn- from right ventricle with classical ECG abnormality of ST-elevation
cope came to forefront as various tools for diagnosis started coming more than or equal to 2 mm in at least two of three right precor-
to the market. Historically, frequent premature ventricular contrac- dial leads with coved morphology associated with incomplete or
tions, generally considered as more than 10 per hour or the pres- complete right bundle branch block (RBBB). They also are rare but
ence of ventricular tachycardia after myocardial infarction has been important causes of syncope and cardiac arrest at rest or during
attributed to various symptoms including syncope and also to sleep.22
sudden cardiac death and increased mortality.19
Cardiomyopathies including dilated and hypertrophic cardio- CONCLUSION
myopathy, idiopathic or secondary, may be the harbinger of ventricu-
lar tachyarrhythmias. The 5-year mortality is approximately 20% with Transient loss of consciousness or syncope is an ominous symptom
30% deaths occurring suddenly in idiopathic familial dilated cardio- in any person. It not only interferes with the day to day activity, but
myopathy as reported by Dec GW et al. in 1993 AD.20 Donald Teare, also may inflict injury or cause death. The present article has high-
a pathologist first described the clinical entity of unexplained left lighted only the salient historical perspectives of the condition. The
ventricular hypertrophy as “benign muscular hamartoma of heart”. journey is long and tedious. But it has attempted to offer scientific
It is now found that the condition is not so benign and called as hyper- insight into a subject which was at some point of time labeled as
trophic cardiomyopathy, a common genetic disorder of heart, mostly weird. It has also attempted to create a sense of inquisitiveness for
autosomal dominant genetic condition caused by sarcomere muta- any worker dealing with Science which knows no language other
tions and accounting for 60% of unexplained cases of LVH. than truth.
REFERENCES
1. Sebastian A. A Dictionary of the History of Medicine. NY 10965, USA: Parthenon Publishing Group Inc. Pearl River; 1999. pp. 377,698,1999.
2. Bellet S. In ‘Clinical Disorders of Heart Beat’, 3rd edition. Philadelphia: Lea & Febiger; 1971. p. 406.
3. Meckenzie J. The cause of heart irregularity in Influenza. BMJ. 1902;2:1411.
4. Laslett EE. Q J Med 2;347,1909. Quoted from Am H J 92, 648-660, 1976.
5. FerrerMI. The sick sinus syndrome. JAMA. 1968;206:645-6.
6. Purkinje JE. ‘Clinical Disorders of Heart Beat’ In: Samuel Bellet (Ed.). 3rd edition. Philadelphia: Lea & Febiger; 1971. pp. 3-4.
7. Kent AFS. In Journal of Physiol. 1958;142:127.
8. Tawara S. ‘Clinical Disorders of Heart Beat.’ In: Samuel Bellet (Ed.). 3rd edition. Philadelphia: Lea & Febiger; pp. 3-4.
9. Keith A, Flack M. J Anat Physiol. 41;172,1907. Quoted from Artificial Cardiac Pacing- Practical Approach. In: Edward K Chung (Ed). 1978. p. 147.
10. Wenckebach KF, Thorel C. In: ‘Clinical Disorders of Heart Beat’. In: Samuel Bellet (Ed.), 3rd edition. Philadelphia: Lea & Febiger; 1971. pp. 3-4.
11. Lenegre J, Moreau PH. Le bloc auriculo-ventriculaire chronique: atude anatomique, Clinique et histlogique. Arch Mal Coeur Vaiss. 1963;56:
867-88.
12. Lev M. Anatomic basis of atrioventricular block. Am J Cardiol. 1964;37:742-8.
13. Rosenbaum MB. Modern concepts of Cardiovascular Diseases. 1970;39:141.
14. Corday E, Irving DW. Disturbances of heart rate, rhythm and conduction. Philadelphia: WB Saunders Co; 1961. pp. 33-5.
15. Barooah AK, Das MK, Kotokey R, et al. Sinus node dysfunction in conduction defects with special reference to infranodal block and sick sinus
syndrome—an electrophysiological evaluation. Ind HJ. 1985;37:260. (Abstract).
16. Barooah AK, Das MK. Status of hypersensitive carotid sinus in conduction defects of heart and sick sinus syndrome. An electrophysiological
evaluation. Ind HJ. 1985;37:261. ( Abstract).
17. Shukla GJ, Zimetbaum PJ. Syncope. Circulation. 2006;113:e715-7.
Chapter 47  History of Cardiac Syncope 339
18. Kapoor WN, Karpf M, Wieand S, et al. A prospective evaluation and follow-up of patients with syncope. NEJM. 1983;309:197-204.
19. Bigger JT, Fleiss JL, Kleiger K, et al. The multi-centre post-infarction research group. The relationship between ventricular arrhythmias, left ven-
tricular dysfunction, and mortality in 2 years after myocardial infarction. Circulation. 1984;69:250-8.
20. Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. NEJM. 1994;331:1564-75.
21. Basso C, Thiene G, Corrado D, et al. Arrhythmogenic right ventricular cardiomyopathy: dysplasia, dystrophy or myocarditis? Circulation. 1996;
94:983-91.
22. Brugada P, Brugada J. Right bundle branch block, persistent ST-elevation and sudden cardiac death: a distinct clinical and electrocardiographic
syndrome. A multicenter report. JACC. 1991;20:1391.
48 History of Markers of Sudden
Cardiac Death
Sinha AK
in approximately 45 seconds in our country and is likely to be highly

ABSTRACT
underreported. It is responsible for nearly 50% of all cardiovascu-
The mystery of sudden cardiac death (SCD) remains unresolved in the lar mortality worldwide.6 SCD occurs in 0.1–0.2% per year in adults
present era of advancement in the field of cardiac electrophysiology. more than 35 years of age. It accounts for 10–15% of total mortality
Despite knowing the risk factors of SCD for almost a century, the practi- and 40–50% of mortality from coronary artery disease (CAD).6 The
cal application is still elusive. The history of markers of SCD is almost main challenge in preventing SCD is that it occurs in the majority
century old and surprisingly way back in 1909 credit of discovery of of patients without known heart disease,7 just like tip of the iceburg
repolarization abnormality manifested by T-wave alternans (TWA) was (Figs 48.1 and 48.2).
given to Hering and Lewis.1,2 Malignant ventricular arrhythmias, such as sustained VT and VF,
Sudden cardiac death is defined as unexpected natural death from are responsible for two-thirds of SCD.8 These malignant arrhythmias
cardiac causes heralded by abrupt loss of consciousness within 1 hour occur unpredictably, even in high-risk patients.7 Structural heart dis-
from the onset of symptoms. Most consensus documents define sud- eases, such as CAD, cardiomyopathy and congenital heart disease,
den as death that occurs within 1 hour or less from the onset of symp- are responsible for up to 65–80% cases of SCD. Approximately 5–15%
toms or that occurs during sleep. This strict time limit allows selecting a of SCD occur in people with primary electrical abnormalities of the
population with more than 90% prevalence of arrhythmic death. Most heart. First known arrhythmic events account for approximately
importantly these arrhythmic events are caused by potentially revers- 85–90% of SCDs, while the remaining 10–15% are due to recurrent
ible ventricular tachyarrhythmias. events. Approximately 60% of SCDs occur outside the hospital set-
Ventricular fibrillation (VF) is the major arrhythmia responsible for ting.6 SCD poses a major economical and social impact because
SCD, but bradyarrhythmias also play a minor role. Although the exact the survival rate to the hospital is very low, and more importantly it
mechanism of VF is unknown, focal source and reentrant mechanism remains low at the time of discharge from the hospital. The survival
are shown to be responsible for initiation and maintenance of VF. VF is rate based on rhythms during resuscitation is 6% for VF and only 2%
initiated and perpetuated by the interplay of several factors including for asystole9 (Fig. 48.3).
tissue heterogeneity, wavebreaks due to disorder of impulse conduc-
tion, restitution properties of myocardium, cardiac memory, altered
intracellular Ca+ transients along with repolarization alternans and
autonomic imbalance. Intracellular Ca+ homeostasis plays a pivotal
role in arrhythmogenesis of VF and polymorphic ventricular tachycar-
dia (VT). Ionic imbalances associated with acute myocardial ischemia,
neurohumoral changes and genetic predispositions are also the major
determinants of VF. However, the mechanism by which unpredictable
episodes of VT or VF occur is not known.
INTRODUCTION
Sudden cardiac death is defined as unexpected natural death from
cardiac causes heralded by abrupt loss of consciousness within
1 hour from the onset of symptoms. SCD causes approximately
180,000–350,000 deaths annually in the United States.3-5 Extrapolat-
ing the data from USA, it is estimated that one person is dying of SCD Figure 48.1: Tip of the iceburg
Chapter 48  History of Markers of Sudden Cardiac Death 341
occur without a preceding VT. Therefore, in a patient presenting with

ARRHYTHMIAS DURING SUDDEN
asystole and pulseless electrical activity (PEA), it is often difficult to
CARDIAC DEATH
determine with certainty whether the initiating event was a brad-
Malignant ventricular arrhythmias are the major offenders for SCD. yarrhythmia or a sustained ventricular arrhythmia. Conversely, an
Wearable ambulatory electrocardiogram (ECG) monitoring of 157 initial bradyarrhythmia producing myocardial ischemia may then
patients during cardiac arrest revealed a higher incidence of ven- provoke VT/VF as seen with pause dependent ventricular torsade de
tricular arrhythmias (84%)10 as compared to bradyarrhythmias (16%) pointes (TdP). With increasing use of implantable cardioverter de-
(Fig. 48.4). The majority of sustained VT culminates into coarse VF. fibrillators (ICDs) in high-risk patients with congestive heart failure
The rhythm subsequently becomes a fine VF and if not resuscitat- (CHF), the incidence of SCD due to VT/VF has reduced substantially;
ed early, asystole ensues. In the initial phase of cardiac arrest, VT however, the incidence of PEA and bradycardic deaths continues to
may be encountered, which itself may result in hemodynamic in- increase in advanced CHF.12
stability in patients with compromised left ventricular (LV) systolic
function.11 If VT does not terminate spontaneously or by any in- Can We Predict the Most Unpredictable?
tervention, then VF may occur. In a minority of patients, VF may
In most cases, SCD occurs in patients with structural heart abnor-
malities, even if previously not recognized. Alteration of cardiac
function may be obvious and easily detectable by clinical examina-
tion and widely available technologies, such as echocardiography
or may be subtle and confirmed only by specialized genetic testing
to identify ion channelopathies. Regardless of the type of cardiac
abnormalities, the presence of both the triggers and the substrate of
an abnormal myocardial structure is necessary to initiate and sustain
an arrhythmia, leading to cardiovascular collapse and death.
Common triggers of ventricular tachyarrhythmia include
myocardial ischemia, ventricular ectopic activity, acute changes in
ventricular pressure or volume, fluctuation in autonomic nervous
activity, electrolyte and metabolic abnormalities and proarrhyth-
mic effect of increasingly large number of drugs. Triggers are often
present transiently and occur erratically, which make their prospec-
tive detection problematic. Structural myocardial abnormalities,
especially in advanced cardiac disease, tend to be progressive and
irreversible. In the uncommon situation of the recovery of a previ-
Figure 48.2: Estimates of incidence and absolute number of SCD
ously abnormal cardiac function (e.g. viral myocarditis), the risk of
cases in various populations with progressively more severe cardiac
disease. Abbreviations: SCD-HeFT, Sudden Cardiac Death Heart Failure SCD changes as well and may require periodic reassessment. Abnor-
Trial; AVID, Antiarrhythmics vs implantable defibrillators; CASH, Cardiac mal electrophysiologic properties of the diseased myocardium such
Arrest study Hamburg; MADIT, Morbidity Events in the Multicenter as depressed conduction and anisotropic refractoriness, changes in
Automatic Defibrillators Implantation Trial the neurohormonal cardiac control, and cardiac scaring/remodeling
Figure 48.3: Percentage proportion of SCDs in different risk markers

These include physical and emotional stress in patients with CAD,

catecholaminergic polymorphic ventricular tachycardia (CPVT),
long QT syndrome 1 (LQTS1) and LQTS2. Swimming or audi-
tory stimuli precipitates polymorphic VT in certain types of LQTS.
Whereas, SCD occurs during sleep or rest in Brugada syndrome and
LQTS3 when the vagal tone is supposed to dominate. SCD also has
a diurnal variation with a risk of 2.6 times during the initial 3 hours
after awakening (when the adrenergic tone is predominant) com-
pared with other times of the day. Additionally, the risk of SCD
Figure 48.4: Underlying arrhythmia of sudden cardiac death is highest in the winter months. These evidences point toward the
(Source: Adapted from Bayes de Luna A. Am Heart J. 1989;117:151-9)
interplay among autonomic nervous system (ANS), environmental
factors, severe acute mental stress and possibly in part, to the genetic
factors in the occurrence of SCD (Fig. 48.6). In spite of abundant
all play a role in the maintenance of arrhythmias resulting in SCD. research, SCD is still a major challenge due to its unpredictability in
Multiple techniques were developed to detect the presence and the a majority of the population. The unpredictability of SCD is mainly
degree of these abnormalities; however, their role in the SCD risk because it is almost impossible to identify the single culprit prema-
stratification remains largely undefined. ture ventricular contraction (PVC) that triggers VF. For example, if a
Although SCD seems unpredictable at first glance, studies of patient has two PVCs per minute (which is not an uncommon find-
the chronobiology of this problem demonstrate conclusively that ing in patients with structural heart disease), it translates into a total
these are not random events. An analysis of the Framingham data- of 1 million PVCs in a year. However, the mechanism by which one
base showed a circadian pattern of SCD.13 Events peak in the early PVC in a million becomes “malignant” to initiate VT/VF is elusive.
morning, with possibly a secondary peak in the late afternoon; and The PVC probably has a special site of origin and explicit timing,
a nadir occurs at night. Peters et al.14 subsequently showed that the which in combination with altered dynamics of repolarization in a
peak of SCD occurs in the first 2 hours after awakening. Interestingly, part of myocardium, initiates a sustained myocardial reentry.
similar diurnal patterns are observed for myocardial infarction (MI)
and strokes; so this may represent the presumed hormonal changes PATHOPHYSIOLOGY OF SCD—HOW DO
that trigger vascular events such as thrombosis or platelet deposition
NONINVASIVE TESTS HELP US
leading to infarction or arrhythmia. A septadian or day of the week,
rhythm is also noted for life-threatening arrhythmias. In a large ICD The conditions that lead to VT/VF may occur transiently or may
database, it was shown that rapid ventricular tachyarrhythmias develop during the course of healing from injury to ventricular myo-
have a peak incidence on Mondays and occur only half as frequent cardium and then persist. Factors known to trigger or modulate VT/
on weekends. This relationship is not observed among patients VF include changes in ANS activity, metabolic disturbances, myo-
receiving beta-blockers, suggesting it is due to changes in adrenergic cardial ischemia, electrolyte abnormalities, acute volume and/or
tone.15 A seasonal variability in SCD and life-threatening arrhyth- pressure overload of the ventricles, ion channel abnormalities and
mias is also observed, with the peak incidence in winter, possibly proarrhythmic actions of cardiac and noncardiac drugs. Death of
reflecting the influence of inflammatory processes on these events. myocardial cells due to ischemia, toxins, infectious agents or chronic
Currently available SCD risk stratification tools use the data pressure/volume overload leads to scar formation, alterations in
acquired noninvasively during the recording of a resting, ambula- chamber geometry, and electrical and anatomic remodeling. The
tory or exercise ECG. Invasive electrophysiology study (EPS) is also a electrophysiological alterations induced by these conditions initi-
valuable technique, especially in patients with ischemic heart ate and maintain VT/VF, most likely via a reentrant mechanism,
disease. Measurements of ventricular mechanical performance and although abnormal automaticity, triggered activity or combinations
evaluation of functional and clinical status provide critical comple- of these mechanisms may be operative. The spectrums of noninva-
mentary data for risk assessment. sive methods reviewed in the sections that follow were developed to
detect the presence of factors known to serve as substrate or triggers
The Major Issue: What Triggers a Malignant of VT/VF or abnormalities in ventricular conduction and repolariza-
tion that are critical to reentry. The specific techniques are those that
Arrhythmia and How is it Triggered at a
detect:
Precise Moment? • Slowed conduction [QRS duration, signal-averaged electrocar-
The studies show that the mechanism of SCD is still elusive and diogram (SAECG)]
appears to be multifactorial in most of the disease states (Fig. 48.5). • Heterogeneities in ventricular repolarization (QT interval, QT
Only a minority of SCD occurs due to a known precipitating factor. dispersion, T-wave alternans)
Figure 48.5: Triggers of SCD (Abbreviations: APD, Action potential duration; EAD, Early after depolarization;
DAD, Delayed after depolarization; AIVR, Acclerated idioventricular rhythm)
• Imbalance in autonomic tone [heart rate variability (HRV), heart unpredictable occurrence of VT/VF has not been elucidated. Even
rate turbulence, heart rate recovery after exercise, baroreceptor abnormalities in combinations of these techniques may fail to detect
sensitivity] the precise pathophysiological abnormalities that precipitate VT or
• Extent of myocardial damage and scar formation [left ventricular VF. The limitations of these techniques, as described in this docu-
ejection fraction (LVEF), 6-minute walk] ment, may therefore be due in part to our inadequate understand-
• Ventricular ectopy (long-term ambulatory monitoring). ing of the milieu responsible for initiating clinical episodes of VT or
Although many studies have explored the value of these tech- VF. Thus, the science of risk stratification will be enhanced by further
niques, the precise relationship between the presence of these research to elucidate the structural, electrophysiological, autonomic,
abnormalities, some of which are persistently present and the genetic and proteomic milieu that precipitates SCD.
Figure 48.6: Daily numbers of sudden cardiac deaths rated to CHD from January 10–23, 1994. On January 17, the day of the earthquake, there
were 24 cases of SCD related to atherosclerotic cardiovascular disease (p < 001)
predictor of SCD. Further supportive evidence exists in the form of

MARKERS OF SUDDEN CARDIAC DEATH
ICD trials that used LVEF either alone or in conjunction with other
Summary of markers of sudden cardiac death has been described in risk stratification methods in the inclusion criteria. The Multicenter
Table 48.1. Automatic Defibrillator Implantation Trial (MADIT)19 demonstrated
that ICDs reduced mortality by nearly half compared with medical
Left Ventricular Ejection Fraction therapy alone in patients with class I to III heart failure, LVEF less
than 35% with nonsustained VT (NSVT) and nonsuppressible (by
Reduced LVEF has been the most consistently reported risk fac- procainamide) ventricular tachyarrhythmia on electrophysiological
tor for overall mortality and SCD in the heart failure population. study. Subsequent analysis of the MADIT data demonstrated that
The relationship between left ventricular systolic dysfunction and the benefit of ICD therapy was greatest in patients with LVEF less
death due to progressive heart failure and ventricular arrhythmias than 26%, especially when other risk factors were present. Likewise,
in patients who have had an MI is well established. Studies dating the Multicenter Unsustained Tachycardia Trial (MUSTT),20 which
back to the advent of cardiac imaging were the first to observe the enrolled patients with LVEF less than 40%, noted that total mortality
association between reduced LVEF and outcome, with the majority and arrhythmic deaths/cardiac arrests occurred more frequently in
of studies concluding that LVEF less than or equal to 40% serves as patients with an LVEF less than 30%. MADIT-II randomized patients
the threshold for identifying high-risk individuals.16-18 The prognos- with prior MI and LVEF less than 30% to medical therapy or ICD
tic value of impaired left ventricular function for overall mortality implantation and demonstrated a significant 31% reduction in the
and SCD has persisted despite progress in treatments for acute MI, risk of death with ICD implantation. Finally, the Sudden Cardiac
including thrombolytic and beta-blocker therapies. An analysis of Death in Heart Failure Trial (SCD-HeFT) randomized 2,521 patients
20 studies that enrolled 7,294 postinfarction patients found that an with class II or III CHF and LVEF less than 35% due to ischemic and
LVEF less than 30–40% was associated with a relative risk of 4.3 for nonischemic cardiomyopathy and demonstrated a significant 23%
major arrhythmic events, with a sensitivity and specificity of 59.1% reduction in mortality in ICD recipients compared with patients
and 77.8%, respectively. Remote prior MI may result in both reduced treated with medical therapy. Because ICDs only have an impact
LVEF and abnormalities of conduction and refractoriness that serve on arrhythmic death, the improvement in overall mortality seen in
as the substrate for ventricular tachyarrhythmias. The association these trials is strong evidence of the high attributable risk of death
between left ventricular dysfunction due to CAD and SCD has been due to arrhythmias in patients with moderate to severe left ventricu-
examined extensively in cohort studies and randomized, controlled lar systolic dysfunction. Although overall risk is higher in patients
trials that evaluated medical therapies and ICDs. Lower LVEF has with LVEF less than 35–40%, the absolute number of SCDs is greater
consistently been demonstrated to be the strongest independent in patients with more preserved LVEF. This epidemiological paradox
TABLE 48.1 Summary of markers of sudden cardiac death (SCD)
Marker Conclusion
Left ventricular ejection fraction (LVEF) Low LVEF is a well-demonstrated risk factor for SCD. Although low LVEF has been effectively used to select high-risk
patients for application of therapy to prevent sudden arrhythmic death, LVEF has limited sensitivity: the majority of
SCDs occur in patients with more preserved LVEF
Electrocardiogram (ECG) QRS duration Most retrospective analyses show increased QRS duration is likely a risk factor for SCD. Clinical utility to guide
selection of therapy has not yet been tested
QT interval and Some retrospective analyses data show that abnormalities in cardiac repolarization are risk factors for SCD
QT dispersion Clinical utility to guide selection of therapy has not yet been tested
Signal-averaged ECG (SAECG) An abnormal SAECG is likely a risk factor for SCD, based predominantly on prospective analyses
Clinical utility to guide selection of therapy has been tested, but not yet demonstrated
Short-term heart rate variability (HRV) Limited data link impaired short-term HRV to increased risk for SCD
Clinical utility to guide selection of therapy has not yet been tested
Long-term ambulatory ECG recording The presence of ventricular arrhythmias (VPBs, NSVT) on Holter monitoring is a well-demonstrated risk
(Holter) factor for SCD
Ventricular ectopy and NSVT In some populations, the presence of NSVT has been effectively used to select high-risk patients for
application of therapy to prevent sudden arrhythmic death. This may also have limited sensitivity
Long-term HRV Low HRV is a risk factor for mortality, but likely is not specific for SCD
Clinical utility to guide selection of therapy has been tested, but not demonstrated
Heart rate turbulence Emerging data show that abnormal heart rate turbulence is a likely risk factor for SCD
Exercise test/functional Increasing severity of heart failure is a likely risk factor for SCD, although it may be more predictive of risk for
Status progressive pump failure
Exercise capacity and NYHA class Clinical utility to guide selection of therapy has not yet been tested
Heart rate recovery and ventricular Limited data show that low heart rate recovery and ventricular ectopy during recovery are risk factors for
ectopy during recovery SCD
T-wave alternans A moderate amount of prospective data suggests that abnormal T-wave alternans is a risk factor for SCD
Clinical utility to guide selection of therapy has been evaluated, but the results to date are inconsistent
Baroreceptor sensitivity (BRS) A moderate amount of data suggests that low BRS is a risk factor for SCD
occurs because the latter subgroup is much larger than the subgroup mortality increases with the severity of heart failure, the proportion
of patients with LVEF less than 35–40%. of deaths due to SCD decreases as deaths due to progressive pump
In patients with nonischemic dilated cardiomyopathy, overall failure increase. The Metoprolol CR/XL Randomized Intervention
mortality has also been associated with LVEF, although few studies Trial in Chronic Heart Failure (MERIT-HF) showed that the overall
addressed the relationship between LVEF and SCD directly. Prospec- mortality rate for patients with New York Heart Association (NYHA)
tive observational studies on patients with nonischemic cardiomyo- class II symptoms was 5% and that 85% of those deaths were sudden.
pathy found that LVEF was the only significant predictor of major In contrast, the overall mortality rate for patients with class IV symp-
arrhythmic events on multivariate analyses. The combination of low toms was 21%, with only 33% of those being SCDs (Fig. 48.7).
LVEF (< 30%) and NSVT on Holter monitoring identified the highest- The biggest question is LVEF less than 30% is enough to stratify
risk subgroup with a relative risk 8.2-fold that of patients with LVEF the risk of SCD. There are abundant data supporting the use of LVEF
less than 30% without NSVT. The SCD-HeFT and Defibrillators in to risk-stratify patients with ischemic and nonischemic cardiomyo-
Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) pathies. There are clinical scenarios, such as the immediate post-MI
trials reported an annual rate of SCD lower than that seen previous- period, in which other causes of mortality may confound the use of
ly in cohort studies, likely as a result of high compliance rates with LVEF as a specific predictor of SCD. Although low LVEF identifies a
appropriate medical therapies. These studies demonstrated a trend group with relatively increased risk, the majority of SCDs occur in
toward reduced mortality rates in patients who received ICDs. patients with more preserved LVEF, which highlights the limited sen-
The primary limitation of the use of heart failure severity to risk- sitivity of this technique. The challenge lies in identifying patients
stratify patients with systolic dysfunction for SCD is that although with heart failure who are at significant risk of arrhythmia and who
duration greater than 120 ms was, in fact, an important indicator of

which patients were likely to benefit from ICD therapy.
Similarly, subgroup analysis from MUSTT concluded that
patients with intraventricular conduction delay or left bundle-branch
block (but not right bundle-branch block) had a 50% increase in the
risk of cardiac arrest and total mortality, independent of LVEF and
results of electrophysiological testing. Data presented from SCD-
HeFT showed that the magnitude of ICD benefit depended on the
definition of the cutoff point. For those patients with QRS duration
greater than 120 ms, the hazard ratio was 0.67 [95% confidence inter-
val (CI), 0.49–0.93] versus a hazard ratio of 0.84 (95% CI, 0.62–1.14)
for those with QRS duration greater than 120 ms. In contrast, when
the QRS duration cutoff was greater than 120 ms, the hazard ratio was
0.80 (95% CI, 0.57–1.13) versus a hazard ratio of 0.74 (95% CI, 0.46–
0.99) for those with QRS duration greater than 120 ms. Finally, in pa-
Figure 48.7: Overall mortality rate for the patients with NYHA of
different classes tients with ICDs, QRS duration has not been found to be a predictor
of VT/VF that requires ICD therapy. These varied findings may reflect
significant differences in the design and inclusion criteria between
studies. In addition, because of the inherent limitations of subgroup
would benefit from an ICD. The MADIT and MUSTT criteria form analyses, any conclusions must be interpreted with caution. The
only a meager 10% of CAD patients, meaning thereby 90% would majority of cohort studies performed on patients with nonischemic
require some other criteria. This would translate into approximately dilated cardiomyopathy have not demonstrated a significant associ-
100,000 ICD implants per year in India. ation between intraventricular conduction delay and SCD. ICD trials
that included patients with nonischemic cardiomyopathy also evalu-
Electrocardiogram QRS Duration ated the independent prognostic value of QRS width. DEFINITE
did not show a relationship between QRS duration and all-cause
The QRS duration is a simple measure of the duration of ventricu- mortality. SCD-HeFT, which enrolled patients with ischemic and
lar activation measured on the 12-lead ECG and is a manifestation nonischemic cardiomyopathies, reported that ICD therapy yielded
of intraventricular or interventricular conduction delay or block. a greater mortality reduction in patients with QRS duration greater
Estimates of the prevalence of QRS prolongation in the population than 120 ms, but specific information on the relationship between
with chronic CHF range between 20% and 50%, which is consistent QRS duration and mortality reduction in patients with nonischemic
with the notion that QRS prolongation becomes more prevalent in cardiomyopathy has not been presented.
patients with advancing heart disease. Observational studies suggest A moderate amount of data shows that increased QRS duration
that QRS prolongation is a significant marker for poor outcome in identifies patients at higher risk for SCD, although the data are not
patients with depressed LVEF, especially due to CAD. QRS pro- uniform. In the absence of prospective trials specifically designed
longation could be simply a surrogate marker for more advanced to address this issue, the use of QRS duration to further risk-stratify
myocardial disease, but it may also contribute directly to increased patients with CHF for SCD is not recommended at this time.
mortality, because dyssynchronous ventricular activation may cause
depression of cardiac function. It has also been suggested that slow
conduction and the associated increase in dispersion of ventricu- QT Interval and QT Dispersion
lar recovery directly promote ventricular arrhythmias. The Coro- The QT interval is a reflection of the summed ventricular action
nary Artery Surgery Study (CASS) registry found that patients with potential durations. It shortens with increasing heart rate and is
bundle-branch block had more extensive CAD, a lower mean LVEF, commonly corrected QT (QTc) by Bazett’s formula (QT interval
and higher 2-year mortality than those with normal QRS duration. divided by the square root of the R-R interval), although limitations
Furthermore, the presence of left bundle-branch block was an inde- of this correction are widely recognized. The normal corrected QT
pendent predictor of cardiovascular mortality due to SCD. MADIT-II interval is slightly shorter in men than in women. The measured QT
found no significant differences in the effect of ICD therapy on over- interval is influenced by the leads available for analysis and QRS
all mortality or mortality due to SCD in subgroup analyses stratified prolongation, which makes assessment of the relative significance
according to QRS duration or the presence or absence of left bun- of QT prolongation alone problematic in many studies. QT-interval
dle-branch block. Independent analysis of the MADIT-II data by the measurements have been shown to be highly reproducible, but
Centers for Medicare and Medicaid Services concluded that a QRS the need for rate correction with suboptimal formulas limits the
comparability of QT data in populations. QT prolongation has been signals from regions of scar may also be obscured if the abnormal
associated with mortality in some observational studies in patients region is depolarized during the QRS. Analysis of transmural ven-
with depressed left ventricular function but not in others. Dynamic tricular activation during sustained VTs from patients with healed
changes in QT interval during a recording period have been sug- infarction has confirmed that reentrant circuits involve intramural
gested as a marker of repolarization instability that might be linked pathways located at the infarct border zone, with delayed conduc-
to arrhythmia susceptibility. The QT/R-R—interval relationship for tion in the midmyocardium or subendocardium constituting a
an individual patient is highly stable over time. A steep slope of the critical part of the circuit. Analysis of sinus beats from these patients
relation between QT interval and preceding R-R interval has been demonstrated that activation of the myocardium that composed the
associated with SCD and mortality in initial observational studies. In reentrant circuit began shortly after the onset of the QRS complex
a substudy of 476 patients who received ICDs for primary preven- and contributed little to the terminal QRS complex or ST segment.
tion of SCD in MADIT-II, increased QT variability was associated Instead, late potentials detected in SAECGs from these patients cor-
with an increase in spontaneous VT or VF, but 22% of patients in the related with the region of myocardium activated last, which was both
lowest quartile for QT variability also experienced arrhythmias, which spatially and temporally remote from that responsible for VT in some
suggests a poor negative predictive value. patients.
Some data exist that link abnormalities in cardiac repolarization The SAECG has been evaluated early after acute MI. Because
with an increased risk for SCD. The present data do not support the the SAECG appears to be linked to the substrate of the underlying
use of QT interval, QT dispersion or QT-interval variability for risk infarction, it would be expected that therapies that alter the sub-
stratification for SCD in patients without the long-QT syndrome. Fur- strate or its development will alter the SAECG and perhaps the risk
ther studies are needed to establish whether there is clinical utility of of SCD. Thus, thrombolytic therapy reduces the incidence of an ab-
these parameters for risk stratification. normal SAECG in MI survivors. SAECG performed early after MI
is abnormal in 15–35% of patients. SCD or cardiac arrest occurs in
Signal-Averaged ECG 3.3–9% of these patients over the following 1–3 years. For the pre-
diction of SCD or arrhythmic events, the sensitivity of an abnormal
During sinus rhythm, delayed ventricular activation, often extending SAECG has been reported to vary from 30% to 76% and the speci-
beyond the end of the QRS complex, is more profound and is detect- ficity from 63% to 96%. The relatively low rate of events, however,
able at more cardiac sites in patients with sustained VT rather than in results in a low positive predictive value for SCD, ranging from 7%
those without VT. Late potentials refer to low-amplitude signals that to 40% (7% and 17%, respectively, in the two largest studies). The
occur after the end of the QRS complex. Late potentials have been negative predictive value is high, exceeding 95%, but this is also re-
recorded in dogs with experimental infarction and correspond in lated to the low event rate.
time with fragmented and delayed electrograms recorded from the Prolonged QRS duration on SAECG is associated with increased
epicardium. In patients, late potentials have been correlated with mortality and increased risk of arrhythmic events. The MUSTT inves-
late fragmented electrograms recorded directly from the heart and tigators assessed the relation of the SAECG to arrhythmic events in
are related to the total mass of slowly activated tissue. Late potentials 1,268 patients with LVEF less than 40% and NSVT who did not have
have been thought to represent a substrate for reentry and have been bundle-branch block. Recent acute MI had occurred in 15% of the
correlated in some studies, but not in others, with the site of earli- subjects. A prolonged filtered QRS greater than 114 ms was associ-
est activation during VT. Signal averaging to reduce noise allows high ated with a 28% risk of arrhythmic events during 5 years of follow-
gain amplification and filtering to expose these signals on the surface up compared with a 17% risk of events for those with shorter filtered
ECG. Three time-domain measures of late potentials are commonly QRS durations (hazard ratio, 1.90; 95% CI, 1.46–2.46). Prolonged QRS
assessed for evidence of late potentials: (1) QRS duration, (2) low- duration was also associated with inducible sustained monomorphic
amplitude signal duration and (3) root mean square voltage of the VT or polymorphic VT induced by two extrastimuli, with a sensitivity
terminal 40 ms of the QRS. of 46%, specificity of 57%, positive predictive value of 42% and nega-
Delayed activation of the ventricle by bundle-branch block can tive predictive value of 62%. The strategy of placing an ICD in patients
obscure detection of late potentials and these patients have been with a positive SAECG was tested in the CABG-Patch study, which
excluded from some analyses. Prolonged filtered QRS duration enrolled patients with LVEF less than 36% who had an abnormal
(> 114–120 ms) appears to be the most robust measure correlated SAECG and were undergoing coronary artery bypass surgery. At the
with outcome. Low-amplitude signal duration and root mean square time of surgery, patients were randomized to receive or not receive
measures were not associated with arrhythmic events in a large an ICD. ICD therapy did not improve survival, although arrhythmic
post-MI study. The SAECG is moderately reproducible, although its deaths were reduced. Revascularization may have reduced the risk
reproducibility is impaired by the presence of late potentials and low of SCD, or the criteria of a low LVEF and a positive SAECG may not
residual noise. The SAECG is either not useful or less useful in have resulted in the selection of a group that was at sufficiently high
patients with right and left bundle-branch blocks. Low-amplitude risk when bypass surgery was being performed. In a series of 561
patients undergoing coronary artery bypass surgery, 72% of whom Ventricular Ectopy and NSVT
had preserved ventricular function, the postoperative SAECG was
abnormal in 27% of patients, but this was not related to outcome. In Although the AECG can reliably record the presence of VPBs and
patients with nonischemic dilated cardiomyopathy, evidence of late NSVT, the day-to-day reproducibility of the frequency of these
potentials detected by SAECG has been associated with a history of arrhythmias is poor. In the 1970s and 1980s, observational studies
ventricular arrhythmias. demonstrated that VPBs (generally 10 or more VPBs per hour) and
Abundant data show that an abnormal SAECG may identify NSVT as recorded by an AECG in post-MI patients were risk fac-
patients with prior MI at risk for SCD. Given the high negative predictors for subsequent mortality. Data suggest that ectopy beyond 10
tive value of this test, it may be useful for the identification of patients VPBs per hour does not convey a further increase in risk.21 It has
at low risk. Routine use of the SAECG to identify patients at high risk also been suggested that VPBs are an independent predictor of mor-
for SCD is not adequately supported at this time. Further studies are tality, whereas NSVT may not be a predictor.22 The initial studies
required to assess the utility of this test. described patients without reperfusion, but a similar relationship
has been observed (although with somewhat reduced risk) in the era
Short-Term Heart Rate Variability of thrombolysis and acute reperfusion. In the Gruppo Italiano per
lo Studio della Sporavvivenza nell’ Infarto Miocardico 2 (GISSI-2)
Analysis of HRV provides a means of assessing ANS modulation of the study,23 mortality was 5.5% at 6 months for patients with greater
sinus node to infer autonomic activity on the rest of the heart, parti than 10 VPBs per hour compared with 2% in those with less frequent
cularly the ventricles. Although the contributions of sympathetic ectopy. The positive predictive value of ventricular ectopy after MI for
and parasympathetic tone may be difficult to dissect in individual predicting cardiac arrhythmic events or death generally ranges from
circumstances, studies using autonomic blockade have demonst 5% to 15%, with a negative predictive value of 90% or more. When
rated that HRV is almost completely due to autonomic input to the combined with reduction of LVEF, ventricular ectopy becomes a
sinus node. HRV then provides a surrogate for the autonomic effects stronger risk factor for mortality. In the European Myocardial Infarc-
in the ventricle that are postulated to be important in the pathogen- tion Amiodarone Trial (EMIAT), among postinfarction patients with
esis of VT and VF. Cardiac arrhythmias are often initiated by or occur LVEF less than 40%, mortality was higher in patients with frequent
in patients with enhanced sympathetic and diminished parasym- or complex arrhythmias on AECG than in those without (20% versus
pathetic tone. Thus, it has been proposed that an analysis of HRV, 10%). Patients with nonischemic cardiomyopathy are at increased
particularly its parasympathetic effects on the sinus node, can risk of SCD and frequently have high-grade ventricular ectopy and
potentially predict mortality. NSVT; however, the relationship between arrhythmias on AECG and
Respiratory sinus arrhythmia mediated by fluctuations in paracardiac arrest is much less clear than in the case of ischemic cardio-
sympathetic tone is a major determinant of the high-frequency com- myopathy. Observational trials make up the majority of data avail-
ponent. Sympathetic nervous activity contributes importantly to able, and NSVT is used more commonly than ventricular ectopy for
low-frequency HRV. Other factors are also involved and the genesis risk stratification, likely in relation to the high frequency of VPBs in
of HRV in health and disease is not completely understood. The rela- this population. The Grupo de Estudio de la Sobrevida en la Insu-
tive roles of heart rate and HRV as indicators of autonomic activity ficiencia Cardiaca en Argentina (GESICA) trial, which included a
and prognosis continue to be debated. Although short-term HRV has majority of patients with nonischemic cardiomyopathy, confirmed
moderate reproducibility in normal subjects, it is less reproducible the prevalence of ventricular arrhythmias on AECG in patients with
in patients with CHF. Furthermore, there is marked inter-individual heart failure and LVEF less than 35%. NSVT was an independent pre-
variation in the relationship of short-term HRV to parasympathetic dictor of mortality, but ventricular couplets appeared to be equally
effect. Thus, the identification of clear limits for the differentiation of predictive. Couplets and/or NSVT were detected in 62.7% of the
normal and abnormal results in an individual may be difficult. study population, with a 50.8% mortality rate. The remaining 37.3%,
Limited data link impaired short-term HRV to sudden death. At without couplets or NSVT, had a lower mortality rate of 26.3%.
the present time, its use for risk stratification for SCD is not recom- The sensitivity of NSVT in relationship to SCD or total death
mended. varies among several studies, ranging from 31% to 71%. The posi-
tive predictive value is low, ranging from 20% to 50%, although the
Long-Term Ambulatory ECG negative predictive value has been cited as 72–93%. There is a long
history of intervention trials designed to reduce mortality in high-
Recording (Holter)
risk patients with VPBs or NSVT. The Cardiac Arrhythmia Suppres-
The ambulatory ECG (AECG) was discovered by Norman Holter in sion Trial (CAST) was a groundbreaking, double-blind, randomized
1957 and since then the clinical utility has expanded and changed study that demonstrated that suppression of ectopy and NSVT after
over the years. MI with type IC antiarrhythmic drug therapy actually increased mor-
tality in this population. CAST demonstrated that markers of risk are Reflexes After Myocardial Infarction (ATRAMI) study showed that
not necessarily appropriate targets for therapeutic interventions. after MI, patients with low HRV had a relative mortality risk of 3.2,
Randomized, controlled trials have used NSVT, often documented with accounting for LVEF and ventricular ectopy. Two recent inter-
by AECG, to identify patients who should undergo electrophysiologi- vention trials used HRV to risk-stratify patients. In DINAMIT, 15,675
cal testing and further treatment if VT was inducible. These studies post-MI patients who had decreased LVEF and low HRV (or elevated
showed significant 50–60% reductions in mortality in the ICD treated heart rate) were randomized to receive or not receive an ICD. There
groups, but intervention was based on electrophysiological testing. was no significant difference in survival between the groups. The
In patients with nonischemic cardiomyopathy and CHF, LVEF ICD reduced arrhythmic mortality, but nonarrhythmic mortality in-
less than 35%, and ventricular arrhythmias (NSVT or an average of creased in the patients who received an ICD. It was believed that low
10 or more VPBs per hour), DEFINITE demonstrated a trend toward HRV in this patient population was an indicator of more advanced
improvement in overall survival (hazard ratio, 0.65; 95% CI, 0.40– hemodynamic disease and patients in the ICD group who received
1.06; P = 0.08) and a reduction in arrhythmic events (hazard ratio, appropriate shocks ultimately died of CHF. A second trial used HRV
0.20; 95% CI, 0.06–0.71; P = 0.006) with ICD therapy. The mortality analysis to divide patients into low- and high-risk groups. Camm et
rate of the non-ICD group was 7% per year, but no comparison group al. studied 3,717 post-MI patients with left ventricular dysfunction
of patients without ventricular arrhythmias was reported. and characterized them into low- and high-risk groups on the basis
There is abundant information linking the detection of ventricu- of the triangular index of HRV. Although the trial was designed to ex-
lar arrhythmias (VPBs, NSVT) on AECG in post-MI patients with left amine the effects of an antiarrhythmic drug (azimilide) on survival,
ventricular dysfunction for risk assessment for sudden death. Use of data on the prognostic importance of HRV were also reported. By
the AECG in this setting has been classified as a class IIb recommen- multivariate analysis, low HRV increased risk of all-cause mortality
dation; however, the incremental risk stratification provided by this with a hazard ratio of 1.46 (95% CI, 1.1–1.94); however, low HRV did
finding in patients with LVEF less than 35% is unclear. On the other not predict arrhythmic mortality. In the Marburg Cardiomyopathy
hand, patients with LVEF between 35% and 40% may warrant AECG Study, 24 of the 263 patients with nonischemic dilated cardiomyopa-
recording to assess for NSVT, because this group has been shown to thy who were in sinus rhythm, low HRV was not a multivariate pre-
benefit from an ICD if VT is induced at electrophysiological study. dictor of transplant-free survival or of arrhythmic events.
Patients with preserved left ventricular function after MI are gener- Abundant data show that depressed HRV is a predictor of total
ally at low risk, and current data suggest that they would not benefit mortality. Despite the theoretical pathophysiological link among
from undergoing risk stratification with AECG recording. Finally, abnormal HRV, autonomic tone and arrhythmogenesis, the present
in patients with dilated cardiomyopathy, DEFINITE24 required the data show that HRV may be a better marker of nonarrhythmic mor-
presence of ventricular ectopy or NSVT on AECG, whereas SCD- tality. Further studies are needed to establish whether HRV has a role
HeFT25 did not; thus, the utility of AECG for risk stratification in this in risk stratification for SCD.
population remains unclear.
Heart Rate Turbulence
Long-Term Heart Rate Variability
Heart rate turbulence describes the short-term fluctuation in sinus
The ability of HRV to predict arrhythmic, cardiac or total mortality has cycle length that follows a VPB. Although the mechanism of heart
been studied in a variety of different populations. In 1987, Kleiger et rate turbulence is not known with certainty, it has been postulated
al. reported a relative risk of 5 for all-cause mortality in patients with that it measures vagal responsiveness in a fashion similar to barore-
low time-domain measures of HRV. Since then, a number of stud- flex sensitivity. After a premature beat and a compensatory pause,
ies have reported an increased mortality in patients with low time- there is a typical increase in blood pressure due to the prolonged fill-
and frequency-domain measures of HRV. The ability of frequency- ing in the cycle of the compensatory pause. Reflex parasympathetic
domain measures to predict mortality appears approximately equiv- activation ensues and slows the heart rate. This parasympathetic
alent to that of time-domain measures. In most studies, patients with reactivation can be defined by the time of onset of the return of the
angina or heart failure and those who had experienced an MI had a heart rate to normal and the slope (turbulence slope) of that return.
higher mortality if HRV was low. In general, the relative risk is in the Heart rate turbulence requires the response to a number of prema-
range of 2–3, but lower numbers have been obtained in large popula- ture beats (15–20) to be averaged. As with other techniques that pur-
tion studies, such as the Framingham study. In different studies, dif- port to measure the effects of autonomic tone on the sinus node, a
ferent time and frequency measures have shown the highest predic- higher slope, which indicates more parasympathetic responsiveness,
tive value for all-cause mortality or sudden death. Overall, HRV was should correlate with improved prognosis. Heart rate turbulence
a better predictor of total mortality than of SCD mortality. In most has been examined primarily in post-MI patients. The relative risk
population studies using multivariate analysis, HRV provides signifi- imparted by low heart rate turbulence in patients who have had an
cant, independent prognostic information. The Autonomic Tone and MI appears impressive. For example, in an ATRAMI substudy, there
was a relative risk of approximately four in multivariate analysis. A found a greater benefit of ICD therapy among patients with class
composite autonomic index, which included baroreflex sensitiv- III heart failure than among patients with class II heart failure. In
ity and time-domain measures of HRV, increased the relative risk MADIT-II, which enrolled only post-MI patients, there were no
to eight. A smaller number of studies of patients with nonischemic significant differences in the beneficial effect of ICD therapy on
dilated cardiomyopathy, chronic CHF or hypertrophic cardiomyo- survival in subgroup analyses stratified according to NYHA class.
pathy (HCM) and patients undergoing revascularization have also Although the syndrome of CHF may predispose to ventricular
suggested a predictive value of heart rate turbulence. In the Marburg arrhythmias and SCD in patients with systolic dysfunction, its value
Cardiomyopathy Study of 242 patients with nonischemic dilated car- as a risk stratification tool is untested. Furthermore, although over-
diomyopathy, heart rate turbulence onset was a multivariate predic- all mortality increases as the severity of heart failure increases, the
tor of transplant-free survival (relative risk, 2.95; 95% CI, 1.11–7.48), proportion of deaths due to sudden cardiac arrest from a treatable
but not of arrhythmic events. ventricular tachyarrhythmia decreases as more patients die of pro-
Heart rate turbulence is potentially attractive as a risk stratifica- gressive pump failure.
tion tool because it can be performed with a relatively small number
of premature beats from 24-hour AECG and does not require blood Heart Rate Recovery and Ventricular
pressure monitoring or intervention, as baroreflex sensitivity does.
Ectopy during Recovery
Further data regarding its reproducibility are needed. Although some
studies suggest it has significant predictive value after MI, only a few Immediately after graded exercise, heart rate normally falls in a
studies have been completed. Follow-up in some studies was not biphasic manner, with an initial rapid decline occurring during the
long term and intervention trials based on heart rate turbulence have first 30 seconds to 1 minute of recovery. Imai and colleagues dem-
not been performed. onstrated that this initial steep descent is marked in athletes and
Emerging data show that abnormal heart rate turbulence is attenuated in patients with heart failure and that it can be elimi-
associated with increased mortality. Further studies are needed to nated by administration of atropine. Thus, parasympathetic reac-
establish whether there is clinical utility of this parameter for risk tivation likely plays a major role in regulating heart rate recovery.
stratification. Because impaired parasympathetic tone correlates with increased
risk of death, it was hypothesized that an attenuated heart rate
Exercise Capacity and NYHA Class recovery would similarly predict an increased risk of death. In a
cohort study of 2,428 patients who were referred for exercise myocar-
Left ventricular dysfunction is well-established as a risk factor for dial perfusion imaging and who were candidates for first-time coro-
sudden death; however, the clinical syndrome of CHF itself can also nary angiography, a 1-minute heart rate recovery less than 12 beats
contribute to arrhythmogenesis in patients with ventricular dysfunc- per minute was associated with a markedly increased risk of all-cause
tion and can increase mortality in patients with either an ischemic death (positive predictive value, 19%; negative predictive value, 95%;
or nonischemic dilated cardiomyopathy, independent of LVEF. Heart confounder-adjusted hazard ratio, 2.0; 95% CI, 1.5–2.7). Subsequent
failure is associated with many factors that predispose to ventricu- investigations have confirmed the link between decreased heart rate
lar arrhythmias, including increased circulating catecholamines, recovery and all-cause death in a variety of groups. Specifically, heart
electrolyte imbalances caused by diuretic use, prolonged repolari- rate recovery has been shown to be predictive of mortality even after
zation, stretch-induced after depolarizations and Purkinje system accounting for the Duke treadmill exercise score, left ventricular sys-
conduction delay. Manifestations of neurohormonal activation, such tolic function, the type of recovery protocol used and angiographic
as hyponatremia and increased plasma norepinephrine, renin and severity of coronary disease. Heart rate recovery predicts mortality
natriuretic peptide levels, have been found to be predictive of mor- along with exercise capacity in men with diabetes mellitus. Among
tality. Some medical therapies for CHF have been shown to reduce patients with imaging evidence of ischemia, a low heart rate recov-
both progressive heart failure and SCD due to cardiovascular causes. ery identifies patients for whom the survival benefit of revasculariza-
ICD trials have found that heart failure symptoms are associated with tion is attenuated; that is, patients with ischemia are most likely to
defibrillator therapies. A recent study, the Triggers of Ventricular realize improved survival if heart rate recovery is normal. Investiga-
Arrhythmias (TOVA), identified NYHA functional class III as the tors from the Paris Civil Servants study reported a link specifically
strongest independent predictor of appropriate ICD therapy. SCD- between heart rate recovery and SCD, but these subjects were all free
HeFT found a mortality benefit from ICD therapy for primary preven- of cardiovascular disease at the time of exercise testing. Despite the
tion among patients with CHF and either an ischemic or nonischem- strong data linking heart rate recovery to mortality, its routine use for
ic dilated cardiomyopathy. Subgroup analysis showed that patients clinical risk stratification has been brought into question. The ideal
with class III heart failure did not appear to benefit compared with recovery protocol and abnormal cutoff value are unclear; some ad-
patients with class II heart failure. On the other hand, DEFINITE, vocate an upright cool-down period with a cutoff value of less than
which enrolled only patients with a nonischemic cardiomyopathy, 12 beats per minute into recovery, whereas others support a sit-down
recovery with a cutoff value of less than 22 beats per minute at 2 min- heart rate with regular R-R intervals, a significant percentage of tests
utes into recovery. When a supine recovery is mandated, as in stress are indeterminate owing to either failure to reach target heart rate,
echocardiography, a cutoff value of less than 18 beats per minute atrial fibrillation, or frequent ectopic activity. TWA is moderately
has been described. In addition, the reproducibility of an abnor- reproducible, with concordance on repeated tests of 65–75% and
mal result may not be sufficient to apply the test for individual (ver- 80–90% when only patients with determinate results are considered.
sus population) risk stratification. There are no substantive data in A number of observational cohort studies have been published that
patients with dilated cardiomyopathy. A phenomenon related to suggest that microvolt TWA may work at least as well as electrophysi-
heart rate recovery is ventricular ectopy during recovery, which ological testing for prediction of SCD or major arrhythmic events.
has also been hypothesized to reflect parasympathetic activity. Recent cohort studies that involved at least 100 patients found that
Occurrence of frequent or severe ventricular ectopy during the first 5 TWA was associated with substantially increased risk and predicted
minutes of recovery after exercise has been linked to risk of death in events as well as or better than other markers, including LVEF, elec-
patients without and with heart failure and/or CAD. trophysiological testing, SAECG, baroreceptor sensitivity (BRS) and
Although heart rate recovery and ventricular ectopy during HRV. Furthermore, TWA predicted risk in patients with CAD and in
recovery are new and interesting markers of mortality, their value as patients with dilated cardiomyopathy. In all of these studies, patients
risk stratification tools for SCD is untested. not manifesting TWA were at low risk for SCD. Two important meth-
odological considerations are the type of stress used to induce TWA
T-Wave Alternans and the threshold for labeling a test abnormal. Although pacing-
induced TWA has been linked to ventricular arrhythmia risk, one
Electrical alternans represents a fundamental change in the car- head-to-head comparison study found that exercise-induced TWA
diac repolarization that occurs on an every-other-beat basis, in an was a better predictor. The typical definition for an abnormal TWA
ABABAB pattern. Alternans can be seen in any segment of ECG test is the occurrence of greater than 1.9 µV of alternans starting at a
waveform including QRS, ST, and T wave. In 1909, Hering was cred- heart rate of less than 110 beats per minute. Tanno and colleagues, in
ited with the first report of electrical alternans. Soon after, Lewis a study of pacing-induced TWA, found that increasing the heart rate
associated the presence of electrical alternans with cardiac pathology. cutoff can increase the negative predictive value to 100% but at the
In 1948, Kalter and Schwartz reported that the presence of electrical cost of a lower positive predictive value. One recent cohort study of
alternans in the ECG was associated with a 62% mortality rate. In 177 patients with CAD and LVEF less than 30% suggested that TWA
1950, Hellerstein and Liebow were the first to suggest the potential may be better than QRS duration for identifying patients likely to
link between electrical alternans and arrhythmogenesis. However, benefit from ICDs. The hazard ratios for 2-year mortality were 4.8 for
because visually obvious TWA on ECG occurred very rarely, it was abnormal TWA and 1.5 for prolonged QRS duration. A multicenter
considered merely as an intellectual curiosity and remained dor- study of 549 patients (49% with CAD) with LVEF less than 40% who
mant for the next 30 years. In the 1980s, Adam et al. detected micro- underwent TWA testing reported that the 2-year event (death or
volt-level TWA in animal studies during coronary interventions that nonfatal sustained ventricular tachyarrhythmia) rate was 12.3% in
enhanced susceptibility to ventricular arrhythmia. It soon became the 162 patients with a positive test, 17.5% in the 198 patients with
possible to measure microvolt-level and visually inapparent TWA in an indeterminate test and 2.5% in the 189 patients with a negative
humans. Since then, multiple studies have shown microvolt TWA as test (hazard ratio 6.5 for an abnormal test). Event rates were signifi-
a strong predictor of ventricular arrhythmias and arrhythmia-free cantly greater in patients with both ischemic and nonischemic heart
survival in a wide spectrum of patient populations including patients disease who had abnormal versus normal TWA (16.8% and 13.3%,
with know ventricular arrhythmia, previous MI and heart failure. respectively, for an abnormal result versus 4.8% and 0%, respectively,
In 1994, Rosenbaum et al. first related TWA to high-risk findings for a normal result). Similarly, an observational study of 768 patients
on electrophysiological testing and to an increased risk of serious with ischemic cardiomyopathy (LVEF < 35%) found that a positive or
arrhythmic events. TWA is a reflection of repolarization alternans indeterminate TWA test was associated with increased mortality risk
at the level of the single cell and most likely arises when heart rate (stratified hazard ratio, 2.24; 95% CI, 1.34–3.75) and increased risk of
exceeds the capacity of cardiac cells to cycle intracellular calcium. arrhythmic mortality (stratified hazard ratio, 2.29; 95% CI, 1.00–5.24).
Therefore, TWA is a rate-dependent phenomenon and tends to In contrast, in the Marburg Cardiomyopathy Study, TWA was neither
occur at relatively lower heart rates in patients susceptible to life- a univariate nor a multivariate predictor of either transplant-free
threatening ventricular arrhythmias. Interestingly, by amplifying survival or arrhythmic events. A meta-analysis of 19 studies includ-
electrical heterogeneities between neighboring cardiac cells, TWA ing 2,608 patients demonstrated that TWA was a strong univariate
has been directly linked to a mechanism of arrhythmogenesis.21 predictor of arrhythmic events in patients with ischemic heart fail-
Detection of TWA requires graded exercise to elevate heart rate, as ure (relative risk, 2.42; 95% CI, 1.30–4.50) and nonischemic heart
well as special electrodes and processing to record the microvolt- failure (relative risk, 3.67; 95% CI, 1.50–8.96). Although data support
level TWA with high fidelity. Because of the need to achieve a target the use of TWA as a risk factor for SCD, the precise role of the use of
this technology is unclear. The value of TWA may be enhanced when the time of hospital discharge. During 21 months of follow-up, there
combined with other major risk predictors. Two large trials pre- were 44 cardiac deaths and 5 nonfatal cardiac arrests. Depressed
sented their findings at the 2006 Scientific Sessions of the American HRV (standard deviation of normal < 70 ms) or BRS (< 3.0 ms/mm
Heart Association regarding the use of TWA. The ABCD trial, which Hg) carried a significant multivariate risk of cardiac mortality [3.2
enrolled 566 patients with CAD and LVEF less than 40%, found that (95% CI, 1.4–7.4) and 2.8 (1.2–6.2), respectively]. Risk increased
a positive TWA test was as predictive of arrhythmic events as a posi- further when both parameters were depressed. The association of
tive electrophysiology study. Importantly, the event rate for patients low BRS or SDNN with a reduced LVEF (< 35%) carried a relative
in whom both tests were negative was low. In contrast, a 490–patient risk of 8.7 (4.3–17.6) or 6.7 (3.1–14.6), respectively, compared with
substudy of SCD-HeFT found no significant difference in arrhythmic patients with better preserved LVEF and less compromised HRV
events between those who had a positive versus a negative TWA test. or BRS. The main conclusion from this important trial is that early
Of note, 41% of the population had an indeterminate result. after acute MI, the analysis of parasympathetic reflexes yields sig-
A moderate amount of data suggests that TWA may be useful nificant prognostic value independent of LVEF or other noninvasive
for risk stratification for SCD. Further information will be required to risk stratifiers. Analysis of BRS adds to the prognostic value of HRV,
determine how to implement this test in clinical practice. which signifies that measures of autonomic tone and parasympa-
thetic reflex activity are not redundant but rather complementary.
Baroreceptor Sensitivity Subsequent analyses showed that when examined in conjunction
with depressed LVEF, BRS contributed in a novel way to risk stratifi-
The BRS refers to the adaptation of cardiac periods (R-R intervals) cation. Specifically, within the group of patients with LVEF less than
to changes in blood pressure. The baroreflex mechanism has been 35%, those with preserved BRS had a significantly better 2-year sur-
established as a central part of the regulation of the cardiovascular vival than those with depressed BRS. This was even more evident for
system, particularly in the control of parasympathetic and sym- major arrhythmic events (3% versus 16%). The latter analysis must
pathetic outflow to the heart and the peripheral vessels. There are certainly be repeated in larger patient populations. In the Marburg
different methods of evaluating BRS, but the one that is most appli- Cardiomyopathy Study, of the 263 patients with nonischemic dilated
cable to routine clinical use is probably the phenylephrine method. cardiomyopathy who were in sinus rhythm, BRS was not a multivari-
In essence, BRS is assessed by this method during a brief period of ate predictor of arrhythmic events but exhibited a trend toward pre-
controlled blood pressure change. Most often, such a provocation is dicting transplant-free survival (relative risk, 1.42; 95% CI, 0.95–2.13).
caused by the injection of an intravenous bolus of phenylephrine (an A moderate amount of data suggests that BRS may be useful for
α-agonist that causes reflex parasympathetic enhancement). Pre- risk stratification for SCD in patients with CAD. Further studies are
cise, simultaneous recordings of the ECG-derived R-R intervals and needed to establish the clinical utility, if any, of this parameter for
systolic blood pressure values are necessary to calculate BRS. Spe- risk stratification.
cifically, BRS is expressed as the slope of the regression line showing
the dependency of R-R intervals on blood pressure values. In healthy Other Testing
individuals, the intravenous administration of 25–100 µg of phenyle-
phrine results in a greater than 20 mm Hg increase in systolic blood In addition to the noninvasive testing described in detail above,
pressure and R-R intervals are prolonged by greater than 10 ms for there are several other tests that may be useful for risk stratification.
each 1 mm Hg of pressure increase. Under optimal experimental Evaluation of myocardial ischemia is clearly important, because this
conditions, BRS is only moderately reproducible, with a coefficient may serve as an important trigger for life-threatening ventricular
of variation of 38% on repeated tests. Extensive experimental work arrhythmias, either in patients with preexisting substrate or, less
convincingly demonstrated a close link between reduced BRS and commonly, as a primary cause. Electrophysiological testing has
increased risk for serious ventricular tachyarrhythmias. La Rovere et demonstrated utility in identifying the substrate for sustained VT and
al. prospectively determined BRS in 78 post-MI patients who were could become an important part of a risk stratification strategy. Final-
followed up for 2 years, during which time 7 cardiovascular deaths ly, newer techniques, such as characterization of infarct size or mor-
occurred, including 4 sudden deaths. BRS was significantly lower phology by contrast-enhanced magnetic resonance imaging, could
in the 7 deceased patients than in the survivors. These results were provide information on susceptibility to ventricular tachyarrhythmias
subsequently confirmed by other studies. An important step toward in patients with CAD and nonischemic dilated cardiomyopathy.
establishing BRS determination for risk stratification after MI was
achieved by the multicenter, prospective ATRAMI study. In contrast B-type Natriuretic Peptide
to most previous studies, ATRAMI was a prospective study evaluating
the accuracy of BRS and HRV in predicting cardiac mortality. The tri- Secreted primarily from left ventricle in response to myocardial wall
al used prospectively defined cutoff values for both autonomic mark- stretch, plasma concentration of this peptide strongly correlates
ers. In 1,284 postinfarction survivors, HRV and BRS were assessed at with degree of LV dysfunction and the risk of death. In a study of 452
patients with ischemic or nonischemic cardiomyopathy and LVEF

less than 35, a plasma B-type natriuretic peptide (BNP) cutoff point
130 pg/ml gave 99% negative predictive value for SCD, with a positive
value of only 19% over 18 months follow-up.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is the most common cause of SCD in
the young, including competitive athletes. HCM is a genetic heart
disease with heterogeneous clinical expression. Although only a
minority of the overall HCM population is at high risk for sudden
death, strategies for risk stratification and isolation of that important
subset have constituted a major investigative focus. It has also been
appreciated that the literature may have previously overestimated
the risks associated with HCM, because many of the published data
had been derived from tertiary referral centers with disproportion-
ate numbers of high-risk patients. In contrast to the ischemic and Figure 48.8: Electrocardiograph of hypertrophic cardiomyopathy
nonischemic cardiomyopathies under consideration in the present
statement, the vast majority of patients with HCM at risk for SCD
are young, asymptomatic (or mildly symptomatic) adolescents or
adults less than 35 years old. These patients may not have reliable • NSVT (usually asymptomatic short bursts of 3–6 beats at > 120
warning signs, and thus, SCD can be the initial disease presentation. bpm) on long-term AECG recordings, particularly if prolonged
However, SCD risk also extends through midlife and beyond; there- or multiple/repetitive on serial studies
fore, achieving any particular age does not itself confer immunity • Attenuated or hypotensive blood pressure response during up-
to sudden death. Many of the tests or parameters described in this right exercise, indicative of hemodynamic instability
statement to assess risk for SCD in ischemic and nonischemic car- • Extreme left ventricular hypertrophy with maximum wall thick-
diomyopathies are generally not applicable to patients with HCM. ness greater than 30 mm on 2-dimensional echocardiography,
These include 12-lead ECG patterns, which are usually abnormal particularly in adolescents and young adults.
and particularly heterogeneous in HCM, with little predictive value Available data suggest that left ventricular outflow obstruction
regarding outcome (Fig. 48.8). Because HCM is characterized by (gradient > 30 mm Hg at rest) assessed by continuous-wave Dop-
hyperdynamic or normal left ventricular function, LVEF has little pler echocardiography can only be regarded as a minor risk factor
or no prognostic power, except in the small minority of patients in for SCD in HCM (positive predictive value of only 7%). Ischemia (or
the end-stage phase with systolic dysfunction due to diffuse LV scar- its consequences) as a prognostic marker in HCM has proved to be
ring. Heart rate recovery, HRV, SAECG and TWA have not been well difficult to assess with standard exercise testing, thallium imaging,
studied as markers of SCD risk in this disease. Because of the rela- echocardiography or magnetic resonance imaging. Positron electron
tively low prevalence of HCM in general cardiological practice, its tomography has shown a significant relationship between myocar-
diverse presentation and mechanisms of death, and skewed patient dial ischemia and the progression of heart failure in HCM, but not
referral patterns, the level of evidence governing risk stratification specifically with sudden death. It has also been proposed, on the
strategies has most often been derived from nonrandomized and basis of genotype-phenotype correlations in a relatively small
retrospective investigations. Furthermore, the long-risk period for number of families, that the genetic defects responsible for HCM
this relatively young patient population and the low SCD event rate could represent the primary determinant of SCD risk, with specific
represent obstacles to developing and testing risk stratification strat- mutations conveying either favorable or adverse prognosis. Howev-
egies. Large-scale controlled and randomized study designs, such as er, the clinical utility of genetic testing for predicting prognosis and
those that have provided important answers regarding the manage- developing individual patient management strategies is uncertain.
ment of CAD and CHF, have generally not been available in HCM Although the available data on risk stratification for SCD are substan-
patients owing to these demographic factors. The highest risk for tial, it is important to underscore that precise criteria for identifica-
SCD26 has been associated with following markers: tion of high-risk patients by clinical risk markers are not complete.
• Prior cardiac arrest or spontaneously occurring sustained VT Although it has been possible to identify many such patients only
• Family history of a premature HCM-related death, particularly if by history taking or noninvasive testing, a minority of HCM patients
SCD occurred in a close relative, or when multiple who die suddenly are without any of the currently acknowledged risk
• Unexplained syncope, particularly in young patients factors.
Observational data regarding risk stratification for SCD in HCM Brugada Syndrome
at present support testing with ECG, AECG, treadmill (or bicycle)
exercise and 2-dimensional echocardiography, in addition to obtain- • In 1992, Brugada and Brugada described a syndrome of a spe-
ing a personal and family history. There are no randomized trials that cific ECG pattern of right bundle-branch block and ST-segment
use these parameters. elevation in leads V1 through V3 without any structural abnor-
mality of the heart that was associated with sudden death.
Primary Electrophysiologic Abnormalities • In 25–30% of these patients, a mutation in SCN5A on chromo-
some 3 is detected. This mutation results in a sodium channelo-
This generally represents a group of abnormalities in which patients pathy. The most common clinical presentation is syncope and
have no apparent structural heart disease but have a primary elec- this mutation is most common in young males and in Asians. It
trophysiologic abnormality that predisposes them to VT or VF. Some is associated with VT, VF and SCD.
imaging techniques have detected abnormal sympathetic neural • Three ECG types of Brugada pattern are described. Only type
function in these patients. An ECG study can provide clues to the 1, which consists of a coving ST elevation in V1 to V3 with
diagnosis; consider a familial component to these conditions. downsloping ST segment and inverted T waves, pseudo RBBB
Normal early repolarization may be associated with increased SCD, pattern with no reciprocal ST changes and normal QTc, is
though this often represents a benign finding. specific enough to be diagnostic for Brugada syndrome when
it is associated with symptoms. The other two ECG patterns of
Wolff-Parkinson-White Syndrome Brugada are not diagnostic, but they merit further evaluation.
• The Brugada ECG pattern can be dynamic and not found on an
The Wolff-Parkinson-White (WPW) syndrome is a recognized index ECG. When clinical suspicion is high, a challenge test with
but rare cause of sudden death. The existence of an atrioven- procainamide or some other Na channel blocker may be diag-
tricular accessory pathway in this syndrome results in ventricu- nostic by reproducing the type 1 ECG pattern.
lar preexcitation, which appears with short PR interval, wide
QRS complex and delta wave on ECG. The refractory period in Catecholaminergic Polymorphic
the anterograde direction of accessory pathway determines the
Ventricular Tachycardia
ventricular rate in the setting of atrial fibrillation and WPW (Fig.
48.9). Most patients with WPW syndrome and SCD develop atrial • The catecholaminergic polymorphic ventricular tachycar-
fibrillation with a rapid ventricular response over the accessory path- dia (CPVT) is a syndrome that presents with polymorphic VT,
way, which induces VF. In a study by Klein et al. of 31 patients with VF syncope or SCD, and in about half of these patients, a mutation
and WPW syndrome, a history of atrial fibrillation or reciprocating in one of two different genes have been detected.
tachycardia was an important predisposing factor. The presence of • The polymorphic VT is characteristically induced by emotional
multiple accessory pathways, posteroseptal accessory pathways and or physical stress (e.g. exercise stress test).
a preexcited R-R interval of less than 220 ms during atrial fibrillation Primary VF occurs in a structurally normal heart due to
are associated with higher risk for SCD. idiopathic etiology:
Figure 48.9: Atrial fibrillation in WPW syndrome

• An estimated 3–9% of cases of VT and VF occur in the absence prognosis. At this time, there is no consensus regarding the level of
of myocardial ischemia. As many as 1% of patients with out- risk that justifies an intervention, based on either the level of benefit
of-hospital cardiac arrest have idiopathic VF with no structural or cost associated with the intervention. This is further compounded
heart disease. As many as 15% of patients younger than 40 years by the fact that the risk-benefit ratio of an intervention in an indi-
who experience VF have no underlying structural heart disease. vidual patient could differ from that observed in large-scale trials. In
Viskin and Behassan noted that of 54 patients with idiopathic addition, individual and societal tolerance for risk may differ. These
VF, 11 patients had histologic abnormalities on endomyocardial issues are not subject to evaluation in clinical trials, and therefore,
biopsy. only sound clinical judgment can be used by the practitioner to
• SCD is often the first presentation of VF in patients at risk but address them. Another important issue is assessing the timing of
who have had no preceding symptoms. In those patients who evaluation. Early attempts at risk stratification focused on evaluating
survive, VF may recur in as many as one-third of patients. patients in the early postinfarction period. Many studies have dem-
onstrated time-dependent changes in many of the risk stratification
Right Ventricular Outflow Tract VT techniques discussed in this statement, including LVEF, ventricular
ectopy, the SAECG and HRV. Although there is a continued and per-
• Right ventricular outflow tract (RVOT) tachycardia is the most haps even an enhanced risk for SCD in patients remote from their
common form of idiopathic VT, comprising 70–80% of all idi- MI, there does remain a heightened mortality risk in the first several
opathic VTs. RVOT tachycardia is a very rare cause of SCD. It also months postinfarction for which the cause is unclear. Most ICD pri-
has been referred to as exercise-induced VT, adenosine-sensitive mary prevention trials have specifically excluded these patients and
VT and repetitive monomorphic VT. only enrolled patients remote from their MI. In contrast, the DINA-
• The RVOT tachycardia occurs in patients without structural heart MIT study, which enrolled patients within 40 days of an MI who had
disease and arises from the RV outflow region. Current data sug- low LVEF (< 35%) and low HRV, did not show a survival benefit for
gest that triggered activity is the underlying mechanism of RVOT those treated with an ICD. Similarly, the CABG-Patch trial enrolled
tachycardia. RVOT tachycardia is believed to be receptor-medi- patients with CAD who had low LVEF and positive SAECGs and also
ated because exogenous and endogenous adenosine can termi- found no survival benefit for those treated with an ICD. Although it
nate this process. Maneuvers that increase endogenous acetyl- is tempting to identify the SAECG or the HRV as the risk stratifica-
choline also have been demonstrated to antagonize this process. tion technique that failed to identify the appropriate high-risk pa-
• Symptoms typical of RVOT tachycardia include palpitations and tients who would benefit from an ICD, it must be emphasized that
presyncope or syncope, often occurring during or after exercise these patients all had low LVEF. Because MADIT-II and SCD-HeFT,
or emotional stress. VT also can occur at rest. The ECG during VT which included patients with similarly low LVEF, demonstrated a
displays a left bundle-branch block/inferior axis morphology. survival benefit with an ICD, it appears likely that the clinical settings
(early postinfarction period or post-CABG surgery) may also affect the
SCIENTISTS REVEAL THE MYSTERY OF etiology of SCD and therefore the utility of the risk stratification tech-
niques. Furthermore, it was recently shown that eplerenone reduced
SUDDEN CARDIAC DEATH
the risk of SCD by 37% at 30 days in a randomized trial of patients
“If other forms of sick sinus syndrome that involve mutations to dif- with acute MI, left ventricular systolic dysfunction and heart failure,
ferent proteins in the heart are affected by nerve activity in the same which suggests that alternative therapies may be required during
way, this may identify a common target to reduce or eliminate risk of this time period to reduce the risk of SCD. The Cardiac Arrhythmias
dangerous arrhythmia” [ScienceDaily (July 7, 2010)]. and Risk Stratification after Myocardial infarction (CARISMA) study
Scientists at The University of Manchester have solved a mystery is a multicenter study enrolling patients with an LVEF less than 40%
connected with why people die from sudden cardiac arrest during after acute MI in whom a loop recorder is implanted to evaluate the
sleep—potentially saving thousands of lives. incidence of tachyarrhythmia and bradyarrhythmia episodes. This
study will specifically evaluate the value of 24-hour AECG, SAECG,
MARKERS OF SCD IN INDIVIDUAL PATIENTS QT dispersion, TWA, and electrophysiological testing as predic-
tors of life-threatening arrhythmias in the early postinfarction pe-
When an individual patient is being evaluated to assess his or her riod. Risk stratification approaches and interventions will need to be
risk for SCD, there are several important issues that should be related to the timing of evaluation in the patient’s disease process.
addressed. First and foremost, the specific goal for risk stratification Further efforts to define the appropriate evaluations and treatments
for the individual patient should be identified. The choice of tests relative to this timing are necessary. There are no data that identify
may vary if the goal is to determine the appropriateness of implant- the optimum risk stratification strategy or combination of tests to be
ing an ICD versus titrating the aggressiveness of medical therapy performed. The optimal strategy should identify the vast majority of
versus providing the patient with information regarding his or her those who will experience sudden arrhythmic death and a minimal
number of those who will not. No existing strategies attain this goal.
There are a large number of clinical studies that have combined avail-
able techniques, with demonstrable improvement in sensitivity and
specificity. Randomized ICD intervention clinical trials have gener-
ally combined depressed LVEF with at most one other risk stratifier.
The inadequacy of these approaches is underscored by the fact that
most victims of SCD do not have low LVEF. Thus, much research is
required to determine which of the myriad available tests should be
performed, whether they should be performed sequentially or simul-
taneously and whether a patient’s risk should be assessed at some
frequency in the absence of a change in clinical status. It is clear
that continued progress in noninvasive risk stratification will benefit
by the determination of whether the suboptimal success achieved
with each approach can be improved with use of tests in combina-
tion and/or refinements in methodology to more completely detect
the pathophysiological determinants of VT/VF. Tremendous efforts
have been made in developing and studying risk stratification tech- Figure 48.10: “Tailor made approach” is better than one size fits all
approach. Let us not forget that poor man’s ICD is a combination of
niques; however, at present, there are no data integrating the use of
beta-blocker (highly underused), antiplatelets, ACE inhibitor and statins
these techniques into a coherent strategy for intervention. Currently,
the primary technique for stratifying risk to determine who is an
appropriate candidate for an ICD for primary prevention of SCD
is the LVEF. It is reasonable to place patients with LVEF less than good sensitivity and specificity, when applied to a population with
30–35% in the highest risk group that can be identified presently. a low incidence of SCD will have a poor positive predictive value.
This applies to patients with CAD and dilated cardiomyopathy. Although it is possible that multiple positive test results could be
Future studies will assess whether further risk stratification within used to identify particularly high-risk individuals, it is also possible
this population can be achieved. This will require the development that such a strategy would limit the proportion of the “at risk” popu-
of a risk stratification test or strategy with high negative predictive lation that can be identified.
value. In patients with CAD and LVEF less than 35%, further testing
with other risk stratification techniques may be used, but data on FUTURE DIRECTION AND MY POINT OF VIEW
how to apply the results of these tests are lacking. If clinical evalua-
tion is consistent with an increased risk, further electrophysiological Given the availability of therapies to prevent SCD due to otherwise
testing may be indicated (Fig. 48.10). fatal ventricular tachyarrhythmias, it is important to differentiate
The field of risk stratification requires substantial further devel- noninvasive risk stratification techniques that enhance the ability
opment. Although the lack of a dominant strategy using these tech- to identify SCD from total mortality. The relative ability for each of
niques is certainly due in part to the absence of clinical trial data, the described techniques varies, and the optimal way to combine
it is also important to consider that there may be limitations to the and use these techniques in clinical practice remains unclear. Low
current techniques. Most of these techniques focus on the evalua- LVEF, which is the most widely used test on which ICD intervention
tion of electrical, autonomic, or anatomic substrates of the patient is recommended, does not have a particularly high discriminatory
at rest, when the risk of SCD is low. Some of the techniques involve ability to identify SCD rather than non-SCD mortality. Although data
evaluations during exercise and the postexercise recovery period, exist supporting the concept that noninvasive risk stratification tech-
times of relatively increased risk for SCD and ventricular arrhyth- niques may be useful to identify patients with low LVEF who are at
mias. Clearly, there are other factors that may be implicated in the low risk for SCD, this requires further testing. There are also data to
pathophysiology of SCD. Recent consensus documents have out- support the concept that noninvasive risk stratification techniques
lined the concepts of vulnerable plaque, vulnerable blood (prone to may be useful to identify patients who do not have low LVEF, who
thrombosis) and vulnerable myocardium. Newer approaches that nevertheless are at substantial risk for SCD. Because most SCDs
encompass a more general evaluation of “vulnerability” to sudden occur in this latter group, substantial effort is justified in evaluating,
death, including genetic profiling, serum markers and new imaging testing and ultimately implementing risk stratification strategies in
approaches, are necessary. Finally, if risk stratification is to be applied this group.
to a population with an overall low risk of SCD to identify a subgroup Understanding the mechanism of SCD needs elaborate coordi-
with more significant risk, it is likely that multiple tests will need to be nated efforts in genetics, molecular science, translational research
incorporated into a risk stratification strategy; a single test, even with and clinical studies. The family history of SCD in patients with MI
needs to be explored further for genetic predictors because CAD impact of SCD, especially in country like India where estimated
is the main offender for SCD. Basic science studies are needed to economic impact of ICD comes to 40 billion rupees from primary
better understand the ion channel mechanism, including Ca; dy- prevention.
namics, which appears to play a pivotal role in the mechanism SCD. Although the history of markers of SCD is almost a century old,
Furthermore, understanding the mechanistic differences between but despite so much of work in this field nothing precise is worked
a “benign PVC” and a potentially “malignant PVC” in relation to a out yet. The biggest question is less than 30% LVEF is sufficient to
focal or reentrant arrhythmias is warranted. It will also help in iden- stratify risk, probably not.26 Need of hour is to incorporate LV func-
tifying the means to suppress or eliminate these “malignant PVCs”. tion with that of ECG markers and autonomic markers may be to
Additionally, suppressing dynamic instability may be a promising include the biochemical markers as well. Let us have some kind of
therapeutic target if it can be accomplished without exacerbating scoring system to short out this issue to save great loss of economy
tissue heterogeneity and risk for proarrhythmia. Translational and and number of ICD implants.
computer modeling, as well as newer imaging techniques, may
provide further insight in the mechanism of VF and planning preven- ACKNOWLEDGMENT
tive strategies for SCD. At present, due to the lack of a precise risk
stratifier the number needed to treat patients with ICD to prevent I acknowledge Dr MK Das, Krannert Institute of Cardiology, Indian-
one death in MADIT-II population is 11, and in SCD-HeFT popula- apolis, USA, my better half Dr Ranjana Verma and Gopal Panday for
tion is 14. Therefore, identification of high-risk populations with a low their valuable suggestions in improving the contents of this manu-
cost test, as well as therapeutic options, will reduce the economical script.
REFERENCES
1. Hering HE. Experimentelle studien an Saugertherien uber das elektrocardiogramm. II. Mittheilung. Z Exp Pathol Ther. 1910;7:363-78.
2. Lewis T. Notes upon alternation of the heart. Q J Med. 1910;4:141-4.
3. Myerburg RJ, Interian A, Mitrani RM, et al. Frequency of sudden cardiac death and profiles of risk. Am J Cardiol. 1997;80(5B):10F-19F.
4. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med.
1993;119(12):1187-97.
5. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis.
2008;51(3):213-28.
6. Turakhia M, Tseng ZH. Sudden cardiac death: epidemiology, mechanisms, and therapy. Curr Probl Cardiol. 2007;32(9):501-46.
7. Zipes DP. Epidemiology and mechanisms of sudden cardiac death. Can J Cardiol. 2005;21:37A-40A.
8. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345(20):1473-82.
9. Herlitz J, Engdahl J, Svensson L, et al. Can we define patients with no chance of survival after out-of-hospital cardiac arrest? Heart. 2004;90(10):
1114-8.
10. Bayés de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data
from 157 cases. Am Heart J. 1989;117(1):151-9.
11. Weiss JN, Qu Z, Chen PS, et al. The dynamics of cardiac fibrillation. Circulation. 2005;112(8):1232-40.
12. Stevenson WG, Sweeney MO. Arrhythmias and sudden death in heart failure. Jpn Circ J. 1997;61(9):727-40.
13. Willich SN, Levy D, Rocco MB, et al. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am
J Cardiol. 1987;60:801-6.
14. Peters RW, McQuillan S, Gold MR. Interaction of septadian and circadian rhythms in life-threatening ventricular arrhythmias in patients with
implantable cardioverter-defibrillators. Am J Cardiol. 1999;84:555-7.
15. Peters RW, McQuillan S, Resnick SK, et al. Increased Monday incidence of life-threatening ventricular arrhythmias. Experience with a third-
generation implantable defibrillator. Circulation. 1996;94:1346-9.
16. Bigger JT, Fleiss JL, Kleiger R, et al. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after
myocardial infarction. Circulation. 1984;69:250-8.
17. Sanz G, Castañer A, Betriu A, et al. Determinants of prognosis in survivors of myocardial infarction: a prospective clinical angiographic study. N
Engl J Med. 1982;306:1065-70.
18. Risk stratification and survival after myocardial infarction. N Engl J Med. 1983;309:331-6.
19. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular
arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:1933-40.
20. Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary
artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation. 2002;106:2466-72.
21. Denes P, Gillis AM, Pawitan Y, et al. Prevalence, characteristics and significance of ventricular premature complexes and ventricular tachycardia
detected by 24-hour continuous electrocardiographic recording in the Cardiac Arrhythmia Suppression Trial. CAST Investigators. Am J Cardiol.
1991;68:887-96.
22. Tavazzi L, Volpi A. Remarks about postinfarction prognosis in light of the experience with the Gruppo Italiano per lo Studio della Sopravvivenza
nell’ Infarto Miocardico (GISSI) trials. Circulation. 1997;95:1341-5.
23. Maggioni AP, Zuanetti G, Franzosi MG, et al. Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction
in the fibrinolytic era. GISSI-2 results. Circulation. 1993;87:312-22.
24. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med.
2004;350:2151-8.
25. Bardy GH, Lee KL, Mark DB, et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardio-
verter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225-37. Erratum in: N Engl J Med. 2005;352(20):2146.
26. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document
on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Docu-
ments and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol. 2003;42:1687-713.
49 History of Women and
Heart Disease
Vinod S, Tsering TP
onset among men as compared with women holds extensively

INTRODUCTION
around the world, across various socioeconomic, climatic and cul-
It has been a long perception that men suffer more often from heart tural environment.2 Despite this delay in onset, mortality from coro-
disease than women but this notion was proved wrong following nary artery disease (CAD) is increasing more rapidly among women
trials, surveys and studies conducted in the recent times. The preva- than men in both the developed and developing world3 (Fig. 49.1).
lence of death occurring in women, according to the American Heart Experts have speculated that this gender age difference due to
Association regardless of race or ethnicity due to heart disease of premenopausal protection from development of atherosclerotic
approximately 500,000 death each year, nearly half of number of coronary disease allowed by circulatory estrogen and similarly, by
death occurred in women and similarly, death resulted from high hormonal replacement therapy (HRT) in postmenopausal women
blood pressure amounted to related proportion. Similarly, the inci- reduce further events leading to CAD.
dence of congenital anomalies, valvular heart diseases, heart fail- Women earlier were excluded from research studies on athero-
ure and arrhythmias was equally shared in terms of ratio as men. sclerosis, in view of an old understanding of male preponderance to
We are now witnessing a time when death due to heart disease has heart insult than women. It was believed that a woman during their
surpassed the combined fatality caused by stroke, lung cancer, lifetime undergoes physiological changes, which include pregnan-
chronic obstructive lung disease and breast cancer.1 Even though cies and in this regard, it was thought that case study drug may cause
mortality from heart disease has reduced gradually among men undue adverse effect to the unborn fetus. Also, men and women with
since 1979, (by 30–50%) but it has not been same for women, which CAD differ in terms of epidemiology, diagnostic test accuracy and
has increased many fold during that period.1 treatment efficacy. Later on, various data collected reflect the need of
The worldwide INTERHEART Study, a large cohort study of including women in the research studies owing to the some impor-
52,000 individuals with myocardial infarction (MI), demonstrated tant facts that women in the age of 45–65 years—one in nine women
for the first time that the approximate 8–10 years difference in age of suffer from some form of heart disease; in later life, women with pre-
Figure 49.1: Coronary vascular disease kills more women than men, surpassing cancer, trauma, chronic obstructive
pulmonary disease and pneumonia as a cause of death. Source: National Center for Health Statistics, 1992
vious coronary heart disease (CHD) and MI are almost twice as likely
CLINICAL ASSESSMENT AND
to perish away within the first 2 weeks as are men; almost one-third
of women above the age of 65 years has some form of cardiovascu-
CHEST PAIN HISTORY
lar disease (CVD); also, within the 1st year preceding a heart attack, Clinical approach and assessment determine the likelihood of CAD
30% of women die as compared with 31% of men. The extent of this prior to deciding whether diagnostic testing is necessary. General
figure would increase with population aging process. All this factors evaluation is based on careful history, including gender-specific,
influenced the National Institute of Health to mandate the need to chest pain quality and risk-factor assessment.
include women in their studies. This has led to increment in the data In clinical practice, as well as in several large studies, angina is
collection of an understanding of natural history of CAD in women in described as a substernal chest discomfort on exertion and relieved
the last decade. The lifetime risk of death occurrence from CVD has by rest or nitroglycerin in less than 10 minutes. In the Coronary Ar-
been tenfold more than breast cancer globally, which has become a tery Surgery Study (CASS),6 this chest pain history was found to pre-
major issue of concern (Fig. 49.2). Recent study have suggested that dict significant CAD in women 72% of the time, whereas the same
CAD in women is underdiagnosed and undertreated compared with history in men was predictive of significant CAD 93% of the time.
CAD in men; for example, women coming with chest pain are less Women tend to develop CAD and MI at an older age (average age,
likely than men to be referred for diagnostic tests and therapeutic 55–60 years) than men (average age, 50–55 years). On an average,
intervention.4,5 Gender-based differences in evaluating and treating women were 5–10 years older at the time CAD was diagnosed. This
cardiac problems in women, it is important for the physician to deem difference in age gender in prevalence of CAD and MI in the CASS-
the benefits of risk-factor modification in women, accuracy of diag- aged population may account for predictive value of chest pain his-
nostic tests as applied to women, treatment strategies, appropriate tory seen in this study.
referral for invasive testing, and outcomes of surgical intervention. There are several gender-specific issues which influence diag-
It is important to understand the clinical presentation, enormity nosing CAD in women. Clinical presentation, such as arthritis or
of CAD in women in a global context, coronary risk factors includ- osteoporosis seen in women may possibly obscure CAD symptoms
ing unmodifiable risk (diabetes, hypertension, hyperlipidemia, ciga- and delay diagnosis. In addition, women are more likely than men
rette smoking and sedentary lifestyle) and potentially modifiable risk to present with atypical symptoms. While they may also have chest
factors (age and family history). In addition socioeconomic status, pain, women have a greater incidence of abdominal pain, difficulty
mitral valve prolapse, pregnancy (including pregnancy-induced breathing (dyspnea), nausea and fatigue. It is universally observed
heart disease), diagnosis, management, gender-bias differences, that women repeatedly postpone seeking medical treatment for
which need further consideration and exploration. Although women their symptoms; for example, many women despite of having brief
with CAD have risk-factor profiles similar to men, slight differences episodes of angina for several years develop full blown MI. Chest
do exist at any level (Table 49.1). pain in women is mostly attributed to other causes, which include
Figure 49.2: At 85 years and older, women in the US had a significantly higher mortality rate from
cardiovascular disease compared with men. Source: National Center for Health Statistics, 1992
Chapter 49  History of Women and Heart Disease 361
TABLE 49.1 Risk classification for cardiovascular disease in women
High Risk At Risk Optimal Risk
Known CAD One or more major risk factors for CV disease: Framingham global risk < 10%
- Cigarette smoking
- Poor diet
- Physical inactivity
- Obesity (especially abdominal location)
- Family history of premature CAD (< 55 years in men, < 65 in women)
- Hypertension
- Hyperlipidemia
Cerebrovascular disease Subclinical vascular disease (i.e. coronary calcification on cardiac OT) Healthy lifestyle
Peripheral arterial disease Metabolic syndrome No risk factors
End-stage renal or chronic Poor exercise capacity on exercise treadmill test and/or abnormal heart rate
kidney disease recovery after stopping exercise
Diabetes 10 years Framingham global risk > 20%
(Abbreviations: CAD, coronary artery disease; CT, computed tomography; CV, cardiovascular; Cardiac OT, cardiac occupational therapy)
Source: Adapted from ACC/AHA Guidelines 2007 update. Circulation. 2007;115(11):1481-501.
anxiety, stress, psychological problems, heartburn, or other noncar- that women with CAD have a propensity to have a positive family his-
diac conditions, not only by women patients but also by their physi- tory of CAD more often than men with the condition. Nurses’ Health
cians.3 Study, however, examined nearly 122,000 women who were 30–55
years old in 1976 and discovered that women whose parents had a
ENORMITY OF CORONARY ARTERY DISEASE history of MI prior to 61 years of age had a relative risk of 5.0% for fatal
CAD, and those whose parents had a history of MI after age 60 had a
IN WOMEN IN GLOBAL CONTEXT
2.6% relative risk.9
Women and men alike, with risk factors like heredity, age, race, blood
pressure, blood cholesterol and smoking, both are equally prone to Cigarette Smoking
develop atherosclerosis and finally CVD. However, women are more
affected by factors such as smoking and diabetes, than are men. In A potent risk factor for CAD has risen among young women.10
addition, pregnancy, consumption of contraceptive pills and post- After awareness campaigning at various level, prevalence of cigarette
menopausal estrogen should be assessed in delineating risk assess- smoking has declined although much more so in men (21%) than in
ment. women (6%).11
In the Framingham Heart Study, smoking was associated with
Age an increase in CAD death in premenopausal women.6 The Nurses’
Health Study demonstrated that angina, MI, and CAD deaths were
It is the most powerful risk factor for progression of CVD and sub- cigarette-dose related. Also, smoking as few as 1–4 cigarettes/day
sequent clinical events. Prevalence in men is more than in women augments the relative risk of fatal CAD and nonfatal MI to 2.4.12
prior to 5th decade, but in 6th decades prevalence equalizes and in Cessation and abstinence of smoking can normalize relative risk
following decades becomes greater in women. after 2 years.13 As per Nurses’ Health Study, it has been noted that
the risk is dose-related; significant risk exists with smoking just a few
Family History cigarettes per day. Also, low nicotine yield cigarettes do not decrease
risk and carry similar risk: one study reported the relative risk of fatal
Family history of CVD is a second unmodifiable risk factor and it has CAD with low-yield cigarettes at 4.7, as opposed to 4.2 for conven-
been well-documented that CHD and death from CVD have a hered- tional cigarettes.14 It is also reported that there are sixfold to seven-
itary component. It has also been depicted that transmission occur- fold increased risk of MI in female smokers compared similar age-
ring in a Mendelian pattern and the predilection for CAD is observed matched nonsmoker; besides the risk from smoking is equivalent to
as monogenic studied in minority of families. An example cited in risk of weighing additional 42 kg more than a nonsmoking women.
a family identified recently to have a mutation in the MEF2A gene. Successful cessation can be facilitated by behavioral therapy pro-
Bullemer and associates7 discovered that family history was an inde- grams that include counseling as well as audiovisual aids and substi-
pendent risk factor in young women. Sullivan and associates8 found tution with other nicotine delivery methods.
Cholesterol and bypass surgery (39%). The results provide a basis for aggressive
lipid lowering in women patient post-MI.
Till age 20, men and women have almost similar lipid profiles; from An elevated level of Lipoprotein(a) has been found to be a pow-
20 years to 55 years of age, most men have higher total cholesterol erful risk factor that dictates the presence and severity of premature
levels than women. However, after 55 years of age, women’s choles- CAD in women and men. Lipoprotein(a) is an important determi-
terol levels increase rapidly and may slightly exceed those of men. nant of CAD in premenopausal women than in postmenopausal. It is
Women’s level of high-density lipoprotein ([HDL], with a low per- known that high level of Lp(a) increases the risk of CAD by a factor of
centage of triglycerides) exceeds men’s HDL level by around 10 mg/ 5 when it is accompanied with hypertension, by factor of 7 with high
dL, even though absolute levels decline following menopause. Dur- total cholesterol/HDL ratio, by a factor of 8 with low HDL and by fac-
ing middle age, triglyceride levels may actually decrease in men, but tor of 9 with high homocysteine. Combination of all increases the risk
continue to increase in women. High-density lipoprotein levels do of CAD by a factor of 122.
not match between the sexes until about age of 70 years.
Increased total cholesterol, decreased HDL and probably Hypertension
increased triglyceride are risk factors for CAD in women. However,
HDL and triglyceride levels may be more powerful predictors of CAD Prevalence of hypertension increases with age in both men and
in women. In the Framingham study, every 10 mg/dL increase in women. However, after the age of 50, more than two times as many
HDL resulted in a 40–50% decrease in CAD risk for women. Also, a women as men develop hypertension.21 The relative risk of hyper-
multivariate analysis of the Framingham study confirmed that a tri- tension for CAD was shown to be elevated in the Framingham Heart
glyceride level of greater than 150 mg/dL was an independent risk Study22 and also found to be as high as 10.5 in the Walnut Creek
factor for CAD, especially when the level exceeded 400 mg/dL.15,16 Health Study.
It is evident that a significant relationship exists between lipids Women were excluded from the randomization in national Mul-
and CAD in women, primary and secondary prevention trials either tiple Risk Factor Intervention Trial, conducted from 1973 to 1982 in
do not include women in significant numbers or do not report data as many as 22 clinical centers, to test whether smoking cessation
on women separately. The Guidelines released in 1996 by the Ameri- and steps to lessen the serum cholesterol and diastolic blood pres-
can College of Physician using serum cholesterol, HDL-C, and tri- sure would reduce mortality from CHD among nearly 13,000 men
glyceride levels for screening purpose, it does not suggest screening aged 35–57.23 With successful treatment of hypertension in women
lipids at all for primary CAD prevention in women younger than 45 reduced incidence of CAD death by 18% in one study as opposed to
years old. This is compared with the recommendation to screen men a reduction of 47% in men.24 Other studies have shown conflicting
35 years of age or older. These guidelines are more concerned against results. In another study, treated women had an increase in mortality
use of medication for primary prevention of CAD.17 of 26.8%.19 It is yet to be determined, whether these conflicting data
The West of Scotland trial is the only primary prevention trial to reflect true gender differences or an inadequate numbers of women
show a clear benefit for drug treatment of CHD that studied high- studied in response to therapy.
risk Scottish men.18 The 4S trial (secondary prevention trial) of 4,444
patients with history of angina or prior MI and elevated cholester- Diabetes
ol, demonstrate a relative risk of cardiac death of 0.70 in a 5.4-year
follow-up.19 In a subgroup analysis of 420 women in the treatment Diabetes is a dominant risk factor for CAD in women, compared to
group (versus 407 on placebo), the relative risk of CHD mortality was what is seen in men. Both women and men with diabetes mellitus of
0.86 (95% cerebral infarction of 0.42–1.74), which is higher than the similar age carry same risk of CAD. It is often observed that diabe-
0.70 but still below 1. In addition, meaningful assessment of these tes is frequently associated with constellation of at least three of the
findings is difficult in view of the small number of women in the following risk factors: abdominal obesity, hypertension (BP of 130/85
treatment group.20 mm Hg or higher), hypercholesterolemia (excessive triglycerides
The double-blind Cholesterol and Recurrent Events (CARE) and/or inadequate HDL cholesterol and fasting glucose concentra-
study establish that pharmacologic cholesterol reduction could ben- tion of 110 mg/dL or greater. The Framingham Heart Study indicated
efit men and women who have normal cholesterol levels and have that women with diabetes mellitus had a relative risk of 5.4% for
survived an MI. The randomization of 4,159 eligible subjects to either CAD compared with women without diabetes; by distinction, men
placebo or the lipid-lowering drug (pravastatin), which includes 576 with diabetes had a relative risk of 2.4%.25 The Nurses’ Health Study
subject women’s substudy of the CARE trial indicate that within 6–12 reported a relative risk of 6.3% for total cardiovascular mortality.26
months after therapy commenced, women who had received pravas- Presence of hypertension and obesity increase this risk three-fold.
tatin had a 43% lesser risk in death from both MI and CHD and a 57% Intensive management of blood glucose level in insulin-depend-
reduction in nonfatal recurrent MI. Also significantly, reduction for ent diabetes leads to improved cholesterol levels, although it does
invasive procedures in women, such as balloon angioplasty (48%) not necessitate any significant improvement in mortality or improve
risk of macrovascular disease. The Diabetes Control and Complica- the life expectancy in India and its subcontinent has increased by
tions Trial investigators27 discovered that intensive insulin treatment around 20–61 years of age. Not only that, from 1960 to 1995, the prev-
reduced low-density lipoprotein level by 34% and macrovascular alence of CAD in adults increased from 2% to 4% in rural Indian and
disease by 41%, although the latter was not that significant. There 3–10% in urban Indians, with women approaching similar rates as
is no separate data available for men and women. The intensively men.30 As per the data of 1990, total death due to CAD was 783,000 in
treated group had a higher incidence of hypoglycemic attacks: 21% of India and it was assumed that the number will double by year 2015
patients had hypoglycemic convulsions or coma during an average of due to mainly urbanization and affluence practice. These figures are
21 months. Also, since this trial was conducted in type I diabetics, its terrifying despite the fact that prevalence of CAD in rural India is
results viewed in respect to type II (noninsulin-dependent) diabetics almost half that of urban India, but this is still two times higher than
should be done with concern. CAD rates in the US. Recent trends indicate that young Indians with
Women suffering with metabolic syndrome carry a subclini- CAD have more extensive coronary atherosclerosis and multivessel
cal CAD as compared to men; a substudy conducted by the Na- disease pattern seen even in premenopausal women, which is rarely
tional Heart, Lung, and Blood Institute sponsored WISE (Women’s observed in the West.
Ischemia Syndrome Evaluation) suggest that women with metabolic For the postmenopausal women, around age 50, risk increases
syndrome have twice the risk for CHD-related events compared with gradually in the 5–10 years after the female hormone estrogen begins
aged-matched women without the metabolic syndrome. National to decline, around age 50. It is postulated that estrogen, which reg-
Cholesterol Education Program Adult treatment Panel-III defined ulates menstruation, protects women against CAD by increasing a
metabolic syndrome in women as the presence of three or more of substance in the blood called HDL, which prevents blockages in the
the following components: arteries. High-density lipoprotein functions by dislodging the cho-
• Waist circumference greater than 35 inches lesterol away from the arteries and finally out of the body. Premeno-
• Fasting triglycerides greater than 150 mg/dL pausal women have much higher levels of HDL cholesterol than men
• HDL-C less than 50 mg/dL of the same age.
• Hypertension (systolic blood pressure ≥ 130 mm Hg, diastolic blood Through a cascade of chain reaction of body chemicals, estrogen
pressure ≥ 85 mm Hg, or use of antihypertensive drug therapy) and prostaglandin both exert a causation and protective mechanism
• Fasting glucose greater than or equal to 110 mg/dL. respectively. Estrogen functions by keeping blood vessels from con-
stricting and reducing blood flow to the heart muscle that leads to a
Obesity reduction in blood flow, which may cause chest pain, dyspnea and
MI. There are findings which suggest that prostaglandins hormones
The effect of obesity on women’s relative risk for CAD has been con- secreted by the uterus in women of childbearing age, may also play a
troversial. The Framingham study observed a relative risk of 2.0%, role in protecting women from heart disease. These substances help
which was independent of other risks.27 In the Nurses’ Health Study, to dilate blood vessels and prevent clotting.
obese women had a similarly elevated relative risk, which also per- Postmenopausal women on replacement of estrogen regimen
sisted after controlling other risk factors.28 A large prospective study appear to reduce their risk of CAD by one-third to one-half. In the
of 262,019 women and 62,116 men aged 30–85 showed that greater majority of studies, it is noticed that women who have not been on
body mass index was associated with higher mortality from all estrogen after menopause are at highest risk of CAD and women who
causes, and from CVD up to age 75.29 Body fat distributions may play have been on estrogen for the first 10 years after menopause carries a
a more important part than total body fat: it was found that the waist- moderate risk, and at lowest risk are women who have been on estro-
to-hip ratio of fat correlated with CAD events in women. gen continuously since menopause. In women with naturally occur-
ring menopause, the risk of a CAD rises gradually.
In spite of estrogen being found to decrease the incidence of
Socioeconomic Status CAD, it may lead to possible increase in risks of uterine and breast
Coronary artery disease is known to be a disease of poor in devel- cancer associated with the use of this hormone. In addition, estro-
oped countries and rich in developing countries. Women with more gen among nonsmokers has been associated with an increased
than high school education fair well in terms of incidence of CAD incidence of stroke. The results till date of several of these studies
mortality compared to less than high school education in the range have been controversial; though, a study called the Nurses’ Health
of 30–40%. Low social safety, psychosocial infliction, hostile environ- Study, suggests that the overall benefits of estrogen replacement
ment and low education aptitude has been associated with CAD. therapy outweigh the risks.
Menopause Hormone Replacement Therapy

With increasing age (around 50 years and thereafter) women are at A woman’s risk for CAD increases significantly after menopause,
more risk to develop CAD. It has been estimated that since 1960, HRT can help to decrease that risk. This risk reduction is accom-
plished mainly by the favorable effect of HRT on the lipid profile, women is lower than that in men until about age 70, and extrapolat-
although there may also be direct effects on coronary vasculature to ing from Bayesian theory, the positive predictive value of a positive
increase compliance.31 Oral estrogens can both raise HDL by 20–30% noninvasive CAD test is lower in women, particularly in young and
and lower LDL levels.32 The randomized, controlled Postmenopau- middle-aged women, than in men.
sal Estrogen/Progesterone Interventions (PEPI) trial examined the There are non-Bayesian factors unique to women, including
effect of various HRT regimens on lipid profile, glucose tolerance and artifacts like, hormonal interactions, and a variety of physical factors,
coagulation status. The results showed that HRT (estrogen, estrogen which are discussed. Hence, the physician is faced with the more
and cyclic progesterone, or daily estrogen and progesterone) favora- dilemma of using tests that are less precise in women to look for a
bly improved cardiac risk-factor profile.33 disease that is less common among women.
Numerous angiography studies have found that postmenopau-
sal estrogen is associated with reduced risk of significant CAD.34 Exercise Electrocardiography
Prospective cohort studies have noted that estrogen use is associated
with reduction in MI and death. Several meta-analyses have con- Exercise electrocardiography (ECG) is the oldest form of tread-
firmed that postmenopausal estrogen replacement reduces cardio- mill testing, and hence has been the most documented exercise
vascular risk by as much as 40–50%.35,36 test in women. Exercise ECG is most accurate in subjects with
By evaluation HRT has been reported to increase the relative normal baseline ECGs who are able to exercise to 85% of maximal
risk for breast cancer from 1.06% to 1.63%. While this risk is greatly predicted heart rate. Circumstances such as mitral valve prolapse
outweighed by the benefits of HRT for CAD, many patients and cli- (more common in women than in men), left ventricular hypertro-
nicians are hesitant to use hormone replacement if there is a per- phy, left bundle-branch block, and digitalis use may show repolari-
sonal or family history of breast cancer. The risk of uterine cancer zation abnormalities that are incomprehensible in cases of stress-
is increased approximately three to five times by HRT, but absolute induced changes.
incidence is still extremely low; adding progesterone substantially In view of non-Bayesian factors as hormonal interactions and
reduces this risk.37 The effect of the addition of progesterone on physical characteristics, the exercise ECG is less accurate in women
women’s cardiovascular mortality remains to be defined, although than in men. In the CASS study, which included the largest number
the PEPI trial results are encouraging. of women (n = 580), the sensitivity and specificity of the exercise ECG
Unfortunately, data demonstrating the benefits of risk-factor were 76% and 64%, respectively, compared with 80% and 74% for
reduction in women are limited. The elevated relative risks of hyper- men (n = 1465).39
tension and diabetes for CAD indicate that aggressive modification is
appropriate, unless definitive data to the contrary emerges. Diet and Exercise Imaging Studies
exercise can be most beneficial for patients with these risk factors.
It is also important to emphasize smoking cessation. Cigarette use Combining treadmill exercise or pharmacologic stress with a form
has risen among women and poses added risk for CAD in women of imaging—either echocardiographic or radionuclide—offers pro-
on HRT; cessation dramatically decreases relative risk. Hormone spective advantages and better accuracy over treadmill alone. Since,
replacement therapy can improve postmenopausal risk-factor pro- the myocardium is imaged directly, these studies are not dependent
files dramatically, and it should be considered for women at high risk on ECG to diagnose ischemia.
for CAD. The benefits of hormone therapy should be weighed care-
fully in patients with breast cancer, a family history of breast cancer
or uterine cancer. Radionuclide Perfusion and
Ventriculography Tests
GENDER DIFFERENCES IN SELECTING THE Exercise perfusion studies employing thallium-201 (Tl-201) scintig-
raphy, technetium-99m (Tc-99m) sestamibi, or Tc-99m teboroxime
APPROPRIATE DIAGNOSTIC TEST
have potential advantages over the exercise ECG. Thallium is taken
Recent meta-analysis has shown that the accuracy of diagnostic test- up by viable myocardium and is used to identify ischemia or infarct
ing is lower for women than for men.38 According to Bayes’ theorem of the myocardium.
that states that the predictive value of a test is determined not only The use of thallium poses special problems unique to women:
by the test characteristics but also by the frequency of disease in the breast tissue causes anterior perfusion artifacts that are actually
test population, suspicion of disease ought to be carefully considered secondary to attenuation, not decreased perfusion. Gender-spe-
when evaluating women for CAD. Combining disease prevalence cific interpretation may improve the accuracy of this technique,
data from age, gender, and risk factors with type of chest pain and whereas, Tc-99m sestamibi, may provide better image resolution
test results provide higher diagnostic certainty than test results alone since it has higher energy with less soft tissue attenuation. This
may suggest CAD in women. Given that the prevalence of CAD in advantage is theoretical and remains to be proven. Unfortunately,
only a small number of studies have been conducted to examine Dobutamine

exercise thallium accuracy in women, and fewer studies have
examined exercise sestamibi. For women who are not capable to exercise, echocardiography is
done in combination with the administration of a pharmacologic
Dipyridamole stress or agent like dobutamine. Dobutamine is a catecholamine
having dual action, positive inotropic activity with mainly β-1
Pharmacologic perfusion studies are useful for patients who cannot effects, also has mild β-2 and ∞-1 agonism. The net result on
exercise to the point of achieving an adequate heart rate and blood peripheral vasculature is generally less, although dobutamine has
pressure for diagnostic testing. Dipyridamole, a commonly used a little vasodilator effects. With higher doses, heart rate and cardiac
agent, primarily measures coronary flow heterogeneity. It causes output rise. As the plasma half-life of the drug is only 2 minutes,
elevated cyclic adenosine monophosphate platelet levels and inhib- dobutamine is given as a continuous infusion. The anticholinergic
its formation of thromboxane A2, a potent vasoconstrictor. When atropine can be added during peak dobutamine infusion if the tar-
injected, the agent acts as a coronary vasodilator, and may be com- get heart rate is not achieved with dobutamine alone. At doses of
bined with radionuclide imaging to create images of the myocardium 20 mg/kg/minute or higher, both chronotropic and inotropic affects
both during vasodilatation and at rest. Dipyridamole side effects, are observed, leading to increased myocardial oxygen demand that
such as flushing, hypotension, and shortness of breath, occurred leads to regional ischemia manifesting as wall motion abnormal-
more commonly in women. ity. Dobutamine echo studies have shown sensitivity (89% overall)
Again, statistics specific for women are limited. In one study of and specificity (80% overall), although gender-specific data are not
71 men and 43 women, test sensitivity was 87% and specificity was available.42
58% in women with multivessel disease compared with 94% and 63%
respectively, in men.40 In women with single-vessel disease, sensitiv- Potential New Diagnostic Technology
ity dropped to 60% compared with 94% in men.
Other nuclear techniques, such as exercise radionuclide ven- Potential noninvasive tests are electron beam tomography (com-
triculography with Tc-99m labeling, is not proven as a helpful indica- puted tomography, or CT), magnetic resonance imaging (MRI), and
tions of CAD in women and hence not recommended. A positive test positron emission tomography (PET). Computed tomography and
is indicated by a lack of increase in ejection fraction with exercise. MRI provide outstanding contrast and spatial resolution, and these
This norm is based on the fact that healthy men generally increase tests may be used to produce a three-dimensional data set of car-
their cardiac output by increasing their ejection fraction. But women diac activity and function. Electron beam CT can sense and quantify
generally increase cardiac output by increasing their end diastolic coronary calcification, which appears to have prognostic signifi-
volume index. Around one-third of women without CAD do not cance.43 An absence of calcification implies extremely low risk of
increase ejection fraction when they exercise. significant CAD. The calcium scoring may be predictive of risk of
future cardiac events, such as fatal and nonfatal MI and need for
Echocardiography percutaneous transluminal coronary angioplasty (PTCA) or coro-
nary artery bypass grafting (CABG).44
There are various advantages of echocardiographic studies for The role of MRI has been to detect complications of MI, but it
diagnosis of CAD in women. Echo offers imaging of the myocardium has the potential to demonstrate coronary perfusion when used
directly as well as imaging of the cardiac valves. Observation of wall with magnetic resonance contrast media. Magnetic resonance an-
motion abnormalities at baseline or with exercise helps in diagnos- giography demonstrates detailed coronary artery imaging. Positron
ing ischemia or infarct of the myocardium. Lastly, echocardiography emission tomography scan allows the evaluation of myocardial
allows the identification of other etiologies of chest pain syndromes metabolism. In present time, PET scans may be used to distin-
in women, such as mitral valve prolapse. In addition, echo is limited; guish between irreversibly injured myocardium and the reversible
in that results may be difficult to interpret, particularly in patients contractile dysfunction of hypoperfused hibernating myocardium,
with pulmonary disease or obesity. It is to be observed that interpre- as well as to evaluate regional myocardial blood flow. Use of PET in
tation of stress echoes requires specially trained personnel. Recent practice is limited by time limits and by the high cost of the cyclotron
data suggests that accuracy of stress echo interpretation is correlated that is required onsite. As of date, these diagnostic modalities have
to volume of images read regularly; in one report, accuracy was 81% not been extensively studied or applied in women.
for high-volume readers (43 studies per month).41
Since, stress echo does not require isotopes, echocardiography Steps in Diagnosing Cardiac Ischemia
is generally less expensive than nuclear medicine imaging studies. In
addition, treadmill echo tests take only about 30 minutes to perform For the diagnosis of cardiac ischemia, careful clinical history with
compared with stress nuclear medicine studies, which take several importance on delineating chest pain characteristics followed by
hours. reviewing the patient’s risk factors, which have stronger predictive
value in women than in men should be gathered.45 This information despite the insufficiency of medical therapy for symptom relief. An
may then be used to estimate the likelihood of disease. For exam- analysis of hospital discharge records conducted by Ayanian and
ple, a 65-year-old woman with typical angina has a 91% chance of Epstein11 also established that men were referred for cardiac cath-
having CAD, a 55-year-old woman with atypical angina has a 32% eterization 15–28% more than women and had 27–45% more CABGs.
chance, and a 45-year-old woman with nonanginal chest pain has a
3% chance.46 This estimate is appropriate in view of low accuracy of Strategies Based on Gender
most of the available noninvasive modalities.
Cardiac catheterization provides anatomic information, and an Basis for lower coronary arteriography rates among women are
exercise test gives functional and prognostic information. When the unclear, but they probably arose from the misperception that CAD
likelihood of disease is intermediate, a noninvasive test, particularly rarely affects women and have tendency to develop advanced CAD,
exercise echocardiography, may be a rational approach in the work- and consequently will have limited benefit from surgery. To avoid
up for CAD. If the likelihood of disease is minimal, then diagnostic under-referral of women for angiography, the clinician must be
tests are doubtful to be helpful and careful clinical observation is aware that: firstly, women may have severe CAD but may present
acceptable. differently from men, secondly, therapeutic intervention and angi-
ography may benefit such patients, and finally, in general, there is a
MEDICAL MANAGEMENT FOR CORONARY tendency toward under-referral of women for cardiac testing.
Further research study is essential to classify “optimal” rates of
ARTERY DISEASE IN WOMEN
cardiac catheterization for men and women. Currently, there is an
inconsistency in referral rates, even when there is objective evidence
Acute Myocardial Infarction of ischemia, even though this gap has narrowed in the last 5 years.
Coronary thrombolysis (with intravenous streptokinase, urokinase, Khan and colleagues50 reviewed 2,297 CABG cases and estab-
or tissue plasminogen activator) appears to have benefits in both lished that women’s operative mortality was nearly twice that of men.
sexes, even if there is a slightly higher rate of intracerebral hemor- However, the researchers and clinician also discovered that upon
rhage in women. In addition, this information is predominantly from referral, more women had unstable angina, postinfarction angina,
earlier thrombolysis studies where dosage was not adjusted as per and congestive heart failure.
smaller body surface area in women.47 Beta-blockers and aspirin
administered in women post-MI appear to be equally efficacious in Coronary artery bypass grafting outcome in women: Women are not
preventing coronary thrombosis. only under-referred for coronary angiography, but they do not fare
as well as men following CABG and possibly coronary angioplasty.50
Gender Bias in Referrals for Diagnostic Testing Following bypass surgery, the CASS showed that the operative
mortality for women was 4.5% in contrast with 1.9% in men.
In 1987, Tobin and colleagues11 described that significant gender Discrepancies were ascribed to technical factors such as smaller
bias existed in the referral for coronary arteriography. Subsequent to vessel size in women. Women also appear to have not that relief of
an abnormal exercise thallium test results, men were ten times more original symptoms after CABG, probably because women have a
likely to be referred for coronary arteriography than were women. tendency to be more ill than men who undergo the procedure. Some
Several data have confirmed that men are referred more frequently series have revealed a higher graft occlusion rate among women.
for cardiac angiography than are women.48,49 Figures from the National Heart Lung and Blood Institute’s reg-
Another study by Kong and associates36 found that from 1988 istry showed that women also have higher procedural mortality for
to 1989, men were still more likely than women to be referred for PTCA, mainly due to smaller body size, older age, and more existing
coronary angiography after an abnormal exercise thallium test. Only comorbidity.
38.0% of women, compared with 62.3% of men, were further evalu-
ated for coronary disease. In a 2-year follow-up, the rate of cardiac FINAL INTERPRETATION
death or MI in women was 6.9% versus 2.4% for men, suggesting that
more aggressive assessment in women might have reduced their Coronary artery disease involves men and women alike and suf-
mortality rate. Women who underwent revascularization did not ficient gender differences exist when the patient is a woman. It is
have adverse cardiac events for 2 years postoperatively.46 observed that noninvasive diagnostic testing is less accurate in
In the Survival and Ventricular Enlargement study, Steingart women, whereas invasive testing is underperformed; CABG has
observed that 50% of women reported that angina limited their phys- higher morbidity and mortality, and advantages of risk-factor modi-
ical activity as opposed to 31% of men however; only 15% of women fication are less apparent for women compared to men.
compared with 27% of men had prior coronary arteriography. As In order to rectify these perceptions, the clinician must make an
would be expected, only 6% of women versus 12% of men had CABG effort and generate awareness of implication of gender, age and chest
pain characteristics as diagnostic tools for CAD, and then needs to tion must surface that suggest new approach to minimize risk, and
understand the advantages, disadvantages and accuracy of the avail- appropriate modification of other risk factors with diet and exercise.
able resources including noninvasive tests. The population is aging and it is estimated that by the year 2010 more
In addition, women with a high possibility of operable disease than 80% of the population, which comprise of persons with 85 years
should be referred for coronary angiography. or older will be women. Hence, the rate of CVD is likely to increase
Also, bypass grafting should be performed more carefully in wom- and this could be monitored effectively if aggressive preventive
en, particularly in women with severe CAD or congestive heart failure. measures are implemented.
Finally, risk-factor stratification and modification is to be under- Some evidence-based guidelines for prevention of heart disease
taken with respect to smoking and possibly HRT. Adequate informa- in women are given in Table 49.2.
TABLE 49.2 Evidence-based guidelines for prevention of heart disease in women

Lifestyle Interventions Major Risk Factor Interventions Preventive Drug Interventions
Class I recommendations
Smoking cessation Maintain optimal BP (< 120/80 mm Hg) with ASA in high-risk women (known CAD,
lifestyle modification cerebrovascular disease, PAD, AAA, ESRD, CKD,
diabetes, and 10-year Framingham risk > 20%)
Exercise 30 minutes of moderate intensity (i.e. Pharmacotherapy for BP when > 140/90 mm Hg Clopidogrel therapy for high-risk women
brisk walking) exercise on most/all days of the (> 130/80 mm Hg in CKD or diabetes) intolerant of ASA
week
Weight loss to BMI < 24.9 kg/m2 and waist Control of lipids through lifestyle modification b-blockers indefinitely in those women after MI,
circumference < 35 inches (LDL-C < 100 mg/dL, HDL-C > 50 mg/ dL, ACS or LV dysfunction
triglycerides < 150 mg/dL, and non-HDL-C (total
cholesterol-HDL-C) < 130 mg/dL)
Cardiovascular rehabilitation in those with recent Pharmacotherapy of lipids in those with CAD or ACE inhibitors in those after MI or with clinical
ACS or PCI, angina, recent CVA, PAD or CHF diabetes to goal LDL-C < 100 mg/dL CHF, LV dysfunction (LVEF < 40%), or diabetes.
If intolerant of ACE inhibitor, ARB can be
substituted.
Diet counseling to promote intake of fruits and Pharmacotherapy of lipids in those with LDL-C Aldosterone blockade after MI in symptomatic
vegetables, whole-grain and high-fiber foods, > 130 mg/dL after lifestyle modification and women with LVEF < 40% who are without renal
and fish at least two times per week. Limit presence of multiple risk factors (or if LDL-C > dysfunction or hyperkalemia and who are
consumption of saturated fat, cholesterol, 160 mg/dL in those with multiple risk factors, already on an ACE inhibitor and b-Blocker
alcohol, sodium, and transfatty acids even if Framingham risk < 10%
Pharmacotherapy of lipids in those with LDL-C >
190 mg/dL regardless of other risk factors
Maintain HbA1c < 7% in diabetes
Class IIA recommendations
Consider depression screening and therapy Goal LDL-C < 70 mg/dL is reasonable in the Low-dose ASA therapy (81 mg daily or 100 mg
very high risk (known CAD + multiple major risk on alternate days) in women > 65 years old if
factors, severe and poorly controlled risk factors, benefits outweigh risk of bleeding
or diabetes)
Pharmacotherapy with niacin or fibrates when
HDL-C is low or non-HDL-C is elevated in high-risk
women (after LDL-C goal reached)
(Abbreviations: BP, blood pressure; ASA, acetylsalicylic acid; CAD, coronary artery disease; PAD, peripheral arterial disease; AAA, abdominal aortic
aneurysm; ESRD, end-stage renal disease; CKD, chronic kidney disease; BMI, body mass index; LDL-C, low-density-lipoprotein cholesterol; HDL-C, high-
density-lipoprotein cholesterol; MI, myocardial infarction; ACS, acute coronary syndromes; LV, left ventricular; CVA, cerebrovascular accident; CHF,
congestive heart failure; LVEF, left ventricular ejection fraction; ACE inhibitor, angiotensin-converting-enzyme inhibitor, HbA1c, hemoglobin A1c)
Source: Adapted from ACC/AHA Guidelines 2007 update. Circulation. 2007;115(11):1481-501.
REFERENCES
1. Thom T, Hasse N, Rosamond W, et al. Heart disease and stroke statistics-2006 updates: a report from the American Heart Association Statistics
Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85-151.
HEAT study): case control study. Lancet. 2004;364(9438):937-52.
3. Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases: part 1: general considerations, the epidemiological transition, risk
factors, and impact of urbanization. Circulation. 2001;104(22):2746-53.
4. Lerner DJ, Kannel WB. Patterns in coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham popula-
tion. Am Heart J. 1986;111(2):383-90.
5. Tobin JN, Wassertheil Smoller S, Wexier JP, et al. Sex bias in considering coronary bypass surgery. Ann Intern Med. 1987;107(1):19-25.
6. Fisher LD, Kennedy JW, Davis KB, et al. Association of sex, physical size, and operative mortality after coronary artery bypass in the Coronary
Artery Surgery Study (CASS). J Thorac Cardiovasc Surg. 1981;84(3):334-41.
7. Barrett-Connor E, Khaw K. Family history of heart attack as an independent predictor of death due to cardiovascular disease. Circulation.
1984;69(6):1065-9.
8. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med.
1990;322(13):883-9.
9. Stevens J, Cai J, Pamuk ER, et al. The effect of age on the association between body-mass index and mortality. N Engl J Med. 1998;338(1):1-7.
10. Centers for Disease Control (CDC). Cigarette smoking in the United States. MMWR Morb Mortal Wkly Rep. 1986;36(35):581-5.
11. US Department of Health and Human Services. Smoking and Health: a National Status Report: a report to congress. Washington, DC, US Depart-
ment of Health and Human Services; 1987.
12. Willett W, Green A, Stampfer M, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J
Med. 1987;317(21):1303-9.
13. Rosenberg L, Miller DR, Kaufman DW, et al. Myocardial infarction in women under 50 years of age. JAMA. 1983;250(20):2801-6.
14. Palmer JR, Rosenberg L, Shapiro S. “Low-yield” cigarettes and the risk of nonfatal myocardial infarction in women. N Engl J Med. 1989;320(24):1569-
73.
15. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70(19):3H-9H.
16. Castelli WP, Anderson K, Wilson PW. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol. 1922;2(1-2):23-28.
17. Guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary
heart disease in adults. Ann Intern Med. 1996;124(5):515-7.
18. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland
Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301-7.
19. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.
1994;344(8934):1383-9.
20. Pedersen TR, Kjekshus J, Berg K, et al. Cholesterol lowering and the use of healthcare resources. Results of the Scandinavian Simvastatin Survival
Study. Circulation. 1996;93(10):796-802.
21. Cornoni-Huntley J, LaCroix AZ, Havlik RJ. Race and sex differentials in the impact of hypertension in the United States. The National Health and
Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Intern Med. 1989;149(4):780-8.
22. Stokes J III, Kannel W, Wolf P, et al. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men
and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation. 1987;75(6 Pt 2):V65-V73.
23. Kjelsberg MO, Cutler JA, Dolecek TA. Brief description of the Multiple Risk Factor Intervention Trial. Am J Clin Nutr. 1997;65(Suppl 1):S191-5.
24. Amery A, Birkenhager W, Birxko P. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial.
Lancet. 1985;1(8442):1349-54.
25. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J. 1985;291(6488):97-104.
26. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke
in women. Arch Intern Med. 1999;151(6):1141-7.
27. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mel-
litus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):976-7.
28. Manson J, Colditz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in
women. Arch Intern Med. 1991;151(6):1141-7.
29. Lapidus L, Bengstsson C, Larsson B, et al. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of par-
ticipants in the population study of women in Gothenburg, Sweden. Br Med J (Clin Res Ed). 1984;289(6454):1257-61.
30. Williams JK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation. 1990;81(5):1680-7.
31. Sullivan JM, El-Zeky F, Vander Zwaag R, et al. Effect on survival of estrogen replacement therapy after coronary artery bypass grafting. Am J Cardi-
ology. 1997;79(7):847-50.
32. Stampfer M, Colditz G, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health
study. N Engl J Med. 1991;325(11):756-62.
33. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med.
1992;117(12):1016-37.
34. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.
Prev Med. 1991;20(1):47-63.
35. Voigt LF, Weiss NS, Chu J, et al. Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet. 1991;338(8762):
274-7.
36. Kwok YS, Kim C, Segal M, et al. Exercise testing for coronary artery disease diagnosis in women: A meta-analysis. Circulation. 1996;I-497:2916.
37. Taillefer R, DePuey EG, Udelson JE, et al. Comparative diagnostic accuracy of Tl-201 and Tc-99m sestamibi SPECT imaging (perfusion and ECG-
gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol. 1997;29(1):69-77.
38. Kong BA, Shaw L, Miller DD, et al. Comparison of accuracy for detecting coronary artery disease and side-effect profile of dipyridamole thal-
lium-201 myocardial perfusion imaging in women versus men. Am J Cardiol. 1992;70(2):168-73.
39. Marwick T, Rimmerman C, Stewart W. Experience vs accuracy of stress echocardiography reading. Importance of high clinical volume. Circula-
tion. 1995;92:I-90.
40. Hashimoto T, Buxton DB, Krivokapich J, et al. Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in
stunned canine myocardium. Am Heart J. 1994;127(5):1250-62.
41. Bach DS, Hepner A, Marcovitz PA, et al. Dobutamine stress echocardiography: prevalence of a nonischemic response in a low-risk population. Am
Heart J. 1993;125(5 Pt 1):1257-61.
42. Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N Engl J Med. 1996;334(20):1311-5.
43. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med. 1979;300(24):1350-8.
44. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. J Am Coll Cardiol. 1988;12(6 Suppl A):3A-13A.
45. Steingart RM, Packer M, Hamm P, et al. Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement In-
vestigators. N Engl J Med. 1991;325(4):226-30.
46. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med.
1991;325(4):221-5.
47. Weintraub WS, Kosinski AS, Wenger NK. Is there a bias against performing coronary revascularization in women? Am J Cardiol. 1996;78(10)1154-
60.
48. Khan SS, Nessim S, Gray R, et al. Increased mortality of women in coronary artery bypass surgery: evidence for referral bias. Ann Intern Med.
1990;112(8):561-7.
49. Bickell NA, Pieper K, Lee K, et al. Referral patterns for coronary artery disease treatment: gender bias or good clinical judgment? Ann Intern Med.
1991;116(10):791-7.
50. Cowley MJ, Mullin SM, Kelsey SF, et al. Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA Registry. Circula-
tion. 1985;71(1):90-7.
50 History of Heart and
Trans-Fat Relationship
Kumar A, Kaur H, Mohan V
hardly any nutritional value. They are ubiquitous in fast food restau-
ABSTRACT
rants and grocery stores. In India, pastries, cakes, samosas, burgers,
Trans-fats are solid fats produced artificially by heating vegetable puris, parothas, tikkis etc. are the richest source of TFAs and con-
oils in the presence of metal catalysts and in the presence of pressur- tribute in a large measure to the epidemic of CAD in India. Every
ized hydrogen gas. In chemical terms, trans-fat refers to a lipid mol- additional 2% of TFA consumption increases the risk of CAD by 25%
ecule that contains one or more double bonds in a trans-geometric within 10 years whereas replacing 2% of food energy from trans-fats
configuration. This man-made poison may be largely responsible with nontrans-unsaturated fats more than halves the risk of coronary
for the epidemic of coronary artery disease (CAD) in the 20th cen- heart disease [CHD (53%)]. They are at least 2 1/2 times more harm-
tury in the developed world and also perhaps in developing coun- ful than saturated fats (ghee, butter, coconut oil etc.) in causing CAD,
tries like India. Eighty-five years ago, margarines/crisco in the west diabetes and stroke. They are also carcinogenic. Their use was started
and vanaspati/vegetable ghee in India were introduced for the first in developed countries in the earlier part of the 20th century espe-
time. Little was known about their harmful potential when these cially in the United States of America and parts of Europe and was
unnatural fats were initially developed. They are now known to soon adopted by the rest of the world.
affect lipids, inflammation and insulin resistance adversely and
are closely associated with cardiovascular diseases (CVD) like CHEMISTRY
CAD and hypertension. The countries all over the world are under
tremendous pressure to withdraw its use and to utilize alternative Unsaturated fat is a fat molecule containing one or more double
cooking oils with ultimate aim to have zero trans-fatty acids (TFAs) bonds between the carbon atoms. The process of hydrogenation adds
content in the preparations without affecting taste and flavor and hydrogen atoms to cis-unsaturated fats, eliminating double bonds
without a significant increase in cost. One of the most favored fats and making them into partially or completely saturated fats. In the
in food and bakery industry of the late 19th and more than half of cis-arrangement, carbon atoms adjacent to their double bonds are
the 20th century is now taking a backseat as its use has led to an on the same side of the double bond, resulting in a kink. In the trans-
unacceptable increase in the incidence of cardiovascular morbid- arrangement, the chains are on opposite sides of the double bond
ity and mortality. and the chain is straight (Fig. 50.1). However, partial hydrogenation
Keywords: Trans-fats, Food industry, Coronary artery disease. converts a part of cis-isomers into trans-unsaturated fats instead of
Abbreviations: TFAs, trans-fatty acids; CAD, coronary artery hydrogenating them completely. Naturally occurring unsaturated
disease. fatty acids have carbon atoms line up in a bent shape, resulting in
a liquid state at room temperature. The trans-molecules have the
INTRODUCTION ability to pack more tightly and form a solid that is more difficult to
break apart. Partial hydrogenation, the process used to create TFAs,
Our consumer culture has produced many environmental hazards in is primarily used to produce solid fats. However, it also removes
the name of progress and convenience. Processed food consumption essential polyunsaturated fatty acids, such as linolenic acid (omega
is linked with a number of health hazards, some attributable to the 3) and linoleic acid (omega 6).
presence of TFAs which are unsaturated solid fats produced indus-
trially by partial hydrogenation of polyunsaturated liquid vegetable SOURCES
oils. They are in fact a “man-made poison” in the form of vanaspati
ghee (in India) and other foods especially baked and fast foods. They Trans-fatty acids are by far the largest amount of artificial chemicals
are produced to prolong shelf life, palatability and chemical stabil- in the American food supply. TFAs are present in a variety of foods
ity (important to food industry) and are relatively cheaper but with but they contribute only 4–12% of total dietary fat intake (2–4% of
Chapter 50  History of Heart and Trans-Fat Relationship 371
duction, secretion, and catabolism of lipoproteins, together with

effects on plasma cholesteryl ester transfer protein (CETP), probably
account for adverse effects of TFAs on serum lipid levels. People who
ate partially hydrogenated oils, which are high in trans-fats, wors-
ened their blood lipid profiles. Trans-fat behaves like saturated fat by
raising the level of low density lipoprotein (LDL) but unlike saturated
fat it has the additional effect of decreasing levels of high-density li-
poprotein (HDL). The net increase in LDL/HDL ratio with trans-fat
is approximately double that is due to saturated fat. It is known that
every one-unit change in the ratio of total cholesterol (TC)/HDL is
associated with a 53% increase in risk for myocardial infarction (MI)
after adjusting for various cardiovascular (CV) risk factors. A signifi-
cant decrease in LDL particle size which is a separate risk factor for
heart disease was found with increasing amounts of dietary TFA.1
Trans-fatty acids also raise triglyceride levels and apolipoprotein A.
A significant increase in Lp(a) lipoprotein levels was reported in 9 of
10 trials, with an average increase of 0.5 mg/dL 2% of energy intake
from trans-fatty acids. High blood levels of Lp(a) lipoprotein have
Figure 50.1: Structure of cis- and trans-fatty acids
been associated in some studies with an increased risk of CHD. There
are decreased omega-3 fatty acids with resultant effects of increased
total energy intake) in the United States. These are common in a omega-6 versus omega-3 ratio. (Ideally this should be less than 2:1).
range of food products including biscuits, chips, doughnuts and
crackers. This hydrogenated vegetable fat is used by food processors Effect on Cell Membranes
because it is solid at room temperature and has a longer shelf life.
The trans-fats content based on food and drug administration Fatty acids are powerful modulators of cell function, altering mem-
data is as follows: brane fluidity and responses of membrane receptors. Trans-fatty
• 51% in baked goods (Cakes, cookies, crackers and pies) acids are unnatural fats. Since they do not occur in nature, our bod-
• 22% in margarines ies do not know how to deal with them effectively and they act as
• 10% in fried potatoes poisons to crucial cellular reactions. Delta 6 desaturase is an enzyme
• 6% in potato chips and corn chips involved in converting essential fatty acids which are components
• 5% in shortening of cell membranes to arachidonic acid and prostaglandins, both of
• 4% in salad dressing which are important to the functioning of cells. Metabolism of ara-
• 1% in breakfast cereals. chidonic acid results in the biosynthesis of mediators with potent
Many people are consuming in excess of 15 g of trans-fat per day physiological effects such as prostaglandins, prostacyclins, throm-
especially when we know that: boxanes, leukotrienes and lipoxins .These eicosanoids are most often
• One McDonald's large fries contains 8 g of trans-fat concerned with clotting, inflammation and the initiation of immune
• A McDonald's apple pie contains 4.5 g of trans-fat defense. However, polyunsaturated trans-fatty acids cannot be used
• A large order of KFC popcorn chicken contains 7 g of trans-fat to produce useful mediators because the molecules have unnatural
• KFC's chicken pot pie contains 14 g of trans-fat shapes that are not recognized by enzymes such as cyclooxygenase
• A typical 3-piece KFC extra-crispy combo meal, with a drumstick, and lipoxygenase. TFAs increase body's proinflammatory hormones
two thighs, potato wedges and a biscuit contains 15 g of trans-fat. (PGE2) and inhibit anti-inflammatory types PGE1 and PGE3. This
undesirable influence exerted by trans-fats on prostaglandin bal-
POTENTIAL MOLECULAR MECHANISMS OF ance may render an individual vulnerable to inflammatory condi-
tions with sick, weakened cells, poor organ function and exhausted
CARDIOVASCULAR EFFECTS OF TRANS-
immune system. A higher intake of TFA is associated with increased
FATTY ACIDS interleukin-6, tumor necrosis factor receptors, soluble cell adhe-
sion molecules, and serum paraoxonase activity.2 The impact of TFA
Effect on Lipids
intake on CVD risk goes beyond the effect of high cholesterol. Emerg-
Trans-fats are metabolized differently by the liver than other fats. ing research shows that TFAs also increase CVD risk by adversely
There is increase in fatty acids, decreased triglyceride uptake and affecting endothelial function and inflammation. TFAs modulate
decrease in cholesterol esterification. Changes in hepatocyte pro- monocyte and macrophage activity with increased production of
inflammatory mediators. Because the presence of inflammation is In 1948, the first McDonald's restaurant opened in San Berna-
an independent risk factor for atherosclerosis, diabetes, and heart dino, California. The American diet began to include more and more
failure, the inflammatory effects of trans-fats may account in part high-fat processed and fast food.
for their effects on cardiovascular health. TFAs alter the membrane’s In 1957, the Lancet published controversial studies by University
protective structure and function and normal transfer of minerals of Minnesota scientist Ancel Keys hinting that a high-fat saturated
and nutrients is also disturbed. diet leads to CHD. Food manufacturers' studies of a possible link
Trans-fatty acids cause denser cell membranes that alter the between trans-fats and cholesterol levels yielded conflicting results.
normal function of cell, by causing dysfunctional receptors and sign- Production of hydrogenated fats increased steadily until the
aling molecules.3 Dietary TFAs alter adipocyte plasma membrane 1960s as processed vegetable fats replaced animal fats in the US and
fatty acid composition and insulin sensitivity. They derange insulin other western countries. At first, the argument was a financial one
cell signaling and also cause insulin resistance. There is a growing due to lower costs; however, advocates also said that the unsaturated
concern that the risk of diabetes increases with trans-fat consump- trans-fats of margarine were healthier than the saturated fats of but-
tion. They also cause increased incidence of hypertension. Collec- ter.
tively the constellation of biological effects of TFAs contribute to the In 1985, studies by HSPH's Sacks showed that beef tallow was
octogeny of atherosclerosis, acute coronary syndrome, sudden car- used in fried fast foods. Media attention prodded restaurant chains
diac death, insulin resistance, dyslipidemias and heart failure. to switch to hydrogenated vegetable oils laden with trans-fats. Health
These synthetic fats replace the natural docosahexaenoic acid aspects of dietary trans-fatty acids, an overview of research prepared
(DHA) in the membrane, which affects the electrical activity of the for the FDA by the Federation of American Societies for Experimen-
cell and thereby cause increased incidence of arrhythmias and sud- tal Biology concluded that trans-fats are probably akin to saturated
den cardiac death (SCD) more so by causing a decrease in omega-3 fats in their cholesterol-raising properties, but that more research is
fatty acids. needed.
In 1987, Netherlands nutrition researcher Martijn Katan asked
HISTORY OF TRANS-FAT DEVELOPMENT European food conglomerate Unilever to fund a study of the effect of
trans-fats on blood lipids.
AND PROGRESS IN FOOD INDUSTRY
In 1890s, Nobel Prize winner Paul Sabatier developed the chemistry TRIALS SHOWING INCREASED RISK OF
of hydrogenation. German chemist Wilhelm Normann showed in
CORONARY ARTERY DISEASE WITH INTAKE
1901 that liquid oils could be hydrogenated and patented the pro-
cess in 1902. It took only 2 years until the hardened fat could be suc-
OF TRANS-FATS
cessfully produced. The initial year's production totalled nearly 3,000 The primary health risk identified for trans-fat consumption is an
tonnes. elevated risk of CHD. There were suggestions in the scientific
In 1909, Procter and Gamble acquired the US rights to the Normann literature as early as 1988 that trans-fats could be a cause of the large
patent. In 1911, they began marketing the first hydrogenated short- increase in CAD. However, by the 1990s, studies began to identify
ening, Crisco (composed largely of partially hydrogenated cotton- trans-fat as a health hazard.
seed oil). Further success came from the marketing technique of
giving away free cookbooks in which every recipe called for Crisco. Nurses’ Health Study
Normann's hydrogenation process made it possible to stabilize
affordable whale oil or fish oil for human consumption, a practice The major evidence for the effect of trans-fat on CHD came from the
kept secret to avoid consumer distaste. Nurses' Health Study (NHS)—a cohort study that has been follow-
In 1903–1950, two world wars and the depression pushed thrifty ing 120,000 female nurses since its inception in 1976. In this study,
US consumers into using economical products containing trans-fats, Hu and colleagues analyzed data from 900 coronary events from the
such as sticks of margarine and Crisco. Little was known about the NHS population during 14 years of follow-up. Hu reported on the
relationship between dietary fats and health. Hydrogenated fat such benefits of reducing trans-fat consumption. Replacing 2% of food
as Crisco and Spry, sold in England, began to replace lard in the bak- energy from trans-fat with nontrans-unsaturated fats more than
ing of bread, pies, cookies, and cakes in 1920. The fat industry found halves the risk of CHD (53%). By comparison, replacing a larger
that hydrogenated fats provided some special features to margarines, 5% of food energy from saturated fat with nontransunsaturated fats
which unlike butter, allowed margarine to be taken out of the refrig- reduced the risk of CHD by 43%.4
erator and immediately spread on a slice of bread. By some minor The Harvard School of Public Health estimated that 30,000 pre-
changes to the chemical composition of hydrogenated fat, they also mature cardiovascular deaths per year could be prevented in USA
found such hydrogenated fat provided superior baking properties by replacing trans-fats in the food supply with liquid vegetable oil
compared to lard. (unsaturated fat). In a study of about 3,500 (urban/rural patients)
randomly selected subjects consuming moderate to high fats , those United States that is 228,000 (19%) CHD events each year could be
eating TFAs (vegetables ghee) plus clarified butter (Indian ghee) had averted by reducing the intake of trans-fat.9
a significant higher prevalence of CAD in both sexes and both in Other nonrandomized, case-controlled studies have also
rural and urban population as compared to those consuming clari- revealed a link between higher TFA intake and CVD outcomes,
fied butter and vegetable oils.5 The positive relationship between specifically first nonfatal MI, death from CHD, or primary cardiac
trans-fat intake and risk of CHD observed in the NHS is gener- arrest (Table 50.1).
ally consistent with several prospective studies conducted in men,
including the Health Professionals’ Follow-up Study in men and the Other Studies
alpha-tocopherol, beta-carotene cancer prevention study which
found that Finnish men with high intakes of trans-fat were more In a study in Australia in 2004 dietary information and a fat biopsy
likely to die from heart disease than those with lower intakes.6 was acquired from 79 people.15 Each had just a first heart attack. Sim-
It was found that TFA intake was associated with an increased ilar information and biopsy samples were obtained from 167 people
risk in CHD in women also.7,8 without heart problems. The heart patients and healthy individuals
A major comprehensive study on the health effects of trans-fats were also matched for age, gender, and socioeconomic background.
was published in April 2006 in the New England Journal of Medicine. Analysis revealed that trans-fats from both animal and vegetable
The study brings together the findings from different studies and tri- sources were significantly more abundant in the fat tissues of heart
als and contains several findings, including the following: On a per- attack patients than in the healthy volunteers. The relationship of
calorie basis, trans-fats appear to increase the risk of CHD more than abundant trans-fats with heart risk remained even after the effect of
any other macronutrient, conferring a substantially increased risk at saturated fats in the participants’ diets was statistically accounted for.
low levels of consumption (1–3% of total energy intake). Even if the In our study (Adarsh Kumar et al. 2007. Data presented at this
intake of 5 g “trans-fat” is increased through our food daily, the pos- 12th World Congress on clinical nutrition held in edmonton, Canada
sibility of heart attack increases by 25%. In a meta-analysis of four from 17–20 June in 2007), 512 cases of CAD admitted in the institu-
prospective cohort studies involving nearly 140,000 subjects, includ- tion (M/F 374/138–73%/27%) aged 29–81 years (mean of 54.2 years),
ing updated analyses from the two largest studies it showed that a 2% 390 (76.2%) cases gave history of consuming solid ghee (dalda/vanas-
increase in energy intake from trans-fatty acids was associated with a pati); fast foods like snacks, French fries, doughnuts, pastries etc. and
23% increase in the incidence of CHD. 10–19% of CHD events in the paronthas/bhaturas/puris etc. (All having TFA content of ≥ 7%) in
TABLE 50.1 Important studies linking trans-fat intake with coronary artery disease
Author Cohort Endpoints Results
Willet et al. 19937 85,095 women Nonfatal MI or death from CHD TFA intake associated with higher risk of
8-year follow-up CHD
Asherio et al. 199410 521 men and women First acute MI Significant increased risk with TFA intake.
(Case control) Boston No association between TFA from animal
sources and risk of CHD.
Health professionals follow-up 43,757 men Incidence of CHD Positive association between TFA intake and
study (Sudden death or MI) 6-year follow-up risk of CHD.
Ascherio et al. 199611
Alpha-tocopherol beta-carotene 21,930 men Significant increased risk with TFA
(prospective) 19976
Hu et al. 1997 (prospective) 80,082 women Nonfatal MI or fatal CHD 2% increase in energy intake from TFA was
NHS8 14-year follow-up associated with increased risk from CHD.
Lemaitre et al. 2002 464 men and women Primary cardiac arrest Trans-isomer of linilinic acid associated with
(Case control)12 threefold increased risk of cardiac arrest.
Oh et al. 200513 78,778 women Nonfatal MI or fatal CHD, 20 year TFA intake associated with increased risk
NHS (prospective) follow-up of CHD
Oomen et al. 200114 667 men of the Zutphen Fatal or nonfatal CHD. TFA intake at baseline was positively
Elderly Study aged 64–84 associated with the 10-year risk of CHD.
years without CAD
addition to mild to moderate consumption of saturated animal fats Role of Trans-Fatty Acids in Cardiac
like desi ghee (Group I). Group II—122/512 (23.8%) cases were using
Arrhythmias
vegetable oils (mustard/saffola etc.—with TFA content ≤ 3%) with no
significant intake of fast foods etc. Their intake of saturated animal Trans-fatty acids affect membrane structure and alter cell mem-
fats was comparable to Group I. The factors like age, sex, BMI, WHR, brane enzymatic pathways that may subsequently induce cardiac ar-
dietary habits, physical activity, smoking and alcohol consumption rhythmias and sudden death.16 Incidence of SCD is more increased
etc. were taken into consideration in both the groups. The level of with 18-carbon isomers particularly trans-18:2. In a study in Seattle,
all lipid parameters was more significantly abnormal in Group I as 179 cases aged 25–74 years with out-of-hospital cardiac arrest were
compared to Group II (Table 50.2). Group I cases (with higher TFA attended by paramedics from 1988 to 1999. 285 controls, matched to
content) had higher incidence of adverse presentations of CAD and the 179 cases by age and sex, were randomly identified from the com-
higher incidence of diabetes mellitus (DM) as compared to Group II munity. Participants were free of previous clinically diagnosed heart
(with lower TFA content (Table 50.3). disease. Blood was obtained at the time of cardiac arrest (cases) or at
the time of an interview (controls) to assess trans-fat intake. Higher
total trans-fat in red blood cell membranes was associated with a
TABLE 50.2 Effect of diet high in TFAs on lipid parameters in 512 cases of modest increase in the risk of primary cardiac arrest after adjustment
coronary artery disease for medical and lifestyle risk factors.17 However, not all studies sup-
Parameter Group I (Diet with Group II (Diet with P-value port these findings. The EURAMIC study, a multicenter case-control
High TFA %) Low TFA %) study of 742 men with acute MI, found no association.18 TFAs also
Serum 162–373 mg 142–306 mg Significant significantly reduce omega-3 fatty acids which are cardioprotective
cholesterol (Mean of 230 mg) (Mean of 206 mg) against arrhythmogenic SCD.
S triglycerides 96–364 mg 84–312 mg Significant
(Mean of 224 mg) (Mean of 183 mg) BAN ON TRANS-FATS
LDL 66–133 mg 55–130 mg Significant
(Mean of 104 mg) (Mean of 67 mg) In the recent past countries such as Denmark, Canada, United States
(New York City and California State in particular) and Australia and
HDL 23–64 mg 25–71 mg Significant
New Zealand have taken the lead in adopting initiatives to reduce
(Mean of 30 mg) (Mean 37 mg)
TFA intake.
Source: Study by Adarsh Kumar et al. 2007. Data presented at this 12th
World Congress on Clinical Nutrition held in Edmonton, Canada from 17–
20th June in 2007. Denmark Model
Abbreviations: TFAs, trans-fatty acids; LDL, low-density lipoprotein; HDL,
high-density lipoprotein Denmark became the first country to introduce laws strictly regu-
lating the sale of many foods containing trans-fats in March 2003,
a move which effectively banned partially hydrogenated oils. The
TABLE 50.3 Effect of diet high in TFAs on clinical manifestations in 512 cases limit is 2% of total fats and oils destined for human consumption. It
of coronary artery disease
should be noted that this restriction is on the ingredients rather than
Cardiovascular Group I-390/512 Group II-122 P-value the final products. This regulatory approach has made Denmark the
Event Cases Cases only country in which it is possible to eat less than 1 g of industri-
(TFA ≥ 7%) (TFA ≤ 3%)
ally produced trans-fats on a daily basis, even with a diet including
Acute coronary 206/390 40/122 (32.8%) < 0.05 prepared foods. It is hypothesized that the Danish government's
syndrome (52.8%) efforts to decrease trans-fat intake from 6 g to 1 g per day over 20
Like unstable
years is related to a 50% decrease in deaths from ischemic heart dis-
angina/AMI
ease. In Denmark, the trans-fats were replaced with cis-unsaturated
Heart failure 90/390 (23.1%) 15/122 (12.3%) < 0.05 fatty acids and some saturated fatty acids from tropical oils or fully
Significant 72/390 (18.5%) 13/122 (10.6%) < 0.05 hydrogenated vegetable oils in certain cookie and bakery products.
tachyarrhythmias This move essentially eliminated the use of trans-fats in Denmark.
(Lanong’s In Norway, Finland, and The Netherlands, similar cooperative efforts
classification)
have resulted in substantial reductions in trans-fat use.
In-hospital mortality 29/390 (7.4%) 7/122 (5.7%) Insignificant
Associated diabetes 14/390 (36.1%) 21/122 (17.2 %) < 0.05
Switzerland Model
Source: Study by Adarsh Kumar et al. 2007. Data presented at this 12th
World Congress on Clinical Nutrition held in Edmonton, Canada from Switzerland followed Denmark's trans-fats ban and implemented its
17–20th June in 2007. own beginning in April 2008.
Trans-Fats in the United States of America day. The AHA also recommends that saturated fat be limited to about
15–19 g/day. Opposition came primarily from food industry associa-
In America, a voluntary organization namely “Ban Trans-fat” was es- tions, including the National Restaurant Association and its state af-
tablished to fight against the demon of “Trans-fat”. It taught a strong filiate and the Grocery manufacturers.
lesson to fast food giant “McDonalds”of America. In 2002, “McDon-
alds” declared that it will drive out “Trans-fat” from all its hotels. New York Trans-Fat Scenario
“McDonalds” company failed to keep its promise and so “Ban Trans-
fat” sued against it. Because of this claim “McDonalds” company was The food department launched an educational campaign to reduce
compelled to pay 7 million dollars as penalty to Heart Association of restaurant artificial trans-fat use. Information was sent to the 30,000
America and to put boards mentioning that their food items are not licensed food outlets in the city, 15,000 suppliers and supermarkets,
free from “Trans-fat” in all its hotels. McDonald's has found a trans- and hundreds of thousands of consumers. Mailings urged restau-
fat-free oil. It deems worthy of its French fries. rants to remove artificial trans-fat from food, suppliers to promote
KRAFT Company of America was using “Trans-fat” in its choc- zero-gram trans-fat products, and patrons to inquire about oils used.
olates. “Ban Trans-fat” warned it. So KRAFT had to stop the use of Press coverage was extensive. Protecting children, who consume
trans-fat laden unsaturated fat in its chocolates. This organization French fries and other quick-service foods that are common sources
made Tiburon, California "America's first trans-fat-free city." Project of artificial trans-fat was particularly important. On September 26,
Tiburon was intended to be an inspiration and model for other towns 2006, the New York City Health Department proposed for public
and cities. comment on two separate initiatives that will affect New York City
In 2002, the Food and Nutrition Board of the Institute of Medi- restaurants.
cine in the USA published a report on the role of trans-fats on health New York City restriction of artificial trans-fat reduction was in
and made recommendations regarding safe levels of intake. In the use in frying, baking, or cooking or in spreads. Data from 2005 to
summary of this report, its authors suggested the: “tolerable upper 2007 are from surveys. July and November 2008 data are based on
intake level of zero trans-fat”. The Institute of Medicine, the American restaurant compliance data collected during regularly scheduled in-
Heart Association, the US department of agriculture, and other lead- spections. Phase 1 of the regulation only covered fats used for frying
ing health organizations recommended minimizing trans-fat intake or as a spread. Phase 2 covered all other foods and ingredients. In
in 2002. The US government's recommendation in its dietary guide- New York City, the evaluation of replacement products and changes
lines for Americans is "keep trans-fatty acid consumption as low as in fatty acid composition are under way, and surveillance of cardi-
possible."19 ovascular disease is ongoing. If New Yorkers replace all sources of
Other organizations with these recommendations included US artificial trans-fat, by even the most conservative estimates, at least
department of health and human services, US department of agricul- 500 deaths from heart disease would be prevented each year in New
ture 2005, American Medical Association House of Delegates 2006, York City. Following the approval of the Health Code amendment,
World Health Organization Food and Agriculture Organization of the more than 50 restaurant chains announced or reiterated their inten-
United Nations, Joint WHO/FAO expert consultation on diet, nutrition to discontinue use of artificial trans-fat-containing products
tion and the prevention of chronic diseases and section report of a nationally, and most have already done so. Dozens of hotel groups,
joint WHO/FAO expert consultation from Geneva. World Health Or- food manufacturers, grocery retailers, and other companies—from
ganization in 2003 recommended, “the safest amount of trans-fats to Disney and Marriott to American Airlines and Kraft Foods—have
consume is none at all.” also announced elimination of artificial trans-fat.
In 2003, the US food and drug administration (FDA) required In January 2007, faced with the prospect of an outright ban on
that all packaged goods display information on trans-fat content by the sale of their product, Crisco was reformulated to meet the United
2006.20 The regulation allows products that contain less than 0.5 g States Food and Drug Administration definition of "zero-gram trans-
of trans-fat per serving to be labeled “zero-gram trans-fat.” This fats per serving" (that is less than 1 g per tablespoon).
prompted a widespread industry response of reformulating prod- By November 2008, the restriction was in full effect in all New
ucts to declare “zero-gram trans-fat” on front-of-package labeling, York City restaurants and estimated restaurant use of artificial trans-
although such products may still contain trans-fat in small amounts, fat for frying, baking, or cooking or in spreads had decreased from
which can add up. Suppose, you eat one serving of Product A, one 50% to less than 2%.
serving of Product B, and one serving of Product C. Let's assume that The second phase, which covered all other products, became ef-
each product contains 0.4 g per serving. You have just consumed fective on 1st July 2008. Nearly 6 months later, adherence was 92%,
1.2 g of trans-fat, despite the fact that each of the labels claims that with most violations due to missing documentation. When Novem-
the products contain zero gram of trans-fat per serving. In June 2006, ber 2008 adherence figures are adjusted to provide approximate
the American Heart Association (AHA) issued its "2006 Diet and Life- comparison with preregulation survey denominators, an estimated
style Recommendations." Limiting the daily intake of trans-fats to 1% 98% of restaurants were not using artificial trans-fat in oils, shorten-
of total calories, which is equivalent to roughly 2–2.5 g of trans-fat per ings and spreads, compared with 50% in 2005.
Preliminary analyses suggest that replacement of artificial trans- On 30th January 2008, the European Commission published
fat has resulted in products with more healthful fatty acid profiles. its proposal for a regulation on the provision of food information to
Public health efforts that change food content to make default choic- consumers. Population goal: an average intake of saturated fats and
es healthier enable consumers to more successfully meet dietary trans-fats should be less than 10% of energy; intake from trans-fats
recommendations and reduce their cardiovascular risk.21 Switching should be less than 1% of energy.
to trans-fat-free frying oil does not increase costs. The trans-fat-free In October 2005, the food standards agency (FSA) asked for bet-
frying oils available today have fry lives just as long as partially hydro- ter labeling in the United Kingdom. In the July 29, 2006 edition of
genated oils. Since New York's measure passed, more than a dozen the British Medical Journal (BMJ), an editorial also called for better
jurisdictions, including California and Philadelphia, have adopted labeling. In January 2007, the British Retail Consortium announced
similar laws, and many national restaurant chains have cut trans-fats that major UK retailers, including Asda, Boots, Co-op, Iceland, Marks
from their menus. A number of chains announced early that replace- and Spencer, Sainsbury's, Tesco and Waitrose intend to cease add-
ment of trans-fat-containing fry oils would also reduce saturated fat ing trans-fatty acids to their own products by the end of 2007. Sains-
by 20–35%. Leading fast food chains decreased the saturated fat in bury's became the first UK major retailer to ban all trans-fat from all
their French fries by 10.5% and the total trans-fat plus saturated fat their own brand foods. On 13th December 2007, the Food Standards
by 54%, on average. Agency issued news releases stating that voluntary measures to
reduce trans-fats in food had already resulted in safe levels of con-
Trans-Fats in Canada sumer intake. On 15th April 2010, a BMJ editorial called for trans-fats
to be "virtually eliminated in the United Kingdom by next year". This
In November 2004, the New Democratic Party (NDP) introduced a call was supported by the National Institute for Health and Clinical
bill in the Canadian Parliament to effectively ban trans-fats. The gov- Excellence (NICE) on 22nd June 2010.
ernment announced the formation of a task force to “develop recom-
mendations and strategies for reducing trans-fats” in Canadian foods Trans-Fats in Australia
to the lowest levels possible. On June 28, 2006, the Task Force issued
its final recommendations. For all vegetable oils and soft, spreadable The Australian federal government has indicated that it wants to
(tub-type) margarines sold to consumers or for use as an ingredient pursue actively a policy of reducing trans-fats from fast foods A draft
in the preparation of foods on site by retailers or food service estab- plan was proposed, with September 2007 time table, in order to
lishments, the total trans-fat content be limited by regulation to 2% reduce reliance on trans-fats and saturated fats. Currently, Australia's
of total fat content. A basic phase-in period be set at 1 year from the food labeling laws do not require trans-fats to be shown separately
date of entry into force of the final regulations. Extended phase-in from the total fat content. However, margarine in Australia has been
periods be specified for certain applications (e.g. baking) and for free of trans-fat since 1996.
small and medium-sized firms, recognizing that in most cases the
transition could be made within 2 years of the date of entry into force Brazilian Picture
of the final regulations. "On June 20, 2007, Health Minister Tony
Clement announced that Health Canada was adopting the Canadian The Brazilian ministry of health established in 2007 a target to reduce
Trans-Fat Task Force’s recommendation on trans-fats in Canadian the total amount of trans-fat in food to a maximum of 2% until the
foods, by calling on Canada’s food industry to limit the trans-fat con- end of 2010. From 31st July 2006 this labeling of trans-fat contents
tent of vegetable oils and soft, spreadable margarines to 2% of the became mandatory.
total fat content, and to limit the trans-fat content for all other foods
to 5%, including ingredients sold to restaurants. It gave the industry Indian Scenario
2 years to reduce trans-fats to the lowest levels possible as recom-
mended by the Trans-fat Task Force. Recent experience in Canada22 In India, vanaspati, margarine, desi ghee, butter etc. are sources of
also suggests that saturated fat content can remain the same or even TFA. Eighty-five years ago, in India when vanaspati/vegetable ghee
be reduced when trans-fat is reduced. was introduced for the first time under the brand name of “DALDA”,
it was strongly protested. People were under the impression that the
European Scenario use of this ghee is injurious to health. At that time in the world, there
was no awareness about “trans-fat” but the belief of people was right.
Now, rules are very strict in Europe. Some countries allow not more Tests found that in all seven brands TFA content ranged from 9.4
than 0.1% TFA content. A 2002 report from European Academy of to 23.7%. In desi ghee, it was 5.3% and 3.7% in butter. In the vanas-
Sciences panel attempted to set a safe intake level for trans-fatty pati brands, trans-fat levels were 5–12 times higher than the world’s
acids. The report confirmed previous findings about the relationship only standard for trans-fat, set in Denmark, at 2% of total oil. A study
of trans-fatty acids and the risk of heart disease, and concluded with found that if all oils are compared against Denmark standard, then
this recommendation: "The only safe intake of trans-fat is zero." no edible oil in the market could claim to be healthy.
Figure 50.2: Levels of trans-fats in India in vanaspati/desi ghee
As tested by the laboratory of centre for science and environ- Proposed Regulations Under Food Safety
ment “Panghat” vanaspati ghee contains 23.7% “Trans-fat”. It is
and Standards Authority of India
found that Raag vanaspati ghee of Adoni Vilmer Company contains
(FSSAI) Studies
23.31% “Trans-fat” and “Gagan” of Amrut vanaspati contains 14.82%
of “Trans-fat”. 15.9% “Trans-fat” was present in “Rath” brand of Agro- The need was felt to regulate the TFAs in partially hydrogenated
tech foods and 9.4% “Trans-fat” was present in “DALDA” of Bange of vegetable oils and this issue was considered in the Third meeting of
India. 12.72% in Gemini and 13.76% in Jindal had shown the pres- the Food Authority held on 26th November 2009 where it was rec-
ence of “trans-fat” (Fig. 50.2). In short, no brand of vanaspati ghee ommended to fix a limit of not more than 10% trans-fatty acids in
in India was safe for health of people. The 20th century epidemic of partially hydrogenated vegetable oils to be brought down to 5% in
CAD may be attributed to increased use of TFAs in the world and 3 years. A phasing in period may be given to industry after the date
more so in India. A survey carried out by National Institute of Nu- of notification. It was also recommended that a national consulta-
trition (NIN) to evaluate the effects of TFA from Indian vanaspati in tion may also be organized to obtain feedback from consumers and
rats showed that both saturated fatty acids and TFA increased insulin industry and the scientific community for implementation of the
resistance. regulation.
India needs an organization like ‘Ban Trans-fat’of the United In rural and urban India, the fat consumption is around 20 and
States of America and some legislation to significantly curtail the 30 g/day respectively according to diet studies (National Consump-
consumption of TFAs. While food regulators in India have accepted tion Survey data). If 10% TFA is permitted in vanaspati, a person
trans-fat as a serious health concern, they are delaying setting the consuming 2,000 kcal derived from food which contains 20 and 30
standard for trans-fat in oils. In 2004, the health ministry’s oil and fats g vanaspati/day will derive 0.9 and 1.35% energy from the TFA. (This
sub-committee began a discussion on a standard for trans-fat and shows that even at 10% TFA level there is a health risk at 30 g of vanas-
accepted that trans-fats are health hazards. It agreed to set stand- pati consumption per day (which exceeds the 1% energy, which is the
ards. In Jan 2008, it forwarded its recommendations to the Central limit for TFA recommended by WHO).
Committee for Food for standards but no decision has been taken
yet. April 16, 2007: Sub-committee recommends to central commit- CONCLUSION
tee for food standards (CCFS) to set a limit of 15% trans-fats content.
CCFS asks committee to consider the matter again and come back. Trans-fatty acids are the tobacco of the nutrition world. The history of
Instead of standards, in September 2008, the health ministry issued trans-fats and heart disease has taken a full circle in the last century
a notification for labeling of trans-fat on oil and food. Oil compa- with the most palatable and delicious fats of the past being consid-
nies easily get away by giving composition in a range, which actually ered the most dangerous and deadly fat today. From the initial stage
consumers do not even know. It is like playing with the health of of promotion, the trans-fats face the stage of ban and elimination
citizens. from the food industry.
The elimination of industrially manufactured nonessential TFA • Generally, the softer the better and liquid is better yet. A table-
should be achievable. This laudable goal needs to be reached with- spoon of stick margarine has about 1.9 g of trans-fat and a table-
out inadvertently replacing TFA with saturated fats. There is also spoon of regular tub margarine, 0.8 g. Check the label for trans-
growing concern that emphasizing the danger of TFA consumption fat-free brands. By government standards, zero trans-fat means
may shift the focus away from the dangers of saturated fat consump- less than 0.5 g per serving.
tion and add to the complexity. The WHO recommends that TFA • When eating out, avoid deep fried foods! A batter-dipped whole
intake be less than 1% of total caloric intake with most of the advice fried onion—an appetizer popular at steak houses has 18 g of
tailored towards reducing industrial TFA. Food labeling may give trans-fats, according to the center for science in the public in-
consumers choice but requires extensive education programs. It is terest. Other trans-fat horrors are cheese fries, onion rings, fried
more pragmatic to eliminate TFA at source and reduce levels in the seafood and fried chicken and fish.
food chain.Healthier alternative oils with high smoke points such • Restrict foods made with "partially hydrogenated" oils as noted
as rice bran oils are now available for deep fat fryers and changed on labels. The higher those words appear in the ingredient list,
formulations have allowed elimination of TFA from margarines. the more trans-fat. Half the fat of a cookie may be trans-fat. A
Food manufacturers are investigating hydrogenation of fatty acids doughnut contains 4–9 g of trans-fat. If a label does not list trans-
without producing the harmful TFA byproduct. There are many fat, add up what is listed (saturated, monounsaturated, polyun-
trans-fat-free cooking oils on the market today which are in use in saturated) and subtract from the total fat grams. The difference is
hundreds of thousands of restaurants across the world. Increased trans-fat. Also, be sure your food is low in saturated fat, a partner
use of Canola oil is being encouraged. In countries with high rumi- that brings on heart disease.
nant TFA intake, a number of methods can be considered to reduce • Newer research techniques of hydrogenation of oils without TFA
TFA levels including manipulating the animal’s diet and filtration production is the need of the hour.
of the milk. • Because of their adverse effects on the lipid profile, increased
incidence of CAD hypertension and diabetes (The Deadly Car-
Recommendations to Avoid Trans-Fats diovascular Triad) and epidemiological evidence of increased
cardiovascular morbidity and mortality strict legislation on the
• Preferably use TFA-free olive oil for all cooking. ‘Danish Model’ is required all over the world to ban/limit the
• Use trans-fat-free margarine—soft tub or liquid margarine use of this killer macronutrient of food and bakery industry to
instead of hard-stick margarine. decrease cardiovascular disease risk.
REFERENCES
1. Mauger JF, Lichtenstein AH, Ausman LM, et al. Effect of different forms of dietary hydrogenated fats on LDL particle size. Am J Clin Nutr.
2003;78:370-5.
2. Lopez-Garcia E, Schulze MB, Meigs JB, et al. Consumption of trans-fatty acids is related to plasma biomarkers of inflammation and endothelial
dysfunction. J Nutr. 2005;135:562-6.
3. Niu SL, Mitchell DC, Litman BJ, et al. Trans-fatty acid derived phospholipids show increased membrane cholesterol and reduced receptor activa-
tion as compared to their cis-analogs. Biochemistry. 2005;44(11):4458-65.
4. Hu FB, Willet WC. Diet and coronary heart disease: Findings from the Nurses’ Health Study and Health Professionals’ Follow-up Study. J Nutr
Health Aging. 2001;5(3):132-8.
5. Singh RB, Niaz MA, Ghosh S, et al. Association of trans-fatty acids (vegetable ghee) and clarified butter (Indian ghee) intake with higher risk of
coronary artery disease in rural and urban populations with low fat consumption. Int J Cardiol. 1996;56:289-98.
6. Pietinen P, Ascherio A, Korhonen P, et al. Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol,
Beta-Carotene Cancer Prevention Study. Am J Epidemiol. 1997;145:876-87.
7. Willet WC, Stampfer MJ. Intake of trans-fatty acids and risk of coronary heart disease among women. Lancet. 1993;341:581-93.
8. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat intake and the risk of coronary heart disease in women. New Engl J Med. 1997;337:1491-9.
9. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans-fatty acids and cardiovascular disease. N Engl J Med. 2006;354:1601-13.
10. Ascherio A, Hennekens CH, Buring JE, et al. Trans-fatty acids intake and risk of myocardial infarction. Circulation. 1994;89:94-101.
11. Ascherio A, Rimm EB, Giovannucci EL, et al. Dietary fat and risk of coronary heart disease in men; cohort follow-up study. BMJ. 1996;313:84-90.
12. Lemaitre RN, King IB, Raghunathan TE, et al. Cell membrane trans-fatty acids and the risk of primary cardiac arrest. Circulation. 2002;105:697-
701.
13. Oh K, Hu FB, Manson JE, et al. Dietary fat intake and risk of coronary heart disease in women: 20 years of follow-up of the Nurses' Health Study.
Am J Epidemiol. 2005;161:672-9.
14. Oomen CM, Ocké MC, Feskens EJ, et al. Association between trans-fatty acid intake and 10-year risk of coronary heart disease in the Zutphen
Elderly Study: a prospective population-based study. Lancet. 2001;357(9258):746-51.
15. Clifton PM, Keogh JB, Noakes M. Trans-fatty acids in adipose tissue and the food supply are associated with myocardial infarction. J Nutr.
2004;134:874-9.
16. Zaloga GP, Harvey KA, Stillwell W. Trans-fatty acids and coronary heart disease. Nutr Clin Pract. 2006;21(5):505-12.
17. Lemaitre RN, King IB, Raghunathan TE, et al. Cell membrane trans-fatty acids and the risk of primary cardiac arrest. Circulation. 2002;105:697-
701.
18. Aro A, Kardinaal AFM, Salminen I, et al. Adipose tissue isomeric trans-fatty acids and risk of myocardial infarction in nine countries: the EURAM-
IC study. Lancet. 1995;345:273-8.
19. American Heart Association Nutrition Committee. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006:
a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114:82-96.
20. U.S. Food and Drug Administration. Food labeling: trans-fatty acids in nutrition labeling, nutrient content claims, and health claims and possible
footnote or disclosure statements. Fed Regist. Washington, DC: U.S. Department of Health and Human Services. 2003;168(133):41434-506.
21. Angell SY, Silver LD, Goldstein GP, et al. Perspectives, cholesterol control beyond the clinic: New York City's trans-fat restriction. Ann Intern Med.
2009;151(2):129-34.
22. Ratnayake WM, L'Abbe MR, Mozaffarian D. Nationwide product reformulations to reduce trans-fatty acids in Canada: when trans-fat goes out,
what goes in? Eur J Clin Nutr. 2009;63:808-11.
51 Coronary Artery Disease and
Homocysteine Relationship
Mohanan PP, Deepesh R
INTRODUCTION Pathway 1
Coronary heart disease (CHD) and cardiovascular disease (CVD) Remethylation (requiring folate and vitamin B12), which converts
are the leading causes of death each year worldwide accounting for HCY back to methionine, occurs under conditions of methionine
nearly 40% of all deaths. Several important risk factors are recog- deficiency.
nized and have been formally encompassed in the Framingham risk
prediction tool. Although traditional risk factors, such as hyperlipi- Pathway 2
demia, smoking, hypertension, and diabetes mellitus, are thought to
explain most CHD, 15–20% of those with CHD have no identified risk Transsulfuration (requiring vitamin B12), which converts HCY
factors and miss the opportunity for primary prevention. For this rea- cysteine and taurine under conditions of methionine excess.
son, epidemiologists and biologists have tried to identify other risk Normal+HCY levels range between 5 µmol/L and 15 µmol/L
factors, particularly modifiable risk factors that predict a portion of (12 µmol/L being the upper reference limit for the populations on a
CHD events and might improve primary prevention efforts. folic acid, fortified diet, as in North America) with elevations of
It was found that children with homocystinuria had elevated ho- 16–30 µmol/L classified as mild, 31–100 µmol/L as moderate and
mocysteine (HCY) concentration in the plasma up to 30 times the more than 100 µmol/L as severe hyperhomocysteinemia. Blood lev-
normal range. Clinical studies in these patients revealed that these els of the HCY are optimally measured in the fasting state, however,
patients developed early atherosclerotic disease and vascular occlu- mild disturbances in HCY metabolism may require measurements
sive disease. From these observations McCully formulated the HCY after methionine load.
theory of atherosclerosis. In 1976, Wilcken and Wilcken published
their work on abnormal HCY metabolism in patients with coronary Causes of Hyperhomocysteinemia
artery disease (CAD).
In mammals, severe elevations of HCY levels due to inborn errors • Genetic: Methylene tetrahydrofolate reductase (MTHFR) gene
of metabolism are associated with several physiologic abnormali- polymorphism (most common of genetic hyper HCY) methio-
ties that might explain increased vascular risk. In humans, moder- nine synthase (MS), cystathionine β-synthase (CBS) (Fig. 51.1)
ate elevations of HCY levels can occur because of less severe genetic • Dietary deficiency: Folic acid, vitamin B12, vitamin B6, methionine
mutations associated with enzyme abnormalities in the metabolic • Lifestyle factors: Chronic alcohol intake, smoking, high coffee
pathway involving folate and HCY. However, inadequate intake of intake
folate and vitamins B6 and B12, which play an important role in HCY • Renal failure
metabolism, causes most elevations of HCY levels. • End stage diabetes
• Systemic lupus erythematous
HOMOCYSTEINE METABOLISM • Hyperproliferative disorders
• Medications (methotrexate, sulfonamides, antacids)
Homocysteine is a sulfur containing amino acid produced by con-
version of methionine, an essential amino acid present in foods Pathobiology of Vessels in
regularly consumed in the diet. Homocysteine is rapidly oxidized
Hyperhomocysteinemia
in plasma to the disulfides HCY and cysteine HCY. Homocysteine
is metabolized through one of the two vitamin dependent pathways The mechanism leading to atherogenic propensity in hyperhomo-
depending on the levels of methionine in the body. cysteinemia is incompletely understood. Experimental evidence
Chapter 51  Coronary Artery Disease and Homocysteine Relationship 381
Figure 51.1: Outline of methionine/homocysteine metabolism
Figure 51.2: Proactive mechanism and effects of homocysteine-induced endothelial dysfunction
suggests that the hyperhomocysteinemia leads to endothelial dys- lium-dependent vasodilator function. This may be caused either
function and injury resulting in decreased vasodilatory capacity, by increased oxidative inactivation of NO by oxygen-derived free
activation of circulating leukocytes and platelets, activation of pro- radicals that are formed during the auto-oxidation of HCY and/or
thrombotic, inhibition of fibrinolytic mechanism and stimulation of accumulate as a consequence of HCY-mediated inhibition of anti
vascular smooth muscle cell proliferation (Fig. 51.2). oxidant enzymes, or by increased endothelial synthesis of the
Exposure of endothelial cells to HCY leads to reduced bio- endogenous NO synthase inhibitor asymmetric dimethylarginine.
availability of nitric oxide (NO) resulting in impaired endothe Decreased bioavailable together with a decrease in the endothelial
synthesis of prostacyclin promotes platelet activation and aggrega- studies. In contrast, a weaker association was observed in the pro-
tion. Elevated HCY levels induce the expression of several chemokines spective studies (20% risk increase). With respect to stroke the risk
and adhesion molecules by endothelial cells that lead to increased was reversed; a nonsignificant 16% higher risk in retrospective stud-
recruitment and adhesion of circulating inflammatory cells. This ies was compared with a significant 30% higher risk in prospective
may be caused by decreased bioavailable NO and/or increased vas- studies. After adjustment for confounding by known cardiovascular
cular oxidant stress leading to increased activation of the redox-sen- risk factors and regression dilution bias, the strength of association
sitive transcription factor NF-KB that may mediate the inflammatory was attended—from a 49% to a 12% increase in the risk IHD and from
response. Homocysteine may further promote thrombosis by acti- 30% to 35% increase in risk of stroke.
vating endothelium-dependent prothrombotic mechanisms, such Almost all of the retrospective case-control studies and most of
as the expression of tissue factor or the activity of factor Va, and by the retrospective studies support the concept of hyperhomocyst-
inhibiting antithrombotic and fibrinolytic mechanism. einemia as a risk factor for CVD, but some observations suggest that
Exposure of endothelial cells to HCY leads to decreased NO elevated homocysteine is an epiphenomenon secondary to the vas-
bioavailability. This may be caused by either increased oxidative cular disease itself.
inactivation of NO by oxygen derived free radicals formed dur-
ing auto-oxidation of HCY and/or accumulate as a consequence of Epidemiological Evidence
HCY mediated inhibition of antioxidant enzymes or by increased
endothelial synthesis of ADMA, decreased NO together with Studies in animal models have shown that elevated HCY levels
decrease in endothelial synthesis of prostacyclin promotes platelet result in increased oxidant stress, impaired endothelial function
activation and aggregation. and increased thrombogenicity, which act together to promote
Elevated HCY levels induce the expression of several chemokines atherosclerosis. Although cross-sectional and case-control stud-
and adhesion molecules by endothelial cells that lead to increased ies have indicated an association between plasma concentrations
recruitment and adhesion of circulating inflammatory cells. This of HCY and the extent of carotid, coronary and peripheral vascular
may be caused by decreased available NO and/or increased vascu- disease, it should be emphasized that the variables measured in
lar oxidant stress leading to increased activation of the redox; sensi- these studies are only surrogate measures of CVD.
tive transcription factor NF-KB that may mediate the inflammatory
response. Homocysteine may further promote thrombosis by acti- Retrospective Studies
vating endothelium dependent prothrombate mechanism, such as
expression of tissue factor or the activity of factor (Va) and by inhibit- In a meta-analysis of 27 observational studies including about 4,000
ing antithrombotic and fibrinolytic mechanisms. subjects, hyperhomocysteinemia (defined as plasma HCY levels
Recent animal studies suggest that HCY not only leads to func- greater than the 90th or 95th percentile of levels in controls) was asso-
tional vascular changes, but also in addition, may promote athero- ciated with an increased risk of atherosclerotic disease. Analysis sug-
sclerotic lesion development and progression. Both in animal mod- gested that an increase in basal total plasma HCY levels of 5 µmol/L
els and humans (severe homocysteinemia accompanying genetic was associated with 60% and 80% increased risk of CHD in men and
defects of homocystinuria), atherogenesis and thrombosis occur by women, respectively, similar to the effect of raising cholesterol by
biologically plausible mechanisms. 0.5 mmol/L. Subsequent observational studies have provided con-
The accumulated data so far provide strong evidence in support sistent support for an association between hyperhomocysteinemia
of the putative (and potentially causal) role of HCY in atherosclero- and atherosclerotic vascular disease. The largest of these, the Euro-
sis. However, it is still unclear whether HCY is a modifiable risk factor pean Concerted Action Project, which included 750 men and women
in atherosclerosis and its causal role in atherosclerosis will only be with arterial vascular disease and 800 controls, showed that an in-
demonstrated when HCY lowering proves to reduce cardiovascular crease in plasma HCY levels was an independent risk factor for CVD.
risk in prospective, randomized clinical trials. Subjects with total HCY levels more than 80th percentile had a 2.2-
fold (95% CI 1.6–2.9) increased risk for CVD compared with those
Homocysteine as a Risk Factor for with HCY levels less than 80th percentile.
Atherosclerosis
Prospective Studies
Case-control and prospective studies demonstrate a graded and
independent association between homocysteine and cardiovascular Findings from prospective cohort studies that evaluated the
risk. The HCY studies collaboration pooled evidence from 1966 to association between an increase in HCY levels and CVD have been
1999. The results showed that a 25% increase in the serum HCY con- inconsistent. Some of these studies reported a statistically signifi-
centration (an increase of approximate 3 µmol/L) is associated with cant positive association between elevated HCY and CHD and stroke
a 49% higher risk of ischemic heart disease (IHD) in the retrospective (Table 51.1). In contrast, other studies failed to demonstrate a
TABLE 51.1 Summary of key prospective studies investigating the association between homocysteine and cardiovascular disease
Study Subjects Major End Points Mean Follow- Mean Total Relative Risk (95% CI)
Up (Years) HCY Level at Baseline (µmol/L)
Cases Controls
Physicians’ Health 271 male cases Fatal and nonfatal 5 11.1 10.5 3.4 (1.3–8.8)a
Study
Stampfer et al. + 271 controls MI, CHD death 7.5 – – 1.7 (0.9–3.3)b
Chasan-Taber et al. 333 male cases + 333 Fatal and nonfatal

controls MI, CHD death
Arnesen et al. 123 male and female Fatal and nonfatal 3.5 12.7 11.3 1.4 (1.16–1.71)c*
cases + 492 controls CHD
British Regional Heart 107 male cases Fatal and nonfatal 12.8 13.7z 11.9z 2.8 (1.3–5.9)d*
Study
Perry et al. + 118 controls stroke
Wald et al. 229 male cases+ 1,126 Fatal CHD 8.7 13.1 11.8 2.9 (2.04–4.1)e*
controls
Rotterdam Study 224 male and Stroke and MI 2.7 Stroke 18.4 15.2 Stroke: (1.19–5.35)f*
Bots et al. female cases MI:17.3 MI: 2.43 (1.11–5.35)f*
+ 533 controls
ARIC 232 male and female All CHD events 3.3 8.9 8.5 1.28 (0.5–3.2)f
Folsom et al. cases + 537 controls
MRFIT 93 male patients with Nonfatal MI, CHD 11–17 MI:12.6 CHD MI:13.1 CHD 0.92 (0.55–1.54)g
Evans et al. MI + 186 controls; 147 death 12.8 12.7 death death
male patients who
die from CHD + 286
controls
North Karelia Project 265 male and female Fatal and nonfatal 9 Men:10.0 Men:9.82 Men: 1.05 (0.56–1.95)b
Alfthan et al. cases + 269 controls MI, stroke Women: 9.2 Women: 9.2 Women: 1.22 (0.66–2.78)b
Abbreviations: MRFIT, Multiple Risk Factor Intervention Trial; ARIC, Atherosclerosis Risk in Communities Study; CHD, coronary heart disease; MI,
myocardial infarction; *, statistically significant; CVD, cardiovascular disease; HCY, homocysteine
Keys
a = For more than 95th percentile versus less than 10% percentile of total homocysteine levels, adjusted for diabetes, hypertension, aspirin assignment,
Quetelet’s Index and total/high-density lipoprotein cholesterol
b = For more than 95th percentile versus less than 95th percentile of total homocysteine levels
c = Per 4 µmol/L increment in homocysteine levels
d = Homocysteine levels more than 20 µmol/L versus levels less than 9 µmol/L
e = Highest compared with lowest quartiles of total homocysteine levels, adjusted for other risk factors
f = Highest compared with lowest fifth of total homocysteine levels
g = Highest compared with lowest quartiles of total homocysteine levels
z = Geometric mean (95% CI)
significant association between plasma HCY and CHD. Data from vention Trial cohort, Atherosclerosis Risk in Communities Study
the Physicians’ Health Study, a nested case-control study including cohort and the North Karelia Project failed to show any significant
333 male patients and 333 controls (from a total population of 14,916 association between elevated HCY levels and risk of major coronary
male patients) followed up for a mean of 7.5 years, failed to dem- events or stroke. Prolonged follow-up from the Physicians’ Health
onstrate any significant association between elevated HCY and risk Study also demonstrated a lack of association between plasma
for myocardial infarction (MI) and CHD death (relative risk 1.7, 95% HCY levels and risk for stroke and angina. It is possible, however,
CI 0.9–33, for subjects with > 95th percentile vs < 95th percentile of that the HCY-lowering effect of folate-fortified flour may have been
total HCY levels). Additionally, the Multiple Risk Factor Inter- a confounder in these later studies. Subsequent meta-analysis of
prospective observational studies of first events demonstrated an alone. Taken together, evidence from case-control studies as well as
association between hyperhomocysteinemia and elevated risk of CVD. prospective studies supports an association between elevated plas-
An increase in plasma HCY levels by 25% (i.e. about 3 µmol/L) was ma HCY levels and increased cardiovascular risk. However, whether
associated with 11% and 19% excess risk for IHD and stroke, respec- lowering HCY levels by administration of folate and vitamins B6 and
tively, after correction for other cardiovascular risk factors. However, B12 is associated with any significant decrease in vascular events in
bias may have existed in this analysis, as the relative risks associated populations at risk remains the subject of ongoing debate.
with elevated HCY (by 3 µmol/L) were 1.49 (95% CI 1.41–1.61) for
IHD and 1.16 (95% CI 0.99–1.37) for cerebrovascular accident (CVA) Evidence from Clinical Trials
in retrospective studies, but 1.20 (95% CI 1.12–1.30) for IHD and 1.30
(95% CI 1.11–1.52) for CVA for prospective studies. Furthermore, the Of a number of large prospective studies initiated to address this is-
numbers of strokes in these studies were relatively small. Similar re- sue, involving a projected total of 52,000 subjects, three have recent-
sults were obtained in a retrospective analysis of 16,849 patients for ly been reported. In the first of these, the Vitamin Intervention for
a 5 µmol/L increase in HCY. Given the definite functional nature of Stroke Prevention (VISP) Study, 3,680 patients who had had a recent
the MTHFR single nucleotide polymorphism and its relationship to stroke were randomly assigned to treatment with folic acid, vitamin
plasma HCY levels, it is possible to perform Mendelian randomiza- B12 and vitamin B6 at either high or low doses. Although there was
tion analyses of cohort studies. In a meta-analysis by Wald et al. com- evidence of a dose-dependent reduction in HCY, there was no sig-
parison of the high risk TT genotype with other genotypes showed a nificant difference between the two groups in the rate of stroke (the
21% (95% CI 6–39%) increased risk of IHD and a nonsignificant 31% primary end point) or a composite of vascular outcomes (recurrent
(95% CI -20% to +215%) increased risk of stroke. A subsequent meta- stroke, CHD event or death) at the end of the 2-year follow-up pe-
analysis of 15,635 cases using Mendelian randomization showed that riod (Table 51.2). However, this trial was limited by its low dose-high
a 1.93 (range 1.38–2.47) µmol/L increase in HCY is associated with dose design, recruitment in the US (where flour is folate-fortified),
a 1.26 (95% CI 1.14–1.40)-fold increase in CVA risk, close to the 1.20 vitamin B12 pretreatment and low rates of stroke. A post hoc analysis
(95% CI 1.13–1.30)-fold increase in risk predicted on plasma levels that excluded those patients with low or very high B12 levels or with
TABLE 51.2 Summary of results of key studies investigating the effect of vitamin supplementation on cardiovascular risk
Study Subjects Treatment Baseline HCY % (actual) Change in Key Findings
HCY
VISP 3,680 men and women with 2.5 mg FA, 25 mg B6,0.4 mg 13.4 µmol/L in At 1 month: 15% No significant effect on
recent stroke B12 (high-dose) vs 0.02 mg FA, each group (2.0 µmol/L) with primary outcome of stroke:
0.2 mg B6, 6 µg B12 (low-dose) high-dose vs 2% (0.3 (RR 1.0, 95% CI 0.8–1.3)
Follow-up for 24 months µmol/L) with low-dose No significant effect on
At end of study: 17% the composite end point
(2.3 µmol/L) with (recurrent stroke, CHD
high-dose event or death)
RR 1.0, 95% CI 0.8–1.1)
NORVIT 3,749 men and women with Four treatment groups 13.1 µmol/L (A) At 2 months: No significant effect on the
MI in the last seven days (A,B,C,D): 0.8 mg FA, 40 mg B6, 12.9 µmol/L (B) A: 28% (3.7 µmol/L) composite primary end
0.4 mg B12 (A) 0.8 mg FA, 13.3 µmol/L (C) B: 26% (3.4 µmol/L) point (recurrent MI, stroke
0.4 mg B12 (B) Placebo (D); 13.2 µmol/L (D) C and D: nochange or sudden CHD death) with
median 40 mg B6 (C) follow-up At end of study A and B vs C and D (RR
40 months A: 27% (3.6 µmol/L) 1.08, 95% CI 0.93–1.25)
B: 24% (3.1 µmol/L) Trend for increased risk
C and D: no change with A vs D (RR 1.22, 95%
CI 1.00–1.50, p=0.05)
HOPE 2 5,522 men and women with 2.5 mg FA, 50 mg B6, 1.0 mg B12 12.2 µmol/L in At end of study: 20% No significant effect on the
vascular disease or diabetes vs placebo; vs Mean follow-up each group (2.4 µmol/L) 6% (0.8 composite primary end
60 months µmol/L) point of CV death, MI and
stroke (RR 0.95, 95% CI
0.84–1.07)
Abbreviations: VISP, Vitamin Intervention for Stroke Prevention; NORVIT, Norwegian Vitamin Trial; HOPE-2, Heart Outcomes Prevention Evaluation 2
Study; FA, folic acid; CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction; RR, relative risk
significant renal dysfunction did, however, indicate a 21% benefit the composite end point of major adverse events (i.e. death, nonfatal
on major cardiovascular events (p = 0.049; adjusted for confounders MI and need for repeat vascularization) after a mean follow-up of 11
p = 0.056) associated with vitamin B12 treatment. months (relative risk 0.68, 95% CI 0.48–0.96, p = 0.03). Another study
The findings of two subsequent studies, the Norwegian Vita- showed, however, that vitamin treatment might increase the rate
min (NORVIT) trial and the Heart Outcomes. Prevention Evalua- of stenosis after coronary stenting. Most recently, a meta-analysis
tion (HOPE) 2 Study, were consistent with those of VISP. Norwegian of 12 randomized controlled studies of folic acid supplementation,
Vitamin was a secondary prevention. including data from 16,958 subjects with pre-existing vascular dis-
Trial including 3,749 men and women with prior MI who were ease, showed that folic acid supplementation did not significantly
randomly assigned to one of four treatments administered once reduce cardiovascular risk or all-cause mortality. The overall rela-
daily: folic acid, vitamin B6 and vitamin B12 (group A); folic acid and tive risks for subjects treated with folic acid supplementation com-
vitamin B12 (group B); vitamin B6 alone (group C); or placebo on top pared with controls were 0.95 (95% CI 0.88–1.03) for CVD, 1.04 (95%
of optimal cardiovascular drug care (group D). After a median fol- CI 0.92–1.17) for CHD, 0.86 (95% CI 0.71–1.04) for stroke and 0.96
low-up of 40 months, combination vitamin treatment lowered mean (95% CI 0.88–1.04) for all-cause mortality. The disparity between
total HCY levels by 27% and increased folate levels by 600–700% in evidence from epidemiological and retrospective and prospective
patients receiving folic acid plus vitamin B12, but had no significant case-control studies and the results of these recent clinical trials could
effect on the primary end point (a composite of recurrent MI, stroke be due to inherent limitations in the observational studies. A wide range
and sudden death due to CHD). Event rates for the primary end point of conditions are known to increase plasma HCY levels, including
were 18% in groups B to D. In the triple therapy group (group A) the renal and hepatic impairment, diabetes and hypertriglyceridemia;
event rate was increased to 22% (95% CI 0–50%, (p = 0.05) and for in addition, other cardiovascular risk factors such as smoking and
nonfatal MI by 30% (p = 0.05), countered by a nonsignificant 17% de- elevated blood pressure are also associated with increased HCY
crease (p = 0.52) in stroke. levels. Furthermore, individuals with pre-existing atherosclerosis
Overall, the event rate for the primary end point with triple have higher HCY levels than those without. Thus, it has been sug-
therapy (group A) compared with the other groups was increased by gested by the HOPE 2 Investigators that HCY is a marker rather than a
20% (95% CI 2–41%). Some analyses of vitamin B6 trial data have sug- cause of vascular disease, and therefore, epidemiological data could
gested that high dose vitamin B6 therapy may increase cardiovascu- be the result of residual confounders. Given the confusing results to
lar events. In NORVIT, a 14% increase in events (p = 0.09) was seen date, further trial evidence is required.
in the vitamin B6 group (29% in a subgroup of smokers; p = 0.05),
comprising increased rate of MI (19%; p = 0.05) and death (19%; Effects of Lipid-Modifying Therapy
p = 0.11). The HOPE 2 study involved 5,522 patients with vascular dis-
on Homocysteine
ease or diabetes treated daily with a combination of 2.5 mg folic acid,
1 mg vitamin B12 and 50 mg vitamin B6 or placebo for an average of Given that dyslipidemia is a prominent risk factor for CVD, recent
5 years, recruited again mostly (70%) in the US. Despite a substan- results indicating that some lipid-modifying agents, including
tial reduction in plasma HCY levels (3.2 µmol/L) in the combination nicotinic acid, colestipol and fibrates, may cause elevated plasma
vitamin group, there was no significant reduction in the risk of the total HCY levels, which have attracted attention. The most likely
primary end point (a composite of death from cardiovascular causes, mechanism for this increase is an alteration of creatine—creatinine
MI and stroke), although there was a marginally significant 25% (95% metabolism and changes in methyltransfer. In contrast, statins have
CI 3–41%, p = 0.03) reduction in stroke in patients receiving vitamins no effect on plasma HCY concentrations. In addition, other agents
compared with those on placebo. A small increase in unstable angina commonly prescribed in patients with CVD affect HCY levels.
admissions was noted with vitamin therapy. Thiazide diuretics are associated with rise in creatinine and a 16%
A Bayesian analysis of vitamin therapy using data from the increase in plasma HCY. An HCY-raising effect of metformin has
NORVIT and HOPE 2 studies suggested that there is little effect of been known since 1971, associated with a deficiency in vitamin B12
supplements on the rates of cardiovascular events, mortality or MI, due to reduced uptake. Studies have shown that metformin re-
although there may be a beneficial effect on the rate of stroke. In a duces vitamin B12 levels by 10–12% and folate by 8% and raises
smaller study (n = 205), treatment with the combination of folic HCY by 13%. The effects of metformin on HCY levels can be amelio-
acid, vitamin B6 and vitamin B12 for 6 months was shown to reduce rated through the use of calcium supplements. More recently, 20%
significantly the rate of restenosis (19.6% vs 37.6% on placebo, p = increases in HCY [10.7 (0.81) to 12.4 (0.81) µmol/L, p < 0.01] have been
0.01), and the need for revascularization of the target lesion (10.8% vs described with rosiglitazone while sulphonylureas have been shown
22.3% on placebo, p < 0.05) after coronary angioplasty. In an exten- to decrease HCY. Combinations of metformin and glitazones are
sion of this study, including 553 subjects who had undergone suc- associated with varying effects with reduction in HCY seen with
cessful angioplasty of at least one significant stenosis, vitamin treat- pioglitazone compared with rosiglitazone. Antacids are also associ-
ment was associated with a significant decrease in the incidence of ated with reductions in acid-induced cobalamin release from food
and hence, secondary decreases in absorption. Both fenofibrate and Screening

bezafibrate have been shown to induce elevation in plasma levels
of HCY. In a direct comparative study in which patients were rand- Routine screening for elevated HCY is not yet recommended.
omized to treatment with fenofibrate or atorvastatin for 6 months There are recommendations for screening and treatment of
(after an initial 6-week placebo run-in period), fenofibrate induced elevated HCY.
a significant 35% increase in HCY levels [from 12.3 µmol/L to 16.4 • Routine screening not yet recommended
(4.6) µmol/L; p < 0.0001], whereas there was no significant change • Screening may be available in individuals who
in the group receiving atorvastatin. More recently, elevated plasma – Manifest disease out of proportion to the traditional risk
total HCY levels associated with treatment with fenofibrate were not- factors
ed in both, the Diabetes Atherosclerosis Intervention Study (DAIS) – Have a family history of premature atherosclerotic disease.
and the Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) trial. Measurement
In DAIS, in 418 patients with type 2 diabetes, treatment with
fenofibrate 200 mg/day was associated with a 55% increase in plasma • Plasma (or serum) total HCY, fasting or post-methionine load
total HCY levels [from 11.5 µmol/L to 16.5 (10.7) µmol/L, p < 0.001]. (more sensitive)
This increase was not related to changes in factors known to modu- • Blood samples must be processed quickly (< 1 hour at room tem-
late plasma HCY levels, including serum levels of vitamin B12 and perature, < 8 hour on ice)
folate, or renal dysfunction. Subsequent analysis showed that base- • Enzymatic or immunologic assays more practical than chroma-
line, but not end-of-study, elevated plasma HCY levels decreased tographic assays
the beneficial effect of fenofibrate on angiographic determinants of • Standardization require to minimize variation among laborato-
focal CAD. Furthermore, HCY levels at the end of the study corre- ries
lated negatively with CAD progression when data from all studied • Normal range: 5–15 µmol/L (12 µmol/L as upper limit with folate
patients were included in the analysis. In the fenofibrate group, there fortification).
was no significant correlation between plasma total HCY levels and
minimal lumen diameter, percent stenosis or adverse clinical events.
Homocysteine Lowering—When is
Thus, the DAIS Investigators concluded that the fenofibrate-mediat-
Pharmacological Intervention Essential?
ed increase in plasma total HCY levels observed did not attenuate the
beneficial effects of fenofibrate on CAD or clinical events. Fenofibrate In the general population, folic acid and B vitamins enhance HCY
Intervention and Event Lowering in Diabetes included 9,795 patients metabolism and their administration consistently lowers plasma
with type 2 diabetes (78% without prior CVD) who were randomized HCY levels, while adherence to Mediterranean diet, which is associ-
to treatment with fenofibrate 200 mg/day or placebo following a 16- ated with high B vitamins and folate consumption, is associated with
week run-in period, comprising 4 weeks of dietary modification, 6 lower plasma HCY, as has been recently shown. Folic acid in dose
weeks of single-blind placebo and 6 weeks of single-blind fenofibrate equal to the RDA (400 mg/day) is associated with a 25–30% reduc-
therapy. The mean duration of follow-up in the study was 5 years. At tion of plasma HCY. An additional 7% reduction can be achieved by
the end of the study, plasma HCY levels were on average 35% higher cobalamin (B12) 0.02–1 mg/day co-administration. However, cur-
in the fenofibrate group than the placebo group (median concentra- rent data do not support pharmacological treatment with folic acid
tions 15.1 µmol/L vs 11.2 µmol/L, p < 0.001). and B vitamins in general population. In contrast, HCY-lowering
However, in a subset of fenofibrate-treated patients who were treatment should be considered when homocysteinemia is present.
restudied after study completion, plasma HCY levels fell from a Moderate homocysteinemia (fasting plasma total HCY 15–30 mol/L)
median of 15.0 µmol/L to 9.5 µmol/L, indicating that the effect of is usually due to poor diet (i.e. vegetarians), mild folate/cobalamin/
treatment was reversible. This effect remains the subject of ongoing vitamin B6 deficiency, heterozygosity for CBS defects, hypothyroid-
subgroup analyses by the FIELD Management Committee. Taken ism, impaired renal function, or use of drugs affecting HCY, folate or
together, these findings indicate that although fenofibrate does cobalamin levels. When the cause of moderate homocysteinemia is
appear to increase plasma total HCY levels, this effect does not established, then the best treatment is reversal of this cause. In the
appear to attenuate or compromise the beneficial effects of treatment, case of increased HCY levels due to the presence of MTHFR 677TT
and is reversible following discontinuation of therapy. Interactions genotype, oral 5-MTHF treatment should be considered, since this
between hypoglycemic agents and lipid-lowering drugs in diabetes agent does not require any conversion by MTHFR. Although there
are likely to be complex and related to baseline renal function, auto- are still not enough data to support that treatment of moderate
immune status, other drugs and supplements, as well as drugs used homocysteinemia would reduce cardiovascular risk, the general
in the management of atherosclerosis. consensus is that HCY-lowering strategies targeting specific causes
are at least not harmful. Intermediate homocysteinemia (fasting cysteinemia after adjustment for these potential confounders
plasma total HCY 30–100 mmol/L) is usually the result of moder- may actually lead to risk underestimation. Notably, most studies
ate/severe cobalamin or folate deficiency or renal failure. Again, suggested that tHCY is independent of and even enhances the risk
diagnosis and reversal of the respective cause should be the main associated with the conventional risk factors, such as smoking,
priority, while most of the patients respond well to folate treatment hypertension, hypercholesterolemia, diabetes, and renal failure.
alone or in combination with vitamins B12 and B6. Severe cobalamin From the close relation between plasma tHCY and renal function,
deficiency and homocystinuria are the main causes of severe homo- it has been inferred that vascular disease may cause hyperhomo-
cysteinemia (fasting plasma total HCY 100 mmol/L), and it should cysteinemia by impairment of renal function. However, there are
definitely be treated accordingly (cobalamin 0.02–1 mg/day), since more than or equal to four prospective studies that consistently
it is associated with increased prothrombotic state. Homocystinuria showed that elevated tHCY is a strong predictor of CVD in patients
includes deficiencies in CBS, MTHFR, MS, reductase and effects in with end-stage renal failure and in renal transplant recipients,
intracellular cobalamin metabolism. There are currently three recog- suggesting that hyperhomocysteinemia is not merely a benign
nized modalities of treatment for CBS deficiency. For those who are epiphenomenon of renal dysfunction. It has been argued that
vitamin-responsive, treatment is with pyridoxine (50–250 mg/day) tHCY increases secondary to the myocardial or cerebrovascular
in combination with folic acid (0.4–5 mg/day) and/or vitamin B12 event. This assumption is based on the observations of low tHCY
(0.02–1 mg/day). For vitamin nonresponders, the treatment is with a in the acute phase (first days) after MI or stroke compared with the
methionine-restricted, cystine-supplemented diet. Pyridoxine, folic convalescent stage. An alternative explanation is a transient drop
acid and vitamin B12 treatment may be needed in pyridoxine nonre- in tHCY during the acute phase, which would weaken rather than
sponders as they are co-factors in methionine metabolism. Betaine, strengthen the tHCY-CVD association. Furthermore, an altered
a methyl donor that remethylates HCY to methionine, has also been tHCY concentration after the CVD event does not affect the inter-
used as an adjunct to treatment. pretation of the prospective data.
• Routine treatment with vitamin supplement not yet recom-
mended CONCLUSION
• Diet rich in folate and B vitamins is encouraged
• Treatment with folate (0.5–5 mg/day) and vitamin B12 (0.5–1 mg/ The case of homocystinuria, the results of most prospective studies
day) may be beneficial in high-risk patients and the relation between hyperhomocysteinemia and preclinical
• Therapeutic targets in high-risk individuals are less than atherosclerosis suggest that elevated tHCY is a causal risk factor for
10 µmol/L (US) and less than 13–15 µmol/L (else where) CVD, including venous thrombosis. Hyperhomocysteinemia as an
• Vitamin B12 status should be determined before therapy. isolated phenomenon probably confers minor risk, but it further
In the absence of definitive evidence, it may be best to recom- increases the risk when it occurs in combination with other factors
mend a healthy diet rich in legumes, fruits and green leafy vegeta- that provoke vascular lesions. Thus, hyperhomocysteinemia seems
bles. Our enthusiasm for the potential of novel preventive strategies to be a particularly strong risk factor in subjects with an underlying
should not diminish our diligence in implementing simple health disease and predicts the short-term outcome in such individuals.
measures and prescribing treatments that are of proven benefit in The impairment of the NO-dependent flow-mediated vasodilata-
CVD. tion during transient hyperhomocysteinemia provides one plau-
sible mechanism accounting for the acute effect. Finally, lack of a
Hyperhomocysteinemia significant association between the C677T MTHFR polymorphism
and CVD does not take way from the concept of HCY as a risk factor
as an Epiphenomenon
because published studies lack the power to detect the risk enhance-
The observation that the TT MTHFR genotype is associated with ment associated with the moderate elevation of tHCY detected in
no or only a minor enhancement of CVD risk is not a valid argu- subjects with the TT genotype. In addition, this genetic variant has
ment against the HCY theory, as outlined above. The fact that total a profound effect on overall intracellular folate distribution, which
homocysteine (tHCY) is related to a diverse array of established may modulate or even reduce CVD risk.
risk factors, including age, sex, smoking, exercise, impaired renal Despite the flourishing literature on HCY as a potential novel risk
function and blood pressure, could suggest that the association factor that is modifiable, uncertainty exists whether HCY elevation is
between tHCY and CVD is due to confounding. The alternative the primary cause of vascular disease or occurs as an epiphenom-
explanation is that the high tHCY concentration partly mediates enon in patients with atherosclerosis. We need to examine its role
the risk associated with some of these factors. If the latter is the in several well designed prospective study population with a long
case, assessment of the CVD risk associated with hyperhomo- follow-up period and a large enough sample size.
BIBLIOGRAPHY
1. Akhtar N. Is homocysteine a risk factor for atherothrombotic cardiovascular disease? J Am Coll Cardiol. 2007;49:1370-1.
2. Alfhan G, Pekkanen J, Jauhiainen M, et al. Relation of serum homocysteine and lipoprotein (a) concentrations to atheroselerotic disease in a pro-
spective Finnish population based study. Atherosclerosis. 1994;106:9-19.
3. Anderson JL, Muhlestein JB, Horne BD, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and CRP in patients
with angiographycally defined coronary artery disease. Circulation. 2000;102:1227-32.
4. Andersson A, Lindgren A, Hultberg B. Effect of thiol oxidation and thiol export from erythrocytes on determination of redox status of homocyst-
eine and other thiols in plasma from healthy subjects and patients with cerebral infarction. Clin Chem. 1995;41:361-6.
5. Anthony S Wierzbact. Homocysteinemia and cardiovascular disease: a review of evidences Diabetes. Vasc Dis Res. 2004;4:143-9.
6. Antoniades C, Antonopoulos AS, Tousoulis D. Homocysteine and coronay atherosclerotic: from folate fortification to the recent clinical trials. Eur
Heart J. 2009;30:6-15.
7. Antoniades C, shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide produc-
tion in human vessels. Circulation. 2006;12;114(11):1193-201.
8. Arnesen E, Refsum H, Bonaa KH, et al. Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24:704-09.
9. Bonaa KH, Njolstad I, Ueland PM, et al. Homosysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med.
2006;354:1578-88.
10. Booth GL, Wang EE. Preventive Health Care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary
artery disease events. CMAJ. 2000;163(1):21-9.
11. Bostom A, Brosnan JT, Hall B, et al. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis. 1995;116:59-62.
12. Bots ML, Launer LJ, Lindemans J, et al. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam study.
Arch Intern Med. 1999;159:38-44.
13. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable
benefits of increasing folic acid intakes. JAMA. 1995:274;1049-57.
14. Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr. 2000;72:315-23.
15. Chasan-Taber L, Selhub J, Rosenberg IH, et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am
Coll Nutr. 1996;15:136-43.
16. Christen WG, Ajani UA, Glynn RJ, et al. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern
Med. 2000;160:422-34.
17. De Lorgeril M, Salen P, Pailard F, et al. Lipid lowering drugs and homocysteine. Lancet. 1999;353:209-10.
18. De Luca G, Suryapranata H, Gregorio G. Homocysteine and its effects on in-stent restenosis. Circulation. 2005;112:e307-11.
19. Eikelboom JW, Lonn E, Genest J Jr, et al. Homocysteine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern
Med. 1999;131:363-75.
20. Evans RW, Shaten BJ, Hempel JD, et al. Homocysteine and risk of cardiovascular disease in the multiple risk factor intervention trial. Arterioscler
Thromb Vasc Biol. 1997;17:1947-53.
21. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related
genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204-10.
22. Frantzen F, Faaren AL, Alfheim I, et al. Enzyme conversion immunoassay for determining total homocysteine in Plasma or serum. Clin Chem.
1998;44:311-16.
23. Genest J Jr. Emerging risk factors associated with cardiovascular disease. Can J Cardiol. 1999;15 (Suppl G):73G-6G.
24. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA.
1997;277:1775-81.
25. Guttermsen AB, Ueland PM, Svarstad E, et al. Kinetic basis of hyperhomocysteinemia in patients with chronic Renal failure. Kidney Int.
1997;52:495-502.
26. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteninemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.
J Clin Invest. 2001;107:675-83.
27. Homocysteine Studies collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002:288:2015-22.
28. International Task Force for the Prevention of Coronary Artery Disease: reducing the risk. Nutr Metab Cardiovasc Dis. 1998;8:229.
29. Kanani PM, Sinkey CA, Browning RL, et al. Role of oxidant stress in endothelial dysfunction produced by Experimental hyperhomocysteinemia in
Humans. Circulation. 1999;100:1161-8.
30. Kaul S, Zadeh AA, Shah PK. Homocysteine hypothesis for atherothrombotic cardiovascular disease. J Ann Coll Cardiol. 2006;48:914-23.
31. Lentz SR. Mechanism of homocysteine induced atherothrombosis. J Thromb Haemost. 2005;3:1646-54.
32. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-77.
33. Malinow MR, Bostom AG, Krauss RM. Homocysteine, diet, and cardiovascular disease: a statement for health care professionals from the Nutri-
tion Committee, American Heart Association. Circulation. 1999;99:178-82.
34. Malinow MR, Bostom AG, Krauss RM. Homocysteine, diet and cardiovascular adverse. Circulation. 1999;99:178-82.
35. Marinou K, Antoniades C, Tousoulis D, et al. Homocysteine: a risk factor for coronaryArtery disease? Hellenic J Cardiol. 2005;46:59-67.
36. Mc Cully KS, Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis Am J Pathol. 1969;56:111-28.
37. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase Deficiency. Am J Hum Genet.
1985;37:1-31.
38. Nevado JB, Imasa MS. Homocysteine predicts adverse clinical outcomes in unstable angina and non-ST elevation myocardial infarction: implica-
tions from the folate intervention in non-ST elevation myocardial infarction and unstable angina study. Coron Artery Dis. 2008;19:153-61.
39. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland and Homocysteine Study. JAMA.
1995;274:1526-33.
40. Paul Kneki. Hyperhomocysteninemia: a risk factor or a concequence of coronary heart disease. Arch Interm Med. 2001;161:1589-94.
41. Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.
Lancet. 1995;346:1395-8.
42. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine: an expert opinion. Clin Chem. 2004;50:418-24.
43. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determination. Clin Chem. 2004;50:3-32.
44. Refsum H, Ueland PM, Nygard O, et al. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.
45. Schnabel R, Lackner KJ, Rupprecht HJ, et al. Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the
AtheroGene study. J Am Coll Cardiol. 2005;45:1631-7.
46. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentration and extra cranial carotid artery stenosis. N Engl
J Med. 1995;332:286-91.
47. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999;19:217-46.
48. Sidney SC, Milani RV, Arnett DK, et al. Atherosclerotic Vascular Disease Conference: Writing Group II: risk factors. Circulation. 2004;109:2613-6.
49. Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related
oxides of nitrogen. J Clin Invest. 1993;91:308-18.
50. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocysteine and risk of myocardial Infarction in US physicians.
JAMA. 1992;268:877-81.
51. Stubbs PJ, Al-Obaidi MK, Conroy RM, et al. Effect of plasma homocysteine concentration on early and late events in patients with acute coronary
syndromes. Circulation. 2000;102:605-10.
52. Stuhlinger MC, Tsao PS, Her JH, et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation.
2001;104:2569-75.
53. Suda O, Tsutsui M, Morishita T, et al. Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice:
involvement of rennin-angiotensin system and oxidative stress. Arterioscler Thromb Vasc Biol. 2004;24:1682-8.
54. Tyagi N, Sedoris KC, Steed M, et al. Mechanism of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol. 2005;289; H2649-56.
55. Ueland PM, Refsum H, Beresford SA, et al. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000;72:324-32.
56. Ungvari Z, Csiszar A, Edwards JG, et al. Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis
factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol. 2003;23:418-24.
57. Van den Berg M, Stehouwer CD, Bierdrager E, et al. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb arth-
erosclerotic disease. Arterioscler Thromb Vasc Biol. 1996;16:165-71.
58. Verhoef P, Hennekens CH, Malinow MR, et al. A prospective study of plasma homocysteine and risk of ischemic stroke. Stroke. 1994;25:1924-30.
59. Verhoef P, Kok FJ, Kruyssen DA, et al. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Throm Vasc Biol.
1997;17:989-95.
60. Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and Beta-carotene on the incidence of primary non fatal myocardial infarction and fatal
coronary heart disease. Arch Intern Med. 1991;58:668-75.
61. Vizzardi E, Nodari S, Fiorina C, et al. Plasma homocysteine levels and late outcome in patients with unstable angina. Cardiology. 2007;107:354-9.
62. Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischemic heart disease: results of a prospective study with Implications regarding prevention.
Arch Intern Med. 1998;158:862-7.
63. Weiss N, Heydrick SJ, Postea O, et al. Influence of hyperhomocysteinemia on the cellular redox state--impact on homocysteine- induced endothe-
lial dysfunction. Clin Chem Lab Med. 2003;41:1455-61.
64. Weiss N, Keller C, Hoffmann U. Endothelial dysfunction and atherothrombosis in mild hyperhomcysteinemia. Vasc Med. 2002;7:227-39.
65. Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006;113:1335-
43.
66. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention
Evaluation Study Investigators. N Engl J Med. 2000;342:154-60.
Savitri Satyawana: The First
52 Described Cardiac Revival
of the Vedic Times
Aggarwal KK
ations where it is felt that resuscitation is not going to prolong the life
INTRODUCTION
of the person.
Vedas describes three aspects of consciousness or life, the senses The story of Savitri also indicates the importance of being with
(mythologically depicted by Gayatri); the prana or the life force (depict- the victim who is at risk of sudden cardiac death. It lays the impor-
ed by Savitri) and the speech or vak (depicted by Saraswathi). The three tance of teaching CPR to the laypersons and especially the family
also represent purity in thought, word and deed (thrikarana shuddhi). members of at risk patients.
Savitri in the Vedic text is equated to the life force or the prana. In the story Savitri marries Satyavan, knowing very well that
In Puranas the story of Savitri and Satyavan is a house hold name. (based on the horoscope, medical investigations of that era) that
Savitri won over the Yama or the Yamaraja and bought the life of her Satyavan will die within a year.
husband back after the death. Satyavan died suddenly in the jungle In his at risk days when he was feeling tired Savitri insisted in go-
while he was with Savitri. ing along with Satyavan at work.
Vedic knowledge of Shruti (original work) and Samriti (reviews) “In the woods, Satyavan suddenly felt dizzy while chopping
in ancient period were propagated to the community through songs the firewood and lay down. Satyavan closed his eyes and began to
(Geeta) or plays and stories (Puranas). Savitri satyavan was one such breathe slowly. Suddenly Lord Yama, the god of death, arrived. He
story with a deeper message. Ramayana and Mahabharta once caught the soul of Satyavan with his noose and headed towards his
considered as the largest Puranas were later classified as epics. kingdom. Satyavan’s body lay dead”. The story typically describes the
It probably indicates that the process of cardio pulmonary signs and symptoms of sudden cardiac death.
resuscitation (CPR) for the revival of victims with sudden death was Her fight with the Yama and bringing back the life of her husband
known in the Vedic era. And the story of Savitri depicts that it is possi- by all means was some sort of CPR attempted by her on his dead
ble to bring back one’s life with dedication and devotion. Dedication body.
probably is for the process of CPR.
Today the process of CPR is well described. The modern CPR INTERNATIONAL SCENARIO IN BRIEF
started somewhere in 1950s and 60s. It is known that clinical death
(UPTODATE.COM)
is different from actual death. The death in the first 4–5 minutes is
reversible, as the brain remains alive during this period. Cardiopulmonary resuscitation as we recognize it today was de-
Sudden death is the death occurring within 1 hour of the onsets veloped in the late 1950s and 1960s. Elam and Safar described the
of symptoms and sudden cardiac death is if the cause is cardiac in technique and benefits of mouth-to-mouth ventilation in 1958.1
origin. It is common in diabetics and heart patients. Kouwenhoven, Knickerbocker and Jude subsequently
The purpose of revival in this period is to attempt cardiac mas- described the benefits of external chest compressions,2 which in
sage with the speed of 100 per minute for the next 10 minutes, combination with mouth-to-mouth ventilation forms the basis of
interrupting every 2 minutes with a cardiac thump. Seventy-five modern CPR.
percent of the cardiac deaths occur suddenly and before a person External defibrillation, first described in 1957 by Kouwenhoven,3
can be reached to the hospital. The only way he or she can be revived has since been incorporated into resuscitation guidelines.
is by doing the chest compression and CPR. The public massage is Basic life support consists of cardiopulmonary resuscitation and,
that instead of beating one’s own chest one should beat or massage when available, defibrillation using automated external defibrilla-
the chest of the dead victim. tors (AED). The keys to survival from sudden cardiac arrest are early
Cardiopulmonary resuscitation may have no value in terminal recognition and early treatment, specifically, immediate initiation of
patients. Do not resuscitate is an order where CPR is not given in situ- high quality CPR and early defibrillation.4
Chapter 52  Savitri Satyawana: The First Described Cardiac Revival of the Vedic Times 391
Cardiopulmonary Resuscitation History in Detail

• 5000 BC: Savitri Satyana Story • 1812: Lifeguards were equipped with a horse which was tied to
• 800 BC: The first resuscitation was Elisha’s mouth-to-mouth the Lifeguard station. When a victim was rescued and removed
(Bible, 2 Kings, iv, 34.). “...And he went up and lay upon the child, from the water, the Lifeguard would hoist the victim onto his
and put his mouth upon his mouth, and his eyes upon his eyes, horse and run the horse up and down the beach. This resulted in
and his hands upon his hands; and he stretched himself upon an alternate compression and relaxation of the chest cavity as a
the child; and the flesh of the child waxed warm.” result of the bouncing of the body on the horse.
• 1530: People used bellows from a fireplace to blow hot air and • 1856: Manual ventilation was given low priority; concentration
smoke into the victim’s mouth. Various manufacturers designed was on maintaining body heat. Significant change in priorities
Bag-Valve-Mask Resuscitators. People, however, did not appreci- occurred when Marshall Hall challenged the conventional wis-
ate the need to extend the victim’s neck in order to obtain a clear dom of the Society. His contention that time was lost transport-
airway. In 1829, Leroy d’Etiolles demonstrated that over disten- ing the victim; that the restoration of warmth without some type
sion of the lungs by bellows could kill an animal, so this practice of ventilation was detrimental; that fresh air was beneficial; and
was discontinued. that if left in the supine position, the victim’s tongue would fall-
• August 1767: Citizens in Amsterdam gathered to form the Society back and occlude the airway. Because the bellows were no longer
for Recovery of Drowned Persons. an option, Marshall Hall developed a manual method in which
• 1711: A new method involved blowing tobacco smoke into the the victim was rolled from stomach to side 16 times a minute.
victim’s rectum. This practice was abandoned in 1811 after In addition, pressure was applied to the victim’s back while the
research by Benjamin Brodie when he demonstrated that four victim was prone (expiratory phase). Tidal volumes of 300–500
ounces of tobacco would kill a dog and one ounce would kill a ml were achieved and soon became adopted by the Royal
cat. Humane Society.
• 1767: Dutch Society for Recovery of Drowned Persons was • 1892: Other methods still used included stretching the rectum,
established. The Dutch recommendations included: Warming rubbing the body, tickling the throat with a feather, waving
the victim (which sometimes required transporting the body strong salts, such as ammonia, under the victim’s nose. Tongue
to a different location) by lighting afire near the victim, burying stretching procedure was described as holding the victim’s
him in warm sand, placing the body in a warm bath or placing mouth open while pulling the tongue forcefully and rhythmi-
in a bed with one or two volunteers; removing swallowed or cally.
aspirated water by positioning the victim head lower than his • 18th century: Paris Academy of Science first recommended
feet and applying manual pressure to the abdomen, vomiting mouth-to-mouth resuscitations as a means to restoring life to
was induced by tickling the back of the throat with a feather; drowning victims.
stimulation of the victim, especially the lungs, stomach and • 1946: During the middle of a Polio outbreak, an anesthesiologist,
intestines by such means as rectal fumigation with tobacco James Elam, applied mouth-to-mouth resuscitation principle to
smoke or the use of strong odors; Restoring breathing with a an older child in an emergency situation.
bellows; and bloodletting. • 1950: Organizations like the American Red Cross began an ag-
• 1770: Inversion was originally practiced in Egypt almost 3,500 gressive education campaign in order to educate the American
years before and it again became popular in Europe. This meth- public. In the 1960s this training was expanded by which life-
od involved hanging the victim by his feet, with chest pressure to guard personnel were instructed in this procedure by perform-
aid in expiration and pressure release to aid inspiration. ing mouth-to-mouth resuscitation in the water using rescue
• 1773: In an effort to force air in and out of the victim’s chest cav- buoys, paddleboards and boats and canoes as flotation supports
ity, the rescuer would hoist the victim onto a large wine barrel while performing this procedure in the water.
and alternately roll him back and forth. This would result in a • 1954: James Elam was the first to demonstrate experimentally
compression of the victim’s chest cavity, forcing air out, and that CPR was a sound technique, and together with Dr Peter
then a release of pressure which would allow the chest to expand Safar he demonstrated its superiority to previous methods.
resulting in air being drawn in. • 1957: Peter Safar wrote the book ABC of resuscitation.
• 1774: England’s Royal Humane Society was founded. • 1959: In Kalamazoo, Michigan, volunteer Roger Mehalek intro-
• 1803: This concept involved reducing the body’s metabolism by duced a breathing trainer called Miss Sweet Breath 1959, a plas-
freezing the body under a layer of snow and ice. Unfortunately, ter and plastic training mannequin he created.
no one realized that the most critical organ which needed to be • 1960: The next major step in resuscitation was closed chest mas-
frozen in order to accomplish a reduction of the body’s metabo- sage, which was introduced in the 1960s by Dr Kowenhoven.
lism was the brain. The crucial aspect of this technique is that the patient receives
oxygen, which is transported to the brain by the development classes and viewed by millions of students. For the film, Gordon
of a minimal blood circulation. On this basis many national and and Adams devised the easy to remember mnemonic of A, B and
international guidelines to perform CPR came out. C standing for the sequence of steps in CPR, airway, breathing,
• 1960: Rescue breathing had been adopted by the National Acad- circulation, which is still used today.
emy of Science, American Society of Anesthesiologists, Medical • 1963: Cardiologist Leonard Scherlis started the American Heart
Society of the State of New York and the American Red Cross as Association’s CPR Committee, and in the same year, the Heart
the preferred method of resuscitation. Association formally endorsed CPR.
• 1960: The formalized system of chest compression was really an • May 1966: The National Research Council of the National Acad-
accidental discovery made by William Bennett Kouwenhoven, emy of Sciences convened an adhoc conference on cardiopul-
Guy Knickerbocker and James Jude at Johns Hopkins University. monary resuscitation. Recommendations from this conference
They were studying defibrillation in dogs when they noticed that were reported in JAMA in 1966.
by forcefully applying the paddles to the chest of the dog, they • 1970: CPR, defibrillation, and a rapid means to provide prehos-
could achieve a pulse in the femoral artery. In 1960 the three pital care were all in place.
investigators reported their findings on 20 cases of in-hospital • 1973: During the Vietnam War the US army introduced CPR
cardiac arrest in JAMA. to the people for the first time. American Red Cross and the
• 1960: The formal connection of chest compression with mouth- American Heart Association (AHA) began a big campaign to
to-mouth ventilation to create CPR as it is practiced today teach the American population this method.
occurred when Safar, Jude, and Kouwenhoven presented their • 1980: The first program to train EMTs to perform defibrillation
findings at the annual Maryland Medical Society meeting on began in King County, Washington and similar programs spread
September 16, 1960 in Ocean City. throughout the United States.
• 1962: Gordon, along with David Adams, produced a 27-minute • 1981: A program to provide telephone instructions in CPR began
training film called “The Pulse of Life.” The film was used in CPR in King County, Washington.
REFERENCES
Savitri Satyawana: The First Described Cardiac Revival of the Vedic Times
1. Safar P, Escarraga LA, Elam JO. A comparison of the mouth-to-mouth and mouth-to-airway methods of artificial respiration with the chest-
pressure arm-lift methods. N Engl J Med. 1958;258:671-7.
2. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA. 1960;173:1064-7.
3. Kouwenhoven WB, Milnor WR, Knickerbocker GG, et al. Closed chest defibrillation of the heart. Surgery. 1957;42:550-61.
4. Vaillancourt C, Stiell IG. Cardiac arrest care and emergency medical services in Canada. Can J Cardiol. 2004;20:1081-90.
BIBLIOGRAPHY
Cardiopulmonary Resuscitation History in Detail

1. Beck CS, Pritchard WH, Feil HS. Ventricular fibrillation of long duration abolished by electric shock. JAMA; 1947. pp. 1230-3.
2. Cary RJ. A brief history of the methods of resuscitation of the apparently drowned. Journal of Johns Hopkins Hospital Bulletin. 1918;270 (1918):243-
51.
3. Committee on CPR of the Division of Medical Sciences, National Academy of Sciences-National Research Council. Cardiopulmonary resuscita-
tion. JAMA. 1966;198:372-9, 138-45.
4. Elam JO. Rediscovery of expired air methods for emergency ventilation, in advances in cardiopulmonary resuscitation. In: Peter Safar, (Ed). New
York: Springer Verlag; 1977. pp. 263-5.
5. Grace WJ, Chadbourn JA. The mobile coronary care unit. Diseases of the Chest. 1969;55:452-5.
6. Johnson A. An account of some societies at Amsterdam and Hamburg for the recovery of drowned persons, London; 1773. p. 119.
7. Karpovich PV. Adventures in Artificial Respiration. New York: Association Press; 1953.
8. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA. 1960;173:94-7.
9. Lown B. Cardioversion of arrhythmias modern concepts of cardiovascular diseases. AHA. 1964;33:863-8.
10. Royal Humane Society, Annual Reports, 1787, 1788, 1789. London.
11. Safar P. History of cardiopulmonary-cerebral resuscitation. In: Kay W, Bircher N, (Eds). Cardiopulmonary resuscitation. New York: Churchhill
Livingston; 1989. pp. 1-53.
53 History of Sildenafil: From Angina
to Erectile Dysfunction
Shrivastava S, Sharma VK
INTRODUCTION
Since time immemorial, man has been preoccupied with potency.
Impotence has a history almost as old as that of the mankind and the
victims of this blight have been noted in all eras—from Egyptian king;
Amasis and Roman emperors; Nero and Honorius to Frankish mon-
arch Charlemagne. In a large US survey, it was found that 52% of men
aged 40–70 years reported some degree of erectile dysfunction (ED).1
For centuries impotence remained a rich field for superstition Figure 53.1: Chemical structure of sildenafil: 5-(2´-Alkoxyphenyl)-
and quackery. Men, traumatized by a fear of impotence have turned pyrazolo-[4,3-d]-pyrimidin-7-ones
to a host of natural aphrodisiacs, rituals and prayers, hormonal treat-
ments and mechanical devices and a growing number of scientific ing prospect of using a needle to generate a medical erection. Then
(and pseudoscientific) drug to address the problem. The cures for came the final revolution, when the little blue pill sildenafil (Fig.
impotence have largely followed the fashions of the day with philoso- 53.1) came on to the scene in 1998. However, its discovery was equal-
phies of one age become the absurdities of the next, and the foolish- ly unanticipated.
ness of yesterday becomes the wisdom of tomorrow.
The Greeks consumed aphrodisiacs that included nettles, chick- HISTORY OF SILDENAFIL
peas and crushed beetles, while according to Ovid, the “right molar
of a small crocodile worn as an amulet guarantees erection in men”. The story of sildenafil, in a way started in 1980, when Robert Furch-
Medieval recipes were equally lip-smacking: the brains of male spar- gott discovered that the endothelium releases a factor, endothelium
rows mixed with goat fat, roasted wolf’s penis or bread that had been derived relaxing factor (EDRF) that relaxes blood vessels and its sub-
kneaded with a woman’s buttocks. Victorian doctors prescribed elec- sequent identification as nitric oxide (NO). Nitric oxide binds to the
tric belts combined with “restorative powders and seminal replen- receptors of an enzyme called guanylate cyclase, which results in in-
isher” or later medical interventions that tested the patient’s nerve creased levels of cyclic guanosine monophosphate (cGMP), leading
and wallet in about equal measure: circumcision, injections of mon- to smooth muscle relaxation. The process is terminated by degrada-
key glands, testicle transplants, vacuum pumps, silicon rods. tion of cGMP by cGMP specific phosphodiesterase.
But what was still missing was a medical treatment for ED. The Obviously, the next thought was that if this cGMP specific
discovery of the first such treatment was an accidental observation phosphodiesterase can be inhibited, it will prolong the vasodilatory
when patients being administered papaverine to lower blood pres- action of NO, which is likely to have many clinical uses including
sure during surgery were observed to get spontaneous erections. This treatment of hypertension and angina pectoris.
discovery was made “immortal” by British physiologist, Giles Brind- In 1996, Nicholas K Terrett, Andrew S Bell, David Brown and Pe-
ley in what is arguably the most outrageous scientific presentation of ter Ellis, working at Pfizer’s research facility in Kent, England tested
all time. He decided to present the results of his study of intracaver- one such compound known as compound UK-92,480 to treat hy-
nosal papaverine injections to the 1983 Urodynamics Society in Las pertension and angina pectoris. The phase I clinical trial to test the
Vegas using himself for live demonstration. efficacy of the drug, done at Morriston hospital in Swansea, Wales,
Professor Brindley’s presentation was enormously effective in threw up a totally unexpected result. It was found that, although
convincing the urologists in attendance of the success of the treat- the drug had little effect on angina, it could induce marked penile
ment and injection of papaverine became a revolutionary, if some- erections.2 This compound was found to be a selective and powerful
what scary treatment for ED. The only problem left was the frighten- inhibitor of cGMP specific phosphodiesterase type 5, which is found
in corpus cavernosum of the penis. It causes smooth muscle relaxa- the former Senator’s prostate cancer operation, during a commercial
tion and dilatation of the helicine arteries, leading to vasodilation break King supposedly asked Dole, mano-y-mano, how he was han-
and increased inflow of blood into the spongy tissue of the penis dling the sexual consequences of the surgery. Dole admitted he was
causing an erection. part of a Pfizer clinical trial of a wonder drug that solved all his prob-
Immediately after these results came to light, Pfizer knew that lems. Alan Greenberg, chairman of Bear Stearns, donated $1 million
they hit the goldmine and decided to market it for ED. They got it pat- to finance sildenafil prescriptions for other equally needy men.
ented in 1996. In March 1998, it was approved by US Food and Drug The medicine was directly advertised on television and the name
Administration (FDA) for use in ED, becoming the first oral treat- “viagra” became so well-known, that many fake aphrodisiacs with
ment approved to treat ED in the United States. Next year in 1999, it similar names hit the market. These included the so-called “herbal
was offered for sale in the United States and rest is history. Viagra” and the tablets imitating the color and shape of Pfizer’s prod-
uct. Those hesitant to ask for it from the drug store, they gave it inno-
THE SUCCESS STORY OF SILDENAFIL vative names like “vitamin V”, “the Blue Pill”, as well as various other
nicknames.
After the FDA approval of sale in United States, in the week of 8 May,
1998—one month after launch—more than 300,000 total prescrip- CONTROVERSIES
tions were written for sildenafil and more than $400 million worth
of sildenafil was sold in its first quarter in the US market.3 The intro- Like all success stories, the story of sildenafil is also not without con-
duction of sildenafil essentially quadrupled the market for treatment troversies. Some experts consider Nicholas Terrett as the father of
of ED (in dollar sales) in the United States in 8 months. At the same sildenafil. First, in 1991 he along with Andrew Bell, Dr David Brown
time, sildenafil cut sharply into the sales of other ED treatments, discovered that chemical compounds belonging to the pyrazolopy-
whose prescriptions fell by about half.4 By the end of 1999, sildenafil rimidinone class were useful in treating heart problems such as an-
accounted for 92% of new prescriptions to treat ED.5 In the first year gina. Second, in I994, he along with Peter Ellis discovered during the
and a half of marketing in the United States, more than 15.6 million trial studies of sildenafil as a heart medicine that it also increased
prescriptions of sildenafil had been filled and as evidence of satisfac- blood flow to the penis, allowing men to reverse ED. He was named
tory use, refills accounted for nearly half of these.5 Over the next 3 in the 1991 British patent for sildenafil (trade name Viagra) as a heart
years (1999–2001), Pfizer sold $1 billion worth of sildenafil. medicine.
The success story in US market was repeated globally. Europe- The British press portrayed Peter Dunn and Albert Wood as the
an registration was granted by the European Medicines Evaluation inventors of the drug and to support their claim, they cite the fact that
Agency (EMEA) in September 1998, and sales began in most Euro- their names appeared on an application by Pfizer to patent (WOW-
pean countries shortly thereafter. Approvals and launches in Latin O9849166A1) the manufacturing process of sildenafil citrate. But,
America followed shortly after the drug’s approval and launch in the Peter Dunn and Albert Wood only worked on the crucial nine-step
United States, and sildenafil is now available in a number of Asian process to synthesize a sildenafil compound into a pill.
countries, Australia, New Zealand and Canada. Japan’s approval, in However, Pfizer maintained that their scientists are paid to work
January 1999, was unprecedented in two respects. First, the 6-month for the company and the company owns their inventions and one
approval was the most rapid Japanese approval ever. Second, for the can not really point to two individuals and say they spawned Viagra.8
first time Japan accepted data from clinical trials conducted else- Nicholas Terret himself was more diplomatic and said that
where.6 “there were three patents put forward for sildenafil. Basically, me and
In many countries, a high-price black market for sildenafil my team discovered how useful the drug might be, they (Wood and
existed before the product was legally available, indicating that Dunn) created a way of mass producing it only”.
consumers were willing to pay more than the market price. News Pfizer’s world-wide patents on sildenafil citrate will expire in
stories reported black-market prices of $20–30 per pill in some 2010–2013. The UK patent held by Pfizer on the use of PDE-5 inhibi-
countries (for example, Malaysia, Hong Kong and Thailand) and tors as treatment of impotence was invalidated in 2000 because of
even in the $50 range in China.7 One reason for the speedy Japanese obviousness; this decision was upheld on appeal in 2002.
approval of sildenafil was for the government to establish control
over the market for the drug, since a black-market was thriving in EXPANDING USES BEYOND TREATMENT
Japan, including purchases over the internet.
FOR ERECTILE DYSFUNCTION
The drug quickly became a social status symbol and became ac-
cepted within mainstream male culture. It was directly endorsed on In less than 5 years, the first selective type 5-phosphodiesterase
television by several celebrities including former United States Sena- inhibitor, sildenafil, evolved from a potential antiangina drug to
tor, Bob Dole and soccer star Pelé. Popular acceptance of a phar- treatment for ED. Soon, another potential use was discovered for
maceutical solution to impotence can be dated to Bob Dole’s 1998 sildenafil when it was realized that, in addition to the arterial wall
appearance on the CNN Larry King show. While the show focused on smooth muscle of penis, PDE-5 is also distributed within the arterial
Chapter 53  History of Sildenafil: From Angina to Erectile Dysfunction 395
wall smooth muscle of the lungs. Thus, it can be used to decrease altitude sickness such as that suffered by mountain climbers. While
the pulmonary artery pressure without decreasing the systemic pres- this effect has only recently been discovered, sildenafil is already
sures, as it does not cause vasodilatation in other areas of the body becoming an accepted treatment for this condition, in particular in
except lungs and penile vasculature. This has overcome one of the situations where the standard treatment of rapid descent has been
major problems with the conventional treatment of the pulmonary delayed for some reason.9
arterial hypertension, as all the medicines to treat this condition also The 2007, Ig Nobel Prize in Aviation (the Ig Nobel Prizes are an
cause profound hypotension. Pfizer submitted an additional regis- American parody of the Nobel Prizes and are given each year in early
tration for sildenafil to the FDA and sildenafil was approved for this October for 10 achievements that “first make people laugh and then
indication in June, 2005. To avoid confusion with Viagra, the prepara- make them think”) went to Patricia V Agostino, Santiago A Plano and
tion was named Revatio and the 20 milligrams tablets are white and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina,
round. for their discovery that sildenafil aids jet lag recovery in hamsters.
Sildenafil has been shown to be useful for the prevention and Their research was published in the proceedings of the national
treatment of high-altitude pulmonary edema associated with academy of sciences.
REFERENCES
1. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging
Study. J Urol. 1994;151(1):54-61.
2. Terrett NK, Bell AS, Brown D, et al. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the
treatment of male erectile dysfunction. Bioorganic and medicinal chemistry letters;6(15):1819-24.
3. IMS Health. Retail and Provider Perspective, 1998 and National Prescription Audit, 1998.
4. Duffy M, Pomerantz S. Viagra Market Update, Week Ending 12/18/98. Viagra Economics Health Affairs. 1998;19(2).
5. Pomerantz S. As evidence of satisfactory use, refills now account for more than half of all prescriptions. Viagra Market Update, Week Ending
11/26/99. 1999 (New York: Pfizer, 13 December 1999).
6. Japanese Women’s Groups Angry after Health Ministry Approves Viagra, Tokyo. Dow Jones News. January 26, 1999.
7. “Viagra Sold Illegally in Malaysian Nightclubs, Pharmacies”, Kuala Lumpur AFP (8 March 1999); Duffy TS, “Viagra Hits Hong Kong, but Will It Re-
place Traditional Impotence Cures?” Hong Kong, APW (10 February 1999); Wannabovorn S, “Thais Say Massage, Herbs, Give That Viagra Feeling”,
Bangkok, Reuters (11 May 1999); and “In the Absence of Viagra, Here’s to Great Brother”, Hong Kong, AFP, Dow Jones News (15 January 1999).
8. Bellis M. Viagra the patenting of an aphrodisiac. [online] Available from website www.about.com. http://inventors.about.com/od/
uvstartinventions/a/Viagra.htm. (Accessed July 2012).
9. Fagenholz PJ, Gutman JA, Murray AF, et al. Treatment of high altitude pulmonary edema at 4240 m in Nepal. High Alt Med Biol. 2007;8(2):139-46.
54 Cardiocutaneous Diseases
Mendiratta V, Malik M
INTRODUCTION telorism, pulmonary valve stenosis, abnormalities of genitalia, retar-

dation of growth, deafness). It is an autosomal dominant disorder of
Skin serves as the mirror of general health and offers vital clues for variable penetrance and expressivity, arising as a result of mutations
the early diagnosis of serious systemic diseases including cardio- in the neuroectodermal layers.2
vascular diseases. Skin and cardiovascular system share an overlap
in the genomic expression and embryologic development.1 Many Clinical presentation: The most frequent cutaneous manifestation is
disorders which have an associated cardiovascular morbidity have lentigines. The lentigines are dark brown, irregular, pinpoint to 5 cm
well recognized cutaneous manifestations namely pseudoxanthoma macules primarily involving face, neck and upper trunk, but occur
elasticum, which is an inherited disorder of elastin and is character- all over the body, including the scalp, genitalia, palms and soles;
ized by the presence of yellowish, waxy skin with excessive skin folds present at birth or develop in early childhood and becoming more
in the neck and axilla along with high risk of coronary artery disease numerous until puberty (Fig. 54.1). Histopathological examination
at a relatively younger age. Certain dermatologic signs act as markers demonstrates presence of large membrane-bound accumulations
or even the hallmark of cardiac diseases. Early recognition of specific of melanin granules within Langerhans cells. Other cutaneous
skin features of cardiocutaneous syndromes by dermatologists and anomalies include axillary freckling, café au lait spots, melanoma,
cardiologists may help in curbing the downhill course of cardiac dis- localized hypopigmentation, interdigital webs, dermatoglyphic
ease. The involvement of skin and cardiovascular system is observed abnormalities, onychodystrophy, multiple granular cell myoblas
in a diverse variety of diseases which include chromosomal disor- tomas, steatocystoma multiplex and hyperelastic skin. The most
ders, connective tissue diseases, disorders affecting collagen and common cardiac abnormality is pulmonary valvular stenosis.
elastin metabolism, autoimmune diseases and disorders of keratini- Hypertrophic obstructive cardiomyopathy may result in mortality
zation as shown in Table 54.1. The realm of disorders which share at an early age, thus necessitating the need of echocardiography
cutaneous involvement with cardiovascular morbidity is vast. This even in asymptomatic individuals. Subaortic stenosis, subpulmonic
chapter highlights important conditions which can be diagnosed stenosis, mitral valve involvement, left and right ventricular outflow
easily with the help of cutaneous signs, thus providing early detec- tract obstructions, ASD, and atrial myxomas have also been reported.
tion of cardiovascular diseases. Defects in the genitourinary system include cryptorchidism
(most common), delayed puberty and hypospadias. Neurological
GENETIC DISORDERS abnormalities comprise of sensorineural hearing loss and mild men-
tal retardation. Ocular hypertelorism, ptosis, mandibular progna-
thism, low-set ears, dental abnormalities, pectus carinatum or exca-
Disorders Associated with Lentigines
vatum, scoliosis, spinal fusion, winged scapulas, hypermobile joints,
LEOPARD Syndrome rib anomalies, hypoplastic digits, syndactyly and short stature may
be seen.
LEOPARD syndrome [multiple lentigines syndrome (MLS), gen- The diagnosis of LEOPARD syndrome is based on a detailed fam-
eralized lentiginosis, centrofacial lentiginosis, lentiginosis profusa ily and genetic history in addition to the clinical findings based on
syndrome, lentiginosis-deafness-cardiomyopathy syndrome, car- the mnemonic. Voron et al. in 1976 proposed the “minimum” criteria
diocutaneous lentiginosis syndrome, progressive cardiomyopathic for diagnosis: (1) if the patient has multiple lentigines, then two other
lentiginosis and Moynahan syndrome]. clinical criteria are required; or (2) in the absence of lentigines, three
In 1969, Gorlin et al. proposed the acronym LEOPARD (lentigi- or more other features, in addition to an immediate family member
nes, electrocardiographic conduction abnormalities, ocular hyper- with MLS are required.
Chapter 54  Cardiocutaneous Diseases 397
TABLE 54.1 Classification of cardiocutaneous diseases
Disease Cutaneous Features Cardiovascular Morbidity
Autoimmune disorders
Antiphospholipid antibody syndrome Livedo reticularis, retiform purpura, Raynaud’s Recurrent arterial and venous thromboses
phenomenon, nailfold and leg ulcers, cutaneous
necrosis and splinter hemorrhages,
Churg-Strauss vasculitis Palpable purpura, infiltrated nodules on scalp or Cardiac granulomas and fibrosis, pericarditis,
limbs, livedo reticularis, retiform purpura, migratory mitral regurgitation (MR) and coronary artery
erythema and Raynaud’s phenomenon vasculitis
Dermatomyositis/polymyositis (Fig. 54.2) Gottron’s papules, Gottron’s sign, periungual Atrioventricular defects, arrhythmias,
telangiectasias, dystrophic cuticles, heliotrope rash, pericarditis, pericardial effusion and dilated
confluent macular violaceous erythema, calcinosis cardiomyopathy
cutis and poikiloderma
Neonatal systemic lupus erythematosus (SLE) Raccoon sign, erythema annulare, vitiligo-like Complete heart block, second-degree heart
eruption, morphea like Lesions and papules on the block, dilated cardiomyopathy, myocarditis and
feet valvular defects
Polyarteritis nodosa Dermal or subcutaneous nodules commonly on Coronary artery vasculitis, hypertension and
distal lower extremities, retiform purpura and digital myocardial infarction (MI)
gangrene
Rheumatoid arthritis Rheumatoid nodules, rheumatoid vasculitis, felty’s Pericarditis, pericardial effusion, aortic
syndrome and pyoderma gangrenosum regurgitation (AR), MR, aortitis and aneurysmal
rupture
Scleroderma Swelling of skin at initial presentation, skin sclerosis Myocardial fibrosis, congestive heart failure
in later stages and Raynaud’s phenomenon (CHF), arrhythmias, pericarditis, primary
pulmonary hypertension (PHT) and cor
pulmonale
Systemic lupus erythematosus Malar rash, discoid rash, photosensitivity, oral ulcers, Pericarditis, pericardial effusion, Libman-sacks
Raynaud’s phenomenon, livedo reticularis and leg endocarditis, atherosclerosis, hypertension, MR
ulcers and AR
Takayasu’s arteritis (Pulseless disease and Erythema nodosum like lesions, erythema induratum Hypertension, AR, pulseness, occlusion of
aortic arch syndrome) like lesions, pyoderma gangrenosum and necrotizing subclavian or carotid arteries and vascular bruits
vasculitis
Temporal arteritis (Giant cell arteritis) Prominence of superficial temporal arteries with Aortitis, aortic aneurysms, angina and MI
presence of focal nodules
Disorders of keratinization
Carvajal syndrome Woolly hair, striate epidermolytic keratoderma, Left-sided dilated cardiomyopathy
transient pruritic blistering and clubbing
Conradi-Hünermann-Happle syndrome Collodion membrane or bullous ichthyosiform Ventricular septal defects (VSD) and patent
erythroderma at birth, patchy atrophy and linear ductus arteriosus (PDA)
pigmentary change following blaschkoid lines in
adults
Lethal acantholytic epidermolysis bullosa Severe skin and mucosal fragility at birth and Cardiomyopathy
alopecia
Naxos disease Woolly hair, diffuse nonepidermolytic, palmoplantar Arrhythmia, arrhythmogenic right ventricular
keratoderma (PPK), hyperhidrosis cardiomyopathy and heart failure
Disorders of lipid metabolism
Cholesterol embolization syndrome/blue toe Livedo reticularis, ulceration, cyanosis, purpura, Myocardial infarction and heart failure
syndrome necrosis, gangrene, and painful nodules commonly
affecting lower extremities
Contd...
Contd...
Xanthelasma Small, yellow papules and plaques involving eyelids Accelerated atherosclerosis and MI
usually near inner canthus
Xanthoma Yellow-orange superficial papules, plaques, or Accelerated atherosclerosis and MI
nodules
Endocrinological disorders
Acromegaly Protruding, thickened lower lip, edema of eyelids, Left ventricular hypertrophy, CHF and
large and furrowed tongue, triangular large ears, skin hypertension
tags and acne
Carcinoid syndrome Flushing, telangiectasias and periorbital edema Right-sided endocardial fibrosis, pulmonary
stenosis (PS), tricuspid incompetence and CHF
Cushing’s syndrome Truncal obesity, “buffalo hump”, “moon facies”, Hypertension, accelerated atherosclerosis and
skin atrophy, fragility and easy bruisability, MI
telangiectasias, striae, hirsutism and acneiform
lesions
Diabetes mellitus Diabetic dermopathy, delayed wound healing, Autonomic disturbances, atherosclerosis,
necrobiosis lipoidica diabeticorum, bullous hypertension and CHF
diabeticorum and xanthelasma
Hyperthyroidism Soft, smooth skin facial flushing, palmar erythema, Palpitations, MR, atrial fibrillation, hypertension,
pruritus, pretibial myxedema, silky hair heart failure
Hypothyroidism Dry, cold skin; madarosis, periorbital puffiness, itch Mild hypertension, sinus bradycardia, coronary
and dry hair artery disease and pericardial effusion
Pheochromocytoma Flushing and increased sweating Supraventricular tachycardia, hypertension,
orthostatic hypotension and heart failure
Genetic disorders
Associated with lentigines
LEOPARD syndrome Lentigines, axillary freckling, café au lait spots, Pulmonary stenosis, hypertrophic obstructive
melanoma, dermatoglyphic abnormalities, cardiomyopathy and myxomas
onychodystrophy and hyperelastic skin
Carney complex Lentigines, blue nevi, subcutaneous myxomas, Atrial myxomas and CHF
splinter hemorrhages and vasculitis like skin lesions
Others
Cardiofaciocutaneous syndrome (Noonan- Sparse curly short hair, eyelashes and eyebrows Pulmonary stenosis, atrial septal defect (ASD)
like short stature syndrome) reduced or absent, dysplastic nails, keratosis pilaris, and cardiomyopathy
PPK, seborrheic dermatitis, eczema, ichthyosis,
hemangiomas, pigmented nevi, café au lait macules
and syringocystadenoma papilliferum
Down’s syndrome (trisomy 21) Soft, velvety skin at birth, dry skin in late childhood, Ventricular septal defects, endocardial cushion
premature wrinkling of skin, cutis marmorata, defects, tetralogy of Fallot (TOF), pulmonary
acrocyanosis, atopic dermatitis, seborrheic hypertension PHT and PDA
dermatitis, elastosis perforans serpiginosa, tinea
infections, norwegian scabies, syringomas, alopecia
areata, vitiligo and angular cheilitis
Edwards syndrome (trisomy 18) Nevus flammeus, hirsutism, hypoplastic nails, cutis Atrial septal defect, VSD, PDA, PS, TOF, bicuspid
marmorata and epicanthic folds aortic valve and PHT
Neurofibromatosis type 1 Café au lait macules, cutaneous neurofibromas, Hypertension, rhabdomyosarcoma and PS
axillary or inguinal freckling
Noonan syndrome Soft, elastic skin, pigmented nevi, nail dystrophy, Pulmonary stenosis, hypertrophic
keloids, transient lymphedema, coarse curly scalp cardiomyopathy, ASD and VSD
hair and ulerythema ophryogenes
Contd...
Contd...
Patau syndrome (trisomy 13) Nevus flammeus, localized scalp defects, cutis laxa, Atrial septal defect, VSD, PDA, PS, Coarctation of
hyperconvex fingernails and hypoplastic toenails aorta (COA) and dextrocardia
Tuberous sclerosis Hypopigmented ash-leaf macules, facial Cardiomyopathy, rhabdomyomas,
angiofibromas (adenoma sebaceum), shagreen supraventricular tachycardia
patch, café au lait macules, forehead fibrous plaque,
periungual/subungual fibromas (Koenen tumors),
port-wine stains and fibroepithelial tags
Turner’s syndrome Small pigmented nevi, keloids, hypoplastic and Coarctation of aorta, bicuspid aortic valve and
hyperconvex nails aortic stenosis (AS)
Immunological and infective disorders
Acute rheumatic fever Erythema marginatum and subcutaneous nodules Valvular disease, pericarditis, myocarditis and
heart failure.
DiGeorge syndrome Short philtrum, recurrent mucocutaneous candida Truncus arteriosus, defects of aortic arch vessels
infections in neonates and septal abnormalities
Infective endocarditis Splinter hemorrhages, osler nodes and janeway Valvular defects, CHF, MI and pericarditis
lesions
Kawasaki disease Rash, edema of hands and feet, erythema of palms Coronary artery aneurysms, arrhythmias, MI,
and soles, periungual desquamation and “strawberry myocarditis, pericarditis and valvulitis
tongue”
Inborn errors of metabolism
Fabry’s disease Angiokeratomas on the lower trunk, perineal Arrhythmias, coronary artery disease,
area, penis, scrotum, oral mucosa, hypohidrosis or hypertension and MR
anhidrosis, and telangiectasias
Homocystinuria Malar rash, large facial pores, livedo reticularis, Atherosclerosis, pulmonary embolism and
tissue-paper scars on hands and fine sparse hair coronary artery thrombosis
Infiltrative disorders
Amyloidosis Smooth, waxy papules or nodules and pinch purpura Congestive heart failure, syncope, arrhythmia,
heart block and MI
Hemochromatosis Gray-brown discoloration on face, flexural creases Arrhythmias, cardiomyopathy and heart failure
and exposed areas, dry skin, koilonychias and hair
loss
Sarcoidosis Translucent, yellow-brown or red-brown papules Arrhythmias, heart block, cor pulmonale and
showing “apple jelly” appearance, alopecia and nail myocardial fibrosis
involvement
Wilson’s disease (Hepatolenticular Bluish discoloration of nail lunula Arrhythmias, cardiomyopathy and autonomic
degeneration) disturbances
Inherited disorders of collagen and elastin
Cutis laxa Loose, wrinkled “bloodhound” appearance of skin Pulmonary stenosis, aortic aneurysms,
returning slowly to its normal shape after stretching cardiomegaly and cor pulmonale
Ehlers-Danlos syndrome Hyperextensible, soft, smooth skin with easy Tetralogy of Fallot, aortic aneurysms, ASD, MR
bruisability atrophic scars, pseudotumors and and spontaneous rupture of large vessels
elastosis perforans serpiginosa
Marfan syndrome Striae, elastosis perforans serpiginosa, frontal Dilatation of aortic root, aortic dissection or
bossing and atrophy of subcutaneous fat rupture, MR, AR and mitral valve prolapse
Osteogenesis imperfecta Thin, translucent skin with easy bruisability, blue Aortic regurgitation, MR, and fragility of large
sclera and cutaneous scarring blood vessels
Contd...
Contd...
Pseudoxanthoma elasticum Waxy yellow papules coalescing to form plaques, Intermittent claudication, coronary insufficiency,
usually on the neck and flexures; severely affected premature calcification of peripheral arteries,
lax, redundant skin resembling “plucked chicken and hypertension
skin”
Miscellaneous
Androgenetic alopecia Patterned hair loss over the crown in both sexes; Metabolic syndrome, atherosclerosis,
fine, short and lightly pigmented or non-pigmented hypertension and MI
hairs
Cardiac bypass surgery Vein graft cellulitis and vein graft dermatitis Arrhythmias, stroke and MI
Progeria Premature ageing of skin, graying and thinning of Atherosclerosis, hypertension and MI
hair, wrinkling of skin, atrophy of subcutaneous fat,
scleroderma like changes and leg ulcers
Psoriasis Red, scaly, well demarcated, indurated papules and Hypertension and heart failure
plaques with silvery white scaling, Auspitz’s sign and
grattage test positive
Tumors
Cardiac myxomas Raynaud phenomenon, petechiae, telangiectasia, Congestive heart failure, arrhythmias, conduction
splinter hemorrhages and livedo reticularis blocks and left atrial hypertrophy
Figure 54.1: Leopard syndrome—multiple Figure 54.2: Dermatomyositis—erythema and

dark-brown irregular lentigines edema in the periorbital area
Carney Complex Other Genetic Disorders

Carney complex includes atrial myxomal syndromes formerly Tuberous Sclerosis Complex (Epiloia, Bourneville’s
reported as the acronyms LAMB (lentigines, atrial myxoma, mucocu-
Disease)
taneous myxomas and blue nevi) or NAME (nevi, atrial myxoma,
myxoid neurofibromas and ephelides).3 It is an autosomal dominant Tuberous sclerosis complex represents autosomal dominant disor-
or X-linked inherited disorder. der of hamartoma formation affecting multiple organ systems, par-
ticularly the skin, heart, eyes, kidneys and nervous system.
Clinical features: Lentigines, blue nevi, subcutaneous myxomas, Dermatologic features include hypopigmented ash-leaf mac-
splinter hemorrhages and vasculitis like skin lesions may be noticed. ules, facial angiofibromas (adenoma sebaceum) (Fig. 54.3), sha-
Single or bilateral cardiac (atrial) myxomas may cause CHF, chest green patch, café au lait macules, forehead fibrous plaques, peri-
pain, pulmonary edema, embolism and death. ungal/subungual fibromas (Koenen tumors), port-wine stains and
Figure 54.3: Tuberous sclerosis—firm discrete Figure 54.4: Down’s syndrome—child with icthyotic skin
red-brown papules angiofibromas
fibroepithelial tags.4 Cardiovascular involvement may lead to rhab-

domyomas, cardiomyopathy, supraventricular tachycardia and con-
genital malformations.
Noonan’s Syndrome
Noonan’s syndrome (NS) being autosomal dominant occurs in
both sexes unlike Turner’s syndrome, though it exhibits phenotypic
resemblance to the same. Skin findings include soft, elastic skin,
pigmented nevi, nail dystrophy, keloids, lymphedema of feet and
legs, coarse curly, lightly pigmented scalp hair and ulerythema
ophryogenes. Cardiovascular system is affected in up to two-thirds
of patients manifesting as pulmonary stenosis, hypertrophic cardio-
myopathy, ASD, VSD and patent ductus arteriosus.5
Down’s Syndrome
It is the most common autosomal dominant disorder. Cutaneous man-
ifestations include soft, velvety skin in early childhood, dry skin in late
childhood (Fig. 54.4), premature wrinkling of skin, cutis marmorata, Figure 54.5: Livedo reticularis—mottled cyanotic skin discoloration
acrocyanosis, atopic dermatitis, seborrheic dermatitis, elastosis per- of the lower extremities in network pattern
forans serpiginosa, superficial fungal infections, norwegian scabies,
syringomas, alopecia areata, vitiligo, angular cheilitis, simian crease,
single flexion crease on fifth finger, increased ulnar loops on the fin- renovascular hypertension, rhabdomyosarcoma, PHT and pulmo-
gers and livedo reticularis (Fig. 54.5). Cardiac findings include VSD, nary stenosis.
endocardial cushion defects, TOF, PHT and patent ductus arteriosus.6
DISORDERS OF KERATINIZATION
Neurofibromatosis
Carvajal Syndrome
Neurofibromastosis type 1 (von Recklinghausen’s NF) presents with
characteristic skin findings, namely café au lait macules, cutaneous Carvajal syndrome (CS) presents as quartet of woolly hair (WH),
neurofibromas (Fig. 54.6) and axillary or inguinal freckling. There striate epidermolytic keratoderma (Brunauer-Fohs-Siemens type
is a high prevalence of cardiovascular abnormalities which include palmoplantar keratoderma), skin fragility and dilated cardiomyo
Figure 54.6: Neurofibromatosis—multiple neurofibromas of the face Figure 54.8: Palmoplantar keratoderma—one of the hallmarks of
Naxo’s disease and Carvajal syndrome
(ARVC).8 Wooly hair is present since birth while PPK (Fig. 54.8)
develops during infancy, both of the aforesaid cutaneous features
precede cardiac symptoms. Hyperhidrosis and nail abnormalities
may also be seen.
Cardiovascular morbidity becomes clinically evident during
adolescence, comprising of arrhythmias, ARVC and cardiac failure.
AUTOIMMUNE DISEASES
Scleroderma is a multisystem disorder characterized by increased
growth of fibroblasts resulting in microvascular disease and fibrosis
of skin, blood vessels, heart and various other visceral organs.9 Dif-
fuse cutaneous sclerodermas carries a higher risk of visceral involve-
ment, especially during first 5 years of the disease. Cardiac morbid-
ity in SLE stems from the deposition of autoantibodies and immune
complexes in skin, and heart among the other internal organs.
Figure 54.7: Woolly hair—fine curly hair with woolly texture
INHERITED DISORDERS OF ELASTIN AND
COLLAGEN
pathy (mainly left-sided).7 Wooly hair refers to hair shaft abnormal- Cutis Laxa (Dermatochalasis, Generalized
ity characterized by curly, sparse, hypopigmented, brittle hair with
Elastolysis)
soft woolly texture (Fig. 54.7). Other skin features are linear kera-
toses in flexural areas, transient pruritic blistering on trunk and fol- Cutis laxa is characterized by progressive loss of skin elasticity re-
licular, as well as psoriasiform keratosis. Cardiac involvement in CS sulting in loose, wrinkled “bloodhound” appearance of skin (Fig.
causes ventricular hypertrophy and dilatation of the left side of heart, 54.9). The skin slowly returns to its normal shape after stretching,
although even the chambers of right side may be affected. thus distinguishing it from Ehlers-Danlos syndrome.10 Cutis Laxa
Type I (generalized cutaneous) and III (acquired) may have cardiac
involvement. Cardiac manifestations include tortuous vessels pro-
Naxos Disease ducing “corkscrew” appearance on angiography, pulmonary steno-
Naxos disease refers to a clinical trial of WH, diffuse non-epider- sis, aortic aneurysms, cardiomegaly and pulmonary emphysema
molytic PPK and arrythmogenic right ventricular cardiomyopathy resulting in cor pulmonale.
Figure 54.9: Cutis laxa—generalized loose and wrinkled skin Figure 54.10: Pseudoxanthoma elasticum—yellowish
waxy papules affecting the neck
Ehlers-Danlos Syndrome
The hallmarks of Ehlers-Danlos syndrome (EDS) are fragility of the
skin and blood vessels, hyperextensibility of skin and joint hyper-
mobility. Unlike cutis laxa, skin retains its normal recoil. Cutaneous
examination may show soft, smooth skin with easy bruisability and
presence of atrophic scarring particularly over the elbows, pseudotu-
mor or elastosis perforans serpiginosa. Cardiovascular abnormalities
may be seen in EDS types I, II, IV and V namely, TOF, aortic aneu-
rysms, ASD, MR and spontaneous rupture of large vessels.10
Pseudoxanthoma Elasticum (Grönblad-

Strandberg Syndrome) Figure 54.11: Xanthelasmas—yellowish papules and plaques
involving the upper and lower eyelids
It is an autosomal recessive inherited disorder of elastic fibers affect-
ing skin, ocular and cardiovascular systems. The characteristic skin
features are waxy yellow papules approximately 2–5 mm in diameter,
coalescing to form plaques, located usually on the neck and flexural
areas (Fig. 54.10).11 The appearance of severely affected lax, redun- or tendons. In the presence of small, bilaterally symmetrical, yellow
dant skin resembles “plucked chicken skin”. Angioid streaks of fun- papules and plaques involving eyelids usually near inner canthus
dus are the most common ocular finding that correlates with cardiac (xanthelasma) (Fig. 54.11), lipid profile examination is warranted
morbidity. Fragmentation and calcification of elastic fibers in small as hereditary lipid disorders, namely, familial hypercholesterolemia,
and medium-sized arteries causes diminution of peripheral pulses, familial dysbetalipoproteinemia and familial combined hyperlipi-
intermittent claudication, coronary insufficiency, premature calcifi- demia have association with the former. Palmar crease xanthoma or
cation of peripheral arteries and hypertension. Diagnosis is based on xanthoma striatum palmar (planar xanthomas seen along the pal-
clinical features and skin biopsy changes; however, lack of cutaneous mar creases) are associated with Type III familial dysbetalipidemia
findings does not exclude the same. thereby predisposing to accelerated atherosclerosis. Cholesterol
embolization syndrome although may occur spontaneously, but
DISORDERS OF LIPID METABOLISM is commonly precipitated by percutaneous or operative vascular
intervention, for instance, angioplasty in males with history of
Xanthomas present as yellow-orange superficial papules, plaques, hypertension, diabetes, obesity, smoking, atherosclerosis or aortic
or nodules because of localized lipid-laden infiltrates in the dermis aneurysms.12
Figure 54.12: Kawasaki syndrome—strawberry tongue Figure 54.13: Erythema marginatum—erythematous lesion with a
raised serpiginous margin
Acute Rheumatic Fever

IMMUNOLOGICAL AND INFECTIVE
DISORDERS Acute rheumatic fever develops approximately 2–3 weeks after the
onset of group A streptococcal pharyngitis. Erythema marginatum
Kawasaki Disease (Mucocutaneous (non-pruritic, erythematous, blanchable skin lesions developing
Lymph Node Syndrome) over the trunk and proximal extremities; with centrifugal spread and
central clearing) may persist even after the resolution of other fea-
Kawasaki disease refers to immune mediated, medium ves- tures (Fig. 54.13). Firm, painless, subcutaneous nodules ranging in
sel vasculitis developing commonly in childhood, often within size from few mm to 2 cm may be observed over tendons and bony
first 2 years of life. The characteristic rash of Kawasaki disease surfaces after first week of illness. Cardiac involvement may lead to
develops 3–4 days after the onset of fever, clinically manifesting as valvular dysfunction, pericarditis, myocarditis, pericardial friction
widespread erythematous, maculopapular exanthem (scarlatini- rub and even heart failure.
form or erythema multiform like in few cases) involving perineum
followed by extremities. On examination, edema of hands and INBORN ERRORS OF METABOLISM
feet, erythema of palms and soles with periungual desquamation
may be seen. Oral findings include erythema, dryness, fissuring, Fabry’s Disease
desquamation of oral cavity; bleeding of the lips and “strawberry
tongue” (erythema with prominent papillae) (Fig. 54.12). Cardio- Deficiency of enzyme a-galactosidase A results in this X-linked lyso-
vascular morbidity and mortality may result from coronary artery somal storage disorder. Angiokeratomas present as violaceous, non-
aneurysms, arrhythmias, MI, myocarditis, pericarditis, valvulitis blanching papules ranging in size from pinhead to a few millimeters
and sudden cardiac death.13 seen on the lower trunk, perineal area, penis, scrotum, and oral mu-
cosa (Fig. 54.14).14 Hypohidrosis or anhidrosis and telangiectasia in
Infective Endocarditis the axillae and on upper chest are other cutaneous findings. Arrhyth-
mias, coronary artery disease, hypertension and MR may result from
Cutaneous involvement of infective endocarditis occurs as a accumulation of glycosphingolipid in myocardium.
result of septic emboli and immune-mediated reactions. Janeway
lesions (nontender, hemorrhagic macules involving palms and Homocystinuria
soles), Osler nodes (painful erythematous nodules affecting pulp
of the fingertips and toes), subungual splinter hemorrhages and It is caused by an underlying defect in cystathionine synthetase.
petechiae over conjunctiva and palate are the common skin findings. Skin manifestations comprise of malar rash (Fig. 54.15), large facial
Cardiac evaluation may suggest presence of valvular damage (mur- pores, livedo reticularis, tissue-paper scars on hands, fine sparse hair
mur), CHF, perivalvular abscesses, MI, pericarditis and heart block. and superficial thrombophlebitis.
Figure 54.14: Fabry’s disease—hyperkeratotic vascular Figure 54.15: Systemic lupus erythematosus—malar rash in a
skin lesion sangiokeratomas middle aged female
It is an independent risk factor for atherosclerosis and throm-

bosis. Increase in plasma homocysteine causes increased platelet
adhesiveness leading to deep venous thromboses, pulmonary embo-
lism and cerebral, peripheral, and coronary arterial thrombosis.
INFILTRATIVE DISORDERS
Amyloidosis
Cutaneous lesions may be seen in localized cutaneous amyloidosis
and primary systemic amyloidosis. These include smooth, waxy pap-
ules or nodules involving the face, neck, chest, periumbilical region,
and perineum and intertriginous areas. Eyelid purpura, after pinch-
ing (“pinch” purpura) and periorbital purpura after proctoscopy
(post-proctoscopic palpebral purpura), coughing, vomiting or Val-
salva maneuver are characteristic of primary amyloidosis. Cardiac
involvement in the form of CHF, syncope, arrhythmia, heart block or Figure 54.16: Androgenetic alopecia—male pattern hair loss
MI may be seen in primary systemic amyloidosis, familial amyloido-
sis, and senile systemic amyloidosis.
Sarcoidosis MISCELLANEOUS
Sarcoidosis is a multisystem granulomatous disease. Most common Androgenetic Alopecia
cutaneous lesions are translucent, yellow-brown or red-brown pap-
ules showing “apple jelly” appearance on diascopy occurring most The essential clinical feature of androgenetic alopecia is patterned
commonly on face and neck. Mucosal papules and plaques, alopecia hair loss over the crown, in both sexes (Fig. 54.16). Pigmented ter-
and nail involvement may be present. Cardiovascular manifestations minal hairs are progressively replaced by fine, short and lightly pig-
include arrhythmias, heart block, cor pulmonale, myocardial fibrosis mented or non-pigmented hairs, beginning at any age after the onset
and even death can occur. of adrenarche and may precede pubarche. The high prevalence of
Figure 54.17: Psoriasis—erythematous well defined indurated Figure 54.18: Progeria—child showing signs of premature ageing
plaques on extensors of lower extremities
metabolic syndrome and carotid atheromatous plaques in patients

with androgenetic alopecia suggests a potential role of cardiovascu-
lar screening for early detection of individuals at risk and initiation
of preventive treatment before cardiac disease becomes established.
Psoriasis
Psoriasis is a common, chronic, inflammatory and proliferative con-
dition of the skin, characterized by red, scaly, sharply demarcated,
indurated papules and plaques, present particularly over the exten-
sor surfaces and scalp (Fig. 54.17). Increased skin blood flow, blood
volume and cardiac output may lead to failure of cardiovascular sys-
tem in patients of psoriasis with pre-existing hypertension, myocar-
dial or valvular heart disease, or anemia.
Progeria Figure 54.19: Systemic sclerosis—tight shiny bound down skin of

face with smoothening of facial expression lines
Individuals with progeria develop features of ageing prematurely
including graying and thinning of hair, wrinkling of skin (Fig. 54.18); changes and leg ulcers. Atherosclerosis, hypertension and MI may
and other features like atrophy of subcutaneous fat, scleroderma like cause cardiovascular morbidity and mortality.
REFERENCES
1. Bolling MC, Jonkman MF. Skin and heart: une liaison dangereuse. Exp Dermatol. 2009;18(8):658-68.
2. Coppin BD, Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet.
1997;34(7):582-6.
3. Irvine AD, Armstrong DK, Bingham EA, et al. Evidence for a second genetic locus in Carney complex. Br J Dermatol. 1998;139(4):572-6.
4. Jóźwiak S, Schwartz RA, Janniger CK, et al. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnos-
tic significance. Int J Dermatol. 1998;37(12):911-7.
5. Chery M, Philippe C, Worms AM, et al. The Noonan syndrome: the Nancy experience revisited. Genet Couns. 1993;4(2):113-8.
6. Towbin JA, Roberts R. Cardiovascular diseases due to genetic abnormalities. In: Alexander RW, Schlant RC, Fuster V, O’Rourke R, Roberts R, Sor-
renblick EH (Eds). The Heart. New York: McGraw-Hill; 1995. pp. 1877-923.
7. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol. 1998:39(3):418-
21.
8. Protonotarios N, Tsatsopoulou A, Patsourakos P, et al. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J. 1986:56(4):321-6.
9. Gilliland BC. Systemic sclerosis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL (Eds). Harrison’s Principles of Internal
Medicine, 15th edition. New York: McGraw-Hill; 2001. pp. 1937-47.
10. Novice FM, Collison DW, Burgdorf WHC, et al. Dysplasias and malformations. Handbook of Genetic Skin Disorders. Philadelphia: Saunders;
1994. pp. 261-384.
11. Sherer DW, Sapadin AN, Lebwohl MG. Pseudoxanthoma elasticum: an update. Dermatology. 1999;199(1):3-7.
12. Y. Fukumoto, H. Tsutsui, M. Tsuchihashi M, et al. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac
catheterization: a prospective study. J Am Coll Cardiol. 2003;42(2):211-6.
13. Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993;87(5):1776-80.
14. Der Kaloustein VM, Kurban AK. Metabolic Disorders. Berlin: Springer-Verlag; 1979.
55 ARBs and CVD Protection
Ray S
Structural modifications were made and the orally active, potent and
INTRODUCTION
selective nonpeptide AT I receptor blocker losartan was developed.
The angiotensin receptor blockers (ARBs), also called angiotensin In 1995, losartan was approved for clinical use in the United States.
(AT I) receptor antagonists or sartans, are a group of drugs that act by
blocking the effects of angiotensin II (Ang II) in the body. Their struc- MODE OF ACTION OF ARB
ture is similar to Ang II and they bind to Ang II receptors as inhibitors.
Angiotensin receptor blockers are widely used drugs with the The actions of Ang II are mediated by angiotensin receptors, AT I and
main indications being hypertension, chronic heart failure, sec- AT II. These receptors are members of the G protein-coupled recep-
ondary stroke prevention, high-risk patients for atherosclerosis and tors family, which are seven transmembrane helices, connected by
nephropathy and more recently, ischemic heart disease. interchanging extracellular and intracellular loops.
Two more angiotensin receptors have been described, AT III and
HISTORY OF DEVELOPMENT OF AT IV, but their role is still unknown.
Blood pressure and fluid and electrolyte homeostasis is regu
ANGIOTENSIN RECEPTOR BLOCKERS
lated by the renin-angiotensin-aldosterone-system. Renin, an
In 1898 physiologist Robert Tigerstedt and his student, Per Berg- enzyme released from the kidneys, converts the inactive plasma
man, experimented with rabbits by injecting them with kidney protein angiotensinogen into Ang I. Then Ang I is converted to Ang II
extracts. Their results suggested that the kidneys produced a protein, with ACE. Ang II in plasma then binds to AT-receptors.
which they named renin that caused a rise in blood pressure. In the ARBs are blocking the last part of the renin-angiotensin pathway
1930s, Goldblatt experimentally constricted the renal blood flow in and block the pathway more specifically than ACE inhibitors.
dogs and found that the ischemic kidneys secreted a chemical that The AT I receptor mediates Ang II to cause increased cardiac
caused vasoconstriction. In 1939, it was discovered that renin cata- contractility, sodium reabsorption and vasoconstriction which all
lyzed the formation of the substances that were responsible for rise of lead to increased blood pressure. By blocking AT I receptors, ARBs
blood pressure, namely, Ang I and Ang II. In the 1970s scientists first lead to lower blood pressure.
observed that Ang II is detrimental for the heart and kidneys and
high levels of renin activity in plasma increased the risk of myocar- THE MEMBERS OF ARB CLASS
dial infarction and stroke. With the introduction of angiotensin con-
verting enzyme (ACE) inhibitors in the late 1970s it was confirmed Losartan, valsartan, candesartan, irbesartan, telmisartan and olme-
that Ang II plays an important role in regulating blood pressure and sartan all contain a biphenyl-methyl group. Losartan is partly metab-
electrolyte and fluid balance. olized to its 5-carboxylic acid metabolite EXP 3174, which is a more
Even before that attempts had been made to develop useful potent AT I receptor antagonist than its parent compound and has
Ang II receptor antagonists. Saralasin and other Ang II analogues been a model for the continuing development of several other ARBs.
were potent Ang II receptor blockers, but the main problem was a Valsartan, candesartan and irbesartan were all developed in
lack of oral bioavailability. 1990.
In the early 1980s, it was noted that a series of imidazole-5-ace- Valsartan is a nonheterocyclic ARB, where the imidazole of
tic acid derivatives diminished blood pressure responses to Ang II losartan has been replaced by an acylated amino acid.
in rats. Two compounds, S-8307 and S-8308, were later found to be Irbesartan is longer acting than valsartan and losartan and it has
highly specific and promising nonpeptide Ang II receptor antago- an imidazolinone ring where a carbonyl group functions as a hydro-
nists, but using molecular modeling it was seen that their structures gen bond acceptor instead of the hydroxymethyl group in losartan.
would have to mimic more closely the pharmacophore of Ang II. Irbesartan is a non-competitive inhibitor.
Chapter 55  ARBs and CVD Protection 409
Candesartan cilexetil is a benzimidazole is an ester prodrug. In failure. In both Val-HeFT and CHARM, addition of an ARB to existing
vivo, it is rapidly converted to the much more potent corresponding therapy reduced combined all-cause mortality and morbidity along
7-carboxylic acid, candesartan. In the interaction of candesartan with symptomatic improvement. Echocardiographic sub-studies of
with AT I receptor the carboxyl group of the benzimidazole ring plays these trials have established that treatment with an ARB significantly
an important role. Candesartan and its prodrug have stronger blood increases left ventricular ejection fraction and improves remodeling.
pressure lowering effects than EXP 3174 and losartan. In the CHARM-PRESERVE trial, in HF with preserved ejection frac-
Telmisartan, which was discovered and developed in 1991, has tion candesartan reduced hospitalization, though did not benefit in
carboxylic acid as the biphenyl acidic group. It has the longest elimi- mortality.
nation half-life of the ARBs of about 24 hours. Telmisartan has been
described as a fourth generation ARB with bimodal function—it not POST-MI SET-UP
only blocks the AT1 receptor, it also activates PPAR gamma pathway
thus improving dyslipidemia and insulin sensitivity. Left ventricular dysfunction and heart failure are common compli-
Olmesartan medoxomil was developed in 1995 and was the new- cations of MI and implicates adverse prognosis. The Valsartan in
est ARB on the market, marketed in 2002. It is an ester prodrug like Acute Myocardial Infarction Trial (VALIANT) has demonstrated the
candesartan cilexetil. In vivo, the prodrug is completely and rapidly statistical non-inferiority of the efficacy of valsartan versus captopril
hydrolyzed to the active acid form, olmesartan. It has a hydroxy- in these high-risk patients . CHARM studies also showed the efficacy
isopropyl group connected to the imidazole ring in addition to the of candesartan in this setting, given that more than half of enrolled
carboxyl group. patients had MI as the cause of heart failure. In contrast, the Optimal
Trial in Myocardial Infarction with the Angiotensin II Antagonist Lo-
ROLE OF ARB IN HYPERTENSION sartan (OPTIMAAL) trial demonstrated a non-significant difference
in total mortality in favor of captopril, although losartan was better
The clinical trials have investigated the role of ARBs in patients with tolerated. Treatment guidelines recommend the use of ARBs, specifi-
hypertension are the Losartan Intervention Endpoint Reduction in cally valsartan and candesartan, as an alternative to ACE-Is in high-
Hypertension (LIFE) trial, Study of Cognition and Prognosis in the risk, post-MI patients and in patients with chronic heart failure.
Elderly (SCOPE) trial and the Valsartan Antihypertensive Long-Term
Use Evaluation (VALUE) trial. In the VALUE trial, while amlodipine- COMBINATION THERAPY
based treatment resulted in a greater BP reduction in the early stages
WITH ACE-I AND ARB
of the trial, the primary endpoint (a composite of cardiac mortality
and morbidity) was not significantly different between the treatment Four studies have explored the utility of combining ACE-I with ARB;
groups at 66 months’ follow-up. The LIFE trial demonstrated the the CHARM-Added study, the Val-HeFT study and the VALIANT
advantage of losartan, titrated to 100 mg once daily, compared with study and ONTARGET. The CHARM-added trial showed a signifi-
atenolol for reducing the composite endpoint (most notably stroke), cant (15%) reduction in the combined end point of CV death or HF
despite similar BP reductions. Moreover, for those patients with left hospitalization with the addition of candesartan therapy to ACE-I in
ventricular hypertrophy losartan induced a greater reduction of left patients with HF. The addition of valsartan to patients with HF with
ventricular mass than atenolol. Similar findings have been observed background treatment of ACE-I in the Val-HeFT Trial was shown
for other ARBs, including valsartan and irbesartan. These results to significantly reduce morbidity without reducing total mortality.
indicate that the cardioprotective benefits of ARBs might extend A post-hoc analysis of mortality and morbidity showed an adverse
beyond BP reduction alone. In the TROPHY trial candesartan was effect of valsartan in the subgroup of patients who were also receiving
used in prehypertension and new onset hypertension was much an ACE-I and a β-blocker. The VALIANT trial compared the effects
lower compared to placebo in the 2-year study period. More impor- of captopril with valsartan and their combination in patients with
tantly, up to 2 years after discontinuation of candesartan the new HF and/or left ventricular dysfunction following acute myocardial
development of hypertension was significantly lower. infarction. The result showed that combining valsartan with captopril
increased the rate of adverse events without improving outcomes. In
ARB IN HEART FAILURE the ONTARGET trial of high-risk patients, ramipril, telmisartan and
their combination were tested. Where individually the two drugs
ARBs in heart failure were evaluated in Evaluation of Losartan in were exact equivalents, the combination had much increased side
the Elderly (ELITE) trial, the Losartan Heart Failure Survival Study effects. In summary, there is little information available about the
(ELITE II), Valsartan Heart Failure Trial (Val-HeFT) and the CHARM cardioprotective effect of the combination therapy with both ACE-I
(Candesartan in heart failure—assessment of reduction in mortality and ARB. The combination of an ACE-I and an ARB should be used
and morbidity) trials. These studies demonstrate the clinical efficacy only for proteinuric renal disease and not for BP reduction. Patients
of ARBs in decreasing morbidity and mortality in patients with heart with proteinuria more than 1 g/day despite optimal BP control with
maximal dose of ACE-I or ARB monotherapy may benefit from a This is again supported by KYOTO and JIKEI studies. Even in VALUE,
combination therapy. valsartan was equipotent to amlodipine when used long-term.
ARB AND CORONARY ARTERY DISEASE ARB AND NEPHROPATHY

In the Kyoto Heart Study with high-risk hypertensive patients, valsar- In the IRMA-2, IDNT, MARVAL, RENAAL and ROADMAP trials all
tan reduced heart failure by 45%, stroke/TIA by 45%, angina by 49% ARBs have reduced microalbuminuria and progression to ESRD in
and new-onset diabetes by 33%. both diabetic and nondiabetic renal diseases. In T2DM, ARBs are
In a meta-analysis of 11 major ARB trials published in 2005, it now the drug of choice to improve renal outcome.
was shown that ARB reduced MI compared to ACEI.
In the JIKEI study of Japanese hypertensive patients with CAD, ARB AND DIABETES
valsartan reduced CV morbidity and mortality by 39% (p = 0.0002),
stroke/TIA by 40% (p = 0.02), HF hospitalization by 47% (p = 0.02) Among all antihypertensives, ARBs are the best to reduce new-onset
and hospitalization for angina by 65% (p = 0.0001). diabetes.
ARB AND STROKE ARB AND AF

In LIFE, MOSES, ACCESS and SCOPE trials, ARBs reduced the first ARBs may reduce new onset AF in hypertensive patients with LVH,
and recurrent events of stroke compared to other antihypertensives. but more trial are required on this field.
BIBLIOGRAPHY
1. Discovery and development of angiotensin receptor blockers [online] Available from http://www.wikipedia.org/ [Accessed July 2012].
2. Lionel H Opie , Bernard J Gersh. Drugs for the Heart. 6th edition. Philadelphia: WB Saunders; 2006.
3. Nickenig G, Ostergren J, Struijker-Boudier H. Clinical evidence for the cardiovascular benefits of angiotensin receptor blockers. J Renin Angioten-
sin Aldosterone Syst. 2006;7:S1-7.
56 Echocardiography: A History
and Perspective
Hage FG, Nanda NC
The history of echocardiography is a series of success stories in the in a noninvasive, versatile and portable modality that is relatively
advancement of the technology to image the heart. This started with inexpensive and is safe to the patient and physician. This is partly
A-mode still images derived by a thin ultrasound beam and advanced why echocardiography has been the mainstay in cardiac imaging
to M-mode (moving) displays (Figs 56.1 and 56.2). Eventually, the over the last half a century and promises to keep its throne, at least
technology advanced to allow for two-dimensional (2D) examination in the near future, due to the continued revolutions in this field that
of the heart in motion (Fig. 56. 3). This was followed by the addition will keep it relevant to the practicing physician in the 21st century.
of conventional Doppler and color Doppler, the recent introduction
of tissue Doppler and speckle tracking imaging, contrast echocar- THE HISTORY OF ULTRASOUND
diography, transesophageal echocardiography, three-dimensional
(3D) transthoracic and transesophageal echocardiographic recon- Ultrasound is a natural phenomenon that is abundant in nature.
struction and ultimately the development of real-time 3D echocar- It was first recognized that bats, although blind, use ultrasound to
diography (Figs 56.4 to 56.7).1-3 Today, echocardiography is the detect their prey as early as the 18th century.4 Since ultrasound is
most frequently utilized imaging modality in cardiology and is at the defined as a frequency that is higher than the upper limit of human
center of our diagnostic and decision-making algorithms in many, hearing, dogs are capable of hearing ultrasound. It is also widely
if not most, cardiac pathologies. With current technology, echocar- appreciated that whales and dolphins use sonar to navigate and
diography can provide useful information regarding cardiovascular hunt. Humans by definition cannot hear ultrasound, but there has
structure and morphology, cardiac function, and hemodynamics been great interest in developing technologies that can detect ul-
trasound for various applications. One of the earliest discoveries
Figure 56.1: One-dimensional echocardiography (M-mode). The

frontal projection of the heart demonstrates the concept that M-mode
is equivalent to extraction of a plug of tissue that corresponds to the
width of the beam passing through the heart. The removed plug is
shown to the right and contains a portion of the right ventricle (RV),
ventricular septum (VS), mitral valve (MV) and left ventricular posterior
wall (LVW). A schematic of structure motion along with the ECG is
included. Abbreviation: ECG; Electrocardiogram. Source: Reproduced Figure 56.2: Dr Navin Nanda pointing to an M-mode echo tracing
with permission from Nanda NC, Gramiak R. Clinical Echocardiography. on the monitor of one of the earliest echo systems manufactured for
St. Louis: The C.V. Mosby Company; 1978. p. 370 clinical use (early 1970s)
414 Section 2  Noninvasive Cardiology
that later allowed for harnessing the power of ultrasound was the
scientific description of piezoelectricity by the French physicists
Paul-Jacques Curie and his brother Pierre Curie. Later, Pierre and
his wife Marie shared the 1903 Nobel Prize in physics with Antoine
Henri Becquerel for the discovery of radioactivity.4 The major stimu-
lus for the development of ultrasound for human use came with the
sinking of the Titanic on April 15, 1912 on its maiden voyage when it
struck an unseen iceberg. In tandem, there was interest in develop-
ing a technology to avert the threat of the German U-boats in sinking
allied ships. By 1918, Paul Langevin, a French physicist, succeeded
in developing a sonar system that was capable of producing ultra-
sound and analyzing returned acoustic echoes.1,4 This led to multiple
discoveries that allowed for the use of sonar technology in naval
warfare during World War II. After the war, scientists worldwide
worked on developing the technology for peaceful purposes.
Figure 56.4
DEVELOPMENT OF CLINICAL CARDIAC
ULTRASOUND: A-MODE AND M-MODE
ECHOCARDIOGRAPHY
The credit for the development of clinical cardiac ultrasound goes
mostly to Inge Edler and Hellmuth Hertz.5 Dr Edler, a cardiologist at
the University Hospital in Lund, Sweden was interested in develop-
ing a diagnostic method for evaluating patients with mitral stenosis
prior to undergoing surgery and identifying patients who have signif-
Figure 56.5
Figure 56.3: Two-dimensional scanning concept (two-dimensional

echocardiography). Real-time, two-dimensional images are equivalent
to slices of the heart that are removed and observed in motion. This
illustration shows the cardiac cavities and valves viewed in the long axis
of the left ventricle and the relationship of this plane to a frontal view of
the heart. Source: Reproduced with permission from Nanda NC, Gramiak
R. Clinical Echocardiography. St. Louis: The C.V. Mosby Company; 1978.
p. 371 Figure 56.6
Chapter 56  Echocardiography: A History and Perspective 415
from the anterior mitral leaflet rather than the posterior wall of the
left atrium. Edler then showed his findings in a movie at the Euro-
pean Congress of Cardiology in Rome in 1960 and published several
manuscripts pertaining to ultrasound cardiography.5,6,8-12 Edler also
described the use of the movement of the anterior mitral valve leaflet
(E-F slope) for the diagnosis of mitral stenosis and for quantitating
its severity. Patients with mitral stenosis had a reduced speed of the
diastolic downstroke E-F slope of the anterior mitral leaflet.6
Dr Hertz developed inkjet technology in order to record the car-
diograms that they obtained, and he was successful in commercially
promoting the use of this new technology for multiple applications.
In the United States, John Reid, at the University of Pennsylvania,
built an ultrasonic reflectoscope and through a collaboration with
Dr Claude Joyner repeated the work of Edler on mitral stenosis and
published the first manuscript on the use of echocardiography in the
Figure 56.7 United States in 1963.13
During the same time Dr Harvey Feigenbaum was interested
Figures 56.4 to 56.7: Progress in echocardiography. The chronology in measuring left ventricular volumes and pressures for the assess-
of the books and video textbooks produced by Dr Navin C Nanda
ment of compliance. He attended the American Heart Association
illustrate the progressive development of echocardiography from
M-mode to two-dimensional, conventional and color Doppler, contrast meeting in 1963 in order to examine a machine that was advertised
and two-and three-dimensional transthoracic and transesophageal to measure cardiac volumes using ultrasound. When he examined
echocardiography the machine at the meeting, it was apparent that it could not deliver
that promise, and he was frustrated. Rather than turning away, he ex-
amined the instrument on his own heart, and the company salesman
icant mitral regurgitation which would preclude them from having explained how the ultrasound signal is produced. Dr Feigenbaum
surgery.6 For this purpose he collaborated with Dr Hertz, a physicist was intrigued and asked what will happen if there is fluid around the
who graduated from the same University and was studying ultra- heart and the salesman answered that fluid should be echo-free.2 He
sound and its applications. Dr Hertz was famous for coming from a thus realized that this technology can be useful for the diagnosis of
well-established scientific family since his father, Gustav Hertz, had pericardial effusion.
won the Nobel Prize in physics in 1925 for his work on the laws gov- After returning to Indiana, he borrowed an ultrasound machine
erning the impact of an electron upon an atom and his uncle Hein- from a colleague in neurology, who was using it to detect deviations
rich Hertz, in whose honor wave frequencies were named in 1930. in the brain caused by intracranial masses, and examined a patient
In the 1950s Edler and Hertz used a pulse-echo sonar machine with pericardial effusion and documented the presence of the echo-
from a shipyard in order to start their experiments.2 Due to the posi- free space. These observations were then confirmed in the animal
tive results of their experiment, the manager of the shipyard com- laboratory and published in 1965.14
pany agreed to lend them the machine over a weekend to continue Despite this, there was general skepticism with regard to the
their research.6 Siemens was impressed by their work and lent them clinical utility of echocardiography. Feigenbaum collaborated with
a reflectoscope for a year in order to perform their work partly due Dodge at the University of Alabama in 1968 to develop M-mode
to Hertz’s family connections at the company.1,7 They realized that echocardiography for the measurement of left ventricular dimen-
by using ultrasound, they can identify the interface between the wall sions. However, they were unable to publish their work until years
of the heart and its fluid-filled cavity. After studying heart speci- later after their findings were reproduced by other investigators.15-17
mens, they proceeded to human studies and it is notable that Hertz’s In the late 1970s, only three cardiac valves, mitral, aortic and tricus-
first human volunteer was himself.2 They documented a signal that pid, could be identified by echocardiography. It was believed that the
moved with cardiac movement which they originally attributed to pulmonary valve was inaccessible since it was situated beneath the
the movement of the left atrial wall. Edler then proceeded to per- lung tissue. Dr Navin C Nanda, who joined the University of Roch-
form “ultrasound cardiography” on patients at their dying bed and ester in upstate New York in early 1971 as a cardiology fellow, was
carefully documenting the site and angle of the ultrasound beam. not convinced that this was true and during discussions with a pa-
After the patient’s demise, he placed an icepick in the direction of thologist at an autopsy of a cardiac patient, it became clear that the
the M-mode beam and dissected the heart to identify the structures pulmonary valve was not covered by lung in a majority of patients.
that the ultrasound beam traversed. Through this elegant approach, Subsequently, he together with Dr Gramiak were successful in imag-
he was able to document that the moving signal was actually arising ing and identifying the pulmonary valve by M-mode echocardiogra-
phy (Fig. 56.8).18 This discovery essentially resulted in the birth and
development of pediatric echocardiography since all four cardiac
valves could now be imaged successfully. This made it possible to
diagnose many congenital cardiac disease entities such as dextro-
transposition of the great vessels.19,20 Dr Nanda remembers often
being called in the middle of the night to perform echocardiograms
on cyanotic newborns to diagnose or rule out dextro-transposition
of the great vessels. Early diagnosis was life saving in these newborns
since it resulted in enlarging the patent foramen ovale (PFO) or per-
forming atrial septostomy in the cardiac catheterization laboratory to
promote improved mixing of pulmonary and systemic circulations.
M-mode echo was also used for the first time to assess pulmonary
hypertension21 and diagnose a congenital bicuspid aortic valve22 and
evaluate intra-atrial baffle dysfunction in transposition of the great
vessels (Figs 56.9 and 56.10).23
Figure 56.8: Echocardiographic detection and validation of the
pulmonary valve. Indocyanine green was injected into the pulmonary In its early development, M-mode echo was most commonly
artery during cardiac catheterization. The left pulmonary cusp is used in a clinical setting to detect pericardial effusion and to diag-
identified by the dense contrast material filling it. The dense linear bands nose mitral stenosis and assess its severity. This was done by measur-
extending anteriorly during early diastole probably originate in another ing the early diastolic slope of the mitral valve M-mode tracing, and
contrast-filled pulmonary cusp which lies above the plane of study it was shown that the slower the diastolic slope, the more severe was
during most of the cardiac cycle. The scattered echoes in front of the
the stenosis with good correlations with cardiac catheterization find-
left pulmonary cusp are probably in the right ventricular outflow tract
as the result of catheter-induced valvular regurgitation. Abbreviations: ings. However, when Dr Nanda relooked at this in a large number
Inj, Injection signal; PCG, Phonocardiogram; ECG, Electrocardiogram; of patients with M-mode echo and using actual left atrial pressures
PV, Pulmonary valve; AV, Aortic valve; LA, Left atrium; RA, Right atrium. measured by the trans-septal approach in the cardiac catheterization
Source: Reproduced with permission from Gramiak R, Nanda NC, Shah laboratory, no significant correlation was found. He attempted to
PM. Echocardiographic detection of the pulmonary valve. Radiology.
publish these findings, but was unsuccessful because it was believed
1972;102:153-7
Figure 56.9: Pulmonary hypertension and right heart failure. The pulmonary valve echo is from a patient with severe pulmonary hypertension
complicated by severe right heart failure. A large 'a’ dip is observed. The valve opens rapidly and the amplitude of the opening movement is large.
The representation of the right ventricular and pulmonary artery pressure tracings was obtained at cardiac catheterization in this patient. The high
right ventricular end-diastolic pressure (38 mm Hg) results in a low gradient (4 mm Hg) across the pulmonary valve in diastole (shaded). The scale
represents pressures in mm Hg. Abbreviations: PV, Pulmonary valve echo tracing; ECG, Electrocardiogram; PA, Pulmonary artery pressure tracing;
RV, Right ventricular pressure tracing. Source: Reproduced with permission from Nanda NC, Gramiak R, Robinson TI, Shah PM. Echocardiographic
evaluation of pulmonary hypertension. Circulation. 1974;50:575-81
were sound, the application was hampered by the slow processing

power of the computers available at that time. The linear scanner
developed by Bom in Rotterdam was the first real-time 2D scanner
that was widely available.28 Current 2D systems are based on the
work of Griffith and Henry who developed a mechanical hand-held
device capable of 2D scanning at the National Institute of Health.29 The
development of real-time 2D echocardiography resulted in an explo-
sive growth in the utility of echocardiography, and it was not long
before practically every large hospital with cardiology service owned
at least one 2D echo system. Among the several clinical applications,
some of the first ones from our group included echocardiographic
assessment of intracardiac pacing catheters,30 pacemaker perfora-
tion,31,32 pacing induced thrombosis and echocardiographic studies
done during sustained ventricular tachycardia (Fig. 56.11).33,34 The
first paper elucidating differentiation of left ventricular pseudoaneu-
rysms from true aneurysms by 2D echocardiography was published
in 1980.35 Other studies included 2D echo features of atrial septal
aneurysms,36 2D echo diagnosis of right ventricular infarction,37
myocardial texture recognition by 2D echo and correlation of 2D
Figure 56.10: Comparison of normal and bicuspid aortic valve. The
echo pattern with histopathology of intracardiac masses (Fig.
aortic root echocardiogram in the upper panel is obtained from a patient
with a tricuspid aortic valve. The valve echoes are observed in diastole in 56.12).38,39 The first study demonstrating the currently popular tech-
the middle of the aortic lumen and the leaflet images appear symmetric. nique of post-treadmill exercise echocardiography in the assessment
The lower panel demonstrates an aortic root echogram obtained from a of coronary artery disease was published from our group in 1981.40
patient with a bicuspid aortic valve. Marked eccentricity of the diastolic It took almost 8 years before another study was published from our
cusp signals with respect to the aortic lumen is present. The anterior Echo Laboratory showing its temporal reproducibility.41 The first
cusp image is large and practically occupies the whole aortic lumen
while the posterior leaflet is miniscule. Abbreviations: AO, Aortic root; study demonstrating to the usefulness of the cold pressor test dur-
RESP, Respirations; PHONO, Phonocardiogram; ECG, Electrocardiogram. ing real-time 2D echocardiography in the assessment of coronary
Source: Reproduced with permission from Nanda NC, Gramiak R, artery disease came out in 1984.42 The same year saw the publication
Manning J, et al. Echocardiographic recognition of the congenital of a study demonstrating comprehensive evaluation of aortic aneu-
bicuspid aortic valve. Circulation. 1974;49;870-5 rysm and dissection by 2D echo/conventional Doppler (Figs 56.13
and 56.14).43 Other studies showing the clinical utility of 2D echo
that this could “destroy” the emerging technique of echocardiogra- in the diagnosis of arrhythmogenic right ventricular dysplasia,44 pul-
phy. He was, however, able to publish it as an abstract.24 Subsequent monary artery branch stenosis45 and pulmonary artery aneurysms46
studies by other investigators supported his findings, and the mitral were also published in the early 1980s.
diastolic slope was no longer used to assess the severity of mitral
stenosis. Two comprehensive books on M-mode echocardiography, CONVENTIONAL DOPPLER ULTRASOUND
one written by Harvey Feigenbaum and the other by Navin Nanda
and Raymond Gramiak also helped publicize echocardiography and The Doppler effect is named after the Austrian physicist Christian
bring into focus the clinical utility of this noninvasive technique.25,26 Doppler who proposed in 1842 that the frequency of a wave to an
observer is higher than the emitted frequency if the source is mov-
TWO-DIMENSIONAL ECHOCARDIOGRAPHY ing toward the observer and lower than the emitted frequency if the
source is receding from the observer.47 Satomura, in Japan, was the
Although M-Mode constituted the real birth of clinical echocardiog- first to utilize Doppler to examine the movement of cardiac struc-
raphy, there was general skepticism about the future of echocardiog- tures in 1956.48 In the United States, Rushner in Seattle worked
raphy because the interpretation of the images was nonintuitive. The on cardiac Doppler in the 1960s and introduced the technique to
development of 2D echocardiography constituted a revolution in the Baker,49 who went on to develop the first pulsed Doppler recording
field unequalled except with the later introduction of 3D echocar- device.50 Holen and Hatle then showed how Doppler can be used to
diography. The group at the University of Rochester, led by Dr Gra- derive hemodynamic data using the Bernoulli equation.51-53 These
miak, envisioned the reconstruction of the information embedded measurements proved quite useful for the assessment of mitral and
in the M-mode to develop 2D and ultimately 3D images of the heart aortic stenosis and popularized the use of Doppler with echocardi-
in the early 1970s.27 Although the principles and the techniques used ography. Many other applications of conventional Doppler followed
Figure 56.11: Pacing catheter perforation. The subcostal four-chamber view shows the temporary pacing catheter (P) passing through the right
ventricular (RV) apex (arrow), with the tip located just beyond the epicardial surface. The echo-free space inferior to the cardiac apex represents a
portion of the patient's stomach (S). When the patient swallowed water, contrast echoes appeared in this space, confirming its relationship to the
gastrointestinal tract. The prominent echo in the right ventricle originates from a Swan-Ganz catheter (SG). Abbreviations: A, Anterior; AW, Anterior
wall; I, Inferior; L, Liver; LA, Left atrium; LV, Left ventricle; MV, Mitral valve; P, Posterior; RA, Right atrium; RB, Reverberation; S, Superior; TV, Tricuspid
valve; VS, Ventricular septum. Source: Reproduced with permission from Gondi B, Nanda NC. Real-time, two-dimensional echocardiographic features
of pacemaker perforation. Circulation. 1981;64:97-106
Figure 56.12: Right ventricular aneurysm due to right ventricular infarction. The right heart apical two-chamber view shows a large aneurysm
(AN) that involves the apical region. Abbreviation: DW, Diaphragmatic wall; L, Liver; RA, Right atrium; I, Inferior; R, Right; P, Posterior; S, Superior;
A, Anterior; L, Left. Source: Reproduced with permission from D’Arcy B, Nanda NC. Two-dimensional echocardiographic features of right ventricular
infarction. Circulation. 1982;65:167-73
including its usefulness in the assessment of coronary arteries and ened the friendship and mutual understanding between USA and
fetal hemodynamics (Fig. 56.15).54-56 The first book on Doppler China”! Our group was the first to use 2D echo/Doppler in cardiac
Echocardiography was published in 1982 by Hatle and Anderson57 pacing to maximize cardiac output, minimize mitral regurgitation
followed by a book from our group.58 Dr Nanda remembers be- and assess atrial capture (Fig. 56.16).59 The incremental value of
ing invited to go to China in early 1982 and introducing the pulsed sequential atrioventricular pacing over regular right ventricular pac-
Doppler technique to that country at a time when it was just opening using a prototype continuous wave Doppler system developed by
ing up to foreigners. He was given a letter to this effect from the Peo- Dr Henry Light of England was also shown by us.60 An increase in
ple’s Liberation Army Hospital in Beijing and the Practical Acoustic stroke volume of up to 25% with sequential atrioventricular pacing
Association of China which also stated his lectures had “strength- was demonstrated (Fig. 56. 17).
COLOR DOPPLER ULTRASOUND

Color Doppler flow imaging was developed in the 1980s which
allowed for the visualization of blood flow noninvasively.61 The
first commercially available color Doppler echo machines were
developed in Japan where Omoto and his group did some of the
early work.62 It was first introduced in the USA as a clinical tool by
Navin Nanda at the University of Alabama at Birmingham in 1984
(Fig. 56.18). His group also pioneered the color Doppler assess-
ment and semi-quantitation of mitral, aortic and tricuspid valvular
regurgitation in a reliable and reproducible manner (Figs 56.19 and
56.20).63-65 Some of the initial work also showed the usefulness of
color Doppler as an adjunct to 2D echo in the assessment of aortic dis-
section, aortic valve stenosis, prosthetic heart valves and fetal hemo-
dynamics (Figs 56.21A to C).66-69 It was used during supine bicycle
Figure 56.13: Two-dimensional echocardiographic evaluation of the exercise to identify development or worsening of mitral regurgitation
aorta. The aorta reconstructed from the root level to the abdominal as a marker for left main or three-vessel coronary artery disease.70
region by assembling Polaroid® images of contiguous segments obtained Color Doppler also began to find application in the evaluation of
from multiple transducer positions. Abbreviations: AA, Ascending aorta; vessels outside the heart.71 Within only a few years of its introduction,
ABA, Abdominal aorta; CC, Common carotid; IN, Innominate artery; PA, color Doppler became an integral part of a clinical echocardiograph-
Pulmonary artery; SC, Subclavian; TA, Transverse aorta; TDA, Thoracic
ic examination. Its popularity was further helped by the publication
descending aorta. Source: Reproduced with permission from Mathew T,
Nanda NC. Two-dimensional and Doppler echocardiographic evaluation of books on the subject in the 1980s.72-74
of aortic aneurysm and dissection. Am J Cardiol. 1984;54:379-85
A B
Figures 56.14A and B: Two-dimensional echocardiographic evaluation of aortic aneurysm and dissection. (A). Ascending aortic aneurysm. This
composite illustration was made by the reconstruction method to show the full extent of the aneurysm. The transverse arch (T) and the descending
aorta (DA) are not involved; (B). Aortic dissection (DeBakey type 1). This composite illustration was also made by the reconstruction method. The
dissection flap (arrows) can be seen in the ascending aorta (AA), transverse arch (TA), thoracic descending aorta (TDA) and in the abdominal segment
(ABA). Abbreviations: AV, Aortic valve; PA; Pulmonary artery. Source: Reproduced with permission from Mathew T, Nanda NC. Two-dimensional and
Doppler echocardiographic evaluation of aortic aneurysm and dissection. Am J Cardiology. 1984;54:379-85
Figure 56.17: Doppler echocardiographic studies in sequential AV

pacing. In this patient with sequential AV pacing, the Doppler transducer
Figure 56.15: Typical Doppler power spectra from the umbilical was placed in the suprasternal notch and angled inferiorly and to the
arteries in a normal pregnancy are shown on the left. Doppler power left, to record blood flow in the proximal descending aorta. The Doppler
spectra from a pregnancy with premature rupture of membranes and blood flow patterns (DS) are denoted by triangular waveforms and the
oligohydramnios is depicted on the right. Source: Reproduced with height of the triangle represents peak aortic blood flow velocity. When
permission from Maulik D, Saini VD, Nanda NC, et al. Doppler evaluation the patient was switched from DVI to VVI mode, a significant decrease
of fetal hemodynamics. Ultrasound Med Biol. 1982;8:705 occurred in the height and size of the triangles, indicative of significant
reduction in the stroke volume and cardiac output (heart rate was kept
constant in both pacing modes). The vertical distance between the
arrows represents 1 m/sec and this scale is common for both VVI and DVI
tracings. Source: Reproduced with permission from Nanda NC, Bhandari
A, Barold SS, et al. Doppler echocardiographic studies in sequential
atrioventricular pacing. Pacing Clin Electrophysiol. 1983;6:811-4
Figure 56.16: Usefulness of Doppler echocardiography in cardiac

pacing. Peak aortic flow velocity at different atrioventricular (AV)
intervals. + = mitral regurgitation present; ++ = increased mitral
Figure 56.18: Aloka 880 color Doppler system
regurgitation; - = mitral regurgitation not evaluated by Doppler. The
Source: Aloka, Tokyo, Japan.
number in parenthesis indicates the maximum percentage change in
peak aortic flow velocity obtained in a given patient as compared to the
VVI value or value at the shortest AV interval (in patients in whom VVI
values were not available). Note that the maximum percentage change
CONTRAST ECHOCARDIOGRAPHY
occurred with pacing at AV intervals between 150 ms and 200 ms. The The history of contrast echocardiography dates back to the early
initials of each patient are given at the right of each Doppler flow velocity days of echocardiography when Claude Joyner noticed the con-
curve. Source: Reproduced with permission from Zugibe FT, Nanda NC,
trast effect using ultrasound following intravenous fluid injection,
Barold SS, et al. Usefulness of Doppler echocardiography in cardiac
pacing. Assessment of mitral regurgitation, peak aortic flow velocity and but these observations were not published. Dr Gramiak, a radiolo-
atrial capture. Pacing Clin Electrophysiol. 1983;6(6):1350-7 gist at the University of Rochester, Rochester, New York, borrowed
a new ultrasound machine from the cardiology department to try the aorta, examined in the parasternal long axis view, as the supe-
it out. He tested the machine on a patient with aortic regurgitation rior vena cava in most instances and only occasionally as the main or
who was undergoing angiography. During the injection of indocya- right pulmonary artery (Fig. 56.22).80 In the 1980s, commercial con-
nine green, he noted the defect in the contrast material caused by trast agents with miniaturized stable microbubbles were developed.
the backflow of blood into the ventricle, and Dr Pravin Shah and he Gelatin-encapsulated nitrogen bubbles were shown to be stable for
developed the technique of contrast echocardiography for the use with ultrasound enhancement,81 and microbubbles sonicated
study of the aortic valve and the aortic root.75 Later work done with from human serum albumin were shown to traverse the pulmonary
Dr Nanda also used contrast injections in the cardiac catheteriza- circulation and opacify the left ventricle.82 Some of the early work
tion laboratory to confirm the detection of pulmonary valve by was pioneered by Dr Steve Feinstein and Sanjiv Kaul. These observa-
echocardiography.18 tions led to the introduction of multiple contrast agents to the market
In the 1970s, saline contrast was used for the delineation of with variable properties. The first agent approved by the Food and
intracardiac shunts, for the identification of right-sided valves Drug Administration (FDA) in the United States in 1994 utilized air
and for better assessment of congenital heart disease.18,76-78 It was as the gas component of the microbubbles, as did other agents at that
also used to identify and assess the severity of right-sided valvular time, which reduced the longevity of the bubbles.78 This is because
regurgitation.79 As recently as 2007, saline contrast was used by us air can leak out of the thin bubble shell and dissolve in the blood.
for the first time to identify and validate the echo free space behind In the 1990s, perfluorocarbon gases were utilized instead of air to
increase the time these bubbles can persist in the circulation. These
newer agents consisted of smaller and more stable microbubbles
that proved to be helpful for the assessment of perfusion as well as
enhancement and opacification and direct detection of coronary
stenosis.78,83,84 The first book to highlight advances in echo imaging
using contrast enhancement was published in 1993.85
Figure 56.19B: Flow acceleration. A simple example of the generation

of flow acceleration can be shown by observing the draining of water
from a household bath tub. Flow acceleration or a localized area of high
velocity develops as the large body of water moves toward the “hole”
or opening in the bottom of the tub through which water flows into
the drain. Adjacent to the “hole,” the area of flow acceleration becomes
Figure 56.19A: Color Doppler assessment of mitral regurgitation. (A) smaller and tends to take the shape and size of the circular “hole”. This
Maximum RJA/LAA% obtained from analysis of all three two-dimensional finding has clinical significance. For example, in a patient with mitral
echocardiographic planes compared with angiography (all 82 patients). regurgitation, inspection of the size and shape of the flow acceleration
Abbreviations: AF, Atrial fibrillation; LAA, Left atrial area; NSR, Normal present adjacent to the mitral valve (MV) may provide a good estimate
sinus rhythm; RJA, Regurgitant jet area. Source: Reproduced with of the size of the anatomical defect in the MV through which the
permission from American Heart Association, Helmcke F, Nanda NC, regurgitation is occurring. Source: Reproduced with permission from
Hsiung MC, et al. Color Doppler assessment of mitral regurgitation with Nanda NC. Atlas of Color Doppler Echocardiography. Philadelphia: Lea
orthogonal planes. Circulation. 1987;75:175-83 and Febiger; 1989. p. 7
Figure 56.20: Chopra HK, Nanda NC, Fan P, et al. Can two-dimensional echocardiography and Doppler color flow mapping identify the need
for tricuspid valve repair? J Am Coll Cardiol. 1989;14:1266-1274. Demonstrated the usefulness of tricuspid valve annulus measurement and color
Doppler flow mapping for the assessment of tricuspid regurgitation
A B
Figures 56.21A to C: Visualization of aortic stenosis (AS) jet. The

right parasternal view shows a narrow band of mosaic signals (AS JET)
originating from the thickened aortic valve during systole. The mosaic
signals indicate the presence of turbulence. The jet is very narrow at
its origin (jet width = 6 mm), implying severe aortic stenosis, but later
broadens out to completely fill the ascending aorta (AA). Abbreviations:
AV, Aortic valve; PA, Pulmonary artery; IVC, Inferior vena cava. Source:
Reproduced with permission from Fan P, Kapur KK, Nanda NC. Color-
guided Doppler echocardiographic assessment of aortic valve stenosis. J
C Am Coll Cardiol. 1988;12:441-9
structures and vessels for abnormalities with the probe positioned in

the stomach (transgastric ultrasonography).92,93 Towards the end of
the examination with the probe positioned in the upper esophagus,
one could evaluate the aortic arch branches and the adjacent veins
in detail94-99 and also with the probe withdrawn into the pharynx, the
carotid bulb on both sides, left and right internal carotid arteries and
extracranial segments of the vertebral arteries can be evaluated for
stenosis and other abnormalities (transpharyngeal ultrasound) (Figs
56.23A and B).100-102 A distinct advantage of the transpharyngeal ap-
proach is the parallel orientation of the Doppler beam to the flow in
the carotids which is practically impossible to obtain with the usual
external approach from the neck.
TISSUE DOPPLER AND SPECKLE

TRACKING IMAGING
Figure 56.22: Validation of the structure behind the aorta as superior Since the velocity of blood is much faster than that of the cardiac
vena cava by saline contrast echocardiography. Two-dimensional tissue, usual Doppler imaging filters out slow moving objects such
transthoracic echocardiographic bubble study. Intravenous injection
of agitated normal saline shows contrast echoes first appearing in the as cardiac tissue in order to enhance the images. With tissue imag-
bounded echo free space (arrowhead) and then in the right ventricle (RV, ing, the reverse is done, whereby the fast velocities of the red blood
arrow). This suggests that the echo free space represents the superior cells are filtered out and the velocity of the tissue is captured. This
vena cava and not the main or right pulmonary artery. Abbreviations: principle was exploited early on in the history of echocardiography
AO, Aorta; LV, Left atrium; RV, Right ventricle. Source: Reproduced in order to image the velocity of the posterior wall as early as 1972.103
with permission from Burri MV, Mahan III EF, Nanda NC, et al. Superior
Development in tissue Doppler imaging in the 1990s allowed for im-
vena cava, right pulmonary artery or both: Real time two-and three-
dimensional transthoracic contrast echocardiographic identification of aging the velocity of myocardial motion and for the analysis of myo-
the echo free space posterior to the ascending aorta. Echocardiography. cardial segments independently of each other.104,105 These improve-
2007;24:875-82 ments facilitated the use of tissue Doppler imaging in the assessment
of left ventricular diastolic function and in the measurement of strain
and strain-rate of the individual myocardial segments. Because of
the limitations posed by the angle dependence of the Doppler beam,
TRANSESOPHAGEAL ECHOCARDIOGRAPHY techniques based on real-time 2D echocardiography, such as veloc-
ity vector imaging106 and speckle tracking imaging,107 were intro-
Transesophageal echocardiography was envisioned as early as 1971 duced a few years ago (Fig. 56.24).
by Side and Gosling for its use with Doppler,86 but it was first devel-
oped with M-mode by Frazin et al. in a classical paper in Circula- THREE-DIMENSIONAL ECHOCARDIOGRAPHY
tion in 1976.87 The use of this new technique was hampered because
of its reliance on large rigid scopes. Hanrath was the first to attach Since 2D echocardiography is not ideal for imaging 3D cardiac struc-
a phased array transducer to the tip of a flexible scope which ush- tures, several attempts were made over the years to develop 3D echo-
ered in the era of clinical transesophageal echocardiography.88 The cardiography.108-114 Morris and Shreve115 introduced the spark gap
technique found popularity because of the superior quality images position-locating approach (an acoustic spacial locating system) to
obtained by the higher frequency probe used and the proximity of provide 3D coordinates, but this method was not capable of record-
the esophagus to cardiac structures. Initially, a monoplane probe ing or viewing 3D images. The Nanda group113 used an approach that
was used but subsequently biplane and multiplane probes were was able to image the left ventricle in 3D by placing a 2D transducer
developed, and papers and books were published delineating the on a mechanical arm that allowed it to rotate around its axis. The
technique for systematic examination of cardiac structures.89-91 transducer was rotated every few degrees in a sequential manner and
It soon found wide application in the intraoperative setting, in the multiple slices of the heart, at end systole and end diastole were ob-
cardiac catheterization laboratory during percutaneous procedures tained (Figs 56.25A and B). These were then reconstructed by a com-
and in the echo laboratory as a valuable adjunct to 2D transthoracic puter to obtain 3D images of the left ventricle. The volumes obtained,
echocardiography. It was found that during a transesophageal exam- using this method, were validated by angiography. This work was fur-
ination, important supplementary information could be provided by ther extended by the same group to successfully incorporate Doppler
examining coronary arteries for stenosis, and imaging the abdominal information and color Doppler reconstruction.116,117
A B
Figures 56.23A and B: Transpharyngeal ultrasound diagnosis of left carotid bulb and internal carotid artery stenosis. (A) Color Doppler
examination demonstrating the ascending pharyngeal (AP) and other branches (arrows) of the left external carotid artery (LEC). The left internal
jugular vein (LIJV) is seen adjacent to the left common carotid artery (LCC); (B) Color Doppler-guided pulsed and continuous-wave Doppler
examination of the proximal LIC shows a peak systolic velocity of 1.8 m/s and a peak diastolic velocity approaching 1.0 m/s, indicative of significant
stenosis. Note that the Doppler beam is aligned parallel to the flow direction in the proximal LIC. Source: Nanda NC, Gomez CR, Narayan VK, et al.
Transpharyngeal echocardiographic diagnosis of carotid bulb and left internal carotid artery stenosis. Echocardiography. 1999;16:671-4
to provide 3D images.118,119 This technique, developed by the TomTec

Company (Munich, Germany), was limited due to the large size of
the probe which precluded routine clinical use. The next step was
to use a biplane transesophageal echocardiography probe for 3D
imaging. In order to determine the probe rotation angle, a protractor
mounted on the probe shaft guard was used. The probe was angu-
lated at 90° and manually rotated in a clockwise direction in small
increments to provide sequential longitudinal images which were
then reconstructed in 3D using both B-mode and color Doppler (Fig.
56.26).120,121 Nanda et al.122 then used a multiplane transesophageal
echocardiography transducer to reconstruct 3D images by ensur-
Figure 56.24: Velocity vector imaging before and after cardiac ing that the probe remained stationary at a given level and rotating
resynchronization therapy. Velocity vector data obtained from the it at 18˚ intervals at a time (Figs 56.27 and 56.28). Since with this
left ventricular short axis view. The radial velocities in the lateral technology the 3D dataset could be sliced in any direction similar to
wall peak in late systole/early diastole prior to biventricular pacing. dissecting a piece of tissue, it allowed for the visualization of cardiac
After biventricular pacing, the septal and lateral wall radial velocities
structures from any direction and the understanding of the complex
are synchronous. Thus, cardiac resynchronization therapy (CRT) has
improved radial myocardial contraction synchrony. Source: Reproduced relationship between structures. Several clinical applications ensued
with permission from Vannan MA, Pedrizzetti G, Lip P. Gurudevan S, from this development (Figs 56.29A to C).123-127
Houle H, Main J, et al. Effect of cardiac resynchronization therapy on With 3D reconstruction imaging, imaging artifact was common
longitudinal and circumferential left ventricular mechanics by velocity due to the time needed for acquisition of images over several cardiac
vector imaging. Description and initial clinical application of a novel cycles with patient and/or probe motion during the procedure in
method using high-frame rate B-mode echocardiographic images.
addition to changes in heart rate. Live/real-time 3D imaging was
Echocardiography. 2005;22;823-60
thus developed and is currently the 3D echocardiography used in
clinical practice. Initial attempts at the development of 3D real-time
Later, 3D transesophageal echocardiography was developed echocardiography resulted in a stand alone system which was able
by mounting a monoplane probe on a sliding carriage within a to provide B-mode images only.128 A matrix probe was then devel-
casing. By moving the probe up and down the esophagus in small oped to provide live/real-time B-mode and color Doppler images,
increments transverse sections at various parallel cardiac levels were therefore, facilitating its use in day-to-day clinical practice.129 These
obtained and the images were then reconstructed using a computer datasets were obtained over 4–8 cardiac beats. Further development
A B
Figures 56.25A and B: (A) Three-dimensional reconstruction of transthoracic echocardiographic images by apical axis rotation method. The
transducer rotation and different planes intersecting the heart are shown here. The transducer was held manually; (B) Subsequently, the transducer
was mounted on a mechanical arm which permitted only 1 degree of freedom—rotation about its axis. Source: Reproduced with permission from
Ghosh A, Nanda NC, Maurer G. Three-dimensional reconstruction of echocardiographic images using the rotation method. Ultrasound Med Biol.
1982;8:655-61
resulted in real-time 3D imaging in which a dataset was obtained of

an entire volume of the heart using only one or more cardiac cycles
which could then be dissected along any direction.130 Another im-
portant innovation was the development of a single transducer to
perform both 2D and live/real-time 3D studies. Subsequently, the
transducer was incorporated in the transesophageal probe and live/
real-time 3D transesophageal echocardiography was born. The first
clinical study was published from the University of Alabama at Bir-
mingham in 2007 (Fig. 56.30).131,132
PERSPECTIVE
The use of echocardiography over the last decades has changed
the practice of cardiology. This modality has successfully evolved
with the changing tides of time to continue to be relevant to prac-
ticing physicians. It started as a research tool with M-mode whose
Figure 56.26: Three-dimensional reconstruction of transesophageal potential was limited to a handful of pathologies and a future that
echocardiographic longitudinal images. Three-dimensional image of looked unpromising. Due to the work of multiple investigators with
superior vena cava zone, showing three-dimensionally reconstructed the vision to enhance this field, 2D echocardiography was developed
longitudinal structures of superior vena cava (SVC), inferior vena cava which helped the clinicians in the evaluation of a wide array of dis-
(IVC), right atrium (RA), left atrium (LA) and right pulmonary artery
eases ranging from congenital and valvular heart disease to coronary
(RPA). Source: Reproduced with permission from Li ZA, Wang XF,
Nanda NC, et al. Three-dimensional reconstruction of transesophageal artery disease. Further developments, including the introduction
echocardiographic longitudinal images. Echocardiography. 1995;12:367- of conventional and color Doppler flow imaging, allowed for the
75 real-time visualization of blood flow and opened the era of nonin-
Figure 56.28: Three-dimensional reconstruction of the left ventricle

using sequential planes obtained from multiplane transesophageal
examination in an adult patient. It shows the “volume cast” of the left
ventricular cavity. Source: Reproduced with permission from Nanda NC,
Pinheiro L, Sanyal R, et al. Multiplane transesophageal echocardiographic
imaging and three-dimensional reconstruction a preliminary study.
Echocardiography. 1992;9:667-76
vasive hemodynamic cardiac assessment. With the introduction of

3D echocardiography, the dream of the early pioneers of visualizing
cardiac structures in a real life perspective using ultrasound was re-
alized. Echocardiography has become so useful to the clinician that
it can be rightfully considered as an extension of clinical cardiac
examination, more so because of the development of small palm
Figure 56.27: Three-dimensional reconstruction of multiplane sized handheld echocardiographic machines which can fit in the
transesophageal echocardiographic images. Sequential multiplanar pocket of a white coat like a stethoscope.133 We have not reached the
transesophageal two-dimensional images of the left ventricle were end of the road. There is still room for improvement in the resolution
obtained by rotating the probe in small angular increments. These of images as well as in the hardware and software used for the various
were then reconstructed to obtain a three-dimensional image of the applications. Education regarding the relevance of the newer ultra-
left ventricle. Abbreviations: LA, Left atrium; LV, Left ventricle; RA,
sound technologies to the cardiologist and echocardiographer is not
Right atrium; RV, Right ventricle. Source: Reproduced with permission
from Nanda NC, Pinheiro L, Sanyal R, et al. Multiplane transesophageal optimal. Nevertheless, there is still reason to believe that echocardi-
echocardiographic imaging and three-dimensional reconstruction a ography will continue to be the chief and most cost-effective cardiac
preliminary study. Echocardiography. 1992;9:667-76 imaging modality for decades to come.
A B
Figures 56.29A to C: Three-dimensional transesophageal echocardiography. (A) Transesophageal three-dimensional reconstruction of stenotic
aortic valve. The aortic valve (AV) shows multiple echo dense areas indicative of severe thickening and calcification. Although the AV is considerably
distorted, three leaflets are easily identified in systole. The aortic orifice is very small and measured 0.7 cm2 by planimetry; (B) Schematic diagram
demonstrating that the maximum dimension of an object (in this case, a cylinder) can be obtained only if the ultrasound beam cuts through its
longest dimension (true long axis) when using a multiplane probe. However, when the two-dimensional planes are stacked together to obtain a
three-dimensional image, the object (cylinder), including its long axis, can be viewed completely, even though it is not oriented parallel to the
ultrasonic beam as it is rotated from 0° to 180°. As demonstrated here, it is not possible to image the true long axis of an intracardiac mass lesion
or defect (such as an atrial septal defect) using multiplane two-dimensional transesophageal echocardiography unless it lies exactly parallel to the
ultrasound beam as it is rotated from 0° to 180°. Therefore, the maximum size of a mass or defect may be underestimated by multiplane two-
dimensional transesophageal echocardiography. On the other hand, with three-dimensional transesophageal reconstruction, multiple sequential
two-dimensional images are stacked to reconstruct the entire object in three-dimensions, permitting accurate assessment of all its dimensions; (C)
Transesophageal three-dimensional echocardiographic examination of coronary arteries. There is a tight stenosis (arrowheads) of the circumflex
coronary artery (LCX) imaged in long axis view in three-dimensions. The arrow points to an atrial branch. Abbreviations: AVA, Aortic valve area; AO,
Aorta; LA, Left atrium; RVO, Right ventricular outflow tract. Source: (A) Reproduced with permission from Nanda NC, Roychoudhury D, Chung SM,
et al. Quantitative assessment of normal and stenotic aortic valve using transesophageal three-dimensional echocardiography. Echocardiography.
1994;11:617-25. (B) Reproduced with permission from Nanda NC, Abd-El Rahman SM, Khatri G, et al. Incremental value of three-dimensional
echocardiography over transesophageal multiplane two-dimensional echocardiography in qualitative and quantitative assessment of cardiac masses
and defects. Echocardiography. 1995;12:619-28; (C) Reproduced with permission from Abd El-Rahman SM, Khatri G, Nanda N, et al. Transesophageal
three-dimensional echocardiographic assessment of normal and stenosed coronary arteries. Echocardiography. 1996;13:503-10
Figure 56.30: Live/real-time three-dimensional transesophageal echocardiography. Mitral valve ring viewed en face by cropping from the atrial
aspect. Arrow points to en face view of Duran ring. Source: Reproduced with permission from Pothineni KR, Inamdar V, Miller AP, et al. Initial
experience with live/real time three-dimensional transesophageal echocardiography. Echocardiography. 2007;24:1099-104
REFERENCES
1. Krishnamoorthy VK, Sengupta PP, Gentile F, et al. History of echocardiography and its future applications in medicine. Critical care medicine.
2007;35(8 Suppl):S309-13.
2. Feigenbaum H. Evolution of echocardiography. Circulation. 19961;93(7):1321-7.
3. Pandian NG, Roelandt J, Nanda NC, et al. Dynamic three-dimensional echocardiography: methods and clinical potential. Echocardiography.
1994;11(3):237-59.
4. Wade G. Human uses of ultrasound: ancient and modern. Ultrasonics. 2000;38(1-8):1-5.
5. Edler I, Hertz CH. The use of ultrasonic reflectoscope for the continuous recording of the movements of heart walls. 1954. Clin Physiol Funct Imag-
ing. 2004;24(3):118-36.
6. Edler I, Lindstrom K. The history of echocardiography. Ultrasound Med Biol. 2004;30(12):1565-644.
7. Gowda RM, Khan IA, Vasavada BC, et al. History of the evolution of echocardiography. Int J Cardiol. 2004;97(1):1-6.
8. Edler I, Gustafson A. Ultrasonic cardiogram in mitral stenosis; preliminary communication. Acta Med Scand. 1957;159(2):85-90.
9. Edler I. Ultrasoundcardiography in mitral valve stenosis. Am J Cardiol. 1967;19(1):18-31.
10. Edler I. Ultrasound cardiography. Ultrasonics. 1967;5:72-9.
11. Edler I. Atrioventricular valve motility in the living human heart recorded by ultrasound. Acta Med Scand Suppl. 1961;370:83-124.
12. Edler I. The use of ultrasound as a diagnostic aid, and its effects on biological tissues. Continuous recording of the movements of various heart-
structures using an ultrasound echo-method. Acta Med Scand Suppl. 1961;370:7-65.
13. Joyner CR Jr, Reid JM, Bond JP. Reflected ultrasound in the assessment of mitral valve disease. Circulation. 1963;27(4 Pt 1):503-11.
14. Feigenbaum H, Waldhausen JA, Hyde LP. Ultrasound diagnosis of pericardial effusion. JAMA. 1965;191:711-4.
15. Feigenbaum H, Popp RL, Wolfe SB, et al. Ultrasound measurements of the left ventricle. A correlative study with angiocardiography. Arch Intern
Med. 1972;129(3):461-7.
16. Pombo JF, Troy BL, Russell RO Jr. Left ventricular volumes and ejection fraction by echocardiography. Circulation. 1971;43(4):480-90.
17. Popp RL, Harrison DC. Ultrasonic cardiac echography for determining stroke volume and valvular regurgitation. Circulation. 1970;41(3):493-502.
18. Gramiak R, Nanda NC, Shah PM. Echocardiographic detection of the pulmonary valve. Radiology. 1972;102:153-7.
19. Gramiak R, Chung KJ, Nanda NC, Manning JA. Echocardiographic diagnosis of transposition of the great vessels. Radiology. 1973;106:187-90.
20. Nanda NC, Gramiak R, Manning JA, et al. Echocardiographic features of subpulmonic obstruction in dextro-transposition of the great vessels.
Circulation. 1975;51:515-21.
21. Nanda NC, Gramiak R, Robinson TI, et al. Echocardiographic evaluation of pulmonary hypertension. Circulation. 1974;50:575-81.
22. Nanda NC, Gramiak R, Manning JA, et al. Echocardiographic recognition of the congenital bicuspid aortic valve. Circulation. 1974;49:870-5.
23. Nanda NC, Steward S, Gramiak R, et al. Echocardiography of the intra-atrial baffle in dextro-transposition of the great vessels. Circulation.
1975;51:1130-5.
24. Nanda NC, Gramiak R, Shah PM. Echocardiographic misdiagnosis of the severity of mitral stenosis. Clinical Res. 1975;23:199A.
25. Feigenbaum H. Echocardiography, 1st edition. Philadelphia: Lea and Febiger; 1972.
26. Nanda NC, Gramiak R. Clinical Echocardiography. St. Louis: The C. V. Mosby Company; 1978.
27. Gramiak R, Waag RC, Simon W. Cine ultrasound cardiography. Radiology. 1973;107(1):175-80.
28. Bom N, Lancee CT, Honkoop J, et al. Ultrasonic viewer for cross-sectional analyses of moving cardiac structures. Biomed Eng. 1971;6(11):500-3, 5.
29. Griffith JM, Henry WL. A sector scanner for real time two-dimensional echocardiography. Circulation. 1974;49(6):1147-52.
30. Reeves WC, Nanda NC, Barold SS. Echocardiographic evaluation of intracardiac pacing catheters: M-mode and two-dimensional studies. Circula-
tion. 1978;58:1049-56.
31. Gondi B, Nanda NC. Real time two-dimensional echocardiographic features of pacemaker perforation. Circulation. 1981;64:97-106.
32. Harris JP, Nanda NC, Moxley R, et al. Myocardial perforation due to temporary transvenous pacing catheters in pediatric patients. Catheterization
and Cardiovascular Diagnosis. 1984;10:329-33.
33. Schuster AH, Zugibe F, Nanda NC, et al. Two-dimensional echocardiographic identification of pacing catheter induced thrombosis. Pacing Clin
Electrophysiol. 1982;5:124-8.
34. Rosenbloom M, Saksena S, Nanda NC, et al. Two-dimensional echocardiographic studies during sustained ventricular tachycardia. Pacing Clin
Electrophysiol. 1984;7:136-42.
35. Gatewood RP, Nanda NC. Differentiation of left ventricular pseudoaneurysms from true aneurysms by two-dimensional echocardiography. Am J
Cardiol. 1980;46:869-78.
36. Gondi B, Nanda NC. Two-dimensional echocardiographic features of atrial septal aneurysms. Circulation. 1981;63:452-7.
37. D’Arcy BJ, Nanda NC. Two-dimensional echo features of right ventricular infarction. Circulation. 1982;65:167-73.
38. Bhandari AK, Nanda NC. Two-dimensional echocardiographic recognition of abnormal changes in the myocardium. Ultrasound Med Biol.
1982;8:663-71.
39. Bhandari AK, Nanda NC, Hicks DG. Two-dimensional echocardiography of intracardiac masses: Echo pattern-histopathology correlation. Ultra-
sound Med Biol. 1982;8:673-80.
40. Maurer G, Nanda NC. Two dimensional echocardiographic examination of exercise induced left and right ventricular asynergy: correlation with
thallium scanning. Am J Cardiol. 1981;48:720-7.
41. Oberman A, Fan PH, Nanda NC, et al. Reproducibility of two-dimensional exercise echocardiography. J Am Coll Cardiol. 1989;14:923-8.
42. Gondi B, Nanda NC. Cold pressor test during real time two-dimensional echocardiography: usefulness in detection of patients with coronary
artery disease. Am Heart J. 1984;107:278-85.
43. Mathew T, Nanda NC. Two-dimensional and Doppler echocardiographic evaluation of aortic aneurysm and dissection. Am J Cardiol. 1984;54:379-
85.
44. Baran A, Nanda NC, Falkoff M, et al. Two-dimensional echocardiographic detection of arrhythmogenic right ventricular dysplasia. Am Heart J.
1982;103:1066-107.
45. Tinker DD, Nanda NC, Harris JP, et al. Two-dimensional echocardiographic identification of pulmonary artery branch stenosis. Am J Cardiol.
1982;50:814-20.
46. Bhandari AK, Nanda NC. Pulmonary artery aneurysms: echocardiographic features in 5 patients. Am J Cardiol. 1984;53:1438-41.
47. Reinold E. “On the colored light of double stars and certain other stars of heaven” and what happened hence. Ultraschall Med. 2004;25(2):101-4.
48. Satomura S. A study on examining the heart with ultrasonics. I. Principles; II. Instrument. Jpn Circ J. 1956;20:227-8.
49. Rushmer RF, Baker DW, Stegall HF. Transcutaneous Doppler flow detection as a nondestructive technique. J Appl Physiol. 1966;21(2):554-66.
50. Baker DW, Rubenstein SA, Lorch GS. Pulsed Doppler echocardiography: principles and applications. Am J Med. 1977;63(1):69-80.
51. Holen J, Simonsen S. Determination of pressure gradient in mitral stenosis with Doppler echocardiography. Br Heart J. 1979;41(5):529-35.
52. Hatle L, Angelsen BA, Tromsdal A. Non-invasive assessment of aortic stenosis by Doppler ultrasound. Br Heart J. 1980;43(3):284-92.
53. Hatle L, Brubakk A, Tromsdal A, et al. Noninvasive assessment of pressure drop in mitral stenosis by Doppler ultrasound. Br Heart J. 1978;40(2):131-
40.
54. Nanda NC, Hodsden J, Santelli S. Pulse Doppler echocardiography of coronary arteries: Methodology and clinical usefulness. Am J Cardiol.
1982;49:932.
55. Maulik D, Saini VD, Nanda NC, et al. Doppler evaluation of fetal hemodynamics. Ultrasound Med Biol. 1982;8(6):705-10.
56. Maulik D, Nanda NC, Saini VD. Fetal Doppler echocardiography: Methodology and characterization of normal and abnormal hemodynamics. Am
J Cardiol. 1984;53:572-8.
57. Hatle L, Angelsen B. Doppler Ultrasound in Cardiology - Physical Principles and Clinical Applications. Philadelphia: Lea and Febiger; 1982.
58. Nanda NC. Doppler Echocardiography. New York: Igaku-Shoin Medical Publishers, Inc.; 1985.
59. Zugibe FT, Nanda NC, Barold SS, et al. Usefulness of Doppler echocardiography in cardiac pacing: assessment of mitral regurgitation, peak aortic
flow velocity and atrial capture. Pacing Clin Electrophysiol. 1983;6:1350-7.
60. Nanda NC, Bhandari A, Barold SS, et al. Doppler echocardiographic studies in sequential atrio-ventricular pacing. Pacing Clin Electrophysiol.
1983;6:811-4.
61. Omoto R, Yokote Y, Takamoto S, et al. The development of real-time two-dimensional Doppler echocardiography and its clinical significance in
acquired valvular diseases. With special reference to the evaluation of valvular regurgitation. Jpn Heart J. 1984;25(3):325-40.
62. Kasi C, Namekawa K, Koyano A, et al. Real-time two-dimensional blood flow imaging using an autocorrelation technique. IEEE Trans Sonics
Ultrasonics. 1985;SU-32;458-64.
63. Helmcke F, Nanda NC, Hsiung MC, et al. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation. 1987;75(1):175-83.
64. Perry GJ, Helmcke F, Nanda NC, et al. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol. 1987;9(4):952-9.
65. Chopra HK, Nanda NC, Fan PH, et al. Can two-dimensional echocardiography Doppler color flow mapping identify the need for tricuspid valve
repair? J Am Coll Cardiol. 1989;14:1266-74.
66. Dagli SV, Nanda NC, Roitman D, et al. Evaluation of aortic dissection by Doppler color flow mapping. Am J Cardiol. 1985;56:497-8.
67. Fan PH, Kapur KK, Nanda NC. Color Doppler assessment of aortic valve stenosis. J Am Coll Cardiol. 1988;12:441-9.
68. Kapur KK, Fan PH, Nanda NC, et al. Doppler color flow mapping in the evaluation of prosthetic mitral and aortic valve function. J Am Coll Cardiol.
1989;13:1561-71.
69. Maulik D, Nanda NC, Hsiung MC, et al. Doppler color flow mapping of the fetal heart. Angiology. 1986;37:628-32.
70. Zachariah ZP, Hsiung MC, Nanda NC, et al. Color Doppler assessment of mitral regurgitation induced by supine exercise in ischemic heart dis-
ease. Am J Cardiol. 1987;59:1266-70.
71. Jain S, Pinheiro L, Nanda NC, et al. Noninvasive assessment of renal artery stenosis by conventional and color Doppler ultrasound. Echocardi-
ography. 1990;7:679-88.
72. Omoto R. Color Atlas of Real-Time Two-Dimensional Doppler Echocardiography. Tokyo: Shindan-To-Chiryo Col, Ltd.; 1984.
73. Nanda NC. Atlas of Color Doppler Echocardiography. Philadelphia: Lea and Febiger; 1989.
74. Nanda NC. Textbook of Color Doppler Echocardiography. Philadelphia: Lea and Febiger; 1989.
75. Gramiak R, Shah PM. Echocardiography of the aortic root. Invest Radiol. 1968;3(5):356-66.
76. Rothbard RL, Nanda NC. Contrast echocardiography. Seminars in Ultrasound. 1981;2:167-72.
77. Nanda NC, Gramiak R, Manning JA. Echocardiography of the tricuspid valve in congenital left ventricular-right atrial communication. Circula-
tion. 1975;51(2):268-72.
78. Miller AP, Nanda NC. Contrast echocardiography: new agents. Ultrasound Med Biol. 2004;30(4):425-34.
79. Nanda NC, Shah PM, Gramiak R. Echocardiographic evaluation of tricuspid valve incompetence by contrast injections. Clinical Res. 1976;24:233A.
80. Burri MV, Mahan III EF, Nanda NC, et al. Superior vena cava, right pulmonary artery or both: real time two- and three-dimensional transthoracic
contrast echocardiographic identification of the echo free space posterior to the ascending aorta. Echocardiography. 2007;24:875-82.
81. Carroll BA, Turner RJ, Tickner EG, et al. Gelatin encapsulated nitrogen microbubbles as ultrasonic contrast agents. Invest Radiol. 1980;15(3):260-
6.
82. Feinstein SB, Shah PM, Bing RJ, et al. Microbubble dynamics visualized in the intact capillary circulation. J Am Coll Cardiol. 1984;4(3):595-600.
83. Nanda NC, Wistran DC, Karlsberg RP, et al. Multicenter Evaluation of SonoVue™ for Improved EBD. Echocardiography. 2002;19:27-36.
84. Nanda NC, Kitzman DW, Dittrich HC, et al. Imagent Clinical Investigators Group: Imagent® improves endocardial border delineation, inter-
reader agreement and the accuracy of segmental wall motion assessment. Echocardiography. 2003;20(2):151-61.
85. Nanda NC, Schlief R. Advances in Echo Imaging Using Contrast Enhancement. Dordrecht: Kluwer Academic Publishers; 1993.
86. Side CD, Gosling RG. Non-surgical assessment of cardiac function. Nature. 1971;232(5309):335-6.
87. Frazin L, Talano JV, Stephanides L, et al. Esophageal echocardiography. Circulation. 1976;54(1):102-8.
88. Hanrath P, Kremer P, Langenstein BA, et al. Transesophageal echocardiography. A new method for dynamic ventricle function analysis. Dtsch
Med Wochenschr. 1981;106(17):523-5.
89. Seward JB, Khandheria BK, Oh JK, et al. Transesophageal echocardiography: technique, anatomic correlations, implementation, and clinical
applications. Mayo Clin Proc. 1988;63:649-80.
90. Nanda NC, Pinheiro L, Sanyal RS, et al. Transesophageal biplane echocardiographic imaging: technique, planes and clinical usefulness. Echo-
cardiography. 1990;7:771-88.
91. Nanda NC, Domanski M. Atlas of Transesophageal Echocardiography. Baltimore: Williams and Wilkins; 1998.
92. Samdarshi TE, Nanda NC, Gatewood RP Jr, et al. Usefulness and limitations of transesophageal echocardiography in the assessment of proximal
coronary artery stenosis. J Am Coll Cardiol. 1992;19:572-80.
93. Chouinard MD, Pinheiro L, Nanda NC, et al. Transgastric ultrasonography: a new approach for imaging the abdominal structures and vessels.
Echocardiography. 1991;8:397-403.
94. Agrawal G, LaMotte LC, Nanda NC, et al. Identification of the aortic arch branches using transesophageal echocardiography. Echocardiography.
1997;14:461-6.
95. LaMotte LC, Nanda NC, Thakur AC, et al. Transesophageal echocardiographic identification of neck veins: value of contrast echocardiography.
96. Nanda NC, Biederman RW, Thakur AC, et al. Examination of left external and internal carotid arteries during transesophageal echocardiogra-
phy. Echocardiography. 1998;15:755-8.
97. Nanda NC, Thakur AC, Thakur D, et al. Transesophageal echocardiographic examination of left subclavian artery branches. Echocardiography.
1999;16:271-27.
98. Nanda NC, Nekkanti R, Melendez A, et al. Transesophageal two-dimensional echocardiographic demonstration of innominate artery and its
branches. Am J Geriatr Cardiol. 2001;10:368-70.
99. Aaluri S, Miller AP, Nanda NC, et al. Transesophageal echocardiographic detection of left vertebral artery origin stenosis. Echocardiography.
2002;19:695-7.
100. Nanda NC, Gomez CR, Narayan VK, et al. Transpharyngeal echocardiographic diagnosis of carotid bulb and left internal carotid artery stenosis.
101. Miller A, Nanda NC, Mukhtar O, et al. Transpharyngeal echocardiographic detection of a left internal carotid artery stent. Echocardiography.
2000;17:739-41.
102. Khanna D, Cheng PH, Nanda NC, et al. Transpharyngeal ultrasound detection of carotid body paraganglioma. Echocardiography. 2004;21:299-
301.
103. Kostis JB, Mavrogeorgis E, Slater A, et al. Use of a range-gated, pulsed ultrasonic Doppler technique for continuous measurement of velocity of
the posterior heart wall. Chest. 1972;62(5):597-604.
104. McDicken WN, Sutherland GR, Moran CM, et al. Colour Doppler velocity imaging of the myocardium. Ultrasound Med Biol. 1992;18(6-7):651-4.
105. Miyatake K, Yamagishi M, Tanaka N, et al. New method for evaluating left ventricular wall motion by color-coded tissue Doppler imaging: in vitro
and in vivo studies. J Am Coll Cardiol. 1995;25(3):717-24.
106. Vannan MA, Pedrizzetti G, Li P, et al. Effect of cardiac resynchronization therapy on longitudinal and circumferential left ventricular mechanics
by velocity vector imaging: description and initial clinical application of a novel method using high-frame rate B-mode echocardiographic im-
ages. Echocardiography. 2005;22:826-30.
107. Geyer H, Caracciolo G, Abe H, et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical
applications. J Amer Soc Echocardiogr. 2010;23:351-69.
108. Dekker DL, Piziali RL, Dong E Jr. A system for ultrasonically imaging the human heart in three dimensions. Comput Biomed Res. 1974;7(6):544-
53.
109. Geiser EA, Lupkiewicz SM, Christie LG, et al. A framework for three-dimensional time-varying reconstruction of the human left ventricle: sourc-
es of error and estimation of their magnitude. Comput Biomed Res. 1980;13(3):225-41.
110. King D, Al-Bana S, Larach D. A new three-dimensional random scanner for ultrasonic/computer graphic imaging of the heart. In: White DN,
Barnes R, (Eds). Ultrasound in Medicine. New York: Plenum Press; 1975. pp. 363-72.
111. Moritz WE, Pearlman AS, McCabe DH, et al. An ultrasonic technique for imaging the ventricle in three dimensions and calculating its volume.
IEEE Trans Biomed Eng. 1983;30(8):482-92.
112. Matsumoto M, Matsuo H, Kitabatake A, et al. Three-dimensional echocardiograms and two-dimensional echocardiographic images at desired
planes by a computerized system. Ultrasound Med Biol. 1977;3(2-3):163-78.
113. Ghosh A, Nanda NC, Maurer G. Three-dimensional reconstruction of echo-cardiographic images using the rotation method. Ultrasound Med
Biol. 1982;8(6):655-61.
114. Handschumacher MD, Lethor JP, Siu SC, et al. A new integrated system for three-dimensional echocardiographic reconstruction: development
and validation for ventricular volume with application in human subjects. J Am Coll Cardiol. 1993;21(3):743-53.
115. Moritz WE, Shreve PL. A microprocessor based spatial locating system for use with diagnostic ultrasound. Proc IEEE. 1976;64:966-74.
116. Raqueno R, Ghosh A, Nanda NC. Four-dimensional reconstruction of two-dimensional echocardiographic images. Echocardiography.
1989;6:323-37.
117. Schott JR, Raqueno R, Ghosh A, et al. Four dimensional cardiac blood flow analysis using color Doppler echocardiography. In: Nanda NC, (Ed).
Textbook of Color Doppler Echocardiography. Philadelphia: Lea and Febiger; 1989. pp. 332-41.
118. Wollschlager H, Zeiher AM, Klein H, et al. Transesophageal echo computer tomography: a new method for dynamic 3-D imaging of the heart
(echo-CT). Computers in Cardiology: IEEE Computer Society; 1990. p. 39.
119. Pandian NG, Nanda NC, Schwartz SL, et al. Three-dimensional and four-dimensional transesophageal echocardiographic imaging of the heart
and aorta in humans using a computed tomographic imaging probe. Echocardiography. 1992;9(6):677-87.
120. Li ZA, Wang XF, Nanda NC, et al. Three dimensional reconstruction of transesophageal echocardiographic longitudinal images. Echocardiogra-
phy. 1995;12:367-75.
121. Li Z, Wang X, Xie M, et al. Dynamic three-dimensional reconstruction of abnormal intracardiac blood flow. Echocardiography. 1997;14(4):375-
82.
122. Nanda NC, Pinheiro L, Sanyal R, et al. Multiplane transesophageal echocardiographic imaging and three-dimensional reconstruction. Echocar-
diography. 1992;9:667-76.
123. Nanda NC, Abd El-Rahman SM, Khatri GK, et al. Incremental value of three-dimensional echocardiography over transesophageal multiplane
two-dimensional echocardiography in qualitative and quantitative assessment of cardiac masses and defects. Echocardiography. 1995;12(6):619-
28.
124. Nanda NC, Roychoudhury D, Chung SM, et al. Quantitative assessment of normal and stenotic aortic valve using transesophageal three-dimen-
sional echocardiography. Echocardiography. 1994;11:617-25.
125. Abd El-Rahman SM, Khatri G, Nanda NC, et al. Transesophageal three-dimensional echocardiographic assessment of normal and stenosed
coronary arteries. Echocardiography. 1996;13:503-10.
126. Nanda NC, Khatri GK, Samal A, et al. Three-dimensional echocardiographic assessment of aortic dissection. Echocardiography. 1998;15:745-54.
127. Nanda NC, Sorrell VL. Atlas of Three-Dimensional Echocardiography. Armonk: Futura Publishing Company; 2002.
128. Sheikh K, Smith SW, von Ramm O, et al. Real-time, three-dimensional echocardiography: feasibility and initial use. Echocardiography.
1991;8:119-25.
129. Salgo I, Bianchi M. Going “live” with 3-D cardiac ultrasound. Today in Cardiology. 2002;5.
130. Hage FG, Nanda NC. Real-time three-dimensional echocardiography: a current view of what echocardiography can provide. Indian Heart J.
2009;61:146-55.
131. Pothineni KR, Inamdar V, Miller AP, et al. Initial experience with live/real time three-dimensional transesophageal echocardiography. Echocar-
diography. 2007;24(10):1099-104.
132. Nanda NC, Hsiung MC, Miller AP, Hage FG. Live/Real Time 3D Echocardiography. Oxford: Wiley-Blackwell; 2010.
133. Mondillo S, Giannotti G, Innelli P, et al. Hand-held echocardiography: its use and usefulness. Int J Cardiology. 2006;111:1-5.
57 History of Cardiac Imaging
Krishna BA
of many cardiac disorders. This discovery also gave birth to kymogra-

INTRODUCTION
phy and the beginning of Angiocardiography.
The necessity of confirming clinical diagnosis stimulated the inven-
tion of diagnostic imaging in clinical medicine. It began on January ANGIOCARDIOGRAPHY
29th, 1896 at the Wirzburg Physical Medical Society where William
Konard Roentgen1 announced the unknown and invisible rays—he The prerequisite for the development of angiocardiography was the
called them X-rays. He showed how these rays glow and produce a demonstration of feasibility of catheterization of human heart. In
mysterious light when allowed to pass through a paper coated with 1929, W Forssmann3 (1904–1979) introduced “a well-coiled 65 cm
barium platinocyanide. This followed public demonstration of an long ureteral Catheter” into his antecubital vein to reach the right
image of the hand of the famous anatomist F Von Kolliker. This was atrium. He followed this up with first human angiocardiography on
the birth of medical imaging. This initiated series of thought pro- himself using 20 cc of 25% sodium iodide which won him Noble Prize
cesses, observations resulting in remarkable discoveries culminat- in 1956. The first successful use of intravenous angiocardiography as
ing in amazing imaging technologies we use in cardiology and other a diagnostic method was reported in 1937 by Castellanos4 and Cow-
clinical branch of medicine. The aim of these imaging technologies orkers in Cuba in a patient with congenital heart disease. They also
is to provide comprehensive evaluation of (patho) anatomy, (patho) were the first to use automatic injector and biplane angiocardiogra-
physiology, prognosis and management. phy. The cinematography was also invented same time as X-ray and
WH Stewart5 merged the cinematography and angiocardiography
X-RAY IMAGING resulting in the first cineangiocardiography in 1939. After the Sec-
ond World War, the modern era of cardiac X-ray imaging began with
The sensational discovery of X-ray lead Thomas Alwa Edison (1847– refined electronics, computer application and development of image
1931) to study chemical substances that would fluoresce more intensifier in 1952, which is a critical tool for analyzing internal car-
brightly than barium platinocyanide and found calcium tungstate diac anatomy and the performing selective coronary arterigraphy. It
to be the best. He constructed the “Fluoroscope” for instant visuali- also minimized the radiation exposure to patient and the operator.
zation of organs. Williams FH2 (1852–1936) while reporting on the
visualization of the heart said, “the outline of the heart, as seen from ULTRASOUND IMAGING
front of the body through fluoroscope corresponds in a general way
to the outline drawn on the skin with percussions as a guide”. He also After the X-ray, cardiac ultrasound is the most important advance
observed that due to constant motion of heart and diaphragm, the in diagnostic cardiology. It was Spallanzam (1729–1799) who recog-
fluoroscopy was more informative than radiography. Moritz in 1902 nized for the first time existence of ultrasound and Jacquer and Pierre
introduced orthodiagraphy, providing measurements of cardiac con- Curie in 1880 discovered the piezo-electric effect in quartz crystals—
tour and size and in 1905 Kohler introduced cardiac telerontgenogra- the basis of cardiac and other ultrasound systems. This was used in
phy. In 1904, Rollins invented a new instrument —“the Seehear”—a World War I as transmitter and receiver and in World War II for ship
combination of fluorescent screen and stethoscope. Heart sounds navigation. In 1941, KT Dussik6 for the first time applied ultrasound
could be auscultated while the image of the heart was visualized— in medical diagnoses and outlined the ventricles of the brain using
making cardiac imaging part of physical examination. eco-transmission. He is referred to as “father of diagnostic ultra-
In 1913, the cardiac measurements became more accurate due sound”. In 1950, WD Keidel7 performed the first cardiac ultrasound
to the invention of tungsten cathode X-ray tube by Loolidge (1873– to measure cardiac output. The first echocardiogram was performed
1975), which was a powerful source of X-rays. In 1919, CS Danger in 1953 by Edler and Hertz8 demonstrating structural details for their
proposed the “cardiothoracic ratio” which became an important sign surgical colleagues. Hertz also produced the first M-mode recording
Chapter 57  History of Cardiac Imaging 433
on ink-jet recorder along with electrocardiogram (ECG) recording. In Blumgart15 developed a radiotracer technique to measure blood
the late 1960s, the fiberoptic recorder was a break through allowing flow velocity and De Hevesy introduced red cell volume measure-
M-mode recording of all structures. ment. However, the major break through was the invention of “di-
lution principle” using the first artificially produced isotope phos-
TWO-DIMENSIONAL ECHOCARDIOGRAPHY phorous-32 by EO Lawrence16 in 1931. This was the birth of nuclear
medicine. The availability of newer radiopharmaceutical gave birth
In 1968, J Somer9 constructed the first electronic—phased array scan- to nuclear imaging. However, clinical application of nuclear imag-
ner and in 1974 J Griffith10 and W Henry introduced the mechanical ing needed detection of radioisotope emissions. The major break
sector scanner. These developments revolutionized cardiac ultra- through occurred in 1949 when B Cassen17 in Los Angeles developed
sound with exquisite detail of cardiac structures in real time mode. the first scintillation detector, which helped in obtaining static imag-
The three-dimensional (3D) echocardiography has made it possible ing of human organs. However, it could not be used for cardiac imag-
to generate volume-rendered data, which display tissue information ing due to dynamic motion of the heart. However, development of
in real time. The transesophageal echocardiography was introduced scintillation gamma camera by Anger18 in 1952 and the application
by Frazin11 et al. to circumvent chest wall problems. The multiplane of computer technology to gamma camera enabled dynamic studies
probe introduced by J Souquet12 in 1985 has made great impact in like cardiac output measurement through time—activity curves. The
transesophageal echocardiography. introduction of technetium-99m isotope widened the application.
The intracardiac shunt detection and quantification of shunt became
DOPPLER ECHOCARDIOGRAPHY possible. The 99mTC-RBC labeled studies enabled the measurement
of ejection fraction of both ventricles during resting phase, after
The Austrian CA Doppler (1803–1853) is credited with the pulsed- exercise and after drug intervention. The computer also enabled
wave Doppler technique, which permitted blood-flow velocity assessment of wall motion, which gave indirect evidence of coronary
interrogation. The pulsed-wave Doppler with two-dimensional (2D) artery disease. In 1970, thallium-201 was introduced by Kawana19
phased array systems allowed blood flow measurement at selected et al. for myocardial perfusion imaging and Strauss et al. showed
regions within an image phase. The Dutch–born scientist Bernoulli linear relationship between thallium and myocardial blood flow.
formulated the relationship of the pressure drop across the inlet of an Thus the thallium mayocardial perfusion imaging became a standard
obstruction in a flow channel to the flow rate through it. This was the technique. The pioneering work of Kuhl and Edwards20 produced the
beginning of understanding hemodynamics across a stenotic orifice. first tomographic clinical system in 1953 and was referred to as single
The further research produced the revolutionary color Doppler flow photon emission computer tomography (SPECT). The tomographic
imaging systems by Kasai13 et al. in 1982. This provided “noninvasive images of myocardium produced high quality images enhancing
angiogram” of normal and abnormal blood flow on a beat to beat sensitivity and specificity in IHD. The introduction of 99mTC-labeled
basis. The current technology combines in one machine M-mode, compounds (Sestamibi TC-MIBI and Myoview TC-Tetrofosmin) and
2D, pulsed–wave, continuous–wave and color Doppler flow ECG gating techniques provided comprehensive information like
providing the most comprehensive integrated structural, functional perfusion, ejection fraction, wall motion and ventricular volumes.
and hemodynamic information. With this vast data, the clinical applications increased overtime. The
introduction of 131I-MIBG (Meta Iodo Benzyl Guanidine) enabled
INTRACARDIAC INTRACORONARY catecholamine receptor imaging with clinical impact.
ULTRASOUND
POSITRON EMISSION TOMOGRAPHY
In 1960, ultrasound transducer was mounted on a catheter to obtain
intracardiac echocardiogram. Five years later Bom et al. placed array Positron emission tomography (PET) is an advanced nuclear imag-
of 32 elements at the tip of an F Catheter. The use of these technolo- ing technique, which was mainly a research tool till recently. The
gies was found NOT necessary and their role diminished. However, tracers used are positrons which have dual energies and the positron
with advances in interventional cardiology, the interest renewed in camera consists of multiple crystals which use coincidence counting
the form of intravascular ultrasonography (IVUS), which allowed technique. The new generation of PET cameras used fusion technol-
circumferential imaging of arterial walls and endothelial surface in ogy where in PET cameras have inbuilt CT images thus providing
characterizing plaques. anatomical detail as well. The PET-CT fused images are opening up
new applications in ischemic heart disease (IHD). The tracer used is
NUCLEAR IMAGING 18-fluoro-deoxyglucose (FDG), which has specific application in de-
tection of viable myocardium with clinical impact in revasculariza-
The radioactivity was discovered by Bacquerel14 few months after tion. The images are referred to as 18-FDG Metabolic Scan. The FDG
Rontgen’s X-ray. Madam Curie in Paris and Rutherford in Cam- PET images have high resolution and demonstrate superior sensitiv-
bridge described the types, source and units of radioactivity. In 1926, ity and specificity in IHD.
difference is X-ray attenuation of tissues is the factor in CT while MRI

COMPUTED TOMOGRAPHY
depends on the tissue behavior when placed in an external magnetic
The first clinical computed tomography (CT) was invented by field. The wide range of tissue contrast provides the potential for my-
G Houns field of EMI Ltd and the first clinical CT was installed in ocardial tissue characterization. This produces excellent delineation
Atkinson Morley hospital in London in 1971. The principle was of soft tissue pathology in the myocardium. The recent advancement
evolved from the work by an Austrian Mathematician J Radon21 who of intravenous contrast agent (gadolinium) and faster imaging tech-
in 1917 had shown that 3D image of an object could be reconstruct- nology has enabled MR angiography, which has opened up newer
ed from infinite number of two-dimensional image of the object. applications in coronary artery disease—notably myocardial viabil-
Though initially it was used for brain scanning, the cardiac applica- ity. The adenosine technique used in nuclear imaging is currently
tions became possible after AM Cormack of South Africa demon- used in MR angiography to detect IHD and this technique is under
strated that attenuation coefficients of a slice of an object could be validation.
reconstructed from a series of angular projections. This was essential
to differentiate X-ray attenuation of normal and infarcted myocar- FUSION IMAGING
dium. The subsequent advances in the speed of scanning and image
reconstruction have enlarged the applications. The multi-detector The increasing cost of all these technologies has stimulated newer
CT (MDCT) with 64 and 128 slices have enabled the evaluation of approaches. The high sensitivity and specificity of nuclear imaging
coronary artery disease with immense potential in female patient and high quality of structures CT images are electronically fused to
and graft patency assessment. It is now possible to assess ventricular produce high resolution functional and anatomical images which
function on these fast CT Scanners. The calcium scoring technique will have a major impact in the evaluation of coronary artery dis-
has come as a boon for IHD screening. The electron beam computed ease. This is not only cost-effective, but also less time consuming and
tomography (EBCT) of heart was introduced by D Boyd22 in 1979 hence patient friendly.
at Imatron. This instrument can acquire image in as little as 50 ms,
obviating the need for ECG gating with a 180 ring of detectors, heart CONCLUSION
can be imaged virtually free of motion artifact.
The evolutions in cardiac imaging have followed the clinical neces-
MAGNETIC RESONANCE IMAGING sities. The advances have contributed greatly in better insights into
disease processes. The progress into patient management has closely
The phenomenon of nuclear magnetic resonance (NMR) was enun- followed progress in imaging modalities. The advances will continue
ciated by F Bloch23 et al. at Stanford and E Purcell24 et al. at Harvard to accelerate and it is difficult to predict the future. The standardized
in 1946. The specific change in the resonating frequency of a nucleus quantitative analysis of cardiac function, coronary anatomy, perfu-
in different chemical compound is the basis of NMR signal. In 1971, sion and metabolism of the myocardium will be analyzed on line in
professor R Damadian25 and P Lautebur described the concept of digital format (DICOM) leading to teleconsulting. The cardiac MRI
MR imaging and in 1973 the first 2D MR image of a heterogenous might grow as a single one-stop noninvasive tool since it provides
object was obtained. In 1977, the duo produced the first heart image. function, myocardial characteristics, perfusion and metabolism. The
However, in 1983, ECG-gated high quality images of the heart were onus is on the cardiologists for cost-effective utilization of these im-
produced. Though the images are similar to CT, the fundamental aging modalities in a given clinical context.
REFERENCES
1. Röntgen CW. Über eine neue Art von Strahlen (Vorläufige Mitteilung). Sitzungsber Physik Med Ges Würzburg. 1895. pp. 132-41.
2. Williams FH. A method for more fully determining the outline of the heart by means of a fluoroscope together with other uses of this instrument
in medicine. Boston Med Surg J. 1896;135:335-7.
3. Forssmann W. Die Sondierung des rechtin Herzen. Klin Wschr. 1929;8:2085-7.
4. Castellanos A, Pereoras R, Garcia A. La angiocardiografia radio-opaca. Arch Soc Estud Clin (Habana). 1937;31:513-96.
5. Stewart WH, Breimer CW, Maier HC. Cinero¨ntgenographic diagnosis of congenital and acquired heart disease. AJR. 1941;46:639-40.
6. Dussik KT. Uber die Moglichkeit Hochfrequente Mechanische Schwingungen als Diagnostisches Hilfsmittel zu Verwerten. Z Neurol. 1941;174:153.
7. Keidel WD von. Uber eine neue Methode zur Registrierung ger Volumanderungen des herzens am Menschen. Zietschr Kreislaufforschung.
1950;39:257.
8. Edler I, Hertz CH. Use of ultrasonic reflectoscope for continuous recording of movements of heart walls. Kurgl Fysiogr Sallad i Lund Forhand.
1954;24:5.
9. Somer JC. Electronic sector scanning for ultrasonic diagnosis. Ultrasonics. 1968;6:153-9.
10. Griffith JM, Henry WL. A sector scan for real time two dimensional echocardiography. Circulation. 1974;49:1147-52.
11. Frazin L, Talan JV, Stephanides L, et al. Esophageal echocardiography (Abstr). Circulation. 1976;54:102.
12. Souquet J, Hanrath P, Zitelli L, et al. Transesophageal phased array for imaging the heart. IEEE Trans Biomed Eng. 1982;29:707.
Chapter 57  History of Cardiac Imaging 435
13. Kasai C, Namekawa K, Koyano A, et al. Real-time two-dimensional blood flow imaging using an autocorrelation technique. IEEE Trans Sonics
Ultrason. 1985;32:460-3.
14. Becquerel H. Sur la radioation invisible emises par les corps phosphorescent. CR Acad Sci. 1896;122:501-3.
15. Blumgart HL, Otto CY. Studies on the velocity of blood flow. J Clin Invest. 1926;4:1-13.
16. Lawrence EO, Livingstone MS. The production of high speed light ions without the use of high voltages. Phys Rev. 1932;40:19-30.
17. Cassen B. The evolution of scintillation imaging. In: Freeman LM, Johnson PM (Eds). Clinical scintillation scanning. New York: Hoeber; 1969.
18. Anger HO. Scintillation camera. Rev Sei Instrum. 1958;29:27-33.
19. Kawana M, Krezek H, Porter J, et al. Use of 199-thallium as a potassium analogue in scanning (Abstr). J Nucl Med. 1970;11:333.
20. Kuhl DE, Edwards RQ. Image separation radioisotope scanning. Radiology. 1963;80:653-62.
21. Radon J. On the determination of functions from their integrals along certain manifolds. Gerichte u¨ber Verhandlungen der ko¨ niglich
Sa¨chsischen Gesellschaft derWissenschaften zu Leipzig. Mathematisch-Physische Klasse. 1917;69:262-77.
22. Boyd DP, Gould RG, Quinn JR, et al. A proposed dynamic cardiac 3-D densimeter for early detection and evaluation of heart disease. IEEE. Trans-
Nucl Sci NS. 1979;26:2724.
23. Bloch F, Hansen WW, Packard ME. Nuclear induction. Phys Rev. 1946;69:127-9.
24. Purcell EM, Torrey HC, Pound RV. Resonance absorption by nuclear magnetic moments in a solid. Phys Rev. 1946;69:37-8.
25. Damadian R. Tumor detection by nuclear magnetic resonance. Science. 1971;117:1151-3.
58 History of Myocardial Contrast
Echocardiography
Chahal NS, Senior R
cated and the gas introduced and this process remains the preferred
OPACIFYING THE MYOCARDIUM
method for ultrasonic contrast agent development today.
The first report of contrast echocardiography was by Gramiak and Much of the seminal research in MCE has been published from
Shah in 19691 who described the improved delineation of the aortic the laboratory of Sanjiv Kaul, and he has remained in the vanguard
root using M-mode echocardiography after saline injection during of basic research and clinical development of this technique. The be-
aortography. Agitated saline was then used increasingly in conjunc- havior of sonicated albumin as an intravascular tracer, capable of tra-
tion with clinical echocardiography from the mid-1970s, principally versing capillary beds, was demonstrated by Keller and Jayaweera,5,6
to opacify the right heart and to detect intracardiac shunts. How- paving the way for the quantification of myocardial blood flow (MBF)
ever, the inherently large size of saline microbubbles, created by using MCE, which will be discussed later. In 1992, Sabia published
forcefully agitating saline and room air between two syringes, pre- a landmark study demonstrating the association between collater-
cluded their opacification of the left heart when injected through a al coronary circulation flow in predicting myocardial viability after
peripheral vein. A number of attempts were made in the early 1980s acute myocardial infarction, using MCE (Fig. 58.1).7 Not only did
to engineer a more stable ultrasound contrast agent that could this paper reaffirm the importance of the collateral coronary circula-
offer left ventricular (LV) opacification. To achieve this, smaller sized tion in predicting functional recovery of the myocardium, but also
microbubbles were required that could resist coalescence, remain heralded the superiority of the technique in assessing collateral ves-
uniform in size and be stable enough to withstand transpulmonary sels compared to the standard method of the time, which was coro-
passage, unlike the crude versions being created by hand agitation. nary angiography. In the same year, Ito and colleagues from Japan
Although the discovery and development of such an agent would published an MCE study vividly illustrating the problem of no-reflow
primarily have been for the purposes of enhancing LV opacification, with residual perfusion defects persisting in 23% of their patients in
it would also have attracted considerable interest from the pioneers whom angiographically successful reflow had been achieved post-
of the time in the experimental field of myocardial contrast echocar- thrombolysis, and were ultimately left with a dysfunctional myocar-
diography (MCE). The gold standard for assessing myocardial perfu- dium.8
sion then was with single-photon imaging which was predominantly
performed by noncardiologist, nuclear physicians working in radiol- ADVANCES IN CONTRAST AGENTS
ogy departments. However, the technique has always been hindered
by the significant radiation dose to the patient, as well as being time The development of novel contrast agents and their subsequent vali-
consuming and expensive. Extending the repertoire of the echocar- dation culminated in the approval of commercial ultrasound agents
diography machine to also assess myocardial perfusion would offer in the mid-1990s, with Albunex launched first in the USA, followed
a radiation-free technique that can be performed within cardiology by Levovist in Europe, and are now referred to as “first generation”
departments, that is relatively inexpensive and less time consuming agents. They could be injected through a peripheral vein and were
than nuclear scintigraphic techniques. licensed to provide LV cavity opacification. However, consistent LV
Early, experimental MCE primarily involved injection of hand- opacification, myocardial perfusion, was difficult even with these
agitated suspensions of renograffin or gelatine-encapsulated nitro- agents because of the fragility of microbubbles and the rapid dif-
gen microbubbles directly into the arteries of dogs.2,3 A major inno- fusion of the encapsulated air into the blood. In patients with low
vation in the field of microbubble engineering was the development cardiac output states, significant LV opacification was observed in
of the technique of “sonication”, by Feinstein and colleagues.4 Soni- less than 50%. Nevertheless, in order to achieve widespread clinical
cation creates populations of by-product microbubbles from the pro- applicability, the clinical performance (efficacy) of the first genera-
cess of cavitation using high-intensity ultrasound. The stability of the tion of ultrasound contrast agents required development. The “sec-
microbubbles generated was dependent on the solution being soni- ond generation” agents generally utilized high molecular weight, low
Chapter 58  History of Myocardial Contrast Echocardiography 437
that tissue did not generate such harmonic signals and it was a sur-
prise to see superior tissue resolution using harmonic imaging, even
during normal unenhanced scans, which has now displaced funda-
mental imaging as the standard for acquiring B-mode ultrasounds.
Together with the second generation ultrasound agents, harmonic
imaging systems began to fulfil the required clinical expectations for
safe, efficient and economical noninvasive imaging of the LV cavity,
but optimal myocardial perfusion imaging was still confounded by
technical factors. Standard harmonic imaging, which is performed
at high mechanical index, results in ongoing microbubble destruc-
tion and poor discrimination between the myocardium and contrast
agent held within. Intermittent or triggered imaging during end-
systolic frames also dramatically improves myocardial opacification.
This was first reported by Porter who during a chance observation
demonstrated that intermittent imaging at specified intervals trig-
gered to the electrocardiogram (ECG) provided significantly better
myocardial opacification than continuous imaging, which results in
greater microbubble destruction by ultrasound.11
To facilitate image analysis and further delineate the degree of
Figure 58.1: Myocardial opacification in a patient with recent inferior myocardial perfusion, early MCE performed on analogue systems
infarction and an occluded right coronary artery. Before angioplasty, underwent offline processing involving image alignment and color
sonicated microbubbles were injected via the left main coronary artery
coding (Fig. 58.2), but several stages were involved and it was time
with homogeneous opacification evident throughout the myocardium,
including the occluded right coronary bed. After successful angioplasty, consuming process. With the advent of digital echocardiography
microbubbles are reinjected this time into the patent right coronary systems, this was replaced by myocardial contrast specific, online
artery, defining viable and perfused myocardium, which received algorithms (Figs 58.3A to D) that enhanced the contrast to tissue
collateral blood flow from the left coronary system when this artery was backscatter signal ratio, exploiting the nonlinear signals produced
occluded. Source: Sabia PJ, Powers ER, Ragosta M, et al. An association
from oscillating microbubbles, whilst suppressing the linear signals
between collateral blood flow and myocardial viability in patients with
recent myocardial infarction. N Engl J Med. 1992;327(26):1825-31 produced by tissue.12
FROM BENCH TO BEDSIDE

soluble (Perflutren) gases encapsulated by impermeable polymer
shells, which promoted efficiency and in vivo persistence, offering Hitherto, MCE had only been performed in humans with a di-
successful in LV opacification in approximately 90% of cases. The rect injection of contrast agents into the coronary arteries, and the
commercially available, second generation, Food and Drug Adminis- feasibility of MCE in diagnosing significant coronary artery stenoses
tration (FDA) currently approved contrast agents for LV opacification following intravenous injection, had only been demonstrated in
are OPTISON9 (GE Healthcare, Princeton, NJ) and DEFINITY10 canines.13 The first clinical study in humans using an intravenous
(Lantheus Medical Imaging, North Billerica, MA), whilst the Europe- contrast agent (OPTISON™) was performed at Northwick Park Hospi-
an Medicines Agency (EMEA) have also approved SonoVue (Bracco tal, Harrow, UK, by Kaul and Senior14 in a phase 2 study. Using sesta-
Diagnostics, Milan, Italy). mibi single photon emission computed tomography (SPECT) as the
“gold standard” for myocardial perfusion assessment, they demon-
IMPROVING MICROBUBBLE VISUALIZATION strated good concordance between MCE and SPECT for detecting
reversible and fixed perfusion defects (Fig. 58.2) findings, which
Although the second generation contrast agents were capable of have since been replicated in eight other studies.15
achieving more reliable LV opacification than their predecessors, Subsequently, MCE was applied to patients presenting with a
reliable myocardial opacification remained elusive until imaging variety of coronary syndromes, stable and unstable, in numerous
systems were developed capable of differentiating the bright and studies. A meta-analysis comparing the sensitivity and specificity of
gray scale echo signals from the myocardial tissue, and those sig- MCE with those of SPECT or stress echocardiography for the detec-
nals generated by the microbubbles within the microcirculation. tion of stable coronary artery disease showed equivalent results16
Accordingly, harmonic imaging was developed specifically by MCE with aggregate values for sensitivity and specificity from published
researchers to capture the unique and high frequency backscatter studies of 83% and 80% respectively for the detection of coronary
generated by the oscillating microbubble. At the time it was believed artery disease. To improve the diagnosis of acute coronary
A B
C D
Figures 58.3A to D: Destruction replenishment imaging with
real-time myocardial contrast echocardiography, during hyperemia:
(A) 1 beat preflash; (B) flash delivered; (C) 1 beat postflash; (D) 2
beats postflash with normal and homogenous opacification of the
myocardium demonstrated. Source: Chahal NS, Senior R. Contrast in
stress echocardiography. In: Neskovic AN, Flachskampf FA (Eds). Stress
Figure 58.2: Examples of fixed perfusion defects from two patients Echocardiography: Essential Guide and DVD. USA: Informa Healthcare;
through the use of four- and two-chamber views. Top panels depict 2010
images obtained with myocardial contrast echocardiography (MCE);
bottom panels show those obtained with single photon emission
computed tomography (SPECT). The first patient (left panels) had an The peak contrast intensity signal, obtained using MCE, repre-
apical and a lateral defect in the four-chamber view that was identical on sents the capillary blood volume at a single point in time. Since capil-
MCE and SPECT. The second patient (right panels) had an anteroapical lary blood volume is correlated with microvascular density and cap-
and a basal posterior defect in the two-chamber view. Perfusion illary area, MCE also offers a method for examining microvascular
appeared to be intact in the inferior wall. The MCE image from the apical integrity or myocardial viability. Contrast intensity defects and the
two-chamber view in this patient is placed on its side to correspond
degree of reduction of resting MBF after intravenous contrast admin-
to the vertical two-chamber view on SPECT. Source: Kaul S, Senior R,
Dittrich H, et al. Detection of coronary artery disease with myocardial istration have been shown to predict transmural extent of necrosis
contrast echocardiography: comparison with 99mTc-sestamibi single- assessed by later gadolinium cardiac magnetic resonance imag-
photon emission computed tomography. Circulation. 1997;96(3):785-92 ing.20,21 Myocardial contrast echocardiography has been proven
to be more sensitive than dobutamine stress echocardiography,22
which does not assess the microvasculature directly and superior in
syndromes (ACS), noninvasive imaging techniques, such as SPECT specificity to SPECT,23 for the detection of hibernating myocardium.
have been utilized even in the emergency department. Likewise, the Myocardial contrast echocardiography has also shown prognostic
role of MCE has also been evaluated in these patients. In a large mul- superiority to clinical, ECG and angiographic parameters of reperfu-
ticenter study, performance of MCE improved the detection of ACS sion in patients postacute myocardial infarction,24-28 and has proven
over and above clinical, ECG and biochemical markers at the time of itself as a useful first line investigation for the assessment of myocar-
presentation and was equivalent to SPECT in the risk stratification dial viability.
of these patients,17 with the advantage offering an immediate, bed-
side assessment of myocardial perfusion in an acute setting. A large QUANTIFYING MYOCARDIAL PERFUSION
study of more than 1,000 patients confirmed the excellent prognosis
of patients presenting to the emergency department with chest pain, Myocardial perfusion reflects both oxygen delivery to and oxygen
normal cardiac function and normal perfusion.18 Vasodilator MCE consumption by a myocyte. Under physiological situations, where
can also be used to safely assess prognosis in patients presenting oxygen consumption is predictable, measurement of MBF is con-
with chest pain, significant risk factor burden, but a negative 12-hour sidered to be an acceptable surrogate of myocardial perfusion. Wei
troponin and nondiagnostic ECG.19 et al.29 developed a technique for the quantification of MBF based
on the ability of ultrasound to destroy microbubbles and observing

their rate of reappearance in the myocardium. During a continuous
infusion of microbubbles in a patient with intact coronary microvas-
culature and normal MBF, destruction of the microbubbles in the
microcirculation by ultrasound (“flash/replenishment imaging”)
is followed by the relatively uniform appearance of contrast in the
coronary microcirculation and homogeneous opacification of the
myocardium. The replenishment of contrast after microbubble de-
struction can be characterized by a time-intensity curve from which
A B
MBF can be determined. Animal studies using a coronary stenosis
model have demonstrated that MBF estimated by MCE correlates
with absolute MBF measured with radiolabeled fluorescent micro-
spheres.29,30 In humans, abnormalities in MBF reserve have been
used to quantify stenosis severity.31 Vogel et al.32 demonstrated that
MCE derived MBF at rest and hyperaemia closely correlated with
MBF assessed by positron emission tomography.
Myocardial perfusion is most commonly assessed qualitative-
ly, using visual assessment at the bed side. Signal intensity can be
quantified using a graded scale reflecting homogenous perfusion, C D
reduced perfusion and absent perfusion. At rest, the red blood cell
Figures 58.4A to D: (A to C) A clear perfusion defect is seen following
velocity in capillaries is 1 mm/sec, therefore, following destruction of vasodilator stress, which persists 3 beats after microbubble destruction
microbubbles in the myocardium, it takes approximately 5 seconds (D), extending from the midseptum to the entire lateral wall. This patient
(at resting heart rate 60–80 seconds) to replenish an ultrasound beam had 70% left anterior descending (LAD) coronary artery stenosis and
of 5 mm. In the presence of hyperaemia, without coronary stenosis, occlusion of the circumflex artery on subsequent coronary angiography
MBF should increase 4–6 fold and homogeneous myocardial perfu- Source: Chahal NS, Senior R. Contrast in stress echocardiography. In:
Neskovic AN, Flachskampf FA (Eds). Stress Echocardiography: Essential
sion within 1–2 seconds (Figs 58.3A to D). In the regions of coronary
Guide and DVD. USA: Informa Healthcare; 2010
stenosis, rate of filling is much slower depending on the severity of
stenosis (Figs 58.4A to D).
SAFETY OF ULTRASOUND CONTRAST by large retrospective analyses, which found no difference in compli-
cation rate to a matched cohort undergoing unenhanced studies.33-36
AGENTS
The FDA reviewed the new restrictions in May and June 2008, and
Concerns regarding ultrasound contrast agents arose primarily after subsequently, lifted the new contraindications replacing them with
a handful of deaths over a 6-year period (estimated at 1 death per warnings instead.37
500,000 contrast injections in the US) that occurred in temporal rela-
tion to contrast administration in patients with significant underly- CONCLUSION
ing, unstable cardiovascular disease. However, it is worth reiterating
that after a temporary withdrawal of the approval for SonoVue for The significant milestones, which have been responsible for the
use in cardiac applications by the EMEA in 2004, the committee soon development of MCE, have been discussed in this review. The
restored its approval for patients not suffering from the suspected development of stable microbubbles behaving as erythrocyte trac-
acute coronary syndrome or unstable heart disease. Likewise, the ers, capable of withstanding transpulmonary passage, was the first
black-box warning issued by the FDA for DEFINITY in 2007 was major technological breakthrough. Consistent visualization of these
reviewed and initially several new contraindications were imposed microbubbles in the myocardium remained elusive until the advent
on its use (acute myocardial infarction, unstable heart failure, un- of harmonic imaging systems and the realization that lower mechan-
stable arrhythmias, respiratory failure, mechanical ventilation and ical index imaging coupled with intermittent ultrasound triggered to
pulmonary emboli), which were felt to be unnecessary and expose end-systole resulted in less microbubble destruction. The ability to
critically unwell patients to alternative, more invasive diagnostic pro- accurately quantify MBF, using MCE, has ushered in renewed opti-
cedures. Moreover, the potential effect of pseudocomplication con- mism for the continued growth of this technique in the field of clini-
founding the interpretation of safety was raised and later confirmed cal myocardial perfusion imaging.
REFERENCES
1. Gramiak R, Shah PM. Echocardiography of the aortic root. Invest Radiol. 1968;3(5):356-66.
2. Armstrong WF, Mueller TM, Kinney EL, et al. Assessment of myocardial perfusion abnormalities with contrast-enhanced two-dimensional echo-
cardiography. Circulation. 1982;66(1):166-73.
3. Tei C, Sakamaki T, Shah PM, et al. Myocardial contrast echocardiography: a reproducible technique of myocardial opacification for identifying
regional perfusion deficits. Circulation. 1983;67(3):585-93.
4. Feinstein SB, Ten Cate FJ, Zwehl W, et al. Two-dimensional contrast echocardiography. I. In vitro development and quantitative analysis of echo
contrast agents. J Am Coll Cardiol. 1984;3(1):14-20.
5. Keller MW, Segal SS, Kaul S, et al. The behavior of sonicated albumin microbubbles within the microcirculation: a basis for their use during myo-
cardial contrast echocardiography. Circ Res. 1989;65(2):458-67.
6. Jayaweera AR, Edwards N, Glasheen WP, et al. In vivo myocardial kinetics of air-filled albumin microbubbles during myocardial contrast echocar-
diography. Comparison with radiolabeled red blood cells. Circ Res. 1994;74(4):1157-65.
7. Sabia PJ, Powers ER, Ragosta M, et al. An association between collateral blood flow and myocardial viability in patients with recent myocardial
infarction. N Engl J Med. 1992;327(26):1825-31.
8. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ven-
tricular function in anterior myocardial infarction. Circulation. 1992;85(5):1699-705.
9. Cohen JL, Cheirif J, Segar DS, et al. Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new
echocardiographic contrast agent. Results of a phase III Multicenter Trial. J Am Coll Cardiol. 1998;32(3):746-52.
10. Kitzman DW, Goldman ME, Gillam LD, et al. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with sub-
optimal baseline left ventricular echocardiographic images. Am J Cardiol. 2000;86(6):669-74.
11. Porter TR, Xie F, Kricsfeld D, et al. Improved myocardial contrast with second harmonic transient ultrasound response imaging in humans using
intravenous perfluorocarbon-exposed sonicated dextrose albumin. J Am Coll Cardiol. 1996;27(6):1497-501.
12. Burns PN. Harmonic imaging with ultrasound contrast agents. Clin Radiol. 1996;51(Suppl 1):50-5.
13. Firschke C, Lindner JR, Wei K, et al. Myocardial perfusion imaging in the setting of coronary artery stenosis and acute myocardial infarction using
venous injection of a second-generation echocardiographic contrast agent. Circulation. 1997;96(3):959-67.
14. Kaul S, Senior R, Dittrich H, et al. Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-
sestamibi single-photon emission computed tomography. Circulation. 1997;96(3):785-92.
15. Senior R, Becher H, Monaghan M, et al. Contrast echocardiography: evidence-based recommendations by European Association of Echocardiog-
raphy. Eur J Echocardiogr. 2009;10(2):194-212.
16. Dijkmans PA, Senior R, Becher H, et al. Myocardial contrast echocardiography evolving as a clinically feasible technique for accurate, rapid, and
safe assessment of myocardial perfusion: the evidence so far. J Am Coll Cardiol. 2006;48(11):2168-77. Epub 2006.
17. Kaul S, Senior R, Firschke C, et al. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and
without ST-segment elevation: a multicenter study. Am Heart J. 2004;148(1):129-36.
18. Rinkevich D, Kaul S, Wang XQ, et al. Regional left ventricular perfusion and function in patients presenting to the emergency department with
chest pain and no ST-segment elevation. Eur Heart J. 2005;26(16):1606-11. Epub 2005.
19. Jeetley P, Burden L, Greaves K, et al. Prognostic value of myocardial contrast echocardiography in patients presenting to hospital with acute chest
pain and negative troponin. Am J Cardiol. 2007;99(10):1369-73. Epub 2007.
20. Janardhanan R, Moon JC, Pennell DJ, et al. Myocardial contrast echocardiography accurately reflects transmurality of myocardial necrosis and
predicts contractile reserve after acute myocardial infarction. Am Heart J. 2005;149(2):355-62.
21. Choi EY, Seo HS, Park S, et al. Prediction of transmural extent of infarction with contrast echocardiographically derived index of myocardial
blood flow and myocardial blood volume fraction: comparison with contrast-enhanced magnetic resonance imaging. J Am Soc Echocardiogr.
2006;19(10):1211-9.
22. Senior R, Swinburn JM. Incremental value of myocardial contrast echocardiography for the prediction of recovery of function in dobutamine
nonresponsive myocardium early after acute myocardial infarction. Am J Cardiol. 2003;91(4):397-402.
23. Shimoni S, Frangogiannis NG, Aggeli CJ, et al. Identification of hibernating myocardium with quantitative intravenous myocardial contrast echo-
cardiography: comparison with dobutamine echocardiography and thallium-201 scintigraphy. Circulation. 2003;107(4):538-44.
24. Greaves K, Dixon SR, Fejka M, et al. Myocardial contrast echocardiography is superior to other known modalities for assessing myocardial reper-
fusion after acute myocardial infarction. Heart. 2003;89(2):139-44.
25. Bolognese L, Carrabba N, Parodi G, et al. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after
primary coronary angioplasty for acute myocardial infarction. Circulation. 2004;109(9):1121-6. Epub 2004.
26. Galiuto L, Garramone B, Scara A, et al. The extent of microvascular damage during myocardial contrast echocardiography is superior to other
known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J Am Coll Cardiol.
2008;51(5):552-9.
27. Khumri TM, Nayyar S, Idupulapati M, et al. Usefulness of myocardial contrast echocardiography in predicting late mortality in patients with ante-
rior wall acute myocardial infarction. Am J Cardiol. 2006;98(9):1150-5. Epub 2006.
28. Dwivedi G, Janardhanan R, Hayat SA, et al. Prognostic value of myocardial viability detected by myocardial contrast echocardiography early after
acute myocardial infarction. J Am Coll Cardiol. 2007;50(4):327-34. Epub 2007.
29. Wei K, Jayaweera AR, Firoozan S, et al. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles adminis-
tered as a constant venous infusion. Circulation. 1998;97(5):473-83.
30. Masugata H, Lafitte S, Peters B, et al. Comparison of real-time and intermittent triggered myocardial contrast echocardiography for quantification
of coronary stenosis severity and transmural perfusion gradient. Circulation. 2001;104(13):1550-6.
31. Wei K, Ragosta M, Thorpe J, et al. Noninvasive quantification of coronary blood flow reserve in humans using myocardial contrast echocardiogra-
phy. Circulation. 2001;103(21):2560-5.
32. Vogel R, Indermuhle A, Reinhardt J, et al. The quantification of absolute myocardial perfusion in humans by contrast echocardiography: algorithm
and validation. J Am Coll Cardiol. 2005;45(5):754-62.
33. Dolan MS, Gala SS, Dodla S, et al. Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography a
multicenter experience. J Am Coll Cardiol. 2009;53(1):32-8.
34. Main ML, Ryan AC, Davis TE, et al. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound con-
trast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol. 2008;102(12):1742-6. Epub 2008.
35. Wei K, Mulvagh SL, Carson L, et al. The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 ad-
ministered contrast doses. J Am Soc Echocardiogr. 2008;21(11):1202-6. Epub 2008.
36. Abdelmoneim SS, Bernier M, Scott CG, et al. Safety of contrast agent use during stress echocardiography: a 4-year experience from a single-center
cohort study of 26,774 patients. JACC Cardiovasc Imaging. 2009;2(9):1048-56.
37. US Food and Drug Administration Alert. (2008) Micro-bubble Contrast Agents (marketed as Definity (Perflutren Lipid Microsphere) Injectable
Suspension and Optison (Perflutren Protein-Type A Microspheres for Injection). [online] Available from www.fda.gov/Drugs/DrugSafety/Post-
marketDrugSafetyInformationforPatientsandProviders/ucm110260.htm. [Accessed July, 2012].
59 History of Stress
Echocardiography
Upadhyayula S, Kapur KK
HISTORICAL PERSPECTIVES Inge Edler and Helmuth Hertz on October 29, 1953, first reported
M-mode recording of posterior wall and anterior mitral leaflet soon
Tennant and Wiggers (1935) found that coronary ligation leads to followed by the continuous recording of the motion of the mitral
cyanotic appearance of the ischemic myocardium followed by dila- valve and the heart walls with a prototype called the “ultrasonic
tation of the ventricle. Additionally, it was observed that contraction reflectoscope” (Figs 59.2 and 59.3).2
pattern of the ischemic myocardium changes drastically, the details Harvey Feigenbaum (1963) took an ultrasonic transducer and
of which were accurately recorded by a myograph (Figs 59.1A to D).1 placed it on his own chest. He was able to find a signal that was
B D
Figures 59.1A to D: (A and B) Wiggers diagrams showing aortic, atrial, left ventricular pressure curves along with electrocardiogram; (C) Wiggers
well-known for the classic Wiggers diagrams; (D) Stress echocardiography is based on the results of the classic experiment of Tennant and Wiggers,
which proved that ischemia leads to contractile dysfunction. A light-weight mechanical myograph was sewn onto the surface of left ventricle which
depicted progressive failure of contraction over a minute following 1 minute of acute coronary occlusion, proving that the anatomically described
inter coronary anastomoses were not functionally adequate immediately after an ischemic insult. Six segments in an animal model showing (I)
control, (II) slow beat, (III, IV and V) evolution changes in left ventricle myogram during acute left coronary ligation, (VI) recovery following reopening
of left coronary artery. Upper curve (aortic pressure), lower curve (myogram)
Chapter 59  History of Stress Echocardiography 443
A B
C D
Figures 59.2A to D: (A) Inge Edler and Hellmuth Hertz with their first ultrasonic reflectoscope; (B) Inge Edler conversing with Hellmuth Hertz;
(C) Inge Edler seen defending his doctoral thesis in 1961; (D) Inge Eddler used M-mode technique to study mitral stenosis and mitral regurgitation.
Edler is recognized as the “Father of Echocardiography” for his fundamental contributions
fascinating. This was likely to be the same echo that Hertz saw about Arthur M Master (1955) developed the “Master two step test”. An
10 years earlier. By assessing the way the signal was moving and by ECG was obtained before and after a patient walked up and down
checking his own pulse, he judged that the signal must be coming two steps a given number of times. However, the ECG abnormalities
from the back wall of the left ventricle (LV) (Figs 59.4A to F).3,4 did not persist long enough. Additionally, the exercise was limited
and difficult to quantitate. The “Master two step test” and “double
STRESS ECHOCARDIOGRAPHY Master's two-step test” were too strenuous for many patients, inad-
equate for the assessment of respiratory and circulatory function and
Probably the first of the many major technological advances in yielded an unacceptable number of “false-positive” and “false-nega-
stress testing was the development of an electrocardiographic (ECG) tive” cases.5-6
system that produced high quality, interpretable tracings during
exercise. Electrocardiographic and clinical monitoring of exercise Treadmill Exercise Testing
has been the mainstay for evaluating patients with coronary artery
disease (CAD) for decades. However, the sensitivity and specific- Sir William Cubitt (1817) introduced treadmills, also known as
ity were low, especially in patients with resting ECG abnormalities treadwheels which were historically used as a method of reforming
and women. It provides only modest localization and relatively poor offenders in prison.
quantitation of myocardial ischemia.3,4 Francis Gano Benedict (1919) did pioneering work in exercise
Stress echocardiography (SE) includes imaging at the time of physiology and energy metabolism not only in man, but also in most
exercise with supine or upright bicycle ergometry, post-treadmill of the animals ranging from the smallest mouse to the largest ele-
imaging and various forms of pharmacological and pacing stress- phant (Figs 59.4A to F).7
ors.2 Stress echocardiography is highly cost-effective, versatile and Wayne Quinton and Robert Arthur Bruce (1952) invented the
informative. In patients with CAD, cardiovascular stress will induce first medical treadmill, which soon became the gold standard for
myocardial ischemia. Stress echocardiography detects ischemia cardiac stress testing and cardiac rehabilitation (Figs 59.4A to F).8
induced regional wall motion abnormality (RWMA) which serves as Robert Arthur Bruce and Paul Yu pioneered the development of
a marker for the presence of CAD.2-4 treadmill exercise stress test, which involved walking on a treadmill
Figures 59.3A to C: (A) World’s first M-mode echocardiogram done on October 29th, 1953. (I, II, III) first M-mode echocardiogram of posterior
left ventricle wall; (IV) first M-mode echocardiogram of anterior mitral leaflet and posterior left ventricle wall; (B) World’s first ultrasonic cardiac
scanner depicting A-mode, B-mode echocardiogram; (C) The Organon Teknika linear echo scanner from 1973 for recording M-mode and two-
dimensional echocardiograms
while the ECG, ventilation volumes and respiratory gas exchanges M-Mode Stress Echocardiography
were monitored, before, during and after exercise. Because the tread-
mill speed and inclination could be adjusted, this physical activity Harvey Feigenbaum (1963), out of "frustration with the limitations of
was tolerated by most patients.8 cardiac catheterization and angiography", borrowed an unused ech-
Bruce et al. (1949) first published minute-by-minute changes in oencephalography machine. He substituted “cardio” for “Encepha-
respiratory and circulatory function of normal adults and patients lo”, which led to the origin of a new field by the name of “Echocar-
with heart or lung ailments during treadmill exercise (Fig. 59.5).8 diography” (Figs 59.3A to C). Reid proceeded to build an ultrasonic
Bruce (1963) developed the multistage test, consisting of several reflectoscope and teamed with Joyner to repeat the work that Edler
stages of progressively greater workloads—the Bruce protocol. The had done with mitral stenosis (MS). Joyner et al. reported the find-
test could detect signs of angina pectoris, a previous heart attack, ings in 1963. It was the first American article on the cardiac use of
ventricular aneurysm and early CAD (Fig. 59.5).8 diagnostic ultrasound, leading to the birth of “Clinical Echocardiog-
raphy”.2-4
Ergometer Exercise Testing Feigenbaum was able to visualize the posterior LV wall (the only
structure detectable to the very low gain settings), record images of
Ergometer was developed in Hamburg, Germany. It was used to posterior pericardial effusion and publish them in 1965.10-12 This
settle disputes between the government officials and pensioners application probably had the greatest impact in stimulating interest
over pension allotments. The work capacity of the workers were in cardiac ultrasound.2-4,10-17
measured electrically by the ergometer and pensions allotted In 1968, a collaborative effort between Feigenbaum’s group at
according to the work capacity. Later on supine and erect versions Indiana and Dodge’s group at the University of Alabama led to the
of the ergometer were developed. Modern ergometers are fitted to a use of M-mode technique for measuring LV dimensions. In 1972,
tilt table, which can be adjusted to any desired angle during exercise Feigenbaum published the first book on echocardiography and also
(Figs 59.6A to D).9 trained the first sonographer.10-17
A B C
D E F
Figures 59.4A to F: (A) Robert Arthur Bruce hailed as the "Father of Exercise Cardiology" for developing the treadmill exercise test; (B) Harvey
Feigenbaum is widely recognized as the "Father of Modern Echocardiography". He coined the words “Echocardiography”, “Stress Echocardiography”,
trained the first cardiac sonographer and wrote the first textbook of Echocardiography; (C) Francis Gano Benedict did pioneering work in exercise
physiology and energy metabolism; (D) Wayne Quinton, co-inventor of the lightweight cardiac treadmill for medical diagnostics; (E) Wayne Quinton
in his treadmill factory; (F) Naveen Nanda did pioneering research on Cold pressor two-dimensional stress echocardiography, treadmill exercise
two-dimensional stress echocardiography, reproducibility of post treadmill exercise two-dimensional stress echocardiography, exercise-induced
mitral regurgitation in two-dimensional stress echocardiography, Correlation of two-dimensional stress echocardiography with thallium scanning
and visualization of vertical steal by adenosine two-dimensional stress echocardiography
In 1973, Feigenbaum, et al. used echocardiography for detection technique for assessing left ventricular RWMA. There was difficulty
of RWMA of the LV. In 1975, Feigenbaum et al. performed the first in acquiring high-quality images during exercise. In order to
recording of a stress-induced wall motion abnormality using overcome this restriction, transesophageal echocardiography with
M-mode echo and supine bike exercise which led to the birth of SE a new transducer gastroscope system was developed, which proved
(Figs 59.7A and B).10-17 to be a useful method of evaluating RWMA during dynamic exercise
As M-mode echocardiography gained increased acceptance, the (Figs 59.8A to C).18
technique was expanded with two-dimensional (2D) transesophage-
al, three-dimensional (3D) echocardiography, etc. by the relentless Two-Dimensional Stress Echocardiography
work of numerous pioneers of echocardiography (Table 59.1).10-19
M-mode echocardiography proved to be a very useful technique.
Transesophageal M-mode two-dimensional stress echocardio However, there were numerous technical limitations with the single-
graphy: M-mode echocardiography is an accurate and reproducible dimensional M-mode for examining the total heart. The first major
advancement was the development of 2D echocardiography—a

vastly superior tomographic technique (Figs 59.9 and 59.10).19-27
Valsalva Maneuver Two-Dimensional

Stress Echocardiography
Parisi et al. (1976, N = 30) showed that echocardiography allows a
new approach to evaluate the left ventricular response to the Valsalva
maneuver. Patients with severely depressed ejection fractions (EFs),
unlike those with normal ventricular function, are unable to alter
stroke output and have a fixed stroke output in response to Valsalva
stress.28
Isometric Handgrip Two-Dimensional

Figure 59.5: Arrangement of equipment for Bruce’s method of Witham et al. (1974, N = 19) found normal hearts responded to
exercise tolerance testing. While one observer remains on the treadmill isometric handgrip by increasing cardiac index through tachycar-
platform with the patient, records blood pressure, electrocardiogram,
dia and pumping the same stroke index against increased after-
symptoms and signs, the other observer seated at the continuous
analyzer records the heart rate respiratory rate, ventilation volume, gas load, without utilizing diastolic volume reserves supporting the
concentrations, and oximeter at 1 minute intervals
A B
C D
Figures 59.6A to D: (A) Germans measuring work capacity of workers using an ergometer. Pensions were allocated according to work, capacity;
(B) Original bicycle ergometer used in Benedict's experiments to assess exercise energy metabolism in 1919; (C) Wayne Quinton, co-inventor of the
lightweight cardiac treadmill for medical diagnostics at Quinton Instruments; (D) A modern tilt table with ergometer device (tilt ergometer)
tively. None of the patients developed angina, ST-T changes or

ectopy. They observed and emphasized the incremental value of CPT
during RT2DE for detecting CAD in patients with suspected CAD but
no RWMA at rest (Fig. 59.11).31
Hyperventilation Two-Dimensional
A Morales et al. (1993) did pioneering work in the diagnosis of myo-
cardial ischemia at rest using hyperventilation 2D SE. Hyperventila-
tion 2D SE is used as a provocative test for coronary artery spasm
in patients of variant angina. It has a sensitivity ranging from 50% in
patients with less active disease to 80% in patients in with frequent
attacks.32
Treadmill Exercise Two-Dimensional

B Nanda et al. (1981, N = 48), at the University of Alabama, first
Figures 59.7A and B: (A) Echocardiograms at rest (left) and peak performed treadmill exercise 2D SE.33 Later, numerous pioneers
exercise (right) from a patient with near total occlusion of left anterior described in detail not only the technique, diagnostic value, accu-
descending coronary artery and normal left circumflex and right coronary
racy, cost-effectiveness, prognostic implications, expanding applica-
arteries. Both septal and posterior wall thickening are the same at rest.
In exercise, at the time of ischemia, posterior wall systolic thickening has tions, limitations, but also compared treadmill exercise 2D SE with
increased while septal thickening falls; (B) Echocardiograms at rest (Left) other techniques.34-46
and exercise (right) in a normal person. Systolic thickening of both walls Treadmill exercise versus supine bicycle exercise: Treadmill ex-
is the same at rest and increases in exercise ercise leads to more vigorous exercise and greater oxygen consump-
tion and myocardial ischemia as compared to supine bicycle exer-
cise. Echocardiograhic images obtained after treadmill exercise are
hypothesis that isometric muscular exercise leads to an augmenta- superior to those obtained during supine bicycle exercise. Treadmill
tion of LV myocardial contractility in normal man.29 exercise is more reproducible because it is more observer-controlled
and the required parameters are achieved with minimal subject co-
Two-Dimensional Stress Echocardiography operation and patients are more familiar with upright exercise. Su-
pine bicycle exercise permits real-time echocardiographic imaging
with Cold Pressor Test
during exercise and can be very helpful in patients with transient
In 1932, Hines and Brown first described cold pressor test (CPT). ventricular asynergy. However, the echocardiographic images ob-
They showed that cold stimulus leads to sharp increase in heart rate, tained during supine bicycle exercise can sometimes be suboptimal.
blood pressure, myocardial oxygen consumption, alpha adrenergic Another major disadvantage of supine bicycle exercise is the “leg
stimulation and coronary vascular resistance leading to myocardial fatigue”. Most patients develop “leg fatigue” leading to termination
ischemia. of exercise much before the onset of clinical angina, thus negating
Spice, et al. (1983, N = 19), observed for the first time that CPT the use of supine bicycle exercise in many prominent cardiac centers
increased left ventricular end diastolic pressure (LVEDP) in patients worldwide.33,47-52
with severe CAD. They conclude that CPT would be ideal for CAD
patients who cannot or should not exercise. Additionally, CPT can be Reproducibility of Two-Dimensional
combined with TME 2D SE to improve the assessment of CAD.30
Nanda et al. did pioneering research on the utility of CPT for
the evaluation of CAD. Nanda et al. (1984, N = 20), published the Nanda et al. (1989, N = 48) showed for the first time that the two main
first detailed study on the combined usage of CPT with real-time parameters commonly assessed in Treadmill Exercise 2D SE are the
2D echocardiography (RT2DE) in the assessment of patients with pre- and postexercise EF and the pre and postexercise wall motion
suspected CAD, who show no asynergy at rest. The sensitivity and score index (WMSI) were highly reproducible, providing a depend-
specificity of CPT-induced RWMA were 69% and 86% respec- able tool for evaluation of CAD.53,54
TABLE 59.1 Pioneers in stress echocardiography

Modality Pioneers Reference
Contraction pattern of the ischemic myocardium recorded on Tennant R, Wiggers CJ Am J Physiol. 1935;112:351-61.
myograph
1D M-Mode SE Feigenbaum et al. Circulation. 1976;53:657-62.
2D SE Feigenbaum et al. J Am Coll Cardiol. 1983;2:1085-91.
Valsalva Maneuver 2D SE Parisi AF et al. Circulation. 1976;54:921-7.
Isometric hand grip 2D SE Witham AC et al. Heart. 1974;36:988-95.
Cold Pressor 2D SE Spice et al. Br Med J. 1983;286:1924-6.
Cold Pressor 2D SE Nanda et al. Am Heart J. 1984;107:278-85.
MR in reversible myocardial ischemia Nanda et al. Am J Cardiol. 1987;59:1266-70.
Correlation of 2D SE with thallium scanning Nanda et al. Am J Cardiol. 1981;48:1266-70.
Hyperventilation 2D SE Distante et al. Eur Heart J. 1993;14:1088-93.
Treadmill exercise 2D SE Nanda et al. Am J Cardiol. 1981;48:1266-70.
Reproducibility of post TME 2D SE Nanda et al. J Am Coll Cardiol. 1989;14:923-8.
Isometric hand grip 2D SE Crawford et al. Circulation. 1979;59:1188-96.
Supine bicycle 2D SE Feigenbaum et al. Circulation. 1979;60:1300-08.
Upright bicycle 2D SE Crawford et al. Circulation. 1979;59:1188-96.
Diastolic 2D SE Marwick et al. J Am Coll Cardiol. 2006;47:1891-900.
Dobutamine 2D SE Berthe et al. Am J Cardiol. 1986;58:1167-72.
Dobutamine + atropine 2D SE Berthe et al. Am J Cardiol. 1986;58:1167-72.
Esmolol + dobutamine + atropine 2D SE Berthe et al. Am J Cardiol. 1986;58:1167-72.
Trimetazidine + dobutamine + atropine 2D SE Luis et al. Coronary Artery Disease. 2007;18:259-63.
Dobutamine (low dose) 2D SE (Viability) Zoghbi WA et al. Circulation. 1995;91:663-70.
Nitroglycerin + dobutamine 2D (Viability) Lijie Ma et al. Circulation. 1997;96:3992-4001.
MCE + bicycle/TME 2D SE Zoghbi WA et al. J Am Coll Cardiol. 2001;37:741-7.
MCE + dobutamine 2D SE Stefanadis et al. Heart. 2008;94:1571-7.
MCE + dipyridamole 2D SE Feigenbaum et al. Am J Cardiol. 2003;91:1293-8.
Arbutamine 2D SE Hammond et al. J Am Coll Cardiol. 1994;23:475-82.
Adenosine 2D SE Emanuelsson et al. Int J Card Imaging. 1993;9:169-77.
Adenosine 2D SE, Visualization of Vertical Steal Nanda et al. Echocardiography. 2001;18:689-94.
MCE + Adenosine 2D SE De Maria et al. Circulation. 2001;103:2724-30.
MCE + Nicorandil 2D SE J Yoshikawa et al. Heart. 2006;92:1331-2.
Ergometrine 2D SE Lee SJ J Am Soc Echocardiogr. 1994;7:607-15.
Enoximone 2D SE Sergio et al. Circulation. 2000;101:1255-60.
Hemodynamic 2D SE Marwick et al. J Am Coll Cardiol. 2006;47:1891-900.
Preload 2D SE Yamada H et al. Circulation. 2009;120:S728
Strain/SR + Dobutamine 2D SE Takeshi et al. Am J Physiol. 2007;292:H921-7.
VVI + Dobutamine 2D SE Jacobsen et al. Eur J Echocardiogr. 2005;6:S92.
MCE + Adenosine + 2D SE Willenheimer et al. Eur J Echocardiogr. 2005;6:31-40.
Dipyridamole Transesophageal 2D SE Marangelli et al. J Am Coll Cardiol. 1994;24:117-24.
Dobutamine Transesophageal 2D SE Marangelli et al. J Am Coll Cardiol. 1994 24:117-24.
Pacing Transesophageal 2D SE Chapman et al. Circulation. 1984;70(3):445-50.
MCE + Real-time 3D SE Takeuchi et al. J Am Soc Echocardiogr. 2006;19:294-9.
Dobutamine + Real-time 3D SE McCulloch M et al. J Am Coll Cardiol. 2001;37:1303-9.
Dipyridamole + Real-time 3D SE Varnero et al. Cardiovasc Ultrasound. 2008;6:31.
Abbreviations: 2D, Two-dimensional; SE, Stress echocardiography; MR, Mitral regurgitation; MCE, Myocardial contrast echocardiography; VVI, Velocity
vector imaging; TME, Treadmill exercise
A C
Figures 59.8A to C: (A) This composite figure shows transesophageal M-mode echocardiograms at the stages of rest and during different
steps of exercise up to a maximum workload of 100 watts; (B) Transesophageal stress echocardiography. Comparison of regional wall motion
abnormality during different modes (AAI vs VVI)/sites (right ventricle versus interventricular septal) of pacing; (C) Extraischemic causes of septal
motion abnormalities during pacing stress echocardiography
A standard symptom-limited Bruce protocol was used to exer- mitral regurgitation (MR) and increased likelihood of triple-vessel
cise 48 patients to exhaustion or progressive chest pain on a tread- disease. They have emphasized that evaluation of MR by color Dop-
mill exercise testing system and 2D SE done in duplicate on the same pler during treadmill exercise 2D SE may provide incremental infor-
set of patients at a median interval of 14 days. There was high degree mation for detecting patients with CAD.55
of interobserver agreement and temporal reproducibility. The esti- It is well-known that RWMA may precede ECG changes or clini-
mates of EF were within 4% (correlation coefficient 0.92) and WMSI cal symptoms of angina in the event of acute myocardial ischemia.
were within 6% (correlation coefficient 0.98) of values measured in Nanda et al. demonstrated for the first time that MR could be the
the first test.53 first detectable sign of acute myocardial ischemia. In a study involv-
Acceptable temporal reproducibility regarding pre and postexer- ing 22 patients, they found that MR preceded RWMA in six patients
cise EF and WMSI were noted not only in normal subjects, but also in and clinical angina in three patients. Nanda et al. showed that the
patients with CAD who underwent coronary artery bypass grafting, sensitivity and specificity of treadmill exercise-induced MR was
thus enhancing the diagnostic and prognostic applications of 2D SE not only comparable to other modalities, but also had incremental
in the assessment of CAD (Figs 59.12A and B).53 value when combined with other competing modalities. Thus, exer-
cise ECG (sensitivity 54%, specificity 88%), exercise-induced RWMA
EXERCISE-INDUCED MITRAL (sensitivity 59%, specificity 100%), exercise-induced MR (sensitivity
59%, specificity 100%) can be used individually or in combination
REGURGITATION
such as exercise ECG + exercise-induced MR (sensitivity 82%, speci-
Nanda et al. (1987, N = 22), first observed that there was significant ficity 88%), exercise ECG + exercise-induced RWMA (sensitivity 82%,
association between the presence of treadmill exercise-induced specificity 88%) for evaluation of CAD (Figs 59.13A and B).55
A B
C D
Figures 59.9A to D: (A) Diastolic and systolic frames of short-axis cross sectional echocardiograms at the level of the chordae tendineae. During
exercise-induced angina pectoris the anterolateral wall of the ventricle became akinetic; (B) After nitroglycerin, wall motion returned to normal;
(C) Diastolic and systolic frames of long-axis cross sectional echocardiograms of the cardiac apex. (Left) Motion of the inferior wall is normal at rest,
but akinesis appeared with exercise-induced angina; (D) After revascularization (coronary artery bypass grafting), inferior wall motion remained
vigorous throughout the exercise test
Correlation of Two-Dimensional Stress Bicycle Ergometer Two-Dimensional

Echocardiography with Thallium Scanning Stress Echocardiography
Nanda et al. (1981, N = 48), first reported that treadmill exercise- Feigenbaum et al. (1979) obtained cross-sectional echocardiograms
induced thallium perfusion defects showed good correlation with at rest, during supine bicycle exercise and after sublingual nitroglyc-
treadmill exercise-induced asynergy as detected with 2D echocar- erin (NTG) administration. They showed that the mechanical con-
diography performed immediately after treadmill exercise for the sequences of exercise-induced regional myocardial ischemia can be
evaluation of patients with high likelihood of CAD.33 detected noninvasively by real-time, 2D, cross sectional echocardi-
In 48 patients, post-treadmill exercise, echocardiographic ography.23
images in standard planes followed by thallium perfusion scans were
obtained. Digital Two-Dimensional Stress
The sensitivity and specificity of thallium scanning correlated
Echocardiography
well with echocardiographic imaging for left ventricular asynergy.
However, thallium scanning does not provide adequate definition of Digital acquisition and display of images has brought a paradigm
right ventricle, while echocardiographic imaging provides excellent shift in the field of SE. It not only improves quality control and effi-
resolution of right ventricular asynergy. Their results show that the ciency, but also reduces respiratory artifacts inherent in SE. Further-
presence of right and left ventricular asynergy is a good indicator of more, by placing the resting and exercise images side-by-side, the
TVE (Figs 59.14A and B).33 interpretation is greatly facilitated. In 1984, Feigenbaum at Indiana
A B
C D
Figures 59.10A to D: (A) End diastolic and end systolic still frames of a long-axis and two-dimensional echocardiogram obtained before atrial
pacing. No regional wall motion abnormality noted; (B) Still frames obtained during transesophageal echocardiography atrial pacing. Akinesis of
distal interventricular septal noted. The patient had a critical occlusion of his left anterior descending artery; (C) End diastole and end systole still
frames of a long-axis two-dimensional echocardiogram obtained before transesophageal echocardiography atrial pacing. No regional wall motion
abnormality noted; (D) An outline of endocardial position at end diastole and end systole shows akinesis in the posterior wall that appeared during
atrial pacing. The patient had significant lesions in both the left circumflex and right coronary arteries
University developed the world’s first all-digital echocardiography Kulbertus et al. (1989, N = 15), showed that stroke volume (SV)
laboratory.3,4,56,57 increased at low-dose dobutamine echocardiography (LDDE) in
Videotapes are difficult to retrieve and interpret. As a result, groups A and B (all patients whether EF increases or not). During
relatively few echocardiograms are seen by any physician other than peak-dose dobutamine echocardiography (PDDE), SV remained
the one who officially interprets the echocardiogram. Cardiologists unchanged in CAD patients who are negative for reversible ischemia.
should be encouraged to look at echocardiograms on their own. While in patients who are positive for reversible ischemia, SV
Having an echocardiographic expert and a clinical expert examine decreased with no change in pulmonary artery wedge pressure.58-62
the same recording improves the overall value of the test.3,4,56,57 Picano et al. (1996) on behalf of the Echo-Persantine Interna-
Digital recordings can be placed on a computer network and tional Cooperative (EPIC) and Echo-Dobutamine International Co-
made available at numerous stations, including clinicians' offices. operative (EDIC) Study Groups published a report stating that there
Examinations are retrieved in less than 30 seconds and are avail- is no consistency between the site of induced ischemia during SE
able 24 hours a day, 7 days a week. The repetitive cine loops can be and the site of future infarction. However, most infarctions occurring
analyzed at one's own speed and multiple or serial studies can be within 1 year of SE are in the sites identified as ischemic.62-68
easily displayed side-by-side.3,4,56,57 Pingitore et al. (1996) on behalf of the EPIC and EDIC Study
Groups showed that dobutamine-atropine and dipyridamole-at-
Dobutamine Two-Dimensional Stress ropine SE are safe and feasible, although submaximal studies are
more frequent with dobutamine. The two stresses have comparable
Echocardiography
accuracy in the detection of angiographically assessed CAD,
Berthe et al. (1986), pioneered in the use of dobutamine stress echo- although dobutamine is marginally more sensitive and dipyridamole
cardiography (DSE) for predicting the extent and location of CAD in marginally more specific. Stratification of the ischemic response in
acute myocardial infarction (MI) patients.58 the space domain is also comparable with the two stresses.62-68
Figure 59.11: Two-dimensional echocardiograms before and during cold pressor test in a coronary artery disease patient showing normal
contractility during rest and dyskinesia of apical inferior and apical septal segments during intervention Abbreviations: I, Inferior; L, Left; LA, Left
atrium; MV, Mitral valve; PW, Posterior wall; R, Right; RA, Right atrium; RV, Right ventricle; S, Superior; TA, Tricuspid annulus
A B
Figures 59.12A and B: Treadmill exercise testing and two-dimensional stress echocardiography done in duplicate on the same set of 19 patients
at a median interval of 14 days; (A) Ejection fractions plot; (B) Wall motion score index plot. There was a high degree of interobserver agreement and
temporal reproducibility. The estimates of ejection fraction were within 4% (correlation coefficient 0.92) and wall motion score index was within 6%
(correlation coefficient 0.98) of values measured in the first test
A B
Figures 59.13A and B: Exercise-induced mitral regurgitation, Color Doppler evaluation at rest and during exercise in a patient with three vessel
disease. (A) No evidence of any reverse flow signals into left atrium during systole at rest; (B) Evidence of reverse flow signals (blue mosaic signals
originating at mitral valve) emanating into left atrium during systole after 3 minutes of exercise
A B
Figures 59.14A and B: (A) Two-dimensional echocardiograms (Parasternal long-axis view) before and after exercise in a coronary artery disease
patient showing no regional wall motion abnormality at rest but marked hypokinesia after exercise; (B) Two-dimensional echocardiograms (Apical
four chamber view) before and after exercise in a coronary artery disease patient showing no regional wall motion abnormality at rest but marked
apical dyskinesia after exercise. These results correlated well with the thallium perfusion scans. Images at top are systolic frames and images at
bottom are diastolic frames Abbreviations: I, Inferior; L, Left; LA, Left atrium; MV, Mitral valve; PW, Posterior wall; R, Right; RA, Right atrium; RV, Right
ventricle; S, Superior; TA, Tricuspid annulus
Sicari et al. (1997) on behalf of the EDIC study groups noted that the coronary flow is diverted from the ischemic to the nonischemic
during dobutamine stress, echocardiographic recognition of myo- regions causing further ischemia in the region of the diseased coro-
cardial viability is more prognostically important than echocardio- nary artery, also known as “Steal Phenomenon” or “Reverse Robin
graphic recognition of myocardial ischemia for predicting unstable Hood Effect”. Adenosine has a much shorter half-life, and thus an
angina, whereas regional wall motion score index (RWMSI) at peak antidote is usually not necessary in the event of an adverse reac-
stress was the best predictor of cardiac-related death. Different tion.78,79 Kanjuh et al. (1996) developed the high-dose adenosine
events can be recognized with different efficiency by various stress SE protocol and also validated the standard dose adenosine SE
echocardiographic variables.62-68 protocol.80
Gramiak and Shah while performing an ultrasound examination
Dipyridamole Two-Dimensional on a patient undergoing cardiac catheterization, found that an indo-
cyanine green dye injection for cardiac output determination pro-
duced a huge cloud of echoes within the heart. Joyner noticed similar
Cortigiani et al. (1998) on behalf of the EPIC and EDIC study groups echoes while injecting saline much earlier, but he never reported that
observed that pharmacologic SE with either dobutamine or dipy- finding.3,4
ridamole is effective in risk stratification of single-vessel disease and De Maria et al. (2001) reported the comparative value of dobu-
can accurately discriminate patients in whom coronary revasculari- tamine and adenosine SE in the detection of coronary stenosis with
zation can have the maximal beneficial effect. These findings have myocardial contrast echocardiography (MCE).81,82 Willenheimer et
a potential favorable impact on the cost-effectiveness of invasive al. (2003) suggested real-time perfusion adenosine SE in the coro-
procedures.67 nary care unit as a bedside tool for predicting coronary artery steno-
Pingitore et al. (1999) on behalf of the EPIC and EDIC study sis in patients with acute coronary syndrome.83-85
groups concluded that in patients at low-to-moderate risk of cardiac
events, pharmacological SE with either dobutamine or dipyridamole Real-Time Myocardial Contrast
allows effective and grossly comparable risk stratification on the
Echocardiography + Supine Bicycle/
basis of the presence, severity and extension of the induced
ischemia.68
Treadmill Exercise Two-Dimensional Stress
Echocardiography
Arbutamine Two-Dimensional Stress Zoghbi et al. (2001) showed that myocardial perfusion and wall
motion can be recorded simultaneously in real-time during supine
Echocardiography
bicycle and post-treadmill exercise echocardiography57,86,87 at low
Hammond et al. (1994), Armstrong et al. (1995) and other groups mechanical index and frame rates. The combination of RWMA and
did extensive work on arbutamine SE. Arbutamine is a synthetic MCE correlates well with single photon emission computed tomog-
beta-adrenoceptor agonist developed specifically designed for car- raphy (SPECT) and adds incremental information to conventional
diovascular stress testing. Arbutamine SE is an effective pharma- SE.54
cologic stress test technique for diagnosing or excluding the pres-
ence of CAD. The ability of arbutamine stress to induce myocardial Real-Time Myocardial Contrast
ischemia, detectable by echocardiography was comparable to that
Echocardiography + Dobutamine-Atropine
for exercise. Arbutamine SE was significantly superior to exercise
testing for either ST change/angina, or for angina alone. Sensitivity,
Two-Dimensional Stress Echocardiography
specificity and accuracy in detecting significant CAD are 76%, 96% Ritter et al. (1976) used contrast to study truncus arteriosus, tetralogy
and 82% respectively.69-77 of Fallot, pulmonary atresia with ventricular septal defect.17 Kronik
et al. (1979) used contrast M-mode echocardiography for diagnosing
Real-Time Myocardial Contrast atrial septal defect in acyanotic patients.12
Polderman et al. (1994) pioneered the dobutamine-atro-
Echocardiography + Adenosine Two-
pine stress echocardiography (DASE) protocol for the diagnostic
Dimensional Stress Echocardiography approach of CAD. The advent of intravenous echo-contrast media
Emannuelson et al. (1993) and Marwick et al. (1997) did extensive signaled their use during SE studies, initially for better endocar-
work on adenosine SE and developed the high-dose and standard dial border delineation and subsequently for myocardial perfusion
adenosine SE protocols. Adenosine is the most powerful endoge- studies. The concurrent use of real-time MCE with stress (both
nous vasodilator. It causes vasodilatation of microcirculation and not exercise and pharmacological) echocardiography has shown high
of epicardial arteries. Additionally, it causes flow maldistribution— diagnostic accuracy in the detection of CAD.63,88-95
Real-Time Myocardial Contrast identification of viable myocardium and predict functional recovery
Echocardiography + Two-Dimensional after revascularization.101
Dipyridamole-Exercise Two-Dimensional
Stress Echocardiography Trimetazidine + Dobutamine + Atropine Two-
Dimensional Stress Echocardiography
Marwick et al. (2004) showed that addition of low-mechanical index
MCE to standard imaging combined dipyridamole-exercise echocar- Luiz et al. from their randomized, double-blind, placebo-controlled
diography provides incremental benefit for evaluation of CAD and DASE study showed that trimetazidine reverses ischemia in patients
enables a more accurate determination of the disease extent.96 with class I or II angina.102
Real-Time Myocardial Contrast Nitroglycerin Two-Dimensional Low-Dose

Echocardiography + Nicorandil Two- Dobutamine Echocardiography
Dimensional Stress Echocardiography Kranidis et al. and Lijie et al. (1999) showed that NTG enhances the
Okajima et al. (2006) showed that MCE with nicorandil stress improvement of wall thickening at LDDE and does not prevent PDDE
may provide comparable diagnostic accuracy for the detection of from inducing ischemia in hibernating myocardium. Thus, NTG
coronary stenosis with fewer adverse reactions than with the augments the biphasic response of wall thickening and improves the
conventional stress MCE with dipyridamole and adenosine.97 accuracy of DSE for detecting viable myocardium.103,104
Intravenous MCE during pharmacological stress has emerged
as a promising tool to detect myocardial perfusion abnormalities in Strain in Two-Dimensional Stress
patients with CAD. Most patients develop certain minor side-effects
Echocardiography
during administration of dipyridamole or adenosine. Nicorandil, a
hybrid adenosine triphosphate-sensitive potassium channel opener Takeshi et al. (2007) showed that myocardial contraction has trans-
and nitrate compound, exerts coronary vasodilatation effect with mural heterogeneity. Myocardial strain, which reflects regional
fewer adverse reactions.97 myocardial function, can be obtained noninvasively. Transmural
myocardial strain profile (TMSP) involves obtaining and mapping
Ergonovine Two-Dimensional Stress of myocardial strain from each wall layer. The combination of TMSP
and DSE may help to demonstrate transmural distribution of viable
Echocardiography
myocardium in subepicardial MI and transmural MI.105
Distante et al. (1999) reported that development of RWMAs due to Transmural myocardial strain profile has shown promise in
coronary vasospasm (CVS) could be detected by echocardiogra- the assessment of transmural differences in local inotropic reserve
phy before any ECG change during spasm provocation testing in within the viable and infarcted myocardium. In subendocardial in-
the catheterization laboratory.98 Song et al. (1996) proposed that a farction, the subepicardial myocardial strain showed an increase in
bedside ergonovine provocation test with 2D echocardiographic contraction with dobutamine which was not observed in transmural
monitoring of left ventricular wall motion could be used as a reliable infarction.105
noninvasive diagnostic method for CVS in patients with near-normal Marwick et al. (2006) reported analysis of segmental peak sys-
angiographic findings.99,100 tolic strain rate (SR) and end-systolic strain derived from automated
SR imaging analysis of DSE response, gives prognostic information
Enoximone Two-Dimensional Stress that is independent and incremental to standard RWMSI.106-108
Echocardiography for Viability

Velocity Vector Imaging in Two-Dimensional
Sergio et al. (2000) enoximone, a nonglycoside, noncatechol, positive
inotropic agent that acts via selective inhibition of the cyclic adeno-
sine monophosphate-specific phosphodiesterase, is widely used for Jacobsen et al. (2005) showed that measurement of radial myocardial
the treatment of heart failure. It does not increase myocardial oxy- velocity and displacement using the novel speckle tracking modality
gen demand and could represent a valid alternative for the detection does not appear to add to the diagnostic power of time velocity inte-
of viable myocardium by means of SE. In patients with congestive gral analysis during DASE.109
heart failure, including those with CAD, enoximone has been shown Saha et al. (2009) showed that the non-Doppler-based speckle
to be extremely safe over a wide range of doses (0.25–3.0 mg/kg). tracking echocardiography (STE) with dobutamine stress can quan-
Additionally, the action of enoximone is not influenced by alpha tify radial, circumferential, longitudinal strain and rotational (tor-
or beta-adrenergic blockade or by catecholamine depletion. sion) mechanics of the LV with favorable signal-to-noise ratio may
Enoximone echocardiography appears particularly suitable for the help risk stratify CAD patients.110-112
Marwick et al. (2010) showed that combination of time veloc- sion SE with Imagify (perflubutane polymer microspheres) showed
ity integral (TVI) with STE during DSE can predict viability. Time results similar to stress perfusion imaging using 99mTc SPECT.
velocity integral strain and SR are most accurate. While TVI measures Imagify perfusion SE was well-tolerated and its diagnostic perfor-
can predict viability in both anterior and posterior circulations, STE mance in chest pain patients is comparable with SPECT perfusion
measurements predict viability only in the anterior circulation.113-119 imaging.139
Pacing Transesophageal Two-Dimensional TWO-DIMENSIONAL AND THREE-

Stress Echocardiography DIMENSIONAL ECHOCARDIOGRAPHY IN
Chapman et al. (1984) introduced transesophageal atrial pacing for
NON-CORONARY HEART DISEASES
detection of ischemic wall motion abnormalities. The safety and ac- Marwick et al. (2000) pioneered the use of SE in non-coronary
curacy of pacing stress echocardiography for detection of CAD are heart diseases. Stress echocardiography is particularly useful in the
comparable to DSE. There are two main applications of pacing stress assessment of left ventricular dysfunction, pulmonary hypertension,
in the echo lab: the noninvasive detection of CAD through induction anthracycline cardiotoxicity and valvular heart diseases.140
of a regional transient dysfunction; and the assessment of contrac-
tile reserve (CR) through peak systolic pressure/end-systolic volume Valvular Heart Diseases
relationship at increasing heart rates to assess global left ventricular
contractility (Figs 59.8 and 59.10).120-127 In aortic stenosis (AS), DSE can distinguish severe from nonsevere
It is difficult to detect myocardial ischemia by noninvasive meth- AS in patients with LV dysfunction, low transvalvular gradients and
ods in patients with a pacemaker. Electrocardiogram at rest and/or a relatively small aortic valve area (AVA). Patients with nonsevere AS
during exercise is an unreliable indicator of ischemia. In this subset present with increased SV and AVA with dobutamine infusion, while
of patients, DSE and exercise SE are reliable indicators of ischemia the transvalvular gradient does not change significantly. In severe
for the detection of CAD.120-127 AS, the pressure gradient and SV increase, but AVA does not. In pa-
tients who fail to increase SV, the severity of the lesion is “indetermi-
REAL-TIME THREE-DIMENSIONAL nate” and the prognosis is very poor.140
In MS patients, exercise may increase mitral valve area, SV and
DOBUTAMINE STRESS
pulmonary artery systolic pressure. The increase in PASP during ex-
ECHOCARDIOGRAPHY ercise in MS patients is usually different from controls with compa-
Mullis-Jansson et al. (1999) followed by numerous other groups rable resting hemodynamics. Thus exercise stress echocardiography
did pioneering work in the field of real-time 3D echocardiography (ESE) provides information which can be helpful to guide medical
(RT3DE). Regional wall motion abnormality in the apical region [left and surgical therapy.140
anterior descending (LAD) artery territory] can be better evaluated The use of SE in patients with regurgitant lesions is still contro-
by RT3DE than 2D echocardiography. Real-time 3D echocardiogra- versial and a subject of investigation. Exercise stress echocardiogra-
phy results when validated using coronary angiography as reference phy following aortic valve replacement can identify impairment of
indicate diagnostic equivalence to 2D echocardiography, with the systolic and diastolic function indicative of “valve prosthesis-patient
advantage of considerable shorter acquisition times.128-146 mismatch”.
Real-time 3D echocardiography has significantly higher global
and regional (in the apical region) WMSI than 2D echocardiography Cardiomyopathies
at peak stress with dobutamine infusion. Thus, RT3DE has higher
sensitivity than 2DE in the LAD artery territory without any signifi- In hypertrophic cardiomyopathy, exercise or pharmacological SE
cant difference in specificity.129-138,147-154 can help in the assessment of the dynamics of left ventricular outflow
tract obstruction.140
REAL-TIME MYOCARDIAL In dilative cardiomyopathy, CR can be assessed by DSE. It can
help in prognostication, management of heart failure, administra-
CONTRAST ECHOCARDIOGRAPHY
tion of cardiotoxic chemotherapeutic agents.140
+ THREE-DIMENSIONAL STRESS
ECHOCARDIOGRAPHY
HEMODYNAMIC TWO-DIMENSIONAL
Takeuchi et al. (2006) followed by many other groups did pio-
STRESS ECHOCARDIOGRAPHY
neering work in the field of contrast-enhanced real-time live 3D
DSE.133-138 Picard et al. (2009) on behalf of the RAMP (real-time Andersen et al. (2010) studied echocardiographic indices of contrac-
assessment of myocardial perfusion-1 and 2) concluded that perfu- tion and filling pressures with invasive measures in 12 ambulatory
left ventricular assist device (LVAD) patients undergoing symptom- easing its detection. Contractile reserve is a predictor of the extent of
limited bicycle exercise. Exercise induced an increase in cardiac reverse remodeling and may help in stratifying responders from non-
output, PASP and diastolic pulmonary artery pressure. Although no responders to CRT. The degree of clinical and echocardiographic
changes in left ventricular dimensions or fractional shortening were response correlated with the extent of peak septal flash seen during
seen on echocardiography, systolic mitral annular motion increased LDDE.146,155
significantly (in parallel with cardiac output) and diastolic E/E' ratio
decreased (correlating inversely with PADP). These findings empha-
size the potential role of ESE in studying hemodynamics in LVAD
patients.141 Abbreviations and Acronyms
AS aortic stenosis
AML anterior mitral leaflet
PRELOAD TWO-DIMENSIONAL STRESS AVA aortic valve area
ECHOCARDIOGRAPHY CAD coronary artery disease
Yamada et al. (2009) observed that the Doppler transmitral flow veloc- CPT cold pressor test
ity pattern has prognostic value in patients with heart failure. Patients CR contractile reserve
with a relaxation failure (RF) pattern (E < A) have better prognosis CVS coronary vasospasm
than those with a pseudonormal or restrictive pattern (E > A). Howev- DASE dobutamine–atropine stress echocardiography
er, this differentiation could not be applied in patients with mild heart DSE dobutamine stress echocardiography
failure, whose flow pattern often show a RF pattern. In order to distin- E early diastolic trans mitral velocity
guish these patients, Yamada et al. (2009) developed “preload SE” in E’ early diastolic tissue velocity
which leg positive pressure was performed during Doppler recording. EF ejection fraction
The change in transmitral flow velocity pattern by preload increment ECG electrocardiogram
provides additional prognostic information over resting conventional ESE exercise stress echocardiography
Doppler echocardiographic parameters. Leg positive pressure is a EPIC echo-persantine international cooperative
useful method for “preload SE” that achieves noninvasive preload EDIC echo-dobutamine international cooperative
augmentation during echocardiographic examination.142 IVS interventricular septal
LAD left anterior descending artery
LDDE low-dose dobutamine echocardiography
DIASTOLIC TWO-DIMENSIONAL STRESS LVAD left ventricular assist device
ECHOCARDIOGRAPHY LV left ventricle
Marwick et al. (2006) showed that increase in LVEDP causes exer- LVEDP left ventricular end diastolic pressure
tional dyspnea which is commonly seen in patients with hyperten- MI myocardial infarction
sive and diabetic heart diseases. Ejection fraction is characteristically MS mitral stenosis
preserved in these patients. Under resting conditions, the ratio of MCE myocardial contrast echocardiography
early diastolic transmitral velocity to tissue velocity (E/E’) correlates MI myocardial infarction
with LVEDP, and an E/E’ of greater than 15 has been found to be a re- MR mitral regurgitation
liable means of predicting an elevated LVEDP. The estimation of E/E’ NTG nitroglycerin
during physical exercise may help in the assessment of the effects of PDDE peak-dose dobutamine echocardiography
changes in LVEDP on exercise capacity. This method can be used to RCA right coronary artery
reliably identify patients with elevated LVEDP during exercise.143-145 RT3DE three-dimensional echocardiography
RWMA regional wall motion abnormality
RWMSI regional wall motion score index
EVALUATION OF CARDIAC RF relaxation failure
RESYNCHRONIZATION THERAPY SV stroke volume
RESPONDERS BY TWO-DIMENSIONAL LOW- SPECT single photon emission computed tomography
DOSE DOBUTAMINE ECHOCARDIOGRAPHY SE stress echocardiography
+ MYOCARDIAL CONTRAST SPECT single photon emission computed tomography
ECHOCARDIOGRAPHY SR strain rate
STE speckle tracking echocardiography
Sutherland et al. (2009) reported LDDE increases and unmasks TMSP transmural myocardial strain profile
left bundle branch block-induced dys-synchronous motion (CR) TVI time velocity integral
ing, etc. and their amalgamation with SE has opened up exciting

CONCLUSION
prospects.
History of SE has been long and varied. Over the years it has Thus as we “crystal gaze” into the future of SE, it is evident that
evolved from a unidimensional qualitative videotaped analysis of this technique is likely to be more quantitative, sophisticated, objec-
stress-induced RWMA to a digital multidimensional and quanti- tive and standardized. The others are likely to pose some challenges.
tative assessment of both myocardial function/perfusion under Stress echocardiography because of its portability, cost-effective-
stress conditions. A quantum leap occurred with the introduction ness, lack of ionizing radiation, repeatability and reproducibility,
of pharmacological stressors like dobutamine, atropine, dipyrida- has an edge over other noninvasive technologies like cardiac MRI,
mole, adenosine, etc. This allowed assessment of ischemia and cardiac CT. It is imperative that attention is devoted to intensive
viability in patients with varying degrees of LV dysfunction. The training of medical and paramedical personnel. With increasing
introduction of newer molecules such as nicorandil, enoximone sophistication the operator’s experience and expertise become even
for pharmacological SE are under investigation. The advent of more important. Thus the old adage that “no information” is far
newer technologies like RT-3DE, tissue Doppler, speckle track- better than “wrong information” is still very much relevant.
REFERENCES
1. Tennant R, Wiggers CJ. The effect of coronary circulation on myocardial contraction. Am J Physiol. 1935;112:351-61.
2. Kamp O. History of echocardiography in the Netherlands: 30 years of education and clinical applications. Neth Heart J. 2008;16(1):16-20.
3. Feigenbaum H. History of echocardiography. ACC Current J Rev; 2001. p. 42.
4. Feigenbaum H. Evolution of stress testing. Circulation. 1992;85(3):1217-18.
5. Arthur M. Myocardial Infarction And Master Two-Step Test. J Am Med Assoc. 1955;158:970.
6. Fitzgibbon GM, Burggraf GW, Groves TD, et al. A double Master’s two-step test: clinical, angiographic and hemodynamic correlations. Ann Intern
Med. 1971;74(4):509-17.
7. Benedict FG. (1938). Vital energetics: a study in comparative basal metabolism. Washington DC: Carnegie Institution.
8. Bruce RA, Lovejoy FW, Pearson R, et al. Normal respiratory and circulatory pathways of adaptation in exercise. J Clin Invest. 1949;28(6 Pt 2):1423-
30.
9. Czell et al. Journal of Neuro Engineering and Rehabilitation. 2004;1:4.
10. Wann LS, Hallam CC, Dillon JC, et al. Comparison of M-mode and cross-sectional echocardiography in infective endocarditis. Circulation.
1979;60(4):728-33.
11. Kisslo J. Comparison of M-mode and two-dimensional echocardiography. Circulation. 1979;60(4):734-6.
12. Kronik G, Slany J, Moesslacher H. Contrast M-mode echocardiography in diagnosis of atrial septal defect in acyanotic patients. Circulation.
1979;59(2):372-8.
13. Dillon JC, Feigenbaum H, Weyman, AE, et al. M-mode echocardiography in the evaluation of patients for aneurysmectomy. Circulation.
1976;53(4):657-62.
14. Corya BC, Rasmussen S, Knoebel SB, et al. M-mode echocardiography in evaluating left ventricular function and surgical risk in patients with
coronary artery disease. Chest. 1977;72(2):181-5.
15. Sahn DJ, DeMaria A, Kisslo J, et al. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardio-
graphic measurements. Circulation. 1978;58(6):1072-83.
16. Rasmussen S, Corya BC, Feigenbaum H, et al. Detection of myocardial scar tissue by M-mode echocardiography. Circulation. 1978;57(2):230-7.
17. Assad-Morell JL, Seward JB, Tajik AJ, et al. Echo-phonocardiographic and contrast studies in conditions associated with systemic arterial trunk
overriding the ventricular septum: truncus arteriosus, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect. Circulation.
1976;53(4):663-73.
18. Matsumoto M, Hanrath P, Kremer P, et al. Evaluation of left ventricular performance during supine exercise by transoesophageal M-mode echo-
cardiography in normal subjects. Br Heart J. 1982;48(1):61-6.
19. Jacobs JJ, Feigenbaum H, Corya BC, et al. Detection of left ventricular asynergy by echocardiography. Circulation. 1973;48(2):263-71.
20. Weyman AE, Feigenbaum H, Dillon JC, et al. Noninvasive visualization of the left main coronary artery by cross-sectional echocardiography. Cir-
culation. 1976;54(2):169-74.
21. Wann LS, Dillon JC, Weyman AE, et al. Echocardiography in bacterial endocarditis. N Engl J Med. 1976;295(3):135-9.
22. Dortimer AC, DeJoseph RL, Shiroff RA, et al. Distribution of coronary artery disease. Prediction by echocardiography. Circulation. 1976;54(5):
724-9.
23. Wann LS, Faris JV, Childress RH, et al. Exercise cross-sectional echocardiography in ischemic heart disease. Circulation. 1979;60(6):1300-8.
24. Heger JJ, Weyman AE, Wann LS, et al. Cross-sectional echocardiography in acute myocardial infarction: detection and localization of regional left
ventricular asynergy. Circulation. 1979;60(3):531-8.
25. Weyman AE, Wann LS, Caldwell RL, et al. Negative contrast echocardiography: a new method for detecting left-to-right shunts. Circulation.
1979;59(3):498-505.
26. Robertson WS, Feigenbaum H, Armstrong WF, et al. Exercise echocardiography: a clinically practical addition in the evaluation of coronary artery
disease. J Am Coll Cardiol. 1983;2(6):1085-91.
27. Folland ED, Parisi AF, Moynihan PF, et al. Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardi-
ography. A comparison of cineangiographic and radionuclide techniques. Circulation. 1979;60:760-6.
28. Pratt RC, Parisi AF, Harrington JJ, et al. The influence of left ventricular stroke volume on aortic root motion: an echocardiographic study. Circula-
tion. 1976;53(6):947-53.
29. Stefadouros MA, Grossman W, El-Shahawy M, et al. Noninvasive study of effect of isometric exercise on left ventricular performance in normal
man. Heart. 1974;36(10):988-95.
30. Seneviratne BI, Linton I, Wilkinson R, et al. Cold pressor test in diagnosis of coronary artery disease: echophonocardiographic method. Br Med J
(Clin Res Ed). 1983;286(6382):1924-6.
31. Gondi B, Nanda NC. Cold pressor test during two-dimensional echocardiography: usefulness in detection of patients with coronary disease. Am
Heart J. 1984;107(2):278-85.
32. Morales MA, Reisenhofer B, Rovai D, et al. Hyperventilation—echocardiography test for the diagnosis of myocardial ischaemia at rest. Eur Heart
J. 1993;14(8):1088-93.
33. Maurer G, Nanda NC. Two dimensional echocardiographic evaluation of exercise-induced left and right ventricular asynergy: correlation with
thallium scanning. Am J Cardiol. 1981;48(4):720-7.
34. Marwick TH, Nemec JJ, Pashkow FJ, et al. Accuracy and limitations of exercise echocardiography in a routine clinical setting. J Am Coll Cardiol.
1992;19(1):74-81.
35. Mertes H, Erbel R, Nixdorff U, et al. Exercise echocardiography for the evaluation of patients after nonsurgical coronary artery revascularization. J
Am Coll Cardiol. 1993;21(5):1087-93.
36. Marwick TH, Anderson T, Williams MJ, et al. Exercise echocardiography is an accurate and cost-efficient technique for detection of coronary ar-
tery disease in women. J Am Coll Cardiol. 1995;26(2):335-41.
37. Arnese M, Salustri A, Fioretti PM, et al. Quantitative angiographic measurements of isolated left anterior descending coronary artery stenosis.
Correlation with exercise echocardiography and technetium-99m 2-methoxy isobutyl isonitrile single-photon emission computed tomography. J
Am Coll Cardiol. 1995;25:1486-91.
38. Kafka H, Leach AJ, Fitzgibbon GM. Exercise echocardiography after coronary artery bypass surgery: correlation with coronary angiography. J Am
Coll Cardiol. 1995;25(5):1019-23.
39. Rallidis L, Cokkinos P, Tousoulis D, et al. Comparison of dobutamine and treadmill exercise echocardiography in inducing ischemia in patients
with coronary artery disease. J Am Coll Cardiol. 1997;30(7):1660-8.
40. Heupler S, Mehta R, Lobo A, et al. Prognostic implications of exercise echocardiography in women with known or suspected coronary artery dis-
ease. J Am Coll Cardiol. 1997;30(2):414-20.
41. Marwick TH, Mehta R, Arheart K, et al. Use of exercise echocardiography for prognostic evaluation of patients with known or suspected coronary
artery disease. J Am Coll Cardiol. 1997;30(1):83-90.
42. McCully RB, Roger VL, Mahoney DW, et al. Outcome after normal exercise echocardiography and predictors of subsequent cardiac events: follow-
up of 1,325 patients. J Am Coll Cardiol. 1998;31(1):144-9.
43. Hoffer EP, Dewe W, Celentano C, et al. Low-level exercise echocardiography detects contractile reserve and predicts reversible dysfunction after
acute myocardial infarction: comparison with low-dose dobutamine echocardiography. J Am Coll Cardiol. 1999;34:989-97.
44. Badruddin SM, Ahmad A, Mickelson J, et al. Supine bicycle versus post-treadmill exercise echocardiography in the detection of myocardial is-
chemia: a randomized single-blind crossover trial. J Am Coll Cardiol. 1999;33(6):1485-90.
45. Arruda AM, Das MK, Roger VL, et al. Prognostic value of exercise echocardiography in 2,632 patients > or = 65 years of age. J Am Coll Cardiol.
2001;37(4):1036-41.
46. McCully RB, Roger VL, Mahoney DW, et al. Outcome after abnormal exercise echocardiography for patients with good exercise capacity: prognos-
tic importance of the extent and severity of exercise-related left ventricular dysfunction. J Am Coll Cardiol. 2002;39:1345-52.
47. Thadani U, West RO, Mathew TM, et al. Hemodynamics at rest and during supine and sitting bicycle exercise in patients with coronary artery
disease. Am J Cardiol. 1977;39(6):776-83.
48. Crawford MH, White DH, Amon KW. Echocardiographic evaluation of left ventricular size and performance during handgrip and supine and
upright bicycle exercise. Circulation. 1979;59(6):1188-96.
49. Currie PJ, Kelly MJ, Pitt A. Comparison of supine and erect bicycle exercise electrocardiography in coronary heart disease: accentuation of exer-
cise-induced ischemic ST depression by supine posture. Am J Cardiol. 1983;52(10):1167-73.
50. Marx GR, Hicks RW, Allen HD. Measurement of cardiac output and exercise factor by pulsed Doppler echocardiography during supine bicycle
ergometry in normal young adolescent boys. J Am Coll Cardiol. 1987;10(2):430-4.
51. Lethen H, Tries HP, Zuercher F, et al. Transthoracic real-time three-dimensional bicycle stress echocardiography- Comparison of this new tech-
nique with conventional two-dimensional bicycle stress echocardiography. Eur J Echocardiogr. 2006;7:S171.
52. Park TH, Tayan N, Takeda K, et al. Supine bicycle echocardiography improved diagnostic accuracy and physiologic assessment of coronary artery
disease with the incorporation of intermediate stages of exercise. J Am Coll Cardiol. 2007;50(19):1857-63.
53. Oberman A, Fan PH, Nanda NC, et al. Reproducibility of two-dimensional exercise echocardiography. J Am Coll Cardiol. 1989;14(4):923-8.
54. Shimoni S, Zoghbi WA, Xie F, et al. Real-time assessment of myocardial perfusion and wall motion during bicycle and treadmill exercise echocar-
diography: comparison with single photon emission computed tomography. J Am Coll Cardiol. 2001;37(3):741-7.
55. Zachariah ZP, Hsiung MC, Nanda NC, et al. Color Doppler assessment of mitral regurgitation induced by supine exercise in patients with coronary
artery disease. Am J Cardiol. 1987;59(15):1266-70.
56. Marangelli V, Iliceto S, Piccinni G, et al. Detection of coronary artery disease by digital stress echocardiography: comparison of exercise,
transesophageal atrial pacing and dipyridamole echocardiography. J Am Coll Cardiol. 1994;24(1):117-24.
57. Cohen JL, Greene TO, Ottenweller J, et al. Dobutamine digital echocardiography for detecting coronary artery disease. Am J Cardiol.
1991;67(16):1311-8.
58. Pierard LA, Berthe C, Albert A, et al. Haemodynamic alterations during ischaemia induced by dobutamine stress testing. Eur Heart J. 1989;10(9):783-
90.
59. Pierard LA, De Landsheere CM, Berthe C, et al. Identification of viable myocardium by echocardiography during dobutamine infusion in patients
with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol. 1990;15(5):1021-31.
60. Berthe C, Pierard L, Hiernaux M, et al. Predicting the extent and location of coronary artery disease in acute myocardial infarction by echocardi-
ography during dobutamine infusion. Am J Cardiol. 1986;58(13):1167-72.
61. Pierard LA, De Landsheere CM, Berthe C, et al. Identification of viable myocardium by echocardiography during dobutamine infusion in patients
with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol. 1990;15(5):1021-31.
62. Picano E. Stress echocardiography: a historical perspective. Am J Med. 2003;114(2):126-30.
63. Pingitore A, Picano E, Colosso MQ, et al. The atropine factor in pharmacologic stress echocardiography. Echo Persantine (EPIC) and Echo Dobu-
tamine International Cooperative (EDIC) Study Groups. J Am Coll Cardiol. 1996;27(5):1164-70.
64. Sicari R, Picano E, Landi P, et al. Prognostic value of dobutamine-atropine stress echocardiography early after acute myocardial infarction. Echo
Dobutamine International Cooperative (EDIC) Study. J Am Coll Cardiol. 1997;29(2):254-60.
65. Varga A, Picano E, Cortigiani L, et al. Does stress echocardiography predict the site of future myocardial infarction? A large-scale multicenter
study. EPIC (Echo Persantine International Cooperative) and EDIC (Echo Dobutamine International Cooperative) study groups. J Am Coll Car-
diol. 1996;28:45-51.
66. Picano E, Sicari R, Landi P, et al. The multicentre trial philosophy in stress echocardiography: lessons learned fom the EPIC study. EPIC-EDIC
Study Project. Echo Persantine International Cooperative Study. Echo Dobutamine International Cooperative Study. Eur Heart J. 1995;16
Suppl J:2-4.
67. Cortigiani L, Picano E, Landi P, et al. Value of pharmacologic stress echocardiography in risk stratification of patients with single-vessel disease: a
report from the echo-persantine and echo-dobutamine international cooperative studies. Echo-Persantine (EPIC) and Echo-Dobutamine Inter-
national Cooperative (EDIC) Study Groups. J Am Coll Cardiol. 1998;32:69-74.
68. Pingitore A, Picano E, Varga A, et al. Prognostic value of pharmacological stress echocardiography in patients with known or suspected coronary
artery disease: a prospective, large-scale, multicenter, head-to-head comparison between dipyridamole and dobutamine test. Echo-Persantine
International Cooperative (EPIC) and Echo-Dobutamine International Cooperative (EDIC) Study Groups. J Am Coll Cardiol. 1999;34(6):1769-77.
69. Hammond HK, McKirnan MD. Effects of dobutamine and arbutamine on regional myocardial function in a porcine model of myocardial is-
chemia. J Am Coll Cardiol. 1994;23(2):475-82.
70. Armstrong WF, Bach DS. Clinical and diagnostic utility of arbutamine for cardiovascular stress testing during echocardiographic monitoring. Eur
Heart J. 1995;16 Suppl M:24-7.
71. Kiat H, Iskandrian AS, Villegas BJ, et al. Arbutamine stress thallium-201 single-photon emission computed tomography using a computerized
closed-loop delivery system. Multicenter trial for evaluation of safety and diagnostic accuracy. The International Arbutamine Study Group. J Am
Coll Cardiol. 1995;26:1159-67.
72. Cohen JL, Chan KL, Jaarsma W, et al. Arbutamine echocardiography: efficacy and safety of a new pharmacologic stress agent to induce myocardial
ischemia and detect coronary artery disease. The International Arbutamine Study Group. J Am Coll Cardiol. 1995;26(5):1168-75.
73. Dennis CA, Pool PE, Perrins EJ, et al. Stress testing with closed-loop arbutamine as an alternative to exercise. The International Arbutamine Study
Group. J Am Coll Cardiol. 1995;26(5):1151-8.
74. Marwick TH. Arbutamine stress testing with closed-loop drug delivery. Toward the ideal or just another pharmacologic stress technique? J Am
Coll Cardiol. 1995;26(5):1176-9.
75. Ketteler T, Krahwinkel W, Wolfertz J, et al. Arbutamine stress echocardiography. Eur Heart J. 1997;18:24-30.
76. Kisanuki A, Segar DS, Ryan T, et al. Arbutamine stimulation detects viable myocardium 4 weeks after coronary occlusion. J Am Soc Echocardiogr.
2001;14(2):138-48.
77. Ruiz M, Takehana K, Petruzella FD, et al. Arbutamine stress perfusion imaging in dogs with critical coronary artery stenoses: Tc-99m-sestamibi
versus (201)Tl. J Nucl Med. 2002;43(5):664-70.
78. Kujacic VG, Jablonskiene D, Emanuelsson HU. Adenosine echocardiography--an alternative to dynamic stress echocardiography. Int J Card Imag-
ing. 1993;9(3):169-77.
79. Marwick TH. Adenosine echocardiography in the diagnosis of coronary artery disease. Eur Heart J. 1997;18:31-6.
80. Djordjevic-Dikic AD, Ostojic MC, Beleslin BD, et al. High dose adenosine stress echocardiography for noninvasive detection of coronary artery
disease. J Am Coll Cardiol. 1996;28(7):1689-95.
81. Lafitte S, Matsugata H, Peters B, et al. Comparative value of dobutamine and adenosine stress in the detection of coronary stenosis with myocar-
dial contrast echocardiography. Circulation. 2001;103(22):2724-30.
82. Winter R, Gudmundsson P, Willenheimer R. Real-time perfusion adenosine stress echocardiography in the coronary care unit: a feasible and ac-
curate bedside tool for predicting coronary artery stenosis in patients with acute coronary syndrome. Eur J Echocardiogr. 2003;4:S136.
83. Winter R, Gudmundsson P, Willenheimer R. Real-time perfusion adenosine stress echocardiography in the coronary care unit: a feasible bedside
tool for predicting coronary artery stenosis in patients with acute coronary syndrome. Eur J Echocardiogr. 2005;6(1):31-40.
84. Hagendorff A, Pearson, M, Werner A, et al. Tissue velocity imaging and myocardial contrast echocardiography with power Doppler harmonic
imaging during adenosine stress. Eur J Echocardiogr. 2003;4:S3.
85. Tiemann K, Ghanem A, Schlosser T, et al. Subendocardial steal effect seen with real-time perfusion imaging at low emission power during adeno-
sine stress: replenishment M-mode processing allows visualization of vertical steal. Echocardiography. 2001;18(8):689-94.
86. Vandenberg BF, Fleagle SR, Skorton DJ. Exercise echocardiography and quantitative angiography: improved identification of physiologically sig-
nificant coronary artery stenoses. J Am Coll Cardiol. 1990;15(5):1052-4.
87. Labovitz AJ. Exercise echocardiography after coronary angioplasty: expanding applications. J Am Coll Cardiol. 1990;15(3): 600-1.
88. Poldermans D, Fioretti PM, Boersma E, et al. Dobutamine-atropine stress echocardiography in elderly patients unable to perform an exercise test.
Hemodynamic characteristics, safety, and prognostic value. Arch Intern Med. 1994;154(23):2681-6.
89. Roman JAS, Vilacosta I, Fernandez A, et al. dipyridamole and dobutamine-atropine stress echocardiography in the diagnosis of coronary artery
disease: comparison with exercise stress test, analysis of agreement, and impact of antianginal treatment. Chest. 1996;110:1248-54.
90. Chen L, Ma L, de Prada, VA, et al. Effects of beta-blockade and atropine on ischemic responses in left ventricular regions subtending coronary
stenosis during dobutamine stress echocardiography. J Am Coll Cardiol. 1996;28(7):1866-76.
91. Smart SC, Knickelbine T, Stoiber TR, et al. Safety and accuracy of dobutamine-atropine stress echocardiography for the detection of residual ste-
nosis of the infarct-related artery and multivessel disease during the first week after acute myocardial infarction. Circulation. 1997;95:1394-401.
92. Smart SC, Dionisopoulos PN, Knickelbine TA, et al. Dobutamine-atropine stress echocardiography for risk stratification in patients with chronic
left ventricular dysfunction. J Am Coll Cardiol. 1999;33(2):512-21.
93. Marwick TH. The balance between speed and efficacy in stress echocardiography: is earlier use of atropine the answer? Eur J Echocardiogr.
2000;1(4):231-2.
94. Smart SC, Bhatia A, Hellman R, et al. Dobutamine-atropine stress echocardiography and dipyridamole sestamibi scintigraphy for the detection
of coronary artery disease: limitations and concordance. J Am Col. Cardiol. 2000;36(4):1265-73.
95. Ferreiro E, Alvarez ME, Bujan L. Dobutamine stress echo in patients treated with beta blockers. New dobutamine atropine protocol. Eur J
Echocardiogr. 2005;6:S189.
96. Moir S, Haluska BA, Jenkins C, et al. Incremental benefit of myocardial contrast to combined dipyridamole-exercise stress echocardiography for
the assessment of coronary artery disease. Circulation. 2004;110(9):1108-13.
97. Okajima K, Kawase Y, Matsushita N, et al. Usefulness of myocardial contrast echocardiography with nicorandil stress for the detection of coro-
nary artery stenosis. Heart. 2006;92(9):1331-2.
98. Rovai D, Distante A, Moscarelli E, et al. Transient myocardial ischemia with minimal electrocardiographic changes; an echocardiographic study
in patients with Prinzmetal’s angina. Am Heart J. 1985;109(1):78-83.
99. Song JK, Park SW, Kim JJ, et al. Values of intravenous ergonovine test with two-dimensional echocardiography for diagnosis of coronary artery
spasm. J Am Soc Echocardiogr. 1994;7(6):607-15.
100. Song JK, Lee SJ, Kang DH, et al. Ergonovine echocardiography as a screening test for diagnosis of vasospastic angina before coronary angiogra-
phy. J Am Coll Cardiol. 1996;27(5):1156-61.
101. Lu C, Carlino M, Fragasso G, et al. Enoximone echocardiography for predicting recovery of left ventricular dysfunction after revascularization: a
novel test for detecting myocardial viability. Circulation. 2000;101(11);1255-60.
102. Cesar LA, Mathias W Jr, Armaganijan D, et al. Trimetazidine to reverse ischemia in patients with class I or II angina: a randomized, double-blind,
placebo-controlled dobutamine–atropine stress echocardiography study. Coronary Artery Dis. 2007;18(4):259-63.
103. Kranidis A, Bouki T, Kostopoulos K, et al. Stress echocardiography using adenosine combined with nitroglycerin- dobutamine in the detection of
viable myocardium in patients with previous myocardial infarction. Angiology. 1997;48(2):127-33.
104. Ma L, Chen L, Gillam L, et al. Nitroglycerin enhances the ability of dobutamine stress echocardiography to detect hibernating myocardium. Cir-
culation. 1997;96(11):3992-4001.
105. Maruo T, Nakatani S, Jin Y, et al. Evaluation of transmural distribution of viable muscle by myocardial strain profile and dobutamine stress echo-
cardiography. Am J Physiol Heart Circ Physiol. 2007;292(2):H921-7.
106. Hanekom L, Mai NV, Har J, et al. Incremental benefit of SRI to the accuracy of novice and expert interpreters of dobutamine stress echocardiog-
raphy. Eur J Echocardiogr. 2006;7:S21.
107. Mai N, Marwick TH. Subclinical right ventricular dysfunction in patients with right coronary territory ischaemia. Findings of strain rate imaging
at dobutamine stress echocardiography. Eur J Echocardiogr. 2006;7:S175.
108. Bjork Ingul C, Rozis E, Marwick TH. Prediction of mortality using strain rate in dobutamine stress echocardiography. Eur J Echocardiogr.
2005;6:S193.
109. Jacobsen P, Mobasseri Y, Roumina S, et al. Does speckle tracking analysis of both radial and longitudinal myocardial motion add to the diagnostic
power of tissue Doppler analysis during dobutamine stress echocardiography? Eur J Echocardiogr. 2005;6:S92.
110. Ingul CB, Stoylen A, Slordahl SA, et al. Automated analysis of myocardial deformation at dobutamine stress echocardiography: an angiographic
validation. J Am Coll Cardiol. 2007;49(15):1651-9.
111. Hanekom L, Cho GY, Leano R, et al. Comparison of two-dimensional speckle and tissue Doppler strain measurement during dobutamine stress
echocardiography: an angiographic correlation. Eur Heart J. 2007;28(14):1765-72.
112. Jeng M, Carbajal M, Brodin LA, et al. Speckle tracking echocardiography (2-D strain) allows diagnosis of left ventricular regional systolic and
diastolic dysfunction in patients with coronary artery disease at rest. Eur J Echocardiogr. 2005;6:S1.
113. Bansal M, Jeffriess L, Leano R, et al. Assessment of myocardial viability at dobutamine echocardiography by deformation analysis using tissue
velocity and speckle-tracking. JACC Cardiovasc Imaging. 2010;3(2):121-31.
114. Yang HS, Mookadam F, Warsame TA, et al. Evaluation of right ventricular global and regional function during stress echocardiography using
novel velocity vector imaging. Eur J Echocardiogr. 2010;11:157-64
115. Govind SC, Gopal AS, Netyo A, et al. Quantification of low-dose dobutamine stress using speckle tracking echocardiography in coronary artery
disease. Eur J Echocardiogr. 2009;10(5):607-12.
116. Rasmussen VG, Poulsen SH, Dupont E, et al. Ergotamine-derived dopamine agonists and left ventricular function in Parkinson patients: systolic
and diastolic function studied by conventional echocardiography, tissue Doppler imaging, and two-dimensional speckle tracking. Eur J Echocar-
diogr. 2008;9:803-8.
117. Helle-Valle T, Edvardsen T, Amundsen BH, et al. Combined assessment of segmental circumferential strain and segmental rotation by speckle
tracking echocardiography in normal and ischemic myocardium. Eur J Echocardiogr. 2005;6:S1.
118. Leal S, Azevedo J, Abecasis J, et al. Optimizing stress echocardiography: diagnostic capabilities of velocity vector imaging analysis for coronary
artery disease. Circulation. 2009;120:S385-6.
119. Sun Y, Ruan W, Xu YQ, et al. Comparison of left ventricular tangential and radial movement in patients with chronic heart failure using vector
velocity imaging echocardiography. Eur J Heart Fail Suppl. 2007;6:128.
120. Chapman PD, Doyle TP, Troup PJ, et al. Stress echocardiography with transesophageal atrial pacing: preliminary report of a new method for
detection of ischemic wall motion abnormalities. Circulation. 1984;70(3):445-50.
121. Lambertz H, Kreis A, Trumper H, et al. Simultaneous transesophageal atrial pacing and transesophageal two-dimensional echocardiography: a
new method of stress echocardiography. J Am Coll Cardiol. 1990;16(5):1143-53.
122. lliceto S, Sorino M, D’Ambrosio G. Papa A, et al. Detection of coronary artery disease by two-dimensional echocardiography and transesophageal
atrial pacing. J Am Coll Cardiol. 1990;16:143-53.
123. Flachskampf FA, Lethen H, Hoffmann R, et al. Transesophageal stress echocardiography. Eur Heart J. 1997;18 suppl D:D37-42.
124. Benchimol D, Mazanomf M, Brocba B, et al. Detection of coronary stenoses by stress echocardiography using a previously implanted pacemaker
for ventricular pacing: Preliminary Report of a New Method. Clin Cardiol. 2000;23:842-8.
125. Lee CY, Pellikka PA, McCully RB, et al. Nonexercise stress transthoracic echocardiography: transesophageal atrial pacing versus dobutamine
stress. J Am Coll Cardiol 1999;33(2):506-11.
126. Rainbird AJ, Pellikka PA, Stussy VL, et al. A rapid stress-testing protocol for the detection of coronary artery disease: comparison of two-stage
transesophageal atrial pacing stress echocardiography with dobutamine stress echocardiography. J Am Coll Cardiol. 2000;36:1659-63.
127. Tress J, Da Costa LS, Victer RC, et al. Echo transesophageal stress with dobutamine: better screening for coronary artery disease. Eur J Echocar-
diogr. 2003;4:S97.
128. Walimbe V, Garcia M, Lalude O, et al. Quantitative real-time 3-dimensional stress echocardiography: a preliminary investigation of feasibility and
effectiveness. J Am Soc Echocardiogr. 2007;20(1):13-22.
129. Aggeli C, Giannopoulos G, Misovoulos P, et al. Real-time three-dimensional dobutamine stress echocardiography for coronary artery disease
diagnosis: validation with coronary angiography. Heart. 2007;93(6):672-5.
130. Varnero S, Santagata P, Pratali L, et al. Head to head comparison of 2D vs real time 3D dipyridamole stress echocardiography. Cardiovasc Ultra-
sound. 2008;6:31.
131. Leung KY, van Stralen M, Nemes A, et al. Sparse registration for three-dimensional stress echocardiography. IEEE Trans Med Imaging.
2008;27(11):1568-79.
132. Sawada SG, Thomaides A. Three-dimensional stress echocardiography: the promise and limitations of volumetric imaging. Curr Opin Cardiol.
2009;24(5):426-32.
133. Takeuchi M, Otani S, Weinert L, et al. Comparison of contrast-enhanced real-time live 3-dimensional dobutamine stress echocardiography with
contrast 2-dimensional echocardiography for detecting stress-induced wall-motion abnormalities. J Am Soc Echocardiogr. 2006;19(3):294-9.
134. Takeuchi M, Lang RM. Three-dimensional stress testing: volumetric acquisitions. Cardiol Clin. 2007;25(2):267-72.
135. Pulerwitz T, Hirata K, Abe Y, et al. Feasibility of using a real-time 3-dimensional technique for contrast dobutamine stress echocardiography. J Am
Soc Echocardiogr. 2006;19(5):540-5.
136. Krenning BJ, Vletter WB, Nemes A, et al. Real-time 3-dimensional contrast stress echocardiography: a bridge too far? J Am Soc Echocardiogr.
2007;20(10):1224-5.
137. Nemes A, Geleijnse ML, Krenning BJ, et al. Usefulness of ultrasound contrast agent to improve image quality during real-time three-dimensional
stress echocardiography. Am J Cardiol. 2007;99(2):275-8.
138. Krenning BJ, Nemes A, Soliman OI, et al. Contrast-enhanced three-dimensional dobutamine stress echocardiography: between Scylla and Cha-
rybdis? Eur J Echocardiogr. 2008;9(6):757-60.
139. Senior R, Monaghan M, Main ML, et al. Detection of coronary artery disease with perfusion stress echocardiography using a novel ultrasound
imaging agent: two phase three international trials in comparison with radionuclide perfusion imaging. Eur J Echocardiogr. 2009;10:26-35.
140. Marwick TH. Application of stress echocardiography to the evaluation of non-coronary heart disease. Eur J Echocardiogr. 2000;1(3):171-9.
141. Andersen M, Gustafsson F, Madsen PL, et al. Hemodynamic stress echocardiography in patients supported with a continuous-flow left ventricu-
lar assist device. J Am Coll Cardiol Img. 2010;3:854-9.
142. Yamada H, Kusunose K, Nishio S, et al. Prognostic value of changes in transmitral flow velocity pattern during leg positive pressure in mild heart
failure: a clinical application of “preload stress echocardiography”. Circulation. 2009;120:S728.
143. Burgess MI, Jenkins C, Sharman JE, et al. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of
ventricular filling pressure with exercise. J Am Coll Cardiol. 2006;47(9):1891-900.
144. Burgess MI, Jenkins C, Cho GY, et al. Development of the diastolic stress test: non-invasive assessment of left ventricular filling pressure post-
exercise. Eur J Echocardiogr. 2005;6:S178.
145. Kort S, Mamidipally S, Madahar P, et al. Real time three-dimensional diastolic stress echocardiography: a new approach for assessing diastolic
function. Circulation. 2009;120:S310.
146. Parsai C, Baltabaeva A, Anderson L, et al. Low-dose dobutamine stress echo to quantify the degree of remodelling after cardiac resynchronization
therapy. Eur Heart J. 2009;30(8):950-8.
147. Zwas DR, Takuma S, Mullis-Jansson S, et al. Feasibility of real-time 3-dimensional treadmill stress echocardiography. J Am Soc Echocardiogr.
1999;12(5):285-9.
148. Ahmad M, Xie T, McCulloch M, et al. Real-time three-dimensional dobutamine stress echocardiography in assessment of ischemia: comparison
with two dimensional dobutamine stress echocardiography. J Am Coll Cardiol. 2001;37(5):1303-9.
149. Sugeng L, Kirkpatrick J, Lang RM, et al. Biplane stress echocardiography using a prototype matrix-array transducer. J Am Soc Echocardiogr.
2003;16(9):937-41.
150. Matsumura Y, Hozumi T, Arai K, et al. Non-invasive assessment of myocardial ischaemia using new real-time three-dimensional dobutamine
stress echocardiography: comparison with conventional two-dimensional methods. Eur Heart J. 2005;26(16):1625-32.
151. Lang RM, Mor-Avi V, Sugeng L, et al. Three-dimensional echocardiography: the benefits of the additional dimension. J Am Coll Cardiol.
2006;48(10):2053-69.
152. Jacobs LD, Salgo IS, Goonewardena S, et al. Rapid online quantification of left ventricular volume from real-time three-dimensional echocardio-
graphic data. Eur Heart J. 2006;27(4):460-8.
153. Eroglu E, D’hooge J, Herbots L, et al. Comparison of real-time tri-plane and conventional 2D dobutamine stress echocardiography for the assess-
ment of coronary artery disease. Eur Heart J. 2006;27(14):1719-24.
154. Ingul CB, Stoylen A, Slordahl SA, et al. Automated analysis of myocardial deformation at dobutamine stress echocardiography: an angiographic
validation. J Am Coll Cardiol. 2007;49(15):1651-9.
155. Parsai C, Baltabaeva A, Anderson L, et al. Can changes in intra-ventricular dyssynchrony during low dose dobutamine stress echo quantify de-
gree of response to cardiac resynchronization therapy? Circulation. 2007;16:554-64.
Role of Echocardiography in
60 Congenital Heart Disease—
Catheter Interventions
Awasthy N, Shrivastava S
ROLE OF ECHOCARDIOGRAPHY IN Shunt Lesions

CONGENITAL HEART DISEASE—CATHETER Atrial Septal Defect
INTERVENTIONS Fossa ovalis type of atrial septal defects (ASDs) are only suitable for
Any invasive therapeutic modality necessitates thorough prepro- the catheter intervention and hence other types of ASDs need to be
cedure evaluation, intraprocedure monitoring and postprocedure excluded on echo before considering for the ASD device closure.
assessment. Echocardiography (echo) is a very essential tool in this Checklist for the same is given in Table 60.2A and the suitability
aspect. The refinement in echo imaging techniques has substituted for percutaneous device closure is given in Table 60.2B. The atrial
echo as the main stay in diagnosis and decision making in patient septum should be visualized from multiple views in order to assess
with congenital heart disease (CHD). Transthoracic echocardiogra-
phy (TTE) provides adequate imaging of cardiac anatomy in children TABLE 60.2A Checklist for evaluation of atrial septal defect
by itself, but in grown up children and adults with limited transtho- • Confirm diagnosis
racic windows, transesophageal echocardiography (TEE) plays an
• A
ssess size and number of defect, all rims, atrial septal length (in
important role in decision making (Tables 60.1A and B). The authors
children)
have classified the present discussion under: (a) closing or creating
• Hemodynamic assessment
shunts/communications; (b) relieving obstructive lesions.
– Direction of shunt, degree of shunt
– Pulmonary artery pressure
• Associated defects
TABLE 60.1A Aim of the echocardiography in catheterization laboratory
– Atrioventricular valve abnormality
• Good Images of lesions in all planes
– Anomalous pulmonary venous connection.
• Relation of the lesion to other structures
• Any lesion needing open heart surgery
• No interferences with sterility
• No interference in use of image intensifier
TABLE 60.2B Criteria for suitability for device closure
TABLE 60.1B Role of echocardiography in catheter intervention • Fossa ovalis ASD, left to right shunt
• Before the procedure – Single/multiple/fenestrated

– Aneurysm of interatrial septum
– Patient selection
– Selection of device/balloon/stent. • R
ight ventricle volume overload suggestive of Left to right shunt
> 1.5: 1
• During the procedure
• A
dequate rims (≥ 5 mm)—SVC, IVC, Atrial, Atrioventricular (AV) and
– Catheter/balloon/device placement
Aortic
– Monitoring the procedure
– Assessing results and complications. Deficient aortic rim is not considered to be important in isolation.
• On follow-up Exclusion of
– Look for the observed therapeutic response Other type ASDs besides fossa ovalis ASD
– The impact on surrounding structures. Other structural heart defects requiring open-heart surgery
TABLE 60.2C Checklist immediately after device pacemaker on • Apical four-chamber (4C) view: This view is mainly used to
transesophageal echocardiography before release of the device measure the total length of atrial septum (septal length) in order
• Check position of right atrial and LA disks to prevent oversizing of device during closure of the defect, to
• Look for excessive mobility this may lead to prolapse of the device access atrioventricular septal rim, to see evidence of right-
• A
ll rims should be seen properly positioned between the left and right sided volume overload and atrioventricular valves abnormali-
atrial disks of the device. ties. By keeping the transducer medially, visualization of atrial
• Encroachment of the device over adjacent structures septum can be optimized especially in patients where subcostal
– P
roximity to mitral and tricuspid valves and regurgitation of windows are not adequate as in adult and obese patients. The
these valves should be assessed. If significant encroachment or shortcoming of the view is that the alignment of the ultrasound
regurgitation is seen the device needs repositioning beam being parallel to the septum leads to false echo dropouts
– Pulmonary venous flow should be laminar in the region of the interatrial septum. Hence subcostal views are
– Superior vena cava and IVC flows should be laminar extremely important to assess the ASDs.
– Device should not be touching the atrial wall • Subcostal coronal view: In this view, the septum is aligned almost
– Residual ASD flow should be ruled out perpendicular to the ultrasound beam, as a result the area of fos-
– Additional ASD should be looked for and if significant size it should sa ovalis is particularly well profiled and it is possible to distin-
be closed on the same sitting guish a true defect from artifactual drop out (latter is misleading
– Ventricular function need to be assessed feature of 4C view). So this is the preferred view for visualization
– P
resence of pericardial effusion should be ruled out. If present of fossa ovalis ASD. Rims addressed in subcostal coronal view are
cause looked for and treated atrial rim and atrioventricular rim. With anterior tilt from stand-
– Any increase in pulmonary arterial pressures should not occur ard coronal view, aortic rim can be visualized.
• Subcostal sagittal view: This view profiles the atrial septum along
its superior-inferior axis. This view is best to profile SVC and IVC
the location, size, shape, number (single or multiple of ASDs) and its rims. The defect may extend superiorly (deficient SVC rim) or
relationship to the adjacent structures particularly to superior vena inferiorly (deficient IVC rim) and needs to be addressed before
cava (SVC), inferior vena cava (IVC), pulmonary veins, coronary taking decision for device closure.
sinus, aorta, atrial wall and crux. Hemodynamic consequences • Parasternal views: Parasternal short and long axis views are used
as right ventricle (RV) volume overload, pulmonary artery (PA) to look for hemodynamic evidence of ASD in form of dilated RV
pressure should also be assessed in other views. Other associated and flattened or paradoxical motion of interventricular septum
lesions like pulmonary valve stenosis or mitral valve disease should with sizeable left to right shunt. Parasternal short axis view is
be carefully looked for (Table 60.2C). very good to profile atrial and aortic rims. These views are also
Various echo views which help to delineate the rims of the ASD useful in evaluation of pulmonary venous connection to left
include (Figs 60.1A to C): atrium.
A B C
Figures 60.1A to C: 2D echocardiographic views with various rims of the atrial septal defect; (A) Subcoastal 4-chamber view shows aortic valve
rim and the atrial rim (arrow); (B) Parasternal short axis view demonstrates aortic rim and atrial rim (marked by X); (C) Subcoastal coronal view at
the level of the inferior vena cava (IVC) shows the superior vena cava and the IVC rim (arrow)
Chapter 60  Role of Echocardiography in Congenital Heart Disease... 465
EVALUATION OF ATRIAL SEPTUM BY Intraprocedure Role of Echocardiography

TRANSESOPHAGEAL ECHOCARDIOGRAPHY
In authors’ institution, the procedure of ASD device closure is done
In adolescents and adults as subcostal windows do not provide ad- under fluoroscopic and TEE guidance under general anesthesia.
equate penetration, TEE is required for detailed profilation of the In the beginning of the procedure, TEE helps in reassessing the
ASD. Views which are most useful for evaluation of ASD (rotating the diameter of the defect and hence choosing the appropriate sized
cursor from 0o to 90°) on TEE are: (a) four-chamber view; (b) basal device and to look for additional defects, size of various rims which
short axis view; (c) bicaval or basal long axis view (Figs 60.2A to C). might suggest modification in the procedure of deployment of the
(a) Four-chamber view: A four-chamber view can be obtained by device across the ASD. If there are two defects, one can easily meas-
keeping the endoscope at the lower part of esophagus. This view ure the distance between the two defects so as to decide if the defects
profiles the atrial septum with fossa ovalis defect in the middle of can be closed by one device or separate devices. TEE also helps in
septum, atrial and atrioventricular valve rims; volume overload- guiding the operator as to which defect is crossed by the catheter in
ed right atrium and RV. By rotating the endoscope we can see the case of presence of multiple defects.
attachment of right and left pulmonary veins to left atrium. During device deployment (Figs 60.3A and B), TEE plays very
(b) Basal short axis view: This view can be obtained by keeping the important role. Left atrial (LA) disk is opened from the preselected
endoscope at the middle part of esophagus. This view provides approach. As LA disk opens, the total assembly should be pulled
imaging of aortic valve (AV) and atrial septum. The aortic and toward the interatrial septum carefully and should be checked on
atrial rims can be best seen in this view. The fossa ovalis defect is TEE, in all planes that no part of the LA disk is prolapsing. After con-
seen in middle part of the atrial septum. firming that device is holding properly across the defect, right atrial
(c) Basal long axis or bicaval view: This view can be obtained by (RA) disk of the device should be opened. Device position should
keeping the endoscope at the same level and rotating the icon then be checked in all views carefully to assess if the device is firm-
to 80–100. This profiles the relation of ASD to superior and IVC, ly holding all the rims or not. With anterior defect, in basal short
fossa ovalis defect is seen in middle part of septum and SVC and axis view the device should straddle the aorta. Color flow mapping
IVC rims can be accurately assessed in this view. should be used to look for any residual defect; small flow through
M-mode, Doppler and color flow imaging are performed for the fabrics is very commonly seen and should not be considered
objective hemodynamic assessment and to confirm the presence of as residual flow. Careful evaluation of atrioventricular valves, SVC,
echo dropout seen on two-dimensional (2D) imaging. The charac- IVC, pulmonary veins and presence of pericardial effusion should be
teristic pulsed Doppler tracing and or color flow imaging confirms done. Before releasing the device, a gentle pull and push maneuver
the echo dropout as a true defect. Interrogation of the atrioventricu- of the device should be done this is called Minnesota wiggle, under
lar and semilunar valves for regurgitation and stenosis is necessary. TEE and fluoroscopic guidance to check for stability of device.
The tricuspid regurgitation (TR) velocity should always be obtained After confirming proper positioning and stability of device, the
to predict the right ventricular systolic pressure and hence indirectly device should be released. Again after device deployment, on TEE
the PA pressure. one should look for residual flow, AV regurgitation, impact on SVC
A B C
Figures 60.2A to C: (A) Transesophageal echocardiography showing four-chamber view; (B) With atrial and aortic valve rims. Basal short axis
view showing atrial and aortic rims; and (C) Basal long axis view showing superior vena cava and inferior vena cava rims
balloon inflated, rest of the septum should be scanned for additional

defect on color flow mapping. With two significant ASDs in differ-
ent planes, it is important to balloon size both the defects under TEE
guidance as two devices will be required to close both the defects,
if the defects are not close to each other. After taking out the sizing
balloon(s), the inflated balloon size is measured on the measuring
plate and appropriate device size should be selected. When there is
aneurysm of interatrial septum with multiple fenestrations, sizing
of defect is not required and usually defect closure is done by single
device though closure with multiple devices has been reported (Figs
60.4A and B).
A B Follow-Up
Figures 60.3A and B: (A) Transesophageal echocardiography with
On follow-up, TTE (2D and color flow mapping) from subcostal, api-
basal short axis view device deployment with the opposition of both
the disks just after the release of the device; (B) Same view showing cal four-chamber and parasternal short axis views is used for profi-
checking for the presence of the residual shunt by color flow mapping lation of device and to see for presence of any residual flow, AV re-
after device deployment gurgitation, flow acceleration in pulmonary vein (PV), SVC or IVC
and assessment of PA pressure. On follow-up M-mode echo is used
to look for right ventricular dimensions and interventricular septal
flow, IVC flow, pulmonary venous flow, ventricular function and motion (paradoxical, flattened or normal).
pericardial effusion.
PATENT FORAMEN OVALE
Balloon Sizing
Before planning for percutaneous device closure of patent foramen
Routinely in single ASDs balloon sizing is not necessary. With mul- ovale (PFO), morphology of PFO needs to be looked carefully on
tiple ASDs, it is very important to assess the catheter passes through echo. As patients requiring PFO closure are usually grown up chil-
the main and largest hole or in the case of fenestrated ASDs through dren and adults, TEE usually required for delineating the morphol-
the central hole. Then a sizing balloon is passed over the guidewire ogy of PFO. Variations in PFO morphology are: simple flap, tunnel
and inflated to occlude the ASD flow. This size of the inflated balloon type PFO (overlap of the septum primum and septum secundum of
will reflect the size of the defect which is to be closed under fluoro- > 6 mm), isolated aneurysm of interatrial septum without a tunnel,
scopic and TEE guidance. The balloon size is measured on TEE. With associated additional ASD.
A B
Figures 60.4A and B: (A) Transesophageal echocardiography images at the level of basal short axis view with balloon occlusion of the defect;
(B) Shows the same patient on color mapping of the defect with flow of additional atrial septal defect after the balloon occlusion
On TEE, basal short axis and four chamber views are used to
define the morphology of PFO. With PFO device closure a higher
device: defect ratio (2:1-3:1) is recommended. It has been noted that
larger device to defect ratio is required to close tunnel type PFO,
septal aneurysm and associated ASD compare to simple flat PFO.
Role of TEE during device deployment is same as with ASD device
closure. Successful PFO device closure is defined as no right to left
shunt on TEE and angiography with Valsalva.
Balloon Atrial Septostomy or Septal Dilatation

Balloon atrial septostomy (BAS) is indicated in certain cyanotic car-
diac conditions with restrictive interatrial communications such as
in: (a) complete transposition of great vessels with or without ven-
tricular septal defect (VSD); (b) tricuspid atresia; (c) pulmonary
atresia, intact ventricular septum, hypoplastic RV; (d) mitral atresia Figure 60.5: 2D echocardiography with subcoastal coronal view at the
or hypoplastic left heart and (e) all admixture lesions with restricted level of atrial septum shows the presence of juxtaposed atrial appendage
PFO. in relation to rest of the cardiac morphology. Abbreviations: RA: right
atrial appendage; RA, right atrium; RV, right ventricle
Preprocedure Assessment
Echocardiography has replaced cardiac catheterization in initial good septostomy. In addition, the torn end of the fossa ovalis can be
evaluation of these patients. Apart from complete anatomic diag- seen easily. If the BAS is inadequate, echo can assess the thickness
nosis, echo also gives precise information about size of PFO/ASD, of atrial septum to decide need for septal dilation. If septal dilation
presence of restriction and thickness of atrial septum. Restrictive is decided, the length of atrial septum can be assessed to choose the
interatrial communication is defined as dilated atria (left or right), balloon size (Figs 60.6A to D).
bulging of interatrial septum to opposite side, on color flow mapping,
presence of turbulent flow and pulsed Doppler interrogation of jet of Ventricular Septal Defect
atrial shunt predicts the gradient between the two atria. These
features help in planning BAS. In addition, echo is extremely use- Echocardiography is important in assessment of a patient with VSD
ful while performing BAS in certain conditions like juxtaposed right for clinical decision-making about the timing of intervention and to
atrial appendage/cardiac malposition to confirm the position of select the subsets (Tables 60.3A and B) for device closure of VSD.
balloon in left atrium before pulling into right atrium. As balloon in The devices used are perimembranous VSD and muscular VSD
juxtaposed right atrial appendage on fluoroscopy can be mistaken device. However with the availability of Amplatzer duct occluder II
for being in left atrium and the position of atrial septum and fossa (ADO II), which is much softer device, it has facilitated the closure
ovalis many be altered in cardiac malposition (Fig. 60.5). of VSDs without the creation of AV loop (as for classical VSD closure)
and probably less chances for heart block (Figs 60.7A to C show the
Intraprocedure Assessment perimemebranous, muscular devices and ADO II after successful
closure).
During procedure echo gives very useful information regarding
intracardiac anatomy and precise balloon position across atrial Preprocedure Assessment
septum. Use of echo in conjunction with fluoroscopic control helps
in avoiding inadvertent injury to adjacent cardiac structures like Ventricular septal defect should be defined from a combination of
AV valves. In fact, echo has replaced fluoroscopic guidance in views, i.e. subcostal, coronal, sagittal, apical four chamber, apical five
performing BAS under certain situations. Echocardiography has chamber, parasternal long axis and parasternal short axis views.
allowed BAS to be performed in critically ill neonates in intensive
care units under echocardiographic guidance (bedside septostomy), Muscular Ventricular Septal Defect
thus also avoiding radiation. Echocardiography is the only reliable
direct modality for evaluating the results of BAS. Size of ASD and flow Muscular defect is bordered entirely by muscle and does not include
across ASD gives immediate information for adequacy of septosto- the fibrous tissue of either the central fibrous body or an atrioven-
my. A laminar flow across the interatrial communication indicates tricular or arterial valve ring. Muscular VSD can occur in any part of
TABLE 60.3A Suitable and unsuitable subsets for ventricular septal defect
device closure
• Suitable
• Perimembranous VSD with septal aneurysm,
• Muscular septum
– Apical septum
– Mid septum
– Anterior muscular septum
• Postoperative residual VSD
• Unsuitable
A B
• True inlet VSD (loss of offsetting of AV valves),
• Doubly committed VSD
• VSD with malignant (anterior or posterior) of outlet septum,
• VSD with aortic valve prolapse
• Small VSD with left to right flow < 1.5:1
• VSD with severe pulmonary vascular disease
TABLE 60.3B Checklist for the evaluation of ventricular septal defect

1. Anatomy of VSD
Morphological location
C D
Size and number of defects
Figures 60.6A to D: (A) 2D echocardiography with subcoastal coronal
view showing inflated balloon in left atrium prior to performing the tug Presence of valvar overriding and septal malignant
for BAS; (B) Shows the same just after the BAS with inflated balloon in 1. Hemodynamic assessment:
right atrium; (C) Shows 2D echocardiography with subcoastal sagittal
a. Direction and degree of shunt
view with restrictive interatrial communication (marked by arrow); and
b. Estimation of pulmonary arterial pressure
(D) Same view with well opened communication after BAS (marked by
arrow). Abbreviations: BAS: Balloon atrial septostomy; RA, right atrium; 2. Identification of associated lesions.
RV, right ventricle
A B C
Figures 60.7A to C: 2D echocardiography with ventricular septal defect at various locations closed by device. (A) demonstrates a four-chamber
view with VSD in a perimembranous location successfully closed by the perimembranous VSD device; (B) Shows a subcoastal short axis view with
successful closure of a midmuscular VSD using muscular VSD device; (C) Shows a subcoastal short axis view with Amplatzer duct occluder 2 device
in a perimembranous location
muscular septum as mid-muscular, inlet muscular, anterior muscu- TABLE 60.3C Checklist prior to release of a ventricular septal defect device
lar, and can be single or multiple requiring multiple devices for clo- • Position of device
sure of VSDs. Mid-muscular VSD are surrounded by muscular rim • Residual flow on color flow mapping
all around and are best suited for device closure. These defects can • Encroachment of semilunar valve or any AV valve
be defined on echo from combination of views, i.e. subcostal sagit-
• Presence of semilunar valve or AV valve regurgitation
tal and coronal, apical four-chamber and parasternal short and long
• Ventricular function
axis views. Anterior muscular VSDs are located in smooth muscu-
lar outlet septum below the anterior portion of the aortic root and • Pericardial effusion
the subpulmonary infundibulum. Best views to profile this type of • Pulmonary artery pressures
defects are subcostal coronal with anterior tilt, subcostal paracoro-
nal and parasternal short axis views. In these views, the defects are
seen to be located mainly in the anterior muscular outlet-septum is opened and pulled toward the ventricular septum. Retracting the
separated from the pulmonary valve by the muscular infundibulum. sheath over the device cable then releases the right-sided disk of the
Muscular defects are suitable for device closure. device. Before releasing the device, things to be checked are listed in
Table 60.3C. Then pulling and pushing the device cable under TEE
Perimembranous Ventricular Septal Defect guidance ensures the stable position of device. Only after confirming
these issues, device should be released with unscrewing the cable.
Perimembranous VSD with aneurysm (which makes a good margin
for it being separated from the surrounding structures particularly Follow-Up
AV) is a good selection criteria for suitability for VSD device closure.
While evaluating a child for closure with perimembranous VSD During follow-up of these patients after VSD device closure, TTE
device, it is very important to look for presence of tissue separating is used to monitor residual shunt, encroachment of device on any
the AV from tricuspid valve. The presence of anterior or posterior adjacent valve (e.g. AV/tricuspid valve), device morphology and left
malalignment [best seen in subcoastal right anterior oblique (RAO) ventricular size and function.
view, parasternal long and short axis view], AV prolapse (best seen
in parasternal long and short axis view) or presence of overriding or PATENT DUCTUS ARTERIOSUS
straddling of AV valves (best seen in four-chamber views: subcostal
coronal and apical for tricuspid valve and in parasternal long axis
Echocardiographic Views
view with mitral valve), suggest unsuitability for device closure.
Patent ductus arteriosus (PDA) can be imaged directly from high
During Percutaneous Device Deployment parasternal short axis and from suprasternal (long axis and modi-
fied arch) views (Tables 60.4A and B). High parasternal short axis
Transesophageal echocardiogram is important for the device with counterclockwise tilt (also called as ductal view) and modified
deployment as it demonstrates the proper deployment of the RV and arch view are the best views to profile the detailed anatomy of duct
LV side disk of the device and its apposition with the septum. Also, it with normally related great vessels. In the ductal view, main pul-
helps to exclude the encroachment of the device on the surrounding monary artery (MPA) is seems to continue as left pulmonary artery
structures like AV, mitral valve. (LPA) and whole length of duct is profiled connecting PDA to the de-
When using AV loop for the device deployment TEE is impor- scending aorta. The size of duct at the pulmonary end and ampulla
tant especially when there are multiple defects in close vicinity. In can be measured from ductal view. In general, the duct is meas-
this situation, an attempt should be made to cross the central defect, ured at its narrowest point. Suprasternal modified view defines the
which can easily be made out on TEE. In patients where size of VSD ductal ampulla, its length and ductal insertion at pulmonary site. In
can not be assessed by TEE, angiography, balloon occlusion as with suprasternal long axis view, duct is seen as arising from descending
ASD sizing needs to be done under TEE guidance. The size of inflated aorta (DAo) just below the left subclavian artery and connecting the
balloon with disappearance of shunt on color flow mapping is tak- LPA. In patient with transposition of great vessels, suprasternal view
en as the size of VSD. The majority of VSDs are closed with device is the best view to define the detailed anatomy of ductus arteriosus.
delivered through a long sheath introduced from the right jugular Patients who had duct dependent pulmonary blood flow in utero
vein or femoral vein over the arteriovenous guidewire loop. During (e.g. pulmonary atresia) may have vertical duct, which in supraster-
the procedure, combination of views as four chamber, long axis view nal long axis view arises from undersurface of arch and connect to
and frequently transgastric short axis view to profile the muscular MPA or one of the branch PA.
septal defect is needed. With TEE imaging, tip of the sheath loaded Catheter interventions for PDA include: (1) percutaneous clo-
with device can be seen in LV and under TEE guidance left-sided disk sure of PDA (coil, device); (2) stenting to maintain ductal patency
with duct dependent systemic blood flow (SBF) or duct dependent

pulmonary blood flow.
PERCUTANEOUS CLOSURE
OF DUCTUS ARTERIOSUS
Preprocedural Assessment
Use of combination of “ductal view” and modified suprasternal
view of TTE, certain features of PDA like (1) length of the PDA, (2)
ampulla of PDA, (3) size of PDA at pulmonary end and (4) size of aorta
and pulmonary arteries in relation to PDA can be carefully evaluated.
In some cases, suprasternal long axis view gives a better profilation
of PDA. These features are extremely important in planning percu-
taneous closure of PDA (by coil/device). The authors’ institutional
policy is that if the PDA is less than 2.5 mm, coil closure is the option
and with larger duct (larger than 2.5 mm) device closure is a better
option. By taking the Doppler velocity across the PDA the PA Figure 60.8: 2D echocardiography with modified parasternal short axis
pressure can be predicted. The left and left ventricular size will reflect view (ductal view) with the PDA device in position (marked by arrow) and
the degree of left to right shunt and left ventricular function should well opened left pulmonary artery after device closure. Abbreviations:
also be assessed. Ao, aorta; MPA, main pulmonary artery; PDA, patent ductus arteriosus
Limitations of Echocardiographic
Imaging of the Duct
There are several limitations of profilation of duct by 2D imaging tion in DAo and LPA due to coil/device (Fig. 60.8). PA pressure by TR
particularly in grown up children and adults and may require angi- velocity and left ventricular function are also assessed.
ography, CT or magnetic resonance imaging (MRI) to define ductal
anatomy: Ductal Stenting
Intraprocedure Monitoring Patent ductus arteriosus stenting is done for duct dependent pulmo-
nary blood flow (PBF), e.g. in pulmonary atresia or critical pulmo-
In authors’ practice closure of the PDA they do not use echocardio- nary stenosis (PS) or in duct dependent SBF, e.g. in hypoplastic left
graphic assessment for monitoring routinely. In selective subsets of heart syndrome (HLHS).
PDA like in patients with PDA in whom large device is used before
release one can assess by echo any impingement of aorta or the LPA, Duct Dependent Pulmonary Blood Flow
this can be confirmed on color Doppler also. In some institutions
PDA closure by coil/device is done under TTE guidance. By deter- Vertical duct: Vertical duct arises from undersurface of arch, has a
mining the position of coil/device, presence of flow acceleration in tortuous course and occurs in VSD with pulmonary atresia group be-
LPA or DAo and degree of residual shunting, TTE can immediately cause of in-utero flow from the aorta to the pulmonary arteries. The
determine the success of the procedure. Presence of residual shunts best view to define vertical duct is suprasternal long axis view. Su-
less than 1 mm and lack of continuous waveform on pulse Doppler prasternal long axis view shows the duct arising from undersurface
would indicate insignificant left to right shunt. Before release of of arch, having ‘S’ curve, associated LPA stenosis at ductal insertion is
device, any obstruction in LPA/DAo should be ruled out. Presence quite common. For catheter intervention (ductal stenting), this type
of flow turbulence and high pulse Doppler velocities in LPA/DAo of ductus is difficult to cannulate.
would suggest significant obstruction.
Subclavian origin: Subclavian origin of ductus occurs with duct de-
Follow-Up pendent PBF with right aortic arch. Suprasternal view is the best view
to define this ductus. It has a straighter course so Doppler alignment
Transthoracic echocardiogram is used to assess coil/device position, is very good. For catheter intervention; it is easy to cannulate this
cessation of residual flow if present earlier and to detect any obstruc- type of ductus arteriosus.
TABLE 60.4A Checklist for the evaluation of patent ductus arteriosus TABLE 60.5A Checklist for the evaluation of coronary-cameral fistula
• The presence of a duct • Involved coronary
• Detailed definition of ductus • S ite of termination of fistula on color flow mapping and size of
– Size of the duct opening, single or multiple
– Type of duct • P
resence of volume overload of receiving chamber and chambers
• The hemodynamic significance of a duct distal to that
– Direction of shunt • Ventricular function

– Pulmonary arterial pressure
TABLE 60.5B Echocardiographic features of coronary-cameral fistula
– Quantification of shunt
• D
ilated proximal coronary in parasternal short axis view or TEE in
• Associated defects
horizontal plane
TABLE 60.4B Limitations of echocardiographic imaging of the duct • C
ontinuous color Doppler flows with high velocity rather than diastolic
1. L imited acoustic access: The duct is profiled in the direction of lateral flows seen in normal coronary arteries
resolution of the equipment, so it is difficult to visualize with certainty • Course of the fistula to its termination
very small duct in small babies. High frequency probe with excellent • V
olume overload of cardiac chambers depending on the magnitude of
lateral resolution are needed. left to right shunt through the fistula.
2. If the duct is long and tortuous, it may be difficult to profile whole
length of the duct
3. Poor acoustic windows as in adults with thick chest
VALVULOPLASTY: PULMONARY
AND AORTIC
Size and length: The size and length of the duct helps in deciding the
stent size. The adequacy of flow across the stent could be easily as- In valvuloplasty procedures accurate assessment of valve annulus
sessed by color flow mapping. is extremely useful to choose the appropriate size of balloon. In au-
thors’ experience the hinge points of valvular attachments are better
Duct Dependent Systemic Blood Flow visualized on two-dimensional echo images than on angiography.
Pulmonary valve is best visualized in parasternal short axis view or
With duct dependent SBF, duct has usual morphology and best pro- tilted long axis view to open up RVOT. Echocardiography is also bet-
filed in ductal view and modified suprasternal view. This type of duc- ter modality to decide if there is organic infundibular obstruction or
tus is easy to cannulate. The diameter of ductus and ductal length only dynamic subvalvular gradients. After balloon dilation residual
both need to be measured for stent selection. After stent deployment gradients and their site can also be easily estimated. In patients of
and during follow-up, the patency of ductal stent could be assessed aortic stenosis, if the fall in gradient is inadequate and one is debat-
by color flow mapping. ing to use bigger balloon size, assessment of aortic regurgitation (AR)
is very important to know this can be easily done by color Doppler
Coronary-Cameral Fistula echo.
Transthoracic echo is a useful modality to evaluate a patient with Valvular Pulmonary Stenosis
coronary cameral fistula with good echocardiographic windows
(Tables 60.5A and B). Clues to the diagnosis are enlarged proximal Echocardiography plays a major role in defining the anatomy and
coronary artery and high velocity turbulent signal in the chamber decision making in cases with pulmonary valvular stenosis.
of drainage. The features of dilatation of the left atrium and LV and While planning for balloon pulmonary valvotomy (BPV), things
the chamber of drainage. At times there are more than one site of to be looked on echo include:
drainage and this need to be defined. In some cases there may be • Morphology of the stenotic pulmonary valve: Thin, domed—90%;
associated ventricular dysfunction. With limited acoustic windows, thick with no domingdysplastic—10%
TEE, cine angiography, spiral CT or MRI will be required to define • Severity of obstruction by peak Doppler velocity across the pul-
the detail anatomy before planning for intervention. After percuta- monary valve and TR velocity
neous closure of fistula, echo is done to look for any residual flow, • Look for associated conditions : RV hypertrophy, interatrial com-
additional fistulae, ventricular function, any wall motion abnormal- munication and direction of flow of PDA if present
ity or pericardial effusion. TTE is very useful in long term follow-up • Size and function of the RV
for these patients. • Rule out any associated lesion needing surgery
into underfilled pulmonary arteries, this can be averted by elective

controlled mechanical ventilation and graded dilatation. In patients
with valvar PS color flow mapping shows turbulent flow starting at
the level of pulmonary valve and the jet is directed more towards the
LPA.
Doppler Interrogation
Continuous wave (CW) Doppler is used to assess severity of ste-
nosis and planning for intervention (Fig. 60.10A). This may pick
additional infundibular gradient which may be dynamic (Fig.
60.10B). Best alignment for Doppler interrogation of pulmonary
valve is obtained from subcostal coronal view with anterior tilt, sub-
costal sagittal view, apical four-chamber view with anterior tilt and
parasternal long axis view with anterior tilt. Color Doppler display of
the PS jet helps in alignment of the Doppler beam parallel with flow
of the jet. The Doppler sample volume is then scanned across the
Figure 60.9: 2D echocardiography with subcoastal long axis view with pulmonary valve until the maximal frequency shift as determined by
anterior tilt showing the measurement of the pulmonary annulus from a well-defined outline of the envelope and good audible signal. Mul-
the hinge point to hinge point tiple transducer positions should be used to calculate the peak veloc-
ity. Tracing the maximum velocity signal recorded from any of these
Pulmonary valve morphology, motion of leaflets during cardiac views which will give the pressure gradient across the RV outflow.
cycle, and pulmonary annulus all can be well defined from paraster-
nal short axis view at the level of great vessels, parasternal long axis Right Ventricular Systolic Function
view with anterior tilt, subcostal coronal with anterior tilt (Fig. 60.9),
subcostal sagittal, and subcostal paracoronal views. In PS thickness The systolic function is preserved in the majority of patients of pul-
of leaflets, systolic doming of the valve, mobility and poststenotic monary valve stenosis. With critical pulmonary stenosis, RV systolic
dilatation of MPA, is seen. Due to dilated pulmonary arteries, the function can be reduced which can be assessed by echo. Decreased
heart shifts rightwards displacing the pulmonary valve anteriorly right ventricular systolic function can be responsible for low Doppler
beneath the parasternal window, permitting recording of the pul- derived gradient across the right ventricular outflow tract (RVOT)
monary valve in short axis view. If the pulmonary valve is thick and and should be carefully looked for.
immobile, it is likely to be dysplastic. The dysplastic valves do not
dome and there is no MPA dilatation. In patients with PS due to dys- Intraprocedure
plastic pulmonary valve, 2D echo shows thickened pulmonary valve,
redundant leaflets, hypoplastic pulmonary valve annulus. Stenosis Balloon pulmonary valvotomy is done under fluoroscopy guidance
occurs due to hypoplastic valve annulus and restricted/immobile with preprocedure angiogram as a useful landmark. During the pro-
valve leaflets. Usually there is absence of poststenotic dilatation of cedure of BPV, echo is used for (Figs 60.10A and B):
MPA and LPA due to absence of jet flow. Domed pulmonary valve • Immediate assessment of residual gradient.
is best suited for BPV with excellent results while with dysplastic • Level of residual obstruction: Residual obstruction can be at the
pulmonary valve, results of BPV are not so good and we believe that level of valve or infundibulum. For significant residual obstruc-
the ideal treatment of these valves is surgery. Though some centers tion at the level of valve, pulmonary annulus and valve anatomy
believe in recommending BPV in patients with dysplastic pulmonary needs to be reassessed to decide whether to go for repeat balloon-
valve. It is very important to define the valve morphology on echo ing with larger balloon size. Some degree of infundibular stenosis
before taking a patient for catheter intervention. often occurs with valvar stenosis and is usually related to right
In case of severe valvar pulmonary stenosis, usually there is RV ventricular hypertrophy. This infundibular hypertrophy usually
free wall and infundibular hypertrophy which needs to be carefully resolves spontaneously after relief of valve obstruction during
evaluated. A cautious approach with volume overloading is required follow-up. On 2D echo the infundibulum opens up during dias-
whenever dealing with such a ventricle to avoid a serious complica- tole and is not fixed as is with organic infundibular stenosis.
tion of severe infundibular spasm so called suicidal RV. • Immediate detection of any complication as pericardial effusion,
Also in case of critical PS one should be prepared for the manage- evulsion of tricuspid or pulmonary valve, severe tricuspid or pul-
ment of pulmonary edema after the procedure due to sudden flow monary regurgitation.
Figures 60.10A to C: (A) Continuous wave Doppler signal across the pulmonary valve showing gradient across the pulmonary valve of 75 mm
Hg; (B) Continuous wave Doppler signal across the right ventricular outflow tract showing gradient. Note the signal showing both the valvular and
the infundibular component (marked by arrow); (C) Continuous wave Doppler signal across the right ventricular outflow tract shows the residual
sickle-shaped signal after balloon pulmonary valvotomy
Follow-Up is the determinant of future management plans whether patient

will go for two ventricle repair, one and half ventricle repair or to
After the procedure, echo is used to monitor residual gradients single ventricle pathway.
across the pulmonary valve (Fig. 60.10C), pulmonary regurgitation • Right ventricle function: Usually there is right ventricular dys-
and to assess right ventricular function. function and bowing of interventricular septum toward left
ventricle with suprasystemic RV pressure. In many cases, peak
INFUNDIBULAR STENOSIS velocity across the pulmonary valve may not be very high as right
ventricular output is low due to severe right ventricular dysfunc-
Surgery is the mainstay in the treatment of infundibular stenosis as tion and right to LA shunt leading to decreased right ventricular
it is a muscular obstruction. However, in complex CHD, balloons stroke volume.
dilatation of RVOT or RVOT stenting, as a palliative procedure may • Another important feature, which needs to be assessed in
be helpful. Factors need to be carefully looked for while planning for these neonates, is presence of ductus arteriosus. Rarely, widely
balloon dilatation of RVOT with Tetralogy of Fallot (TOF) physiology patent ductus will cause elevation of pulmonary arterial pressure
with diffuse pulmonary hypoplasia is valvar and infundibular com- and one can underestimate the pulmonary stenosis. So it is very
ponent of obstruction. When there is both valvar and infundibular important to define the detailed anatomy of PDA by 2D
component of obstruction, balloon dilatation relieves obstruction at echo, color flow mapping and Doppler interrogation. Ductus
the level of valve and infundibular component protect the pulmo- patency usually needs to be maintained for several weeks with
nary arteries from increased PBF leading to pulmonary edema. So it ductal stenting. During and in follow-up of the patients of ductal
is very important to assess this associated infundibular obstruction stenting, echo with color flow mapping is very useful to assess
before planning balloon dilatation in patients with TOF physiology. efficacy.
• Interatrial communication: In conditions where the RV is
Critical Pulmonary Valve Stenosis or hypoplastic and patient can not go for two-ventricle or one and
a half ventricular repair, adequacy of interatrial communica-
Pulmonary Atresia with Intact Ventricular
tion is most important and can be very well assessed by echo.
Septum in Neonates On echo, with restrictive interatrial communication, interatrial
Echocardiography from subcostal sagittal, coronal and paracoro- septum bows towards left with right to left shunt. The flow across
nal views and parasternal short axis view shows thickened pulmo- the interatrial communication may or may not be turbulent. In
nary valve, restricted opening, and usually hypoplastic pulmonary this scenario, before going for ductal stenting or BT shunt, BAS
annulus, on color flow mapping small forward flow or atretic RVOT should be done to enlarge the interatrial communication and
is seen. Interatrial septum bulging toward left atrium with PFO or relieve systemic venous pressure; this can be done on echocar-
small ASD shunting right to left are seen. On echo, following features diographic guidance. During and after the procedure of valvoto-
should be carefully assessed: my, echo is useful to assess the factors listed in Table 60.6. The
• With patent OT, degree of infundibular hypertrophy: It is very efficacy of the procedure also can be assessed on echo by the size
important to define the subvalvar area. There is usually signifi- of the communication and the color flow jet across the interatrial
cant infundibular hypertrophy which leads to significant residu- septum.
al gradient after pulmonary valvotomy and in this condition, the In intraprocedure assessment of patients of pulmonary atresia,
baby usually requires additional source of blood supply to lungs position of the catheter is extremely important. This can be precisely
as ductal stenting or Blalock-Taussing (BT) shunt. With atretic seen on 2D echo and inadvertent perforation of right ventricular out-
pulmonary outflow, it is very important to define whether it is flow can be avoided.
muscular atresia or valvar atresia, with valvar atresia—how is the
infundibular area? Because surgery remains the procedure of
choice for muscular atresia while imperforate pulmonary valve
(valvar atresia), is amenable to catheter treatment with radiofre- TABLE 60.6 Checklist of evaluation of a neonate with critical pulmonary
quency or laser perforation followed by balloon dilatation. stenosis
• Right ventricular size: Right ventricle size can be assessed by 2D • Pressure gradient, level of obstruction
echo by tracing RV cavity area in four-chamber view in diastole • RV pressure by peak velocity of TR jet
but usually it is difficult to assess the RV size due to severe RV • RV function: Systolic and diastolic
hypertrophy and presence of trabeculation which makes it dif-
• Interatrial communication, direction and degree of shunting
ficult. Studies have shown that tricuspid valve annulus correlates
• Ductal patency
well with RV cavity and can be measured in apical four-chamber
view and parasternal long axis view with inferior tilt. Size of RV • Pericardial effusion
TABLE 60.7 Checklist for echocardiographic evaluation of aortic valve planning balloon aortic valvotomy (BAV) in pediatric patients with
stenosis isolated valvular aortic stenosis. Checklist for the evaluation is listed
• Morphology of aortic valve, aortic valve annulus in Table 60.7.
• Severity of obstruction Morphology of valve-on TTE, parasternal short axis view at the
• Presence of aortic regurgitation level of great vessels and parasternal long axis view are used to assess
• Left ventricular hypertrophy and function the valve morphology. Normally, the AV is tricuspid, having three
cusps of equal size. The stenotic valve can be bicuspid (common-
• Associated anomalies
est), unicuspid, quadri, penta or hexa cuspid or congenitally stenotic
tricuspid AV.
The correct assessment of aortic annulus is very crucial for
LEFT VENTRICULAR OUTFLOW TRACT proper selection of balloon size and is best assessed in parasternal
OBSTRUCTION long axis view, which clearly shows the hinge points of the valve
leaflets. In addition to measuring the AV annulus, parasternal long
Aortic valvar stenosis: Left ventricular outflow tract (LVOT) obstruc- axis view also shows thickened AV leaflets and restricted mobility
tions can occur at valve level, subvalvar and supravalvar level (Fig. of AV cusps with systolic doming. AR can be assessed on color flow
60.11A to D). mapping. If it is more than mild, BAV is not recommended as it can
result in significant increase in AR after BAV.
Valvar Aortic Stenosis
Severity of Stenosis
Valvar aortic stenosis may manifests in neonatal period with duct
dependent SBF or present as progressive obstruction in an inher- Direct quantitative assessment of the severity of aortic stenosis can
ently abnormal AV. TTE is not only diagnostic but also helpful is be obtained by use of Doppler echo. At the same time one should
A B
C D
Figures 60.11A to D: (A) 2D echocardiography with parasternal long axis view showing domed valve of valvular aortic stenosis; (B) Same view
with color flow mapping showing turbulent flow across the valve; (C) Same view with, measurement of the annulus; (D) Shows continuous wave
Doppler across the aortic valve with significant gradient across the valve
look for indirect measures of AV stenosis and its hemodynamic con- dilation of discrete subaortic stenosis with less than 3 mm thick dis-
sequences in the form of left ventricular hypertrophy, left ventricular crete membrane which is not very close to the AV. Their results were
failure and pulmonary hypertension. For Doppler assessment, jet comparable to the surgical results. However, catheter intervention
velocity from multiple views is recorded, i.e. subcostal coronal with remains the mainstay of treatment of pediatric valvular aortic steno-
anterior tilt, apical five chamber with anterior tilt, right parasternal sis
and suprasternal long views. Only well defined envelops should be
used for quantification of velocities. The velocity of the aortic steno- COARCTATION OF AORTA
sis jet is defined as the highest CW Doppler signal obtained from any
window. Echocardiography provides not only the assessment of the need of
Transthoracic echocardiogram also helps in diagnosing other intervention, but also an accurate, noninvasive assessment of coarc-
associated cardiac anomalies (e.g. in neonate and infants associated tation anatomy in most patients. High quality ultrasound images can
patent ductus arteriosus, hypoplastic aortic annulus, coarctation be obtained in infants, but may be somewhat difficult to obtain in
of aorta (CoA), arch hypoplasia, mitral stenosis or hypoplastic LV), larger children and adolescents (Figs 60.12A and B). The checklist
which may preclude the procedure of aortic valvoplasty. for echocardiographic assessment of a patient with coarctation is
given in Tables 60.8A and B.
Intraprocedure Arch of aorta is best imaged from suprasternal views. The echo-
cardiographic examination using the suprasternal long axis view
Transthroracic echocardiogram greatly contributes to (1) real time provides an image of the entire arch, with the area of coarctation seen
assessment of proper balloon placement across the AV; (2) immedi- near the origin of subclavian artery. When imaging the arch, one
ate assessment of residual gradient across the AV and degree of AR must be absolutely certain that the entire arch is imaged, particularly
after balloon dilatation; (3) ventricular function; and (4) immedi- in the region of the left subclavian artery, inadequate imaging in this
ate recognition of unpredicted complications as cardiac perforation area may lead to missed diagnosis of CoA.
(pericardial effusion), AV evulsion causing severe AR. Type of coarctation may either be a long segment narrowing
Transthroracic echocardiogram remains the primary modality or, more commonly short segment obstruction caused by posterior
for careful long-term follow-up of these patients following proce- endothelial shelf projecting into the aorta. In the region of the ductus
dure—for monitoring the occurrence of restenosis, progression and arteriosus, an anterior shelf may normally exist just proximal to the
effect of AR, if developed during procedure and LV function. aortic origin of ductus. It is important not to mistake this for coarcta-
Generally for subvalvar and supravalvar LVOT obstruction, sur- tion shelf.
gery is the treatment of choice There are occasional case reports of Certain intracardiac findings suggest the possibility that a CoA
balloon dilatation of supravalvar stenosis, but results are not encour- may exist before the arch is imaged. Significant right or left ven-
aging. A recent study, however, has shown good results of balloon tricular hypertrophy without obvious explanation and the absent or
A B
Figures 60.12A and B: (A) 2D echocardiography with suprasternal long axis view with discrete coarctation of aorta (arrow), suitable for balloon
dilatation of the coarct segment; (B) Shows the continuous wave Doppler echocardiography with measured gradient across the stenosed segment.
Note the diastolic spill in the signal demonstrating severe obstruction
TABLE 60.8A Checklist for evaluation of coarctation of aorta tion in a peripheral artery with a pressure gradient extending into
• Is there discrete stenosis or long segment stenosis: Isthmus diameter, diastole. As the severity of obstruction increases, the pressure above
diameter of descending aorta the coarctation remains elevated for longer period of the cardiac
• Is there arch hypoplasia: Transverse arch diameter cycle, and thus the jet extends into diastole. From the peak velocity of
• A
re there associated cardiac anomalies, in particular bicuspid aortic the jet (V2) and the simplified Bernoulli equation (P = 4 V22), the peak
valve, left-sided obstructive lesions as aortic stenosis, subaortic instantaneous pressure gradient across the coarctation can be cal-
membrane, hypoplastic left heart? culated. Many patients with CoA have multiple left heart obstructive
• Presence of associated patent ductus arteriosus lesions (e.g. bicuspid AV, valvar aortic stenosis, subaortic membrane,
• Is ventricular function normal, degree of ventricular hypertrophy etc.) that can lead to an increased peak flow velocity proximal to the
coarctation jet. If the peak velocity proximal to the coarctation (V1)
• Degree of pulmonary artery hypertension (in neonates and infants)
exceeds 1 m/s recorded by pulsed Doppler echo from suprasternal
TABLE 60.8B Measurement in a case of coarctation of aorta
long axis view, then the expanded Bernoulli equation (P = 4[V22 –
V12]) should be used to avoid a significant overestimation of the peak
• Ascending aorta: At the level of the take off of the 1st branch
gradient. The gradient also depends on the shape and length of the
• Transverse arch coarctation segment, the patient’s cardiac output, and the presence
• Isthmus and extent of collateral flow, the gradients can be overestimated or
• Descending aorta at the level of the diaphragm underestimated, these factors should be kept in mind.
Values expressed in z score, less then –2 indicated severe hypoplasia In those patients with inadequate suprasternal notch echocar-
diographic images or Doppler signals, pulsed Doppler echocardio-
graphic recordings from the abdominal descending aorta shows a
continuous antegrade flow signal with no evidence of flow reversal
reduced pulsation in descending aorta as imaged from the abdomen or cessation, the time of peak velocity is prolonged, and the mean
suggest the possibility of CoA. acceleration rate is decreased suggesting severe obstruction. The
Before planning for catheter intervention, in addition to defin- exact gradient will be obtained only on cardiac catheterization or
ing coarctation, it is important to define origin of arch vessels and MRI in such situations.
involvement of arch vessel in CoA in suprasternal views (short and
long axis). With left aortic arch, first arch vessel (right innominate) Follow-Up of Patients after Balloon Dilatation
point toward right and bifurcate into right subclavian artery and
or Stent Implantation
right carotid artery, second branch left carotid and last branch is left
subclavian artery. Absence of bifurcation of first arch vessel indicate The echocardiographer evaluating a patient with CoA postballoon or
aberrant right subclavian artery (origin of right subclavian artery as stent deployment can get following information by 2D and Doppler
4th arch vessel after left subclavian artery and this arch vessel will be echo:
likely to be involved in coarctation segment. It is also very important • Is there evidence of restenosis? Sometimes Doppler gradient
to assess if the coarctation is discrete or long segment and presence may be fallacious in postprocedural period and may overesti-
of arch hypoplasia is associated with hypertension or not. The best mate the gradients because of irregularity of tissue around the
results of balloon dilation are observed with discrete coarctation area interrogated. In this situation, presence of diastolic spill
without arch hypoplasia. In patients above the age of 9 years and in strongly suggests the presence of significant restenosis. Also slow
adults, stent placement is preferred over balloon dilation because of rise of pressure slope in the initial phase will suggest significant
near complete abolition of gradients and achievement of adult aortic obstruction. After stent deployment, recoarcatation can be due
diameters and low restenosis rate on follow-up. to somatic growth when stent is deployed in early childhood.
Owing to limited clinical information concerning stent redilata-
Doppler Features of Aortic Coarctation tion, the currently available stent should be implanted in older
children, more than 9 years, in whom the normal aortic diameter
Doppler echo can assist in determining the hemodynamic severity of overlaps that of young adults.
CoA. First, color flow imaging of the descending aorta is performed, • Stent in situ: The information regarding the position of stent dur-
looking for a high velocity jet in the region of coarctation. Once the jet ing the follow-up visits is of immense importance to rule out any
is imaged on the color Doppler examination, the CW Doppler beam stent migration. This is important especially because the stent
is directed into the area for turbulent flow. The Doppler recording placed in aorta is exposed to high systolic and diastolic blood
usually shows a high velocity jet with antegrade flow extending well pressures. Any suspicion of stent migration on echo can help in
in into diastole. This flow pattern is characteristic of severe obstruc- planning further work-up.
• Is there evidence of gradient across origin of subclavian artery? Fetal Interventions

The length of stent used is crucial since stents margins can
encroach on the origin of subclavian artery and may hence Fetal echo has facilitated not only prenatal diagnosis of various disor-
affect the flow through the subclavian artery. Flow gradi- ders it has now made possible the diagnosis of various cardiac malfor-
ent measurement across the subclavian artery can provide mations which are known to progress in fetal life such as premature
valuable information regarding this aspect during follow-up closure of ductus arteriosus and PFO. Severe aortic stenosis or PS dur-
visits. ing early fetal life may progress to hypoplasia of left or right ventricle,
• Is there evidence of any stent thrombosis can be detected on respectively. Serial echo in mid-gestation can identify the fetuses who
2D and color flow evaluation. Patients who had stent deploy- are at risk and help in deciding need of intervention. Timely interven-
ment rarely can develop dissection and aneurysm. However, tions facilitated by echo in these fetuses have showed restoration of
echo has its shortcoming in complete evaluation of dissection near normal physiology and improved fetal and neonatal survival.
and aneurysm formation poststent deployment. So if there is Echocardiography with its nonteratogenic properties unlike fluoros-
any suspicion angiography, spiral CT thorax or MRI which have copy is an indispensible part of any such procedure. Several studies
better sensitivity in detecting these should be done. MRI again have showed that timely and successful intervention in severe aortic
has its limitation after stent placement since metallic artifact stenosis in fetal life may halt the progression to HLHS and lead to two
prevents detailed evaluation of the aortic aortic segment within ventricle circulation at birth. Echocardiographic monitoring of ideal
the stent. Intravascular ultrasound can be used in evaluation of fetal position, course of catheter and monitoring the response to ther-
patients who have undergone coarctation balloon angioplasty. apy during intervention proved to be necessary for procedural success.
Intravascular ultrasound is more sensitive than angiography in
detecting the vascular changes as intimal tear and dissection Hybrid Procedures
and aneurysm.
Hybrid laboratories form a recent advance in pediatric cardiac sur-
PERICARDIOCENTESIS gical theaters with provision of the fluoroscopy, surgical provisions
and echocardiographic equipment in the same room. Procedures
Echo has been found most useful in diagnosing, deciding the need such as echo-assisted balloon dilatation of the valvar pulmonary
for intervention and guiding the aspiration in pericardial effusion. It atresia, VSD device closure and stent placements can be easily
gives exact information regarding extent of pericardial effusion, type accomplished on operative table with echo assistance in conjunc-
of effusion and degree of hemodynamic compromise. Apart from tion with other surgical procedures. Some complex VSDs are better
this information, it also helps in doing the procedure, predicting closed as hybrid procedures. The surgeon exposes the heart and the
success rate of the procedure by assessing. interventionalist performs the device placement under echocardio-
• Echodensity of pericardial fluid, ehcodense collection suggests graphic guidance. Many such procedures may be done on a beating
presence of blood clots, which are unlikely to be drained by nee- heart under echocardiographic guidance, thus avoiding the side
dle aspiration. effects of cardiopulmonary bypass.
• Presence of echodense strands suggests fibrin strands within
pericardial cavity. Special Situation
• Presence of loculated or distant (posterior) collection where
access by needle may be difficult. Valvuloplasty during pregnancy under echo guidance can be done
In case of cardiac tamponade developing during cardiac to avoid radiation.
catheterization, TTE gives quickest information and helps in taking
immediate actions. CONCLUSION
Intravascular Ultrasound, 3D and 4D Echocardiography (TTE and TEE) is extremely useful modality in
preprocedure selection and planning, during and postprocedure for
Echocardiography
interventions in CHD. It is indispensible part of all procedures. It is
These newer techniques have shown better presentation of the vis- extremely useful for later evaluation after procedure and long-term
ualized defect for various interventional procedures and may see follow-up.
greater role in near future. They give better delineation of special Echocardiography is also very useful in defecting complication
morphology of atrial and VSDs and the morphology of the device. We • Cardiac tamponade
do not use these due to limitation of availability in cardiac catheter • Valve tear or avulsion
laboratory and the cost. • Myocardial or papillary muscle rupture
BIBLIOGRAPHY
1. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and management of pediatrics patients during and after seda-
tion for diagnostic and therapeutic procedures. Pediatrics. 1992;89:1110-5.
2. Arora R, Trehan V. Role of Echocardiography in Cardiac Catheterization Laboratory. J Ind Acad Echocardiogr. 1996;1(2):68-75.
3. Ashfaq M, Houston AB, Gnanapragasam JP, et al. Balloon atrial septostomy under echocardiographic control: six years’ experience and evaluation
of the practicability of cannulation via the umbilical vein. Br Heart J.1991;65:148-51.
4. Brochet E, Vahanian A. Echocardiography in the catheterization laboratory. Heart. 2010;96:1409-17.
5. De Lezo JS, Romero M, Segura J, et al. Long-term outcome of patients with isolated thin discrete subaortic stenosis treated by balloon dilation: a
25-year study. Circulation. 2011:124;1461-8.
6. Dev V, Radhakrishnan S, Rajani M, et al. Echocardiographic assessment of the size of aortic and pulmonary valve annulus before balloon valvo-
plasty. Ind Heart J. 1990;42(3):195-7.
7. Hellenbrand WE. Interventional Cardiac Catheterization. Curr Opin Cardiol. 1991;6(1):110-8.
8. Kimball TR, Meyer RA. Echocardiography. In: Allen JD,Gutsesell HP, Clark EB, Driscoll DJ (Eds). Heart disease in Infant, Children, and Adoles-
cents, 6th edition. Philadelphia: Lippincott Williams and Wilkins; 2000. pp. 204-33.
9. Lange LW, Sahn DJ, Allen HD, et al. Subxyphoid cross-sectional echocardiography in infants and children with congenital heart disease. Circula-
tion. 1979;59:513-24.
10. Liang CD, Ko SF, Huang SC. Echocardiographic Guidance for Transcatheter Coil Occlusion of Patent Ductus Arteriosus in Catheterization Labora-
tory. J Am Soc Echocardiogr. 2003;16:476-9.
11. Martin AC, Rigby ML, Penny DJ, et al. Bedside balloon atrial septostomy on neonatal units. Arch Dis Child Fetal Neonatal Ed 2003;88:F339-40.
12. Nishimura RA, Miller FA Jr, Callahan MJ, et al. Doppler echocardiography: theory, instrumentation, technique, and application. Mayo Clin Proc.
1985;60:321-43.
13. Rosenhelk R, Binder T. Monitoring of Invasive Procedures – The Role of Echocardiography in Cathlab and Operating Room. J Clin Basic Cardiol.
2002;5:139-43.
14. The normal echocardiographic examination. Snider AR, Serwer AG, Ritter SB (Eds). Echocardiography in pediatric heart disease. 2nd edition.
Mosby: 1997. pp. 22-75.
15. Tofeig M, Patel RG, Walsh KP. Transcatheter Closure of Mid-muscular Ventricular septal defect with amplatzer VSD occluder device. Heart.
1999;81:438-40.
16. Tomar M, Radhakrishnan S. Role of echocardiography in catheter interventions in congenital heart defects. Indian Heart J. 2008;60:4;D1-21.
17. Tworetzky W, Wilkins-Haug L, Jennings RW, et al. Balloon dilatation of severe aortic stenosis in fetus. Circulation. 2004;110:2125-31.
18. Vermilion PR. Basic physical principles. In: Snider AR, Serwer AG, Ritter SB (Eds). Echocardiography in Pediatric Heart Disease, 2nd edition.
Mosby; 1997. pp. 1-10.
19. Weyman AE, Feigenbaum H, Dillon JC, et al. Noninvasive visualization of the left main coronary artery by cross sectional echocardiography. Cir-
culation. 1976;54:169-74.
20. Zhong-Dong D, Hijazi ZM. Transcatheter Closure of Ventricular Septal Closure. Presented at 2nd Virtual Congress of Cardiology-2001.
61 History of Fetal Cardiology
Chaddha V, Kapoor N
prenatal detection of CHD, a screening test, based on a routine ultra-

INTRODUCTION
sound examination of the fetus, was required.
Fetal cardiology is the field of medicine that focuses on diagnosis
and management of heart problems in the developing fetus as well THE HISTORY OF THE FOUR-CHAMBER
as rhythm and cardiac problems that result from cardiac anomalies
VIEW
and obstetrical issues. The ability to examine the structure of the fetal
heart in real-time started over 30 years ago. The field has seen very With the widespread use of routine ultrasound examination in preg-
great advances since then, both in terms of technical improvements nancy, the four-chamber view of the fetal heart was proposed as a
in ultrasound equipment and in dissemination of operator skills. A screening test for CHD.4 When ultrasound was first used in the early
great deal has been learnt about normal cardiac function in the hu- 1980s to identify the fetal heart, investigators were uncertain as to
man fetus throughout gestation and how it is affected by patholo- the approach that should be used to identify congenital heart defects
gies of pregnancy. There is increasing recognition of abnormal heart (Fig. 61.1).5
structure during routine obstetric scanning, allowing referral for spe-
cialist diagnosis and counseling. It is now possible to make accurate
diagnosis of cardiac malformations as early as 12 weeks of gestation.
Early diagnosis of a major cardiac malformation in the fetus can lead
to prompt evaluation of genetic syndromes and analysis of the fetal
karyotype and provide the parents with a comprehensive prognosis,
enabling them to make the most informed choice about the manage-
ment of the pregnancy. Early diagnosis allows physicians and fami-
lies to better plan for a baby’s care before, during and after birth at a
specialized cardiac care center for neonatal management. Prenatal
diagnosis of congenital heart disease can improve the outcomes of
infants with severe cardiac malformations. In some instances diag-
nosing congenital heart disease prenatally can be life-saving.
Congenital heart disease (CHD) is the most common congenital
abnormality in the human fetus with a prevalence of 5 per 1,000 live
births, and it accounts for more than half of the deaths from congeni-
tal abnormalities in childhood (Table 61.1).1
During antenatal life, the prevalence of cardiac anomalies is
higher because of a high selection rate of affected fetuses.
Several risk factors for CHD, including maternal and fetal factors,
were identified. Fetal echocardiography was shown to identify the
majority of structural cardiac abnormalities2 and it was traditionally
reserved for pregnancies at high risk for CHD. Most neonates with
CHD, however, had no identifiable risk factor. In fact, of all pregnant
Figure 61.1: The thorax and abdomen of an 18-week fetus to show
women referred for fetal echocardiography, the highest incidence the orientation of the heart in relation to the other organs. Source:
of CHD (50%) occurs in those in whom there was a suspected CHD Echocardiographic and anatomical correlates in the fetus. Allan LD,
on a routine ultrasonographic examination.3 In order to improve the Tynan MJ, Campbell S, et al. Br Heart J. 1980 Oct;44(4):444-51
Chapter 61  History of Fetal Cardiology 481
When the ultrasound beam was directed perpendicular to the fetal chest. It was obtainable in all fetal positions and in more than
chest of the fetus, four chambers of the fetal heart were identified. 95% of ultrasound examinations performed after 19 weeks of gesta-
These chambers consisted of the right and left atrial and ventricular tion.8 A four-chamber view of the fetal heart was considered normal
chambers, with their respective valves that connect the atrial with only when the following conditions were met:
the ventricular chambers. In 1985, Dr DeVore suggested that because • The fetal situs was normal.
of fetal circulation, abnormal cardiac anatomy could alter the way in • The size of the heart in relation to the chest was normal (one-
which the four-chamber view appeared.6 third).
The four-chamber view of the heart had several features that • The two atria were equal in size and the flap of the foramen ovale
made it a good screening test for CHD. It was a part of the basic was seen within the left atrium.
obstetric ultrasound examination. It did not require specialized • The two ventricles were equal in size and contractility, with the
ultrasound skills, as it was easily imaged in transverse view of the moderator band imaged in the apex of the right ventricle.
• The atrial and ventricular septae were normal appearing.
TABLE 61.1 Classification of congenital heart disease by the dominant • The atrioventricular valves were normal appearing where the tri-
lesion in complex cases (Diagnoses are listed in decreasing order of cuspid valve appears inserting more apically on the ventricular
importance)7 septum (Figs 61.2A to C).
• Absent atrioventricular connection Fetal autopsy was used as an adjunct to support the radiologi-
cal diagnosis (Figs 61.3 to 61.6). Several specific cardiac abnormali-
• Double inlet atrioventricular connection
ties were not diagnosable using four-chamber view of the fetal heart.
• Atrioventricular discordance with ventriculoarterial discordance
This represented a major limitation for the routine use of the four-
(congenitally corrected transposition)
chamber view in screening for CHD in pregnancy. Table 61.2 shows
• Hypoplastic left heart syndrome
a list of cardiac abnormalities that were commonly associated with a
• Truncus arteriosus normal four-chamber view of the fetal heart.
• Atrioventricular concordance with ventriculoarterial discordance The validity of the four-chamber views in screening for CHD in
(complete transposition) the fetus was evaluated by several investigators.3,9-14
• Interrupted aortic arch In general, studies evaluating the four-chamber view in low-risk
• Atrioventricular septal defect populations were associated with a low sensitivity for the detection
of CHD (Table 61.3). Even within the same ultrasound laboratory,
• Double outlet ventricle
a significant difference in the sensitivity of the four-chamber view
• Coarctation of aorta
was noted between that in low-risk pregnancies and that in high-risk
• Absent pulmonary valve syndrome pregnancies.
• Ebstein’s anomaly For a CHD screening program to be effective, major training
• Pulmonary atresia at primary scan levels and modification of the timing or the initial
• Tetralogy of Fallot ultrasound examination was required. A high level of suspicion for
the presence of CHD and attention to anatomic details would have to
• Pulmonary stenosis
be part of every ultrasound examination, especially when involving
• Cor triatriatum
low-risk pregnancies.
• Total anomalous pulmonary venous connection
• Aortopulmonary window
The Five-Chamber View
• Hypertrophic obstructive cardiomyopathy
• Aortic stenosis Rotational Technique
• Persistent ductus arteriosus
This technique was first described by Dr DeVore in 1992. After imag-
• Pulmonary artery anomalies
ing the four-chamber view, the physician rotated and then rocked the
• Atrioventricular valve anomalies transducer to image the ascending aorta and the main pulmonary
• Myocardial disease artery. This maneuver identified that the main pulmonary artery and
• Atrial isomerism aorta were perpendicular to each other as they exited their respec-
• Peripheral pulmonary stenosis tive ventricles, these vessels were similar in size, and the aortic and
pulmonary valves were normal, and the aortic arch was seen. They
• Systemic arteriovenous fistula
found that the evaluation of the great vessels (aorta and pulmonary
• Pulmonary arteriovenous fistula
artery) was crucial for the detection of some of the most common
• Secundum atrial septal defect heart defects, such as tetralogy of Fallot and transposition of the great
Figure 61.3: Cardiac tumor obliterating the four-chamber view
C B
Figures 61.2A to C: The thorax and abdomen 18-week fetus to Figures 61.4A and B: Fetal autopsy showing rhabdomyoma
show the orientation of the heart in relation to the other organs in previous scan of Figure 61.3
A
Figure 61.6: Figure showing microscopic cardiac rhabdomyoma
TABLE 61.2 Cardiac abnormalities associated with a normal four-

chamber view of the heart
• Tetralogy of Fallot
• Transposition of great arteries
• Double outlet right ventricle
• Small ventricular septal defects
• Small atrial septal defects
B
• Mild semilunar valves stenosis (pulmonary, aortic)
Figures 61.5A and B: Figure showing cut
• Mild coarctation of the aorta
section of cardiac rhabdomyoma
TABLE 61.3 The four-chamber view of the heart, and screening for CHD in the fetus
Author (Ref.)/ Year No. in Study Incidence of CHD Risk Status Sensitivity (%)
Copel 19873 1,022 72/1,000 High risk 92
Sharland 19929 23,861 2.8/1,000 Low risk 77
Vergani 199210 5,336 5.9/1,000 Low risk 81
Achiron 199211 5,347 4.3/1,000 Low risk 48
Bromley 199212 mixed 63
Wigton 199313 10,004 3.6/1,000 Low risk 38
Kirk 199414 5,111 10/1,000 Low risk 47
arteries. Although many abnormalities of the great vessels could be Sweep Technique
recognized indirectly by an abnormal four-chamber view, the detec-
tion of the ductus-dependent lesions often required evaluation of the This technique was described by Yoo et al. and Yagel et al. and
aorta and pulmonary artery outflow tract15 (Figs 61.7 and 61.8). involves sweeping the transducer beam in a transverse plane from
Figure 61.7: Figure showing rotational technique for delineating the Figure 61.8: Figure showing rotational technique for delineating the
left outflow tract by DeVore right outflow tract by DeVore
the level of the four-chamber view towards the fetal neck. By doing monary trunk, proximal aorta, and ductus arteriosus are identi-
so, the outflow tract vessels are observed.16,17 fied. The distal aorta, superior vena cava, and trachea are also
The sweep consists of the following views: four-chamber view, visualized (Figs 61.9 and 61.10).
five-chamber view, main pulmonary artery or three-vessel view and
the trachea. Color Doppler of the Four-Chamber View
• The most caudal view was the transverse view of the upper abdo-
and the Outflow Tracts
men, demonstrating the fetal stomach, as well as the abdominal
aorta, spine, and the liver. This was helpful to determine the fetal The use of color Doppler ultrasound for evaluation of the fetal heart
situs. and detection of birth defects was first reported by Dr DeVore in
• The traditional four-chamber view. 1987. Since this first publication over 200 articles have been pub-
• The third plane is the five-chamber view of the heart. In this view, lished in the medical literature describing the use of this technology
the aortic root is identified most centrally, as well as the two for evaluating the fetal heart, color Doppler displays the flow of blood
ventricles and the two atria (Table 61.4). based upon its direction of flow, red-orange towards the transducer,
• A transverse view above this level revealing the bifurcation of blue away from the transducer.20
the pulmonary artery. The cross-sectional view of the major Real-time gray-scale ultrasound identified anatomic relation-
vessels is a quick and accurate method to identify the great vessels, ships but did not provide information regarding blood flow. Because
including the bifurcation of the left and right pulmonary arteries the fetal heart consists of two components, anatomy and blood flow,
and cross-sections of the ascending and descending aortas. color Doppler ultrasound is useful during the screening examination
• The fifth short axis view complements the traditional planes and of the heart. Color Doppler uses the principle of velocity change to
includes the three vessels and the trachea. In this view, the pul- display the color pixels on the screen. Using color Doppler, the direc-
TABLE 61.4 The five-chamber view of the heart and screening for CHD in the fetus
Author (Ref.)/ Year No. in Study Incidence of CHD Risk Status Sensitivity (%)
Ott 199518 1,136 12/1,000 Low risk 14.3
Bromley 1992 Mixed 83
Kirk 1994 5,111 10/1,000 Low risk 78
Beinder 199319 1,600 25/1,000 Low risk 81
Figure 61.9: Five-chamber view. This is the level of the five-chamber Figure 61.11: Demonstration of four-chamber view with intact
view and illustrates the aorta (AA) exiting the left ventricle. Abbreviations: septum on color Doppler
RV = Right ventricle, RA = Right atrium, LV = Left ventricle, LA = Left atrium
Figure 61.10: Three-vessel view. This is the three-vessel view because Figure 61.12: Color Doppler used to demonstrate tricuspid
three vessels are observed; the superior vena cava (SVC), the cross- regurgitation
section of the ascending aorta (AA) and the full length of the main
pulmonary artery (PA). Abbreviation: DA = Ductus arteriosus
tion and velocity of moving objects such as blood can be detected. of the infant in utero, review of this technique used in combina-
The color spectrum is usually displayed on the side of the real-time tion with both cross-sectional and M-mode echocardiography was
image21 (Figs 61.11 and 61.12). done in the mid-80s. Where previous examinations had suggested
some abnormality or where there was a risk factor for congenital
Pulsed Doppler Examination of the Heart heart disease, pulsed Doppler examination of the fetal heart was
found to be valuable in three areas: (1) quantitation of hemodynam-
Pulsed Doppler echocardiography (PDE) had proven to be of value ics; (2) characterization of cardiac rhythm; and (3) identification
in the examination of the infant or child with known or suspected of certain congenital cardiovascular structural anomalies22 (Figs
CHD. In order to assess how PDE might be useful in the evaluation 61.13A and B).
Figures 61.13A and B: Pulsed Doppler demonstration

B of various heart valves
Current Trends in Fetal Cardiology 3D/4D Multiplanar Imaging

This technology enabled the examiner to view an unlimited number
3D-4D Scanning of Fetal Heart
of 2D images from the volume dataset. This is useful for identify-
Display of cardiac gated data permits the reviewer to slow down the ing the four-chamber, five-chamber, and outflow tracts of the heart.
heart and evaluate the anatomy from various orientations in multi- While the 3D image is useful, it only represents a static or non-mov-
ple planes throughout the cardiac cycle. Display of cardiac and great ing image of the heart. When 4D imaging is used the 2D images are
vessel anatomy includes multiplanar and volume-rendered images. displayed as a single cardiac cycle. The benefit of this is that cardiac
Multiplanar techniques can be used to identify a specific struc- structures are easier to examine when the heart is beating versus
ture or location in various planes simultaneously. For example, the when it is a still image (Fig. 61.14).
optimal view of the aorta may be found by identifying a portion of the
aorta in one plane, moving the cursor to that point, and rotating the 3D/4D Rendered Imaging of the Heart
volume until the optimal view is obtained. Volume-rendered images
of the cardiac cavities (ventricles, atria, and vessels) and valves may Creating a 3D/4D rendered image means that the image will have
be helpful in assessing chamber geometry, valve configuration, and the appearance of depth. This type of imaging was first described by
great vessel anatomy. Animation sequences with rotation and gated Dr DeVore in 2003. There are a number of image displays that can be
cine-loop displays throughout the cardiac cycle assist in understand- used to examine the heart in this manner.24
ing cardiac anatomy as well as function.23
Figure 61.14: 3D-4D scanning of fetal heart Figure 61.15: 3D-4D scanning of fetal heart. 3D/4D tomographic
ultrasound imaging (TUI)
Spatiotemporal image correlation (STIC) is a new approach for 3D/4D Rendered Imaging of the Surface
clinical assessment of the fetal heart. It offers an easy to use tech- Anatomy of the Heart
nique to acquire data from the fetal heart and to aid in visualiza-
tion with both two-dimensional and three-dimensional (3D) cine Another method that can be used to examine the fetal heart is to ren-
sequences. The acquisition is performed in two steps: First, images der the surface anatomy. This is performed using an INVERT filter
are acquired by a single, automatic volume sweep. Second, the sys- that allows the examiner to reconstruct the surface anatomy, similar
tem analyzes the image data according to their spatial and temporal to what is observed if one were looking at a heart specimen.
domain and processes, an online dynamic 3D image sequence that
is displayed in a multiplanar reformatted cross sectional display and/ First-Trimester Echocardiography
or a surface rendered display. The examiner can navigate within the
(11–14 Weeks)
heart, re-slice, and produce the entire standard image planes neces-
sary for a comprehensive diagnosis. The advantages of STIC for use The association between congenital heart disease and extracar-
in evaluation of the fetal heart are as follows: the technique deliv- diac malformations and karyotypic aneuploidy was established
ers a temporal resolution which corresponds to a B-mode frame in the early 90s. Paladini et al. tried to determine the incidence of
rate of approximately 80 frames/sec; it provides the examiner with aneuploidy among fetuses with congenital heart disease scanned
an unlimited number of images for review; it allows for correlation between 16 and 38 postmenstrual weeks. In their series of 31 fetuses
between image planes that are perpendicular to the main image with heart disease and complete follow-up, 48% also had an abnor-
acquisition plane; it may shorten the evaluation time when complex mal karyotype with trisomy 21 being the most common karyotypic
heart defects are suspected; it enables the reconstruction of a 3D abnormality followed by trisomy 18, trisomy 13 and triploidy. The
rendered image that contains depth and volume which may provide most commonly encountered congenital heart disease with abnor-
additional information that is not available from the thin multiplanar mal karyotype was atrioventricular septal defects and ventricular
image slices (e.g. for pulmonary veins, septal thickness); it lends itself septal defect.25
to storage and review of volume data by the examiner or by experts Bronshtein et al. found 47 cases of congenital heart disease
at a remote site; it provides the examiner with the ability to review all among 12,793 fetuses scanned transvaginally at 12–16 postmen-
images in a looped cine sequence. strual weeks. Sixty-two percent of the affected fetuses had extra-
cardiac anomalies. Among the pregnancies karyotyped 36% were
3D/4D Tomographic Ultrasound Imaging (TUI) aneuploidy. The anomalies detected were ventricular septal defect,
common atrioventricular canal, hypoplastic left heart, transposition
Tomographic ultrasound imaging, (TUI) is a technique in which of the great vessels, Ebstein’s anomaly, single ventricle and coarcta-
the volume dataset is divided into multiple slices, simultaneously tion of the aorta.26
displayed on the ultrasound screen. TUI was first described by Achiron et al. found eight cases of congenital heart disease
Dr DeVore in 2005 (Fig. 61.15). among approximately 1,000 fetuses scanned transvaginally between
10 and 12 postmenstrual weeks. Only one fetus had an abnormal kar-

yotype (45, XO), but all fetuses showed extracardiac abnormalities.
The most common extracardiac abnormalities were cystic hygroma
and pericardial effusion with or without hydrops. The heart anoma-
lies detected were ventricular septal defect, atrioventricular septal
defect, ectopia cordis, giant right atrium and tachycardia.27
Fetal cardiac activity is consistently detected from 6 postmen-
strual weeks or from a fetal pole size of 2–4 mm. The heart rate of the
fetus steadily increases during the first-trimester.28 The mean heart
rate increases from approximately 110 beats per minute at a CRL of
3–4 mm to 171–178 beats per minute at a CRL of 15–32 cm.29,30
Using TVS, the fetal heart, specifically the four-chamber view,
can be imaged from 10 weeks. Different authors have reported on the
earliest gestational age at which the fetal heart can be consistently
imaged and this ranges from 12 to 14 postmenstrual weeks.31-35 But
all the authors agree that by 14 postmenstrual weeks on, the four-
chamber view can be imaged in all patients in which this view was
attempted, in addition, the great arteries can also be imaged from 11 A
postmenstrual weeks and similarly to the four-chamber view, they
can be consistently imaged from 13 weeks to 14 weeks onward.26,32,36
It has been reported by several authors that at 12–16 postmenstrual
weeks the sensitivity of the four-chamber view to detect a cardiac de-
fect was 77% versus up to 92% sensitivity reported beyond 18 post-
menstrual weeks using transabdominal sonography.3,35
First-Trimester Markers and

Cardiac Anomalies
Screening for congenital heart disease is performed using nuchal
translucency measurement. Extensive studies have now established
that increased NT is also a nonspecific finding in chromosomally
normal fetuses, and it is associated with a wide range of fetal struc-
tural defects, genetic syndromes and intrauterine lethality. The prev-
B
alence of birth defects and adverse outcome including miscarriage
and intrauterine fetal death increases with increasing NT measure- Figures 61.16A and B: (A) Normal nuchal; (B) Abnormal nuchal
ment (Figs 61.16A and B).
Among the structural anomalies, CHD are the most common in
both chromosomally normal and abnormal fetuses. An association 95th or 99th percentile for gestational age identified 56% and 40%
between increased NT and cardiac defects was first noted by Hyett of the fetuses respectively with congenital heart abnormalities for a
et al. in pathologic studies after surgical termination in both chro- specificity of 93.8% and 99%.40 In this population the prevalence of
mosomally abnormal and normal fetuses.37-39 This has subsequently major cardiac defects increased exponentially from 0.8 per 1000 for
been confirmed by a number of studies.40,41 NT below 95th percentile, 5.3/1,000 for NT between 2.5 and 3.4 mm,
Despite the association between increased NT and cardiac 3% for NT between 3.5 and 4.4 mm, 9% for NT 4.5–5.4 mm, and 19.5%
defects, it is not clear if NT screening can be an effective method to for NT above 5.5 mm.
identify those pregnancies at risk for cardiac anomalies. The hypoth- A normal NT was associated with a two-fold reduction in the
esis that NT measurement may act as a screening test for CHD in background risk for major CHD and a NT above 95th percentile was
fetuses without other risks factors has been extensively evaluated associated with a nine-fold increase. This detection rate exceeds
and several studies have reported on the screening performance of that expected from second-trimester cardiac screening in low-risk
NT thickness for the detection of cardiac defects.42-44 populations. If reproducible, universal first-trimester NT assessment
In a large retrospective study of an unselected low-risk popula- could surpass the traditional four-chamber view for routine CHD
tion of over 29,000 pregnancies, it was found that NT measurements screening.
Other studies however have failed to reproduce these results and Ductus Venosus and Congenital Heart Defects
similar levels of diagnostic accuracy have not been reported in the
literature. Josefsson, Michalidis and Hafner report detection rates of The ductus venosus (DV) is a venous shunt that provides a means of
38.5%, 36.4% and 25.9%, respectively.45,46 regulating the flow of well-oxygenated blood returning from the pla-
Later studies by Bahado-Singh, Westin and Müller report simi- centa via the umbilical vein. The ductus venosus allows flow to by-
lar detection rates of around 15% and conclude that NT measure- pass the fetal liver, and by preferential streaming, directs blood into
ment cannot discriminate reliably between fetuses with and without the right atrium, across the foramen ovale and into the left atrium
CHD.47 providing the coronary and cerebral circulations with an oxygen-rich
A multicenter study by Simpson et al. on a population of over blood supply.
34,000 unselected pregnancies reported an overall low performance Absent or reversed flow during atrial contraction in the DV is ab-
of NT screening for CHD.44 normal and indicates impaired diastolic function with atrial contrac-
Based on these data, for every 100 patients referred for fetal tion occurring against increased ventricular impedance to forward
echocardiography with a NT of 99th percentile or more, three will flow (Figs 61.17A and B).
have a major cardiac anomaly. Abnormal flow in the DV at 11–14 weeks of gestation is associat-
Simpson looked at various cut-offs of NT enlargement for refer- ed with an increased risk of chromosomal abnormalities and cardiac
ral to specialized units for fetal echocardiography. They suggest that defects.53-56
a NT greater than 99th percentile (> 3.5 mm) should be considered In a large study by Maiz, multivariate analysis demonstrated that
as an indication for fetal echocardiography. Allan advocated perin fetuses with major cardiac defects the prevalence of an abnormal
forming a fetal echocardiogram at 14 weeks in all fetuses with a NT A-wave in the DV was independent of fetal NT thickness.57
of 3.5 mm or higher.48,49 Thus, based on the currently available data, In summary however, the high prevalence of abnormal flow in
screening for CHD in the general population using NT has significant the ductus venosus in fetuses with major cardiac defects suggests that
limitations. As with any screening test with such a low sensitivity, a Doppler assessment of this vessel may provide an effective method
negative test does not reliable exclude the risk of an abnormality and for early screening for such defects. However the studies confirming
in fact the majority of fetuses affected by CHD will have a normal this association are confined to fetuses with increased NT and it is
NT measurement. Notwithstanding, screening by NT yields a detec- therefore uncertain whether in fetuses with cardiac defects and nor-
tion rate of around 30% which compares favorably with the reported mal NT the ductus venosus is also abnormal.
sensitivity of 26% using the four chamber view of the heart at 16–22
weeks.
The CHD described in the literature in fetuses with an increased
NT include septal defects and right and left obstructive lesions.
Most studies have failed to identify obvious relationships between
enlarged NT and particular types of cardiac anomaly.50,51
Several hypotheses have been put forward regarding the under-
lying mechanism linking the increased NT and CHD. These include
narrowing of the aortic isthmus causing excessive fluid accumula-
tion in the first-trimester, transient cardiac failure and a delay or dis-
A
turbance in the development of lymphatic vessels in the neck that
might explain the excessive nuchal fluid accumulation.37 Against the
idea of cardiac failure is the fact that the heart is not enlarged and has
normal systolic function.48,49
NT could be used concomitantly for both chromosomal and car-
diac screening at 10–14 weeks of gestation and that patients found to
have increased NT should undergo formal early fetal echocardiogra-
phy additional to traditional second-trimester screening techniques.
Improvements in the resolution of ultrasound equipments have
made possible to undertake detailed cardiac scanning at the first-
B
trimester of pregnancy. Late first or early second-trimester echocar-
diography in referral centers may obtain diagnostic images in up to Figures 61.17A and B: (A) Normal ductus venosus; (B) Abnormal
98% of cases, with a sensitivity of 75–80%.52 ductus venosus with reversal in a wave
First-Trimester Tricuspid Regurgitation Fetal Heart Block

and Congenital Heart Defects
The incidence of congenital heart block (CHB) in the offspring of
The presence of tricuspid regurgitation (TR) determined by pulsed anti-Ro-positive women is approximately 1–2%, and the risk of re-
wave Doppler has been shown to be a marker for trisomy 21 fetuses currence is 10 times higher in the subsequent pregnancies.61 Non-
at 11–14 weeks of gestation but also for congenital heart diseases.58 fluorinated steroids (prednisone, prednisolone and methylpred-
Tricuspid regurgitation was found in 46% (58 of 126) of chromo- nisolone) are recommended only for maternal indications, not for
somally abnormal fetuses and in 8.8% (12 of 136) of chromosomally prevention of CHB in anti-Ro/SSA-positive women. Fluorinated
normal fetuses. The frequency of congenital heart defects in fetuses steroids (dexamethasone or bethametasone) are not metabolized by
with TR was 50% in chromosomally normal fetuses and 58.6% in the placenta and are available to the fetus in an active form. Routine
chromosomally abnormal fetuses. Faiola reported the association prophylactic therapy with fluorinated steroids is not recommended
between TR and abnormal karyotype or congenital heart defects at even in women who previously had children with CHB or skin rash
the 11 to 13 + 6 week scan.59 Tricuspid regurgitation was present in since this therapy has its own side-effects. Intravenous immunoglob-
39 (8.5%) of the 458 chromosomally normal fetuses, in 82 (65.1%) of ulin had been used to prevent the development of CHB in high-risk
the 126 with trisomy 21 and in 44 (53%) of the 83 with trisomy 18 or mothers (anti-Ro/SSA positive and previous pregnancy with CHB),
13. The study also demonstrated that the prevalence of TR decreases and in 12.5% cases CHB recurred. At present, the only sure recom-
with gestation, increases with fetal NT thickness and is substantially mendation that can be made in these women is that in the presence
higher in those with, than in those without a cardiac defect. In the of reliable positivity for anti-Ro/SSA antibodies serial echocardio-
chromosomally normal fetuses, the prevalence of TR in those with grams and obstetric sonograms should be performed at least every
cardiac defects was 46.9% and 5.6% in those without cardiac defects, 2 weeks starting from the 16th week of gestational age: the goal is to
and the likelihood ratio of TR for cardiac defects was 8.4. A further detect early fetal abnormalities, such as premature atrial contrac-
study by the same group confirmed this findings.60 tions or moderate pericardial effusion, that might precede com-
The diagnosis of TR has been based on the presence of regurgita- plete atrioventricular block and that might be a target of preventive
tion during at least half of the systole and with a minimum velocity of therapy. Fluorinated steroids should not be used in the absence of
80 cm/s examined with the use of pulsed-wave Doppler, rather than symptoms; in the presence of alarming symptoms, betamethasone
color flow mapping. It has been found that at 11–14 weeks, color-flow seems safer.61 Maternal dexamethasone therapy may be associated
mapping is unreliable for the detection of TR probably related to the with demonstrable clinical improvement in fetuses with congenital
small size of the tricuspid orifice (mean of 2 mm) coupled with the complete heart block. Hydrops may be resolved and the level of heart
high heart rate at this time59 (Figs 61.18A and B). block improved. Maternal dexamethasone may be a reasonable op-
A B
Figures 61.18A and B: (A) Normal tricuspid valve flow; (B) Abnormal tricuspid valve flow
tion when certain prerequisites are fulfilled, including recent onset by fetal echocardiography. Early knowledge of these conditions not
of the block, fetal serous fluid collections or hydrops, and an absence only permitted a better understanding of the progression of these
of contraindications to steroid therapy. malformations but encouraged some researchers to explore new
Adverse obstetric outcomes were often seen here and major minimally invasive therapeutic options with a view to early pre- and
concerns have been raised by pediatricians about the safety of fluori- postnatal cardiac palliation. Attempts are being made to prevent fetal
nated steroids, owing to the results of animal studies, retrospective hydrops due to congenital heart defects, to recruit hypoplastic ven-
data and randomized trials. Because fluorinated steroids have not tricles, to create a two-ventricle circulation after birth and to remodel
been shown to improve prophylactic treatment of CHB in pregnant the fetal pulmonary vascular bed whose outlet is obstructed. Open
women at high risk, their use is questionable by many authors.62 heart surgery in the fetus has yet to be done successfully, but inter-
IVIG at low doses consistent with replacement does not prevent the ventions for improved cardiac outcomes are now being tested. Their
recurrence of CHB or reduce maternal antibody titers.63 outcomes will depend, in large part, on their successful physiologi-
cal effects. How to measure these and quantitate the effects of our
Fetal Cardiac Intervention interventions will require further advances in the understanding of
these diseases, both their natural and unnatural courses. New ultra-
Fetal cardiac intervention is in a rapid state of progress now. New- sound techniques and assessment tools to assess fetal cardiac well-
borns with hypoplastic left heart syndrome (HLHS) or right heart ness could enhance the limited progress in fetal intervention in the
syndrome or other malformations with a single ventricle physiol- heart so far. The upcoming expansion of fetal cardiac intervention to
ogy and associated hypoplasia of the great arteries continue to be ameliorate critically progressive fetal lesions intensifies the need to
a challenge in terms of survival. The vast majority of these forms of address issues about the adequacy of technological assessment and
congenital heart defects related to abnormal morphogenesis dur- patient selection as well as the morbidity of those who undergo these
ing early intrauterine development and can be diagnosed accurately procedures.64
REFERENCES
1. Hoffman JIE, Christianson R. Congenital heart disease in a cohort of 19502 births with long term follow-up. Am J Cardiol. 1978;42:641.
2. Allan LD, Sharland GK, Milburn A, et al. Prospective diagnosis of 1,006 consecutive cases of congenital heart disease in the fetus. J Am Coll Car-
diol. 1994;23:1452.
3. Copel JA, Pilu G, Green J, et al. Fetal echocardiographic screening for congenital heart disease: the importance of the four-chamber view. Am J
Obstet Gynecol. 1987;157:648-55.
4. Cullen S, Sharland GK, Allan LD, et al. Potential impact of population screening for prenatal diagnosis of congenital heart disease. Arcg Dis Child.
1992;67:775-8.
5. Allan LD, Tynan MJ, Campbell S, et al. Br Heart J. 1980;44(4):444-51.
6. DeVore GR. The prenatal diagnosis of congenital heart disease—a practical approach for the fetal sonographer. J Clin Ultrasound. 1985;13(4):229-
45.
7. Allan LD, Crawford DC, Anderson RH, et al. Spectrum of congenital heart disease detected echocardiographically in prenatal life. Br Heart J.
1985;54(5):523-6.
8. Shultz SM, Pretorius DH, Budorick NE. Four-chamber view of the fetal heart: demonstration related to menstrual age. J Ultrasound Med.
1994;13(4):285-9.
9. Sharland GK, Allan LD. Screening for congenital heart disease prenatally. Results of a 2 ½-year study in the South East Thames region. Br J Obstet
Gynecol. 1992;99:220-5.
10. Vergani P, Mariani S, Ghidini A, et al. Screening for congenital heart disease with the four-chamber view of the fetal heart. Am J Obstet Gynecol.
1992;167:1000-3.
11. Achiron R, Glaser J, Gelernter I, et al. Extended fetal echocardiographic examination for detecting cardiac malformations in low risk pregnancies.
Br Med J. 1992;304:671.
12. Bromely B, Estroff JA, Sanders SP, et al. Fetal echocardiography: accuracy and limitations in a population at high and low risk for heart defects. Am
J Obstet Gynecol. 1992;166:1473-81.
13. Wigton TR, Sabbagha RE, Tamura RK, et al. Sonographic diagnosis of congenital heart disease: comparison between the four-chamber view and
multiple cardiac views. Obstet Gynecol. 1993;82:219-24.
14. Kirk JS, Riggs TW, Comstock CH, et al. Prenatal screening for cardiac anomalies: the value of routine addition of the aortic root to the four chamber
view. Obstet Gynecol. 1994; 84(3):427-31.
15. DeVore GR. The aortic and pulmonary outflow tract screening examination in the human fetus. J Ultrasound Med. 1992;11(7):345-8.
16. Yoo SJ, Lee YH, Kim ES, et al. Ultrasound Obstet Gynecol. 1997;9(3):173-82.
17. Yagel S, Cohen SM, Achiron R. Examination of the fetal heart by five short-axis views: a proposed screening method for comprehensive cardiac
evaluation. Ultrasound Obstet Gynecol 2001;17:367-369.
18. Ott WJ. The accuracy of antenatal fetal echocardiography screening in high- and low-risk patients. Am J Obstet Gynecol. 1995;172:1741-9.
19. Beinder E, Voigt HJ, Hofbeck M. Screening for fetal heart defects in the four chamber view with evaluation of larger arteries: possibilities and lim-
its. Z Geburtshilfe Perinataol. 1993:197(4):165-71.
20. DeVore GR, Horenstein J, Siassi B, et al. Fetal echocardiography. VII. Doppler color flow mapping: a new technique for the diagnosis of congenital
heart disease. Am J Obstet Gynecol. 1987;156(5):1054-64.
21. Allan LD, Chita SK, Al-Ghazali W, et al. Doppler echocardiographic evaluation of the normal human fetal heart. Br Heart J. 1987;57(6):528-33.
22. Huhta JC, Strasburger JF, Carpenter RJ, et al. Pulsed Doppler fetal echocardiography. J Clin Ultrasound. 1985;13(4):247-54.
23. Nelson TR. Three-dimensional fetal echocardiography. Prog Biophys Mol Biol. 1998;69:257-72.
24. DeVore GR, Falkensammer P, Sklansky MS, et al. Spatio-temporal image correlation (STIC): new technology for evaluation of the fetal heart. Ul-
trasound Obstet Gynecol. 2003;22(4):380-7.
25. Paladini D, Calabro R, Palmieri S, et al. Prenatal diagnosis of congenital heart disease and fetal karyotyping. Obstet Gynecol. 1993;81:679-82.
26. Bronshtein M, Zimmer EZ, Gerlis LM, et al. Early ultrasound diagnosis of fetal congenital heart defects in high-risk and low-risk pregnancies.
27. Achiron R, Rotstein Z, Lipitz S, et al. First-trimester diagnosis of fetal congenital heart Disease by transvaginal ultrasonography. Obstet Gynecol.
1994;84:69-72.
28. Laboda LA, Estroff JA, Benacerraf BR. First trimester bradycardia. A sign of impending fetal loss. J Ultrasound Med. 1989;8:561-3.
29. Mentenegro N, Beires J, Leite LP. Reverse end-diastolic umbilical artery blood flow at 11 weeks’ gestation. Ultrasound Obstet Gynecol. 1995;5:141-
2.
30. Bronshtein M, Siegler E, Eshcoli Z, et al. Transvaginal ultrasound measurements of the fetal heart at 11 to 17 weeks. Am J Perinatol. 1992;9:38-42.
31. Timor-Tritsch IE, Monteagudo A, Peisner DB. High-frequency transvaginal sonographic examination for the potential malformation assessment
of the 9-week to 14-week fetus. U Clin Ultrasound. 1992;20:231-8.
32. D’Amelio R, Giorlandino C, Masala L, et al. Fetal echocardiography using transvaginal and transabdominal probes during the first period of preg-
nancy: a comparative study. Prenat Diagn. 1991;11:69-75.
33. Murta CG, Moron AF, Avila MA. Reversed diastolic umbilical artery flow in the first trimester associated with chromosomal fetal abnormalities or
cardiac defects. Obstet Gynecol. 2000;95:1011-3.
34. Gembruch U, Knopfle G, Bald R, et al. Early diagnosis of fetal congenital heart disease by transvaginal echocardiography. Ultrasound Obstet Gy-
necol. 1993;3:310-7.
35. Dolkar LA, Reimers FT. Transvaginal fetal echocardiography in early pregnancy normative data. Am J Obstet Gynecol. 1991;165:688-91.
36. Gembruch U, Knopfle G, Chatterjee M, et al. First-trimester diagnosis of fetal congenital heart disease by transvaginal two-dimensional and Dop-
pler echocardiaography. Obstet Gynecol. 1990;75:496-8.
37. Hyett JA, Moscoso G, Nicolaides KH. First trimester nuchal translucency and cardiac septal defects in fetuses with trisomy 21. Am J Obstet Gy-
necol. 1995;172:1411-3.
38. Hyett JA, Moscoso G, Papapanagiotou G, et al. Abnormalities of the heart and great arteries in chromosomally normal fetuses with increased
nuchal translucency thickness at 11-13 weeks of gestation. Ultrasound Obstet Gynecol. 1996;7:245-50.
39. Hyett JA, Moscoso G, Nicolaides KH. Abnormalities of the heart and great arteries in first trimester chromosomally abnormal fetuses. Am J Med
Genet. 1997;69:207-16.
40. Hyett J, Perdu M, Sharland G, et al. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks gestation: a popu-
lation based cohort study. BMJ. 1999;318:81-5.
41. Clur SA, Mathijssen IB, Pajkrt E, et al. Structural heart defects associated with an increased nuchal translucency: 9 years experience in a referral
center. Prenat Diagn. 2008;28:347-54.
42. Westin M, Saltvedt S, Bergman G, et al. Is measurement of nuchal translucency thickness a useful screening tool for heart defects? A study of 16383
fetuses. Ultrasound Obstet Gynecol. 2006;27:632-9.
43. Müller MA, Clur SA, Timmerman E, et al. Nuchal translucency measurement and congenital Heart defects: modest association in low-risk preg-
nancies. Prenat Diagn. 2007;27:164-9.
44. Simpson LL, Malone FD, Bianchi DW, et al. Nuchal translucency and the risk of congenital heart disease. Obstet Gynecol. 2007;109:376-83.
45. Josefsson A, Molander E, Selbing A. Nuchal translucency as a screening test for chromosomal abnormalities in a routine first trimester ultrasound
examination. Acta Obstet Gynecol Scand. 1998;77:497-9.
46. Michailidis GD. Economides DL. Nuchal translucency measurement and pregnancy outcome in karyotypically normal fetuses. Ultrasound Obstet
Gynecol. 2001;17:102-5.
47. Bahado-Singh RO, Wapner R, Thom E, et al. First-trimester maternal serum biochemistry and fetal nuchal translucency screening study group.
Elevated first-trimester nuchal translucency increases the risk of congenital heart defects. Am J Obstet Gynecol. 2005;192:1357-61.
48. Allan LD. The mystery of nuchal translucency. The Mannheimer Lecture, 2005. Cardiol Young. 2006;16:11-17.
49. Simpson JM, Sharland GK. Nuchal translucency and congenital heart defects: heart failure or not? Ultrasound Obstet Gynecol. 2000;16:30-6.
50. Ghi T, Huggon C, Zosmer N, et al. Incidence of major structural cardiac defects associated with increased nuchal translucency but normal karyo-
type. Ultrasound Obstet Gynecol. 2001;18:610-4.
51. Makrydimas G, Sotiriadis A, Huggon IC, et al. Nuchal translucency and fetal cardiac defects. A pooled analysis of major fetal echocardiography
centres. Am J Obstet Gynecol. 2005;192:89-95.
52. Simpson JM, Jones A, Callaghan N, et al. Accuracy and limitations of transabdominal fetal echocardiography at 12-15 weeks of gestation in a
population at high risk for congenital heart disease. BJOG. 2000;107:1492-7.
53. Zoppi MA, Putzolu M, Ibba RM, et al. First-trimester ductus venosus velocimetry in relation to nuchal translucency thickness and fetal karyotype.
Fetal Diagn Ther. 2002;17:52-7.
54. Haak MC, Twisk JW, Bartelings MM, et al. Ductus venosus flow velocities in relation to the cardiac defects in first-trimester fetuses with enlarged
nuchal translucency. Am J Obstet Gynecol. 2003;188:727-33.
55. Gembruch U, Meise C, Germer U, et al. Venous Doppler ultrasound in 146 fetuses with congenital heart disease. Ultrasound Obstet Gynecol.
2003;22:345-50.
56. Favre R, Cherif Y, Kholer M, et al. The role of fetal nuchal translucency and ductus venosus Doppler at 11-14 weeks of gestation in the detection of
major congenital heart defects. Ultrasound Obstet Gynecol. 2003;21:239-43.
57. Maiz N, Plasencia W, Dagklis T, et al. Ductus venosus Doppler in fetuses with cardiac defects and increased nuchal translucency thickness. Ultra-
sound Obstet Gynecol. 2008;31:256-60.
58. Huggon IC, DeFigueiredo DB, Allan LD. Tricuspid regurgitation in the diagnosis of chromosomal anomalies in the fetus at 11-14 weeks of gesta-
tion. Heart. 2003;89:1071-3.
59. Faiola S, Tsoi E, Huggon IC, et al. Likelihood ratio for trisomy 21 in fetuses with tricuspid regurgitation at the 11 to 13+6 week scan. Ultrasound
60. Brucato A. Prevention of congenital heart block in children of SSA-positive mothers. Rheumatology (Oxford). 2008;47 Suppl 3:iii35-7.
61. Fesslova V, Vignati G, Brucato A, et al. The impact of treatment of the fetus by maternal therapy on the fetal and postnatal outcomes for fetuses
diagnosed with isolated complete atrioventricular block. Cardiol Young. 2009;19(3):282-90.
62. Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D, et al. Questions about dexamethasone use for the prevention of anti-SSA related congenital
heart block. Ann Rheum Dis. 2003;62(10):1010-2.
63. Friedman DM, Llanos C, Izmirly PM, et al. Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital
heart block: Results of a multicenter, prospective, open-label clinical trial. Arthritis Rheum. 2010;62(4):1138-46.
64. McElhinney DB, Marshall AC, Wilkins-Haug LE, et al. Predictors of technical success and postnatal biventricular outcome after in utero aortic
valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome. Circulation. 2009;120(15):1482-90.
FURTHER READING
1. Maulik D, Saini VD, Nanda NC, et al. Doppler evaluation of fetal hemodynamics. Ultrasound Med Biol. 1982;8:705-10.
2. Maulik D, Nanda NC, Saini VD. Fetal Doppler echocardiography: Methodology and characterization of normal and abnormal hemodynamics. Am
J Cardiol. 1984;53:572-8.
3. Maulik D, Nanda NC, Hsiung MC, et al. Doppler color flow mapping of the fetal heart. Angiology. 1986;37:628-32.
4. Maulik D, Nanda NC, Singh V, et al. Live 3-dimensional echocardiography of the human fetus. Echocardiography. 2003;20:715-21.
62 Cardiac MRI: Present Status
Gulati P, Saini L
rapidly flowing blood appears darker than myometrium. Rapid im-

INTRODUCTION
age acquisition results in low spatial resolution, but provides an ini-
The continual motion of the heart is a principal challenge of car- tial assessment of pertinent anatomy to enable setup of cardiac ex-
diovascular magnetic resonance imaging (MRI). Its cyclical motion amination planes.
and the diaphragm on which it sits requires relatively high temporal Gradient echo sequences are also called as white blood tech-
(< 50 ms) and spatial (< 2 mm) resolution to avoid blurring of images nique as rapidly flowing blood appears white/bright. This provides
for accurate definition of cardiac and coronary artery anatomy and additional information about myocardial function and flow dynam-
ventricular function. One of the main advantages of cardiac MRI is ics, especially when viewed in a cine format (i.e. magnitude- and
the lack of ionizing radiation, which is substantial with SPECT and velocity-encoded images).
computed tomography (CT). The other main strength of cardiac Cardiac function is evaluated using cine gradient echo
MRI, as compared to CT, is its superior temporal and contrast resolu- sequences, often known as “bright blood” sequences. These
tion, however, the spatial resolution of CT is superior. The very high sequences are typically used in conjunction with segmented
resolution images show a lot of image contrast which give us the k-space acquisition.
ability to get good quantitative data about cardiac function. Details
about regional wall motion are exquisite. For example, one can pro- CONTRAINDICATIONS
vide quantitative assessment of systolic and diastolic dysfunction of
each segment of the left (and right) ventricular myocardium. This is Patients with absolute contraindications should not be examined
important for the early diagnosis of subtle disease and also for moni- and these include:
toring therapies. MRI is one modality that can provide comprehen- • Electronically, magnetically and mechanically activated im-
sive evaluation of the heart. plants
As the number of cardiac MRI applications is broad, the number • Ferromagnetic or electronically operated active devices like au-
of potential imaging techniques is correspondingly broad. Motion tomatic cardioverter defibrillators
compensation is done by ECG triggering and K-space segmenta- • Cardiac pacemakers
tion. The easiest way to compensate respiratory motion is to ask to • Metallic splinters in the eye
patient to hold their breath using image acquisition. An alternative • Ferromagnetic hemostatic clips in the central nervous system
to breath-hold cine sequences is the navigator-gated technique. (CNS)
One of the main advantages of the MRI is its multiplanar imaging
capability. The main cardiac imaging planes are oblique to one an- Cardiac MRI at 3Tesla
other. As the cardiac imaging planes are also at arbitrary angles with
respect to the scanner, they are called “double oblique” planes. The The ability to scan with the strength of 3Tesla (T) has multiple poten-
three main cardiac imaging planes are short axis, horizontal long axis tial benefits. First of all, 3T MRI results in an increase in SNR com-
(also known as the four-chamber view) and vertical long axis (also pared with 1.5T MRI, an SNR that is roughly twice that of a 1.5T scan-
known as the two-chamber view). The long axis is the line from the ner. This gain in SNR can be used to either improve image quality or
center of the mitral valve orifice to the left ventricular apex. decrease the scan time in contrast to 1.5T imaging.
Other imaging planes that may be useful include a left ventric- An increase in chemical shift with 3T MRI results in better MR
ular outflow tract view for ascending aortic pathology and a three- spectroscopy (MRS) imaging when compared with MRS at 1.5T,
chamber view. The three-chamber view displays the aortic and mi- due to a doubling of chemical shift with 3T MRI. This results in
tral valves immediately adjacent to one another. improved spectral resolution or the ability to visualize changes in
The basic imaging pulse sequences are spin echo and gradient peaks in metabolites. Fat-water suppression techniques are also
echo. Spin echo sequence is also called as dark blood technique as improved at 3T.
Chapter 62  Cardiac MRI: Present Status 495
With the increased SNR at 3T, heart perfusion images have integrity. Delayed contrast-enhanced MRI with an inversion recov-
improved in providing a better visual delineation of perfusion ery sequence allows visualization and monitoring of scar tissue in
abnormalities and cardiac ischemic evaluation. patients with myocardial infarction (MI) or cardiomyopathy (hyper-
The downside of 3T imaging, particularly for cardiac applica- trophic, inflammatory like sarcoidosis, etc).
tions, is that there are greater susceptibility artifacts. Analysis of function and pattern of contrast uptake—wall motion
at rest and wall motion during dobutamine stress are assessed visu-
Cardiac MRI at 7Tesla ally and described as normal, hypokinetic, akinetic or dyskinetic. A
positive response to dobutamine is defined as any improvement in
Worldwide, 7T scanners are still confined to research; they are not contractile status (e.g. akinetic to hypokinetic, hypokinetic to nor-
licensed for clinical routine. Besides these, scanners, with the mal).
strength of about 1,500,000 times that of the earth’s magnetic field For analysis of perfusion, the uptake pattern of contrast medium
(between 30 and 60 micro-tesla), are currently too expensive for by myocardial tissue is assessed. Distinct uptake of contrast medium
clinical use. Experiments in animals have shown exciting results. during the capillary phase is described as normal perfusion. The
absence of uptake or clearly diminished uptake is described as
APPLICATIONS OF CARDIAC MRI abnormal perfusion.
Delayed hyperenhancement is classified as absent or pre-
Applications of cardiac MRI are briefly described as follows: sent. If delayed enhancement is observed, the transmural extent is
• Ischemic heart disease determined in the middle of the segment and is classified as 1–25%,
• Congenital heart disease 26–50%, 51–75% or 76–100%.
• Valvular heart disease On first-pass MRI, hypoenhancement has been found to be pre-
• Cardiomyopathies dictive of a poor functional outcome after 7 weeks, particularly in the
• Cardiac masses absence of delayed hyperenhancement. On the other hand, the pres-
• Pericardial pathology ence of hyperenhancement on delayed MRI without hypoenhance-
• Evaluation of coronary arteries ment on the first-pass MRI is associated with good functional recovery.
• Evaluation of myocardial oxygenation Analysis of global function—for calculation of the end-diastolic
• Evaluation of cardiac transplant volume and ejection fraction, all short-axis cine images and the hori-
zontal long-axis images using a modified Simpson rule model and
Myocardial Ischemia are analyzed using commercially available software. For each slice,
end-systolic and end-diastolic phases are defined, and the inner
Magnetic resonance imaging can be used to assess patients with and outer borders of the left ventricular myocardium are contoured
ischemic heart disease who are being considered for revascularization manually. The LV end-diastolic volume (LVEDV) index (LVEDV/
to distinguish between myocardial infarction, viable but ischemic body surface area ratio) is calculated for normalization. Myocardial
myocardium and normal myocardium. For the entire myocardium, tagging is used to track segmental motion and can help in directly
the relative volume of normal, diseased but salvageable, and non- distinguishing impaired myocardium from myocardium that may
salvageable myocardium can be calculated and used to compare move abnormally because of its proximity to a disease area.
treatment options.
The extent of myocardial injury after an acute ischemic event is Assessment of Ischemia
strong predictor of patient outcome. In the setting of coronary ar-
tery stenosis or occlusion, myocardial ischemia may result in three On routine spin echo images, myocardial edema characterizing
types of functionally altered states commonly referred to as stunning, acute myocardial necrosis is noted as increased signal intensity on
hibernation and true infarcted myocardium. Stunned and hibernat- T2W images. Viable myocardium is defined as segment of increased
ing myocardial segments have a good chance to recover fully when signal intensity but preserved wall thickness, but this is largely su-
treated properly. Positron emission tomography (PET) and dobu- perseded by inversion recovery late enhancement imaging with Gd-
tamine stress sonography are widely used to differentiate among DTPA.
these states and to help identify those patients who are likely to The infarct core is seen as hypoenhanced area (due to micro-
benefit from revascularization. MRI noninvasively can differentiate vascular obstruction) on contrast enhanced MR within the infarcted
viable myocardium from nonviable myocardium. territory on early scans (1–4 m). This region nearly triples in size
The MRI study in a case of ischemia consists of an evaluation of from 2 to 8 hours. The reperfused infarcted myocardium appears as
first-pass contrast-enhanced MRI for assessment of tissue perfusion, hyperenhancement on late images (>10 m) following contrast bo-
assessment of contractile reserve/function at rest and during dobu- lus because of delayed contrast washout. The infarct size is graded
tamine stress and delayed hyperenhancement to evaluate cellular as large if more than 30% of ventricle is involved, mild if 18–30% of
ventricle is involved and or small infarcts if less than 18% is involved. several years and thus has become an essential complementary tool
“At risk” myocardium and severe reversible ischemic injury (even in in the diagnosis and follow-up of congenital heart disease in adult
the setting of stunning) does not exhibit hyperenhancement. Acute and pediatric populations.
myocardial infarction is hyperenhanced region with contractile dys- Cardiac MRI serves as a vital complementary tool when addi-
function. Injured but viable myocardium is defined as region of hy- tional anatomic and functional information is desired and is particu-
perenhancement, but contractile function present, whereas normal larly useful in patients who have complex congenital heart disease
myocardium is the region of normal function/contraction with no (CHD) and follow-up of surgical repair. Multiplanar and cine acqui-
hyperenhancement. sition capabilities permit evaluation of cardiac chamber morphology
Identification of residual viable myocardium is of clinical impor- and function, valvular disease, and shunt physiology. A larger field
tance to plan therapeutic strategy since revascularization improves of view compared with echocardiography enables improved char-
left ventricular function. Myocardium is viable if it shows severe dys- acterization of extracardiac structures, particularly the mediastinal
function at baseline, but recovers spontaneously (stunned myocardi- great vessels and pulmonary circulation.
um) or following mechanical revascularization (hibernating myocar- CHD can be classified into shunt, obstructive and anatomic dis-
dium). Pathologically, stunned myocardium reveals subendocardial orders.
infarction whereas hibernating myocardium shows transmural scar
with predominant subendocardial scar. Transmural scars with thick- Shunt Lesions
ness of less than 5.5 mm are nonviable with less potential for recov-
ery. Atrial Septal Defect
The three patterns of enhancement based on a combination
of first pass perfusion and delayed contrast images are as follows: There are four major types of atrial septal defects (ASDs), classified
(1) HYPO, i.e. hypoenhancement on first-pass images and normal by location in the interatrial septum: ostium secundum, sinus veno-
enhancement on delayed images; (2) HYPER or normal enhance- sus, ostium primum, and unroofed coronary sinus. Defects are seen
ment on first-pass images and hyperenhancement on delayed readily in horizontal long-axis views, because of the linear nature of
images; and (3) COMB, or hypoenhancement on first-pass images the interatrial septum.
and hyperenhancement on delayed images. Ostium secundum defects, which are the most common, affect
Stress cardiovascular magnetic resonance (CMR) techniques can the midseptum in the region of the fossa ovalis. These should not be
evaluate perfusion and wall motion abnormalities during state of rest confused with a patent foramen ovale (PFO), in which incomplete
as well as during stress. CMR perfusion imaging has the capacity to fusion between the septum primum and septum secundum creates a
detect, localize and semiquantitate myocardial perfusion. Since exer- flap-like opening at the foramen ovale. Bright-blood cine images aid
cise is not practical in the magnet, pharmacological stress is given. greatly in this distinction.
Most commonly used pharmacological stress agents include Sinus venosus defect is not a defect of the atrial septum. Rather,
vasodilators (dipyridamole and adenosine) and B agonists (dobu- the mouth of the caval vein, usually the superior vena cava (SVC), has
tamine). In the presence of significant coronary stenosis, myocardial biatrial connections overriding the rim of the oval fossa, producing
flow heterogeneity is induced which can be detected by perfusion an extraseptal interatrial communication. It is this overriding of the
techniques. This reduction in perfusion pressure distal to stenosis, caval vein across the atrial septum that forms the basis for the imag-
reduction in collateral flow and redistribution of flow from suben- ing diagnosis of the sinus venosus defect. Depending on the region
docardium to subepicardium can cause ischemia and wall motion affected, a superior- or inferior-type sinus venosus ASD may result.
abnormalities which can be detected by CMR. Therefore, the preferred views for the sinus venosus defect are the
The use of susceptibility agents like ferromagnetic/super para- transverse and sagittal planes that are perpendicular to the border
magnetic agents in perfusion studies is still in experimental stage. between the SVC and the left atrium. SSFP cine imaging in these
planes produces better delineation of blood-tissue borders. Cine
Congenital Heart Disease phase-contrast velocity flow mapping can high-light the location and
size of the sinus venosus defect.
Indications of cardiac MRI in congenital heart diseases include: (1) Ostium primum defects are located in the lower portion of the
when transthoracic echocardiography is incapable of providing the atrial septum, directly above the atrioventricular valves. They also are
required diagnostic information, (2) when clinical assessment and associated with endocardial cushion (AV canal) defects and trisomy
other diagnostic tests are inconsistent, (3) as an alternative to diag- 21. Ostium primum defects may present earlier than other types of
nostic cardiac catheterization with its associated risks and higher ASD, due to insufficiency from an associated cleft mitral valve and
cost and (4) to obtain diagnostic information for which CMR offers early development of pulmonary hypertension.
unique advantages. MRI has unique and widespread applications Unroofed coronary sinus defects are located in the p osteroinferior
having undergone significant technical advancements over the last atrial septum. These result from failure of wall formation between
the coronary sinus and left atrium. There is a strong association with tricle, abnormal RV compliance, tricuspid regurgitation and right-
persistent left superior vena cava (Raghib syndrome), caused by fail- to-left intra-atrial shunting. A large PFO (patent foramen ovale) is
ure of degeneration of the left anterior cardinal vein. present in most cases, caused by septal stretching from right atrial
dilatation.
Ventricular Septal Defect
Pulmonary Atresia
Ventricular septal defects (VSDs) are classified into four types based
on their location in the ventricular septum: inlet, perimembranous, Pulmonary atresia with intact ventricular septum is a defect involv-
muscular/trabecular and supracristal/outlet. ing complete discontinuity between the RV outflow tract and main
Because of the curved nature of the interventricular septum, pulmonary artery. Frequently, there is a hypoplastic right ventricle
multiplanar imaging may be necessary for lesion identification and and a rudimentary pulmonary artery confluence. The right and left
characterization. Functional effects depend on the shunt volume pulmonary arteries are supplied by either a patent ductus arteriosus
and pressure gradient across the defect. Small- and moderate-size or systemic bronchial and intercostal collaterals.
VSDs are generally restrictive, meaning that a pressure gradient be-
tween the left and right ventricles is maintained. Large defects are Valvular Stenosis
usually nonrestrictive with equalization of ventricular pressures. In
addition, supracristal and perimembranous defects can lead to aor- Valvular lesions can obstruct either the semilunar or atrioventricu-
tic valve prolapse and insufficiency. lar valves, and may be located at the valvar, subvalvar or supravalvar
levels. Aortic stenosis is the most common, accounting for 3–6% of
Patent Ductus Arteriosus congenital cardiac lesions. Valves are usually bicuspid or dysplas-
tic, caused by fusion of the valve commissures with resulting leaflet
Patent ductus arteriosus (PDA) refers to a persistent connection rigidity and reduction of the aortic orifice. A stenotic jet of antegrade
between the proximal descending aorta and left pulmonary artery, flow is seen on bright-blood images, often with post-stenotic aortic
which normally closes after birth. The size, shape and nature of flow dilatation and left ventricular hypertrophy.
within PDAs are variable, necessitating acquisition of images in mul-
tiple planes. A turbulent flow jet can be demonstrated in the region Valvular Regurgitation
of the defect on bright-blood images.
Valvular regurgitation/insufficiency generally is caused by failure of
OBSTRUCTIVE DISORDERS the papillary muscles or chordae tendineae. Other conditions, such
as rheumatic fever, autoimmune disease, dilated cardiomyopathy,
Tricuspid Atresia and annular valve calcification, also can damage valve leaflets and
prevent their coaptation. On bright-blood cine images, a regurgitant
Tricuspid atresia is a rare congenital heart defect involving failure of jet of retrograde flow is demonstrated.
tricuspid valve formation with absence of direct communication be-
tween the right atrium and right ventricle. In type 1, the great arteries Coarctation of the Aorta
are related normally; in type 2, the vessels are dextro (D)-transposed
(20%), and in type 3, the vessels are levo (L)-transposed (10%). Mag- Aortic coarctation, one of the most common congenital cardiac
netic resonance findings include fat deposition in the right atrioven- anomalies, refers to a constriction of the aortic arch in the region
tricular groove and absent flow across the atretic valve. Hypoplastic of the embryologic ductus arteriosus. The narrowing can be long-
right ventricle, supracristal VSDs, and pulmonary stenosis are asso- segment or focal, and may be located in the preductal, ductal, or
ciated findings. Complications include right heart failure with nut- postductal regions. Preductal coarctation, which usually presents in
meg liver, mural thrombus, and dilation of cardiac/systemic veins. infancy, occurs proximal to the ductus arteriosus and is the result of
decreased blood flow across the aortic isthmus with tubular hypo-
Ebstein’s Anomaly plasia. There is a strong association with other congenital lesions,
including PDA, VSD and subaortic obstruction. In extreme cases, in-
Ebstein’s anomaly is a rare defect in which the septal and posterior terruption of the aortic arch may occur. In this scenario, left ventricu-
leaflets of the tricuspid valve are displaced inferiorly into the RV cav- lar output supplies the ascending aorta, and RV output supplies the
ity. The anterior leaflet is located normally, but may be enlarged and/ descending aorta by means of a PDA. Ductal coarctation, which oc-
or possess abnormal attachments. This partitions the right heart into curs at the insertion of the ductus arteriosus, tends to present shortly
a right atrium, an atrialized portion of the right ventricle and a right after birth when the ductus arteriosus closes. Postductal coarctation,
ventricular cavity. MRI findings include atrialization of the right ven- which usually presents after the neonatal period, occurs distal to the
insertion of the ductus arteriosus and is likely the result of muscular

ANATOMIC DISORDERS
ductal extension into the aorta. Lesions usually are isolated, except
for a 70% association with bicuspid aortic valve. Given the marked Tetralogy of Fallot
outflow obstruction and pressure gradient, maintenance of blood flow
to the lower body requires formation of systemic collateral vessels. Tetralogy of Fallot accounts for 10% of congenital heart defects and
Preoperatively, MRI offers useful information on location and is the most common cyanotic cardiac condition. It is caused by ante-
severity of the narrowed aortic segment. The coarctation segment is rior and cranial displacement of the infundibular septum, resulting
best seen on oblique coronal and sagittal images. Besides MRI de- in pulmonic stenosis, overriding aorta, malalignment (transcristal)
lineates the collateral pathways, that involves subclavian, internal VSD and RV hypertrophy. When an atrial septal defect is present, the
mammary, intercostals, dorsal scapular and epigastric arteries. condition is termed pentalogy of Fallot. In some cases, absence of
Pseudocoarctation of the aorta is a condition in which the aorta the pulmonary valve results in markedly dilated pulmonary arteries.
is markedly dilated and distorted. Periductal kinking or buckling is Peripheral pulmonary stenosis and coronary artery anomalies also
present, but does not produce a pressure gradient. Therefore, there is may be present. Approximately 25% of cases are associated with right
no formation of collateral vessels. aortic arch and mirror-image branching.
Partial/Total Anomalous Pulmonary Truncus Arteriosus

Venous Return
Truncus arteriosus is a cyanotic condition associated with DiGeorge
In partial/total anomalous pulmonary venous return (PAPVR/ syndrome. There is a strong association with right aortic arch and
TAPVR), some or all of the pulmonary veins drain into the systemic mirror-image branching.
circulation. On cardiac MRI, anomalous vessels may be identified in Anatomically, a single truncal vessel arises from the heart and
axial true FISP and black-blood images, although chest MR angiog- supplies blood to both the aorta and pulmonary arteries. The truncal
raphy is a more reliable detection tool. vessel receives blood from both ventricles by means of a high VSD,
Partial anomalous pulmonary venous return can occur from and is associated with a single semilunar or truncal valve. This results
one or multiple lung lobes. Right upper lobe PAPVR is most com- in complete mixing of systemic and pulmonary venous blood with
mon in children, and commonly is associated with sinus venosus resulting systemic arterial desaturation, pulmonary hypertension,
ASD. Anomalous veins may drain into various locations, including truncal valve insufficiency and ventricular volume overload. Surgical
the right atrium, SVC, coronary sinus, azygos vein, IVC (scimitar syn- intervention is required in the first few weeks of life. MRI is helpful in
drome), hepatic vein, portal vein, left brachiocephalic vein, hemia- identifying relevant surgical anatomy, and for postoperative follow-
zygos vein and left SVC. Transverse imaging is best suited to detect up.
these connections because that plane allows cross-sectional visuali-
zation of the caval veins and the RA. Flow from the pulmonary vein Transposition of the Great Arteries
into the RA can be confirmed with cine phase-contrast velocity flow
mapping. The most common left anomalous venous connection is Transposition of the great arteries is characterized by abnormal ori-
that of the left upper pulmonary vein to a vertical vein that drains gins of the great vessels. Dextro-transposition of the great arteries
up to the brachiocephalic vein and from there to the SVC. CE-MRA (D-TGA) is a cyanotic condition that accounts for approximately 8%
is better for definition of both right and left anomalous connec- of congenital cardiac malformations and has a slight male predomi-
tions. Patients are generally asymptomatic unless the shunt fraction nance. There is a strong association with right aortic arch and mirror-
(Qp:Qs ratio) exceeds 1.5:1, at which point surgery is recommended. image branching. On axial images, the aorta is positioned anterior
Total anomalous pulmonary venous return is classified into su- and to the right of the pulmonary artery. The pulmonary artery arises
pracardiac (type 1), cardiac (type 2), infracardiac (type 3) and mixed from the left ventricle and the aorta from the right ventricle, creat-
(type 4) types, depending on the route(s) of venous drainage. There is ing parallel pulmonary and systemic circulations. In this situation,
also an obligatory interatrial communication through a PFO or ASD. there is fibrous continuity between the mitral and pulmonary valves,
Supracardiac defects are the most common and present with a snow- whereas the tricuspid and aortic valves are separated by the RV in-
man sign on coronal views. Infracardiac defects tend to cause severe fundibulum. Survival depends on bidirectional shunting, and 40% of
obstruction of pulmonary venous flow at the level of the diaphragm patients have a VSD, ASD, or PDA. Surgical intervention is necessary
or portal sinusoids. for long-term survival.
Cardiac MRI must be performed when sinus venosus defect or Congenitally corrected or levo-transposition of the great
PAPVC is suspected on echocardiography or clinically and in the arteries (L-TGA) accounts for 0.5% of congenital heart lesions
case of patients with RV dilatation for whom no cause has been de- and is characterized by both atrioventricular and ventriculoarte-
termined by other diagnostic means. rial discordance. The morphologic right ventricle is located to the
left of the morphologic left ventricle and gives rise to the aorta, Aortic Stenosis
which is anterior and to the left of the main pulmonary artery. As
a result, blood flow through the pulmonary and systemic circuits Magnetic resonance imaging can directly demonstrate LV hypertro-
occurs in normal series fashion. Ninety-seven percent of patients phy and post-stenotic dilatation of the ascending aorta. Calcification
have associated defects, including VSD, pulmonary stenosis, of the aortic valve is frequent and can be seen as foci of signal void
tricuspid valve malformations and atrioventricular conduction within the valve on bright-blood images. However, CT is a much more
abnormalities. effective modality for detecting calcification. MRI can also be used to
measure peak velocity directly and to determine pressure gradients.
Interventional and Surgical Procedures
Aortic Insufficiency
Shunt and Valve Repairs
The pathophysiology of aortic insufficiency involves volume over-
Magnetic resonance imaging can be used to evaluate the effec- load of the left ventricle, resulting in increased LV diastolic pressure
tiveness of interventional and surgical procedures such as PDA and reduced aortic diastolic pressure. Ventricular dilatation and in-
closure, ASD/VSD patching and valve repair/replacement. Although creased LV compliance are compensatory mechanisms that allow
calcification and metallic artifacts may obscure small lesions, increased stroke volume and preservation of cardiac output despite
major complications such as abscess, leakage and dehiscence can be large regurgitant volumes. When LV function begins to deteriorate,
identified. both end-systolic and end-diastolic volumes increase, end-diastolic
pressure rises, and myocardial perfusion is diminished, resulting in
ischemia and further compromise of function.
Palliative Shunts and Corrective Surgeries Secondary signs of aortic insufficiency demonstrated with MRI
Magnetic resonance imaging is also useful for evaluating the anat- include LV dilatation and variable dilatation of the aorta. Aortic in-
omy and physiology of palliative shunts and corrective surgical sufficiency is usually graded by regurgitant volume (volume of re-
operations. The most common extracardiac palliative shunts are the gurgitant flow across the valve per heartbeat) or regurgitant fraction
Blalock-Taussig and Glenn shunts. (regurgitant volume divided by forward stroke volume.
VALVULAR LESIONS Mitral Stenosis

Echocardiography is the primary modality for investigation of The pathophysiology of mitral stenosis involves development of a
valvular heart disease. It is fast, cheap, and portable. The supe- pressure gradient across the mitral valve. Left atrial pressure rises to
rior spatial and temporal resolution of echocardiography is clear maintain flow across the valve, and this in turn leads to increased
advantages over MRI in evaluation of valve morphology. The ma- pulmonary venous and capillary pressures, resulting in interstitial
neuverability of echocardiography is an advantage in achieving and eventually alveolar pulmonary edema. Pulmonary hypertension
the optimal angulation for measurement of peak velocities. The can develop as a response to chronic elevated left atrial pressure,
disadvantage of echocardiography in this regard is the occasional leading to increased pressure loads on the right ventricle and even-
patient with a poor acoustic window. This can be overcome with a tual right ventricular failure. MRI may demonstrate increased signal
transesophageal examination. MRI generally allows more accurate intensity within the lungs, corresponding to pulmonary edema. The
and reliable quantification of ventricular mass and function, of- left atrium and left atrial appendage are dilated, and right ventricular
ten important parameters clinically, than does echocardiography. dilatation and hypertrophy may also be seen. Mitral stenosis is typi-
Quantitative measurement of velocity and flow can be achieved cally graded by valve area and transvalvular pressure gradient.
on a pixel-by-pixel basis. MRI is probably more accurate at quan-
tification of ancillary findings in valve disease; it is the standard of Mitral Insufficiency
reference for measurement of ejection fraction, cardiac volumes,
and ventricular mass. Direct measurement of flow is possible with Regurgitant blood in the left atrium increases left atrial pressure,
MRI but not with echocardiography. and a volume stress is placed on the left ventricle as the regurgitant
Role of imaging in valvular heart disease is: (a) to define valvu- volume returns during diastole. The left ventricle dilates to maintain
lar morphology; (b) grade the severity of stenosis/ regurgitation; (c) cardiac output, and the left atrium enlarges as well. Chronic decom-
assess other structures affected by valvular dysfunction (atrial) ven- pensation usually presents as low cardiac output manifesting as fa-
tricular volumes, myocardial mass, atrial thrombi and post-stenotic tigue and weakness. MRI reveals left atrial and LV dilatation. Mitral
dilatation, etc. insufficiency is usually graded by regurgitant volume.
Tricuspid and Pulmonic Valve Disease Cardiac MRI has become an important imaging technique for
the diagnosis and follow-up of CMP. Cardiac MRI allows a reproduc-
Tricuspid stenosis is almost always related to rheumatic heart dis- ible and accurate evaluation of myocardial morphology, function,
ease and is rarely an isolated finding; the aortic and mitral valves perfusion and tissue damage in a noninvasive and “one-stop shop”
are usually also involved. Other causes of tricuspid stenosis include way. For these reasons, cardiac MRI has become an important diag-
congenital atresia and carcinoid syndrome. Tricuspid insufficiency nostic tool for CMP and is the new reference standard for the assess-
is most commonly the result of dilatation of the right ventricle and ment of cardiac function.
tricuspid annulus rather than intrinsic valvular disease. This is also Black blood imaging allows reliable assessment of morphology
the most common valvular lesion in intravenous drug abusers with as a result of its high spatial resolution and soft-tissue contrast. Cine
infectious endocarditis, since left-side valves are protected by the imaging is important in the evaluation of cardiac volumes and kine-
lungs, which act as a filter. sis and is now considered the reference standard for the assessment
Pulmonic stenosis is almost always due to congenital deformity of cardiac function. Transvalvular flow can be studied by means of
of the valve. A pressure gradient develops across the valve, eventually phase-contrast sequences. Late-enhancement imaging is funda-
resulting in right heart failure. mental in the characterization of myocardial tissue abnormalities in
Pulmonic regurgitation is most commonly caused by dilatation CMP.
of the valve ring secondary to pulmonary hypertension. Infective en-
docarditis is the second leading cause of pulmonic insufficiency. Dilated Cardiomyopathy
Imaging in Patients with Mechanical Valves Dilated CMP is associated with dilatation and dysfunction of the
LV or of both ventricles. Ventricles can have normal or thin walls,
Metal valves are not ferromagnetic, hence up to 3T, there is no but always have increased cavitary volumes and low ejection frac-
effect of the magnetic field on the working of the valve. Therefore tions (EFs). Atrial dilatation and valvular dysfunction may be asso-
presence of heart valves does not preclude CMR/general MR of ciated. In black blood images, enlarged cardiac chambers and thin
another organ system. The metal portion of the prosthesis is not vis- myocardial walls are evident. Cine images usually show LV hypoki-
ible by CMR and there is distortion of the applied magnetic field and nesia and increased volumes. Roughly, the end-diastolic volumes
loss of signal from tissue for a variable distance around the prosthesis. that constitute a dilated CMP are more than 140 ml for the LV and
This effect is small in spin-echo images, and neighboring structures more than 150 ml for the RV; Phase-contrast sequences may show
are seen normally but much larger in gradient echo images. Evalu- impaired diastolic function of one or both ventricles. In particular,
ation of these valves is feasible by CMR and not by Doppler ultra- the transvalvular flow may be characterized by a restrictive pattern,
sound techniques since the multiple orifices of these valves generate with a narrow blood inflow jet in early diastole and an early peak-
complex flows. CMR can evaluate patterns of flows downstream atrial peak ratio > 2, or by an early peak-atrial peak ratio <1, due to the
from the valve. early diastolic filling decrease and compensatory atrial contraction.
Late-enhancement areas in the myocardial walls are noted with
Future Developments a pattern (subendocardial and transmural) that cannot be distin-
guished from the typical ischemic pattern, and with a mesocardial
Parallel imaging techniques can be used to decrease acquisition distribution of late-enhancement areas; therefore, the differentiation
times by a factor of two or more, again offering possibilities for between these subgroups may be fundamental in the therapeutic
increased spatial or temporal resolution. Combining fast imaging and prognostic approach to the patients. The possible persistence of
techniques with increased reconstruction speed should allow the autoimmune inflammatory processes may give rise to typical late-
MR imaging equivalent of color flow Doppler imaging: superposition enhancement patterns.
of color-coded velocity information over cine images of the heart. Evaluation of the degree of fibrosis is of prognostic significance
Velocity and flow information obtained from two- and three-dimen- as patients with midwall myocardial fibrosis, since they have more
sional phase-contrast sequences can be used to study complex flow incidences of sudden cardiac death and ventricular tachycardia.
patterns and calculate shear stress in vessel walls.
Hypertrophic Cardiomyopathy
CARDIOMYOPATHIES
The main feature of hypertrophic CMP is LV wall thickening, more
Cardiomyopathies (CMPs) are myocardial diseases associated with often asymmetric and involving the interventricular septum. A
cardiac dysfunction. They are classified as dilated CMP, hypertrophic marker of hypertrophic CMP may be LV outflow tract obliteration,
CMP, restrictive CMP, arrhythmogenic right ventricular (RV) CMP, with the occurrence of systolic gradients (obstructive form). LV EF
specific CMP and non-classified CMP. can be normal or increased, whereas cavitary volumes can be nor-
mal or reduced. Diastolic function may also be impaired because Arrhythmogenic Right
of the altered ventricular compliance. Valve insufficiency may co- Ventricular Cardiomyopathy
exist.
On black blood images, increased LV wall thickness is usually Arrhythmogenic RV CMP is characterized by progressive fibrous or
evident. Cine imaging allows the assessment of LV systolic function, fibrofatty replacement of the myocytes of the RV walls, which can
which can be increased with reduced volumes and the evaluation of extend to the entire RV and also to the LV. The clinical manifesta-
outflow tract obstruction. Impaired diastolic function is well inves- tions of arrhythmogenic RV CMP may vary but usually include ven-
tigated using phase-contrast sequences. In particular, evaluation of tricular tachycardia with left bundle-branch block, which can lead to
transvalvular flow may depict decreased LV compliance, with a nar- sudden death. Therefore, the diagnosis of arrhythmogenic RV CMP is
row blood inflow jet in early diastole and an early peak–atrial peak fundamental and cardiac MRI is now considered an important tool
ratio greater than 2. for this purpose.
The myocardium in patients with hypertrophic CMP is histo- Black blood images with and without fat suppression may show
logically characterized by fibrotic scars and signs of myocardial mi- fibrofatty replacement of the RV free walls, even if this finding is rare-
croischemia. These phenomena have a correlation with cardiac MRI ly the only abnormality in arrhythmogenic RV CMP.
because they are seen in the late-enhancement areas, the extent of
which is associated with the progression and seriousness of the dis- Hemochromatosis
ease; and an increased risk of sudden death exists because myocar-
dial scarring can be the substrate for fatal arrhythmia. Extensive iron deposits lead to wall thickening, ventricular dilata-
tion, and progressive loss of function with congestive heart failure.
Restrictive Cardiomyopathy There is a predominant subepicardial deposition of iron, hence
endocardial biopsy may fail to confirm the diagnosis on MK, these
Restrictive CMP is characterized by reduced ventricular filling deposits results in signal loss in T1W, T2W and T2 STAIR weighted
and diastolic volume, leading to atrial dilatation and venous stasis, images. This pattern of focal signal loss in dysfunctional myocardium
usually with preserved systolic function. Restrictive CMP may be combined with a dark liver confirms the diagnosis of hemochroma-
idiopathic, secondary to infiltrative and storage diseases (such as tosis useful in patients with thalassemia major. Intensified chelation
amyloidosis and sarcoidosis), or associated with myocardial dis- therapy may improve LV function; CMR is an ideal tor for follow-up
orders such as hypereosinophilic syndrome. Morphologic images infiltration and LV parameters.
in restrictive CMP may show atrial enlargement. The RV may also
enlarge if pulmonary hypertension coexists. Cine images allow CARDIAC TUMORS
assessment of the altered diastolic ventricular filling. Restrictive CMP
is characterized by a restrictive diastolic filling pattern, with a nar- Magnetic resonance imaging has been a major advance in the as-
row blood inflow jet in early diastole and an early peak–atrial peak sessment of cardiac mass. Approximately 75% of all primary cardiac
ratio greater than 2. Systolic function of the LV is either preserved or tumors are histologically benign. Among the benign cardiac masses,
reduced. the most common in the adult population are myxomas (52%), fol-
Cardiac MRI is a fundamental diagnostic tool because it helps lowed by papillary elastomas (16%), lipomas (16%) and hemangio-
in the differentiation between restrictive CMP and constrictive peri- mas (6%). In children (including infants), the most prevalent type of
carditis, which have different therapeutic approaches. Although benign cardiac masses are rhabdomyomas (52%), followed by fibro-
reduced ventricular filling and diastolic volumes may be features mas (18%), and teratomas (12%) and hemangiomas (10%). Approxi-
of both diseases, pericardial thickening (>4 mm) is typical of con- mately 25% of all primary cardiac tumors are malignant. Ninety-five
strictive pericarditis. Pericardial thickening can be assessed with percent of these are sarcomas (with a predominance of angiosarco-
morphologic T2-weighted black blood images; unfortunately, the mas in the adult population and rhabdosarcomas in children) and
pericardium may be only minimally thickened or even normal in 5% are lymphomas. The prevalence of secondary malignancies that
patients with constrictive pericarditis. For the evaluation of dubi- invade the heart and the pericardium from nearby organs or metas-
ous cases, cine MRI allows assessment of diastolic ventricular sep- tases, such as the lung, breast, liver and kidney, is much higher than
tal movements and real-time cine MRI evaluation of septal motion primary cardiac tumors (100-to 1000-fold).
during respiration. These techniques show that in restrictive CMP, Echocardiography is the most commonly used noninvasive
septal convexity is maintained in all respiratory phases, whereas in imaging technique in diagnostic cardiology. Masses are typically
constrictive pericarditis, septal flattening can be observed in early found with echocardiography, and the characterization of the mass
inspiration. is based on the specific location of the mass, its shape and mobility.
Although some tissue characterization is possible and some masses in CMR is hypointensity on T2-weighted images (from the fibrous
show specific echogenic properties, echocardiography in general rather than solid nature of the tumor matrix), but isointense relative
has limitations for tissue characterization and requires advanced to myocardium on T1-weighted images. In most cases, fibromas are
research techniques (ultrasonic backscatter, tissue Doppler imag- reported as non-enhancing masses, consistent with the lack of vas-
ing with strain rate analysis, or contrast perfusion imaging). CMR is cularity of the tumor.
three-dimensional, providing an excellent tool for the visualization
of masses over the entire mediastinum, including the mediastinum Lipomas
and extracardiac structures.
The various endogenous contrast responses to T1-weighted, Fatty masses demonstrate high signal intensity on T1-weighted spin-
T2-weighted, proton-density, and other specialized sequences echo images and medium signal intensity on T2-weighted spin-echo
help characterize masses by detecting fat, fluid, or blood products. images. Lipomas are clearly identified by comparing the signal inten-
The use of intravenous contrast enhancement can also be used to sity on a nonfat-suppressed and a fat-suppressed image. A smooth
improve mass characterization, as well as help to define normal contour and capsule also help to characterize lipomas. Because of
anatomic variants or “pseudotumors” found on echo. Bright-blood lack of vasculature, lipomas do not enhance. These characteristics
imaging methods, based on steady-state free precession methods establish the differential diagnosis of the malignant counterpart
(SSFP), yield images with excellent contrast between blood and liposarcoma, which is irregular, multilobular, and does not contain fat.
myocardium, high spatial and moderate temporal resolution. These
provide an excellent means for evaluating the effect of the mass on Leiomyomatosis with Intracardiac Extension
global and regional cardiac function. Blood flow velocity measure-
ments can also provide important information on the hemodynamic Intravenous leiomyomatosis is seen only in women mostly
disturbances caused by a mass. premenopausal arising from a uterine myoma/wall of the vessel. This
Both MRI and MRA are superior to echocardiography for detect- is seen as a large mobile mass in right atrium. Preoperative evaluation
ing or excluding cardiac tumors, for finding the precise location of included assessment of all cardiac chambers and IVC. Signal inten-
cardiac tumors (i.e. paracardiac, mural, or intracavitary), for deter- sity is similar to that of muscle.
mining the extent of disease, for detecting the presence of effusions,
and for detecting the presence of metastases. Other Tumors
Myxomas Infective like Echinococcal/Hydatid Cysts

Ninety percent of myxomas are sporadic and 10% are related to a Cardiac involvement occurs by invasion of the myocardium, first
genetic disorder (Carney syndrome). Most myxomas are solitary through the coronary artery circulation. The second route of infesta-
masses in the left atrium, either broad-based or pendunculated. In tion is the pulmonary vein from rupture of pulmonary echinococcal
some cases, they may invade the fossa ovalis and penetrate into the cysts into the vein. The left ventricle is more often involved than the
right atrium. A non-mobile myxoma can certainly be better char- right ventricle, possibly because of the dominance of the left coro-
acterized with CMR than with two-dimensional echocardiography. nary artery, which brings blood to the left ventricle; the greater myo-
Tissue plane delineation is superior with CMR than 2D echo and cardial mass in the left ventricle, which provides optimal conditions
the exact attachment and extent of the mass is more likely deter- for development of the parasite.
mined. Moreover, myxomas appear “hypointense” to myocardium Magnetic resonance imaging depicts the exact anatomic loca-
on T1-weighted images and “hyperintense” on T2-weighted images. tion and nature of the internal and external structures and is the
Regions of low signal intensity on T2-weighted images within the technique used for post-treatment follow-up. The appearance of a
myxoma may be noted due to calcification or the presence of hemo- hydatid cyst on MRI is usually a characteristic oval lesion that is hy-
siderin in thrombi attached to the mass. Contrast-enhanced CMR pointense on T1-weighted images and hyperintense on T2-weighted
shows heterogeneous enhancement. images. A typical finding on T2-weighted images is a hypointense pe-
ripheral ring, which represents the pericyst (a dense fibrous capsule
Fibromas from the reactive host tissue). However, the multivesicular nature of
the cystic mass and membrane detachment indicate the true diagno-
In echocardiography, cardiac fibromas may be hidden entirely or sis. The cysts may be single or multiple (uniloculated or multiloculat-
may appear as large non-contractile regions of the myocardium. If ed and thin or thick walled. More specific signs include calcification
not differentiated from the myocardium, it may mimic hypertrophy of the cyst wall, presence of daughter cysts and membrane detach-
of the ventricular septum and result in the inappropriate diagnosis of ment. The mass becomes solid and can be difficult to differentiate
hypertrophic cardiomyopathy. A characteristic feature of a fibroma from heart tumors.
Pseudotumors ma is often necrotic and favors the left atrium. Angiosarcomas often
have high signal intensity on T1-weighted images.
Non-neoplasms or pseudotumors include thrombi or other variants Although it is not possible to definitely differentiate malignant
of cardiac anatomy, such as a prominent pulmonary vein orifice, from benign cardiac tumors, certain findings such as right-sided
right atrial Chiari network or crista terminalis, valvular vegetation, involvement, tumor size greater than 5 cm, ventricular infiltration,
thrombi within a left ventricular aneurysm, lipomatous hypertrophy dissemination across tissue planes or enhancing lesions (moderate
of the interatrial septum, rheumatoid nodules, pulmonary collapse, to marked), hemorrhagic pericardial or pleural effusions, undoubt-
a ruptured chordae tendineae, intracardiac varices, tumors outside edly raise the likelihood of malignancy. All inhomogeneous tumors
the heart and pericardium (which can resemble cardiac masses such located in the right heart with concurrent pericardial effusion are
as phrenic nerve tumors), and anatomic structures such as hiatal mostly malignant, whereas homogeneous tumors located in the left
hernias. Postoperative changes, pacemaker wires, and intracardiac heart without pericardial effusion are mostly benign.
catheters are other examples of potential pseudotumors that may
mimic pathology. Metastases
Lipomatous hypertrophy of the interatrial septum (LHIAS) is a
transformation of tissue (pseudotumor) rather than an actual neo- Metastatic disease may result from contiguous extension, lymphang-
plasm. It has signal characteristics similar to lipomas, i.e. high signal itic spread or hematogenous spread. Metastases to the heart tend to
intensity on T1-weighted images. These can occur in any location, involve the myocardium rather than the valves or the endocardium.
but a classic location is the interatrial septum, typically sparing the Most common metastatic cardiac tumors are bronchogenic carcino-
fossa ovalis. mas, breast carcinomas, lymphomas, leukemia, carcinoid tumors,
or melanomas. CMR is also well-suited for the characterization of
Thrombus metastatic tumors. Because of its ability of imaging the heart and its
surrounding organs in multiple planes, the extent of the lesion and
A diagnostic dilemma may arise in the differentiation of thrombus its dissemination can be investigated.
from myxoma, which can appear hypointense because of its calci- Contiguous extension of a tumor may originate from primary
fication and high hemoglobin content secondary to hemorrhage. or metastatic disease. For example, metastases to the lung can
Myxoma usually originates from the interatrial septum, it can be pe- invade the mediastinum by means of local extension, such as by
dunculated or sessile and its contour is mostly smooth. Thrombus a malignant thymoma. Liver cancer, such as hepatocellular car-
occupies the atrial appendage, is broad based, and has an irregular cinoma, can extend cephalad via the inferior vena cava into the
contour. Myxoma can prolapse through the mitral valve at cine GE heart. Other abdominal tumors can affect the heart. Extension of a
imaging, whereas thrombus usually is associated with mitral valve tumor thrombus via the inferior vena cava into the right atrium is
disease. However, both can originate from the posterior atrial wall in a well-recognized complication of advanced renal cell carcinoma.
a minority of patients. Fresh thrombus is hyperintense on T1W and This can also occur with cervical carcinoma and renal angiomy-
T2W spin echo images. Subacute thrombus (after 2 weeks) shows olipomas. Benign uterine leiomyomatosis can affect the heart in-
hyperintensity on T1W and hypointensity on T2W images. Chronic travenously. Germ cell tumors (e.g. testicular teratomas), embryo-
thrombus is hypointense on all sequences. Compared to thrombus, nal cell carcinomas, and choriocarcinomas can metastasize to the
slow flowing blood shows increased SI on T2W and on GRE images, heart; thyroid metastases have been identified; and musculoskel-
flowing blood appears bright and thrombus has low SI. On GD– etal tumors, such as hemangiopericytomas, can metastasize and
DTPA administration, thrombi do not enhance whereas tumor grow in the heart.
enhances. The presence of a clot in the right atrium is suggestive of
a tumor thrombus and should prompt further exploration. The most Pericardial Tumors
likely source is renal, hepatic or adrenal.
Primary pericardial tumors include malignant spindle cell tumors,
Malignant Tumors localized fibrous tumors (also called localized fibrous mesothelio-
ma), pericardial cysts, liposarcomas, lipomas, and teratomas. Car-
Sarcomas diac angiosarcomas tend to involve the pericardium secondarily and
produce hemorrhagic pericardial effusions.
Angiosarcomas are the most common malignant primary cardiac Pericardial mesotheliomas are frequently associated with asbes-
tumor and leiomyosarcomas are the second most common. Leio- tos exposure. Lymphomas are frequently found in patients who are
myosarcoma frequently invades the mitral valve and pulmonary immunocompromised and they frequently involve the pericardium.
veins, and it frequently involves the left atrium. Other common sar- Liposarcomas are rare tumors that tend to be extracardiac and form
comas include rhabdomyosarcomas and fibrosarcomas. Fibrosarco- large infiltrating masses.
Pericardial Lesions pericardial width greater than 4 mm should be regarded as abnor-

mal. Moderate effusions (between 100 ml and 500 ml of fluid) are
The normal pericardium is a thin, avascular, relatively inelastic, flask- associated with a greater than 5 mm pericardial space a nterior to
shaped sac enveloping the heart. the right ventricle. Similar to ventricular volumetric quantification,
Cardiovascular magnetic resonance integrates anatomic and a multislice approach can be used to quantify the precise amount
functional information within a single examination. Its ability for tis- of pericardial fluid.
sue characterization and to determine the presence and degree of Transudates typically have a low signal intensity on T1-weighted
inflammation and activity of disease, and accurately assess the rest of spin-echo CMR, and a high signal intensity on T2-weighted sequenc-
the heart, in particular the myocardium is helpful in the differential es. Exudates, having a high protein and cell content, increase T1-
diagnosis. relaxation (higher signal intensity) and shorten T2-relaxation (lower
Normal pericardium is visible on spin-echo CMR as a thin, signal intensity). However, because of motion artifacts, pericardial
smooth, low-intensity curvilinear structure surrounded by high- fluid characterization is not always feasible. In particular non-linear
intensity mediastinal and epicardial fat, or medium-intensity myo motion of pericardial fluid during cardiac motion may falsely cause
cardium. The transverse pericardial sinus, preaortic and retroaortic high signal on T1-weighted spin-echo CMR within the effusion
recesses can be identified in the majority of patients. On CMR, n ormal even in the presence of a simple transudate. The signal intensity of
pericardium measures 1.2 mm in diastole to 1.7 mm in systole, which a hemorrhagic pericardial effusion is dependent on the duration of
are larger than those found in anatomical studies of the heart, i.e. 0.4– the disease. With balanced SSFP-gradient-echo techniques, o ften
1 mm. The overestimation of pericardial thickness on CMR is due to a better characterization of the pericardial fluid content can be
motion of pericardial layers, lack of sufficient spatial resolution and achieved such as the visualization of fibrinous strands or presence
chemical shift artifacts at the fat-fluid interface on cine CMR. of coagulated blood.
Pericardial Cyst Pericardial Inflammation

Pericardial cysts are congenital encapsulated cysts implanted on the Pericarditis can also present in acute, subacute or chronic forms. In
pericardium that are not connected with the pericardial cavity. They the acute phase, inflammation of the pericardial layers is character-
typically occur in the cardiophrenic sulcus (90%), most often right- ized by formation of young, highly vascularized granulation tissue
sided (70%). On chest radiography, they present as a well-defined with fibrin deposition. Chronic inflammation is characterized by
outpouching on the lateral heart border. On CMR, they appear as a a progressive sclerosing pericarditis with fibroblasts, collagen and
well-defined homogeneous paracardiac structure, having the signal a lesser amount of fibrin deposition. This may progress towards an
characteristics of water. Pericardial cysts should be differentiated end-stage, chronic fibrosing pericarditis with fibroblasts and col-
from encapsulated pericardial effusions, and other cystic structures lagen. The main feature of this end-stage is a stiff pericardium with
such as bronchogenic cysts and thymic cysts. constriction of the heart (constrictive pericarditis).
Cardiovascular magnetic resonance shows thickening of peri-
Pericardial Effusion cardial layers which becomes more irregular in cases of chronic peri-
carditis and associated pericardial effusion. Pericardial enhance-
Imaging is often required to confirm the presence, severity and ex- ment on gadolinium-enhanced CMR studies is noted with streaky
tent of fluid; to characterize the nature of fluid; to rule out pericardial enhancement of the surrounding fat and enhancement of adjacent
inflammation; to determine the hemodynamic impact on the heart; myocardial tissue, indicating associated epicarditis or myocarditis,
and to guide pericardiocentesis. For this purpose, echocardio respectively. Tagging CMR techniques may be of use to well depict
graphy is the standard. However, image quality and interpretation fibrotic adhesions of pericardial layers.
may be hampered by acoustic window, and in obese patients. CMR
is superior to detect the distribution and amount of fluid accumula- Constrictive Pericarditis
tion than with echocardiography. Although CMR can detect peri-
cardial effusions as small as 30 ml, a clear-cut relationship between Chronic fibrosing pericarditis is characterized by a thickened, fi
brotic
the measured width of the pericardial space and total fluid volume and/or calcified pericardium, not infrequently constricting the heart
cannot be established because pericardial fluid accumulation is and impairing cardiac filling.
often not homogeneously spread. Due to the gravitational depend- Pericardial constriction is most commonly idiopathic but can be
ency, focal fluid accumulation posterolateral to the left ventricle and the end result of any cause of inflammatory pericarditis. Tuberculo-
along the inferolateral wall of the RV are not infrequent. Another sis, cardiac surgery and radiation-induced pericarditis are important
common location is the superior pericardial recess. In general, a causes.
Tubercular Pericarditis in cardiac filling (i.e. enhanced RV filling on inspiration, enhanced

LV filling on expiration). Real-time velocity CMR is a potential alter-
Thickened pericardium shows isointense signal intensity to muscle native to echo-Doppler to assess the effects of respiration on cardiac
with hypointense lesions in inner surface of thickened pericardium. filling, though ideally slice-tracking techniques are needed to com-
These hypointense lesions reflect ferromagnetic elements after hem- pensate for through-plane motion.
orrhage into pericardial sac, as well as fibrosis of the pericardium.
Linear low intense signals in pericardial sac represent strands of NEOPLASTIC DISEASES
granulation tissue accompanying caseous necrosis. On contrast,
tramline like enhancement is noted at the site of fibrous hypertrophic Pericardial neoplastic disease is much more frequently encountered
parietal and visceral pericardium. than cardiac neoplasms.
In non-tubercular pericarditis, pericardial thickening and cal-
cification may be less prominent. In radiation therapy, systolic Benign Neoplasms
dysfunction may accompany constriction and is a marker of poor
prognosis after pericardiectomy. Moreover, in extensive cases the The most common benign tumors include lipoma, teratoma, fibroma
fibrosing process may be adherent or even involve the myocar- and hemangioma. Most of these lesions exhibit fairly typical features,
dium. including well-defined margins. Lipomas on MRI demonstrate high
signal intensity on T1- and T2-weighted images with signal void of
Morphological Abnormalities short tau inversion recovery or frequency selective fat-saturation
sequences.
The typical morphological presentation of constrictive pericarditis is Fibromas appear as low intensity T2-weighted MR images with
a more or less generalized thickening of the pericardium. This thick- little or no enhancement. Hemangiomas, however, demonstrate an
ening is usually most pronounced over the right heart side (right intense blush upon CT or MR contrast enhanced imaging.
ventricle and anterior atrioventricular groove), and the pericardial
delineation is often irregular. The underlying cardiac cavities may be Malignant Pericardial Neoplasms
constricted by the abnormal pericardium, having a flattened or tubu-
lar-shaped appearance. Indirectly, as a result of the increased cardiac Pericardial mesothelioma is the most common primary malignant
filling pressures, unilateral or bilateral atrial enlargement, dilatation tumor of the pericardium, and is often presents as hemorrhagic
of caval and hepatic veins, pleural effusion, ascites are encountered. pericardial effusion and nodular thickening of the pericardium. It is
Useful criteria to assess pericardial thickness by CMR are: (a) related to pleural mesothelioma, which has a propensity to invade
pericardial thickness 2 mm or less: normal, (b) pericardial thickness into the pericardial sac. Other primary tumors include malignant
greater than 4 mm: suggestive of pericardial constriction in patients fibrosarcoma, angiosarcoma, and benign and malignant teratoma.
with the appropriate clinical presentation, (c) pericardial thickness Pericardial metastases arise from hematogenous or lymphatic
greater than 5–6 mm: high specificity for constriction. metastatic spread or direct invasion of a non-pericardial primary
The thickened fibrotic and/or calcified pericardium has a low malignancy, with lung cancer, breast cancer, leukemia, or lymphoma
signal not only on T1- and T2-weighted spin-echo CMR but also on and melanoma. They are often associated with a large and hemor-
cine imaging. In end-stage chronic fibrosing forms of constrictive rhagic effusion that is disproportionate in size to the amount of tu-
pericarditis there is no enhancement after gadolinium. Pericardial mor present. Since metastatic pericardial implants are often small,
enhancement is suggestive of residual inflammation. they might be difficult or even not visible on CMR.
Myocardial enhancement patterns on GE CMR may be strongly
indicative of specific myocardial infiltrative or storage diseases, while Others
T2*-weighted CMR may be used to non-invasively depict iron depo-
sition cardiomyopathy. Other entities that have a mass-like appearance are pericardial he-
matoma and pericardial gossypiboma. The appearance and CMR
Functional and Hemodynamic Abnormalities signal characteristics of a pericardial hematoma depends on the age
of the collection. Pericardial gossypiboma or foreign body granulo-
Velocity-encoded CMR typically shows a restrictive filling pattern ma should be considered in patients with previous cardiac surgery.
with an enhanced early filling, and decreased or absent late filling, In the pericardium, it includes surgical sponges in the pericardial
depending on the degree of pericardial constriction and increased space overlooked after pericardiectomy.
filling pressures. Also the venous flow patterns may show restrictive
physiology with diminished or absent forward, or even reversed sys- CORONARY MR ANGIOGRAPHY
tolic flow, and increased early diastolic forward flow and late back-
flow. Constrictive pericarditis, in contrast with restrictive myocardi- Coronary MR angiography (CMRA) emerged as a unique clinical
tis, is typically characterized by a strong respiratory-related variation imaging tool with applications in selected populations. CMRA with
definite advantages, namely, the absence of radiation exposure and Function

the nephrotoxicity that is due to the iodine contrast material prom-
ised a lot however, its long scan time, inability to demonstrate the Minimal volumes of both atria are significantly larger, fractional
calcified plaques and the sophistication of the techniques, in com- emptying is smaller in transplanted hearts. Both reservoir and
parison with CT coronary angiography with using multi-detector CT, stroke volumes are smaller and conduit volumes are larger. Atrial
have impeded its application in routine practice. With improvements filling and emptying rates are lower. Left ventricle mass is signifi-
in multi detector CT technology CT coronary angiography has practi- cant higher in transplant s leading to significant reduction in end
cally replaced the MR coronary angiography. systolic wall stress/volume ratio. Cyclosporine may be responsible
for this early left ventricle remodeling and reduced myocardial con-
TRANSPLANTED HEART tractility.
MR angiography reveals a 25 degree clockwise /anterior rotation
Heart transplantation is a lifesaving therapy for selected individuals of right coronary artery ostium with a corresponding realignment of
with end-stage heart failure. Despite significant advances in anti-re- left main coronary artery ostium. This quantification of anterior rota-
jection therapy, allograft rejection remains a leading cause of mortal- tion can be used to guide coronary interventions if required. MRA
ity with one in four transplant patients dying within five years after can demonstrate focal stenoses.
surgery. Screening for organ rejection is a critical component of care
for patients who have undergone heart transplantation. Endomyo- CMR Correlates of Heart Transplant
cardial biopsy is the gold standard screening tool, but noninvasive
Rejection
alternatives are needed. CMR is well suited to provide an alternative
to biopsy because of its ability to quantify ventricular function, mor- T2-weighted CMR
phology and characterize myocardial tissue.
Acute cellular rejection is the most common form of heart trans- Myocardial T2 signal intensity: Despite its utility in other myocardial
plant rejection. Cardiac transplant recipients have between one and disease states, T2 signal intensity has shown mixed results in diag-
three episodes of acute cellular rejection within the first year after nosing heart transplant rejection.
transplantation. The ability of CMR to characterize ventricular mor- Myocardial T2 quantification: Long T2 relaxation times are associ-
phology, systolic function, diastolic function, and myocardial in- ated with acute rejection and T2 relaxation times increase with his-
flammation makes it an excellent candidate to non-invasively diag- tologic rejection. Prolongation of T2 relaxation times observed in
nose and screen for acute heart transplant rejection. transplant rejection could be prevented by the addition of immuno-
suppressive agents such as cyclosporine.
Normal Features of Transplanted Heart The relationship between T2 relaxation and rejection is highly
sensitive and very unlikely to miss any cases of advanced rejec-
Myocardial T2 Signal Intensity tion.
T2 relaxation time is the decay time constant of magnetic signal after T1-weighted CMR
an excitatory pulse. T2 relaxation time is calculated by plotting the
spin echo signal intensity against varying echo times and is believed Myocardial T1 signal intensity: T1 signal intensity does not signifi-
to lengthen in proportion to the degree of myocardial edema. cantly correlate with rejection as diagnosed by endomyocardial bi-
Patients screened in the first 24 days post-transplantation have opsy.
elevated T2 relaxation times irrespective of their biopsy results. After Myocardial T1 quantification: The T1 relaxation time can be calcu-
24 days, a T2 relaxation time of more than 46 ms (i.e. two standard lated from a series of images acquired with an increasing delay fol-
deviations above control T2 relaxation times) is specific for detecting lowing an inversion or saturation of the magnetization. T1 relaxation
rejection. T2 relaxation times cannot discriminate rejecting and non- times are prolonged in rejecting hearts compared to non-rejecting
rejecting allografts in the perioperative period due to normal inflam- hearts.
mation and edema that occurs early after heart transplantation.
T1 Contrast Agents (Gadolinium)
Myocardial T1 Quantification
Early Enhancement
As with T2 relaxation time, T1 relaxation time within the first 24 days
post-transplantation are presumably influenced by perioperative Intravenous gadolinium increases signal intensity on T1-weighted
factors unrelated to rejection. images acquired early after contrast administration, in proportion to
the degree of tissue perfusion and is thought to reflect the hyperemia Twisting Mechanics
seen in inflamed tissue. Early enhancement alone is too insensitive
for diagnosing myocarditis, but was useful when used in combina- Left ventricular twisting mechanics have also been studied in normal
tion with T2 values and late gadolinium enhancement in a scoring and transplanted hearts. There is 25% decrease in torsional deforma-
system for the diagnosis of rejection. In two human trials of trans- tion amplitude and peak systolic torsion during periods of rejection
plant rejection, post contrast signal intensity tended to increase with compared to pre-rejection values.
degree of rejection although it could not consistently identify the full
spectrum of abnormal endomyocardial biopsies diagnostic of rejec- T1 and T2 Contrast Agents (Iron oxide particles)
tion. An increase in myocardial enhancement in rejectors is noted
compared with non-rejectors. However, myocardial enhancement Iron oxide contrast agents contain superparamagnetic particles with
cannot discriminate rejection severity. an iron oxide crystal core wrapped in an outer coating (i.e. dextran)
which shorten both T1 and T2/T2* relaxation. Over time, iron oxide
Late Enhancement particles are taken up by macrophages which shortens their T2/T2*
properties. Thus, accumulation of macrophages, which contain iron
Late enhancement by Gadolinium can also be used in CMR to de- oxide, in inflamed tissue can be visualized as a signal loss on T2-
tect areas of myocardial scar or myocardial fibrosis. The rate at which weighted images.
gadolinium is cleared from the myocardium is slower in areas with Cardiovascular magnetic resonance with iron oxide particles
fibrosis compared to healthy myocardium. T1-weighted images tak- is a novel and potentially powerful method to evaluate inflamma-
en several minutes (“late”) after contrast injection will show higher tion in the heart. T1 imaging in early post iron oxide contrast injec-
concentrations of gadolinium in areas of myocardial fibrosis making tion can identify increased vascular permeability, while delayed T2
these areas appear bright. Late gadolinium enhancement (LGE) has imaging gives information into in vivo macrophage accumulation.
correlated well to pathologic assessment of myocardial fibrosis in is- Various animal studies have shown that myocardial T1 signal in-
chemic and non-ischemic myocardial injury. tensity in rejecting allografts was significantly elevated compared
to immunosuppressed allografts within four minutes post contrast
Ventricular Wall Thickness and Systolic Function injection. The rapidity of the change in signal intensity suggests al-
tered vascular permeability is responsible for the increase in sig-
Myocardial wall thickness has been shown to increase in transplant nal. T2 signal intensity decreased 24 hours after iron oxide parti-
rejection and decreases as the rejection episode resolves. Wall thick- cle injection. Treatment of the rejection episode by cyclosporine
ness however cannot accurately identify the severity of a rejection reversed the increase in signal intensity. Immunohistochemistry
episode. Left ventricular wall thickness also increases in patients confirmed accumulation of iron oxide containing macrophages in
with rejection (ISHLT ≥ grade 2). areas of rejection.
Hearts undergoing rejection have reduced ejection fraction and Human trials of transplant rejection and iron oxide contrast
stroke volume, although these changes are only significant when agents are needed.
rejection is moderate or severe. Despite the excellent spatial resolution
of CMR, these variables are probably of insufficient sensitivity to detect Spectroscopy
the early and milder forms of rejection that are of clinical interest.
31P spectroscopy reveals decreased PCr/ATP even in mild ejection.
Potential CMR Correlates of MRS can also evaluate viability of a human donor before implanta-
tion. MRS can also evaluate response to immunotherapy in rejection.
Heart Transplant Rejection
Combining multiple CMR measures into a transplant rejection
Diastolic Dysfunction scoring system can be done to improve the sensitivity in detecting
heart transplant rejection and possibly reduce, if not eliminate, the
Diastolic dysfunction is one of the earliest measurable features of need for endomyocardial biopsy.
heart transplant rejection. Measuring diastolic function with CMR To summarize cardiac MRI is the noninvasive modality which
may improve sensitivity in diagnosing rejection; however work in can provide invaluable information about cardiac morphology as
this area would need to differentiate changes in diastolic proper- well as the cardiac function. Although multi slice CT have replaced
ties due to rejection and those due to the fibrotic and hypertrophic MR as far as coronary evaluation is concerned it scores over CT in
remodeling that accompanies heart transplantation even in the ab- most of the other situations specially evaluation of congenital anom-
sence of rejection. alies and patients of myocardial ischemia.
60s and early 70s Raymond Damadian, an American medical doc-

HISTORY OF MRI
tor at the State University of New York in Brooklyn, demonstrated
Magnetic resonance imaging, as with all medical imaging tech- that a NMR tissue parameter (termed T1 relaxation time) of tumor
niques, is a relatively advanced technology with its foundations be- samples, measured in vitro, was significantly higher than normal tis-
ginning during the year of 1946. Felix Bloch and Edward Purcell in- sue. He suggested that these differences could be used to diagnose
dependently discovered the magnetic resonance phenomena during cancer, though later research would find that these differences, while
this year and were later awarded the Nobel Prize in 1952. Up until the real, are too variable for diagnostic purposes. Damadian’s initial
1970s MRI was being used for chemical and physical analysis. Then methods were flawed for practical use,2 relying on a point-by-point
in 1971 Raymond Damadian showed that nuclear magnetic relaxa- scan of the entire body and using relaxation rates, which turned out
tion times of tissues and tumors differed motivating scientists to use to not be an effective indicator of cancerous tissue.3
MRI to study disease. With the advent of computed tomography (us- Later on Paul Lauterbur, a Professor of Chemistry at the State
ing computer techniques to develop images from MRI information) University of New York at Stony Brook, expanded on Carr’s tech-
in 1973 by Hounsfield, and echo-planar imaging (a rapid imaging nique and developed a way to generate the first MRI images, in 2D
technique) in 1977 by Mansfield, many scientists over the next 20 and 3D, using gradients. In 1973, he published the first nuclear mag-
years developed MRI into the technology that we now know today. netic resonance image.4,5 In this seminal paper Lauterbur described
Felix Bloch, working at Stanford University, and Edward Purcell, a new imaging technique, which he termed zeugmatography6 (from
from Harvard University, found that when certain nuclei were placed the Greek zeugmo meaning yoke or a joining together). This referred
in a magnetic field they absorbed energy in the radiofrequency to the joining together of a weak gradient magnetic field with the
range of the electromagnetic spectrum, and re-emitted this energy stronger main magnetic field allowing the spatial localization of two
when the nuclei transferred to their original state. The strength of the test tubes of water. He used a back projection method to produce an
magnetic field and the radiofrequency matched each other as ear- image of the two test tubes. This imaging experiment moved from
lier demonstrated by Sir Joseph Larmor (Irish physicist 1857–1942) the single dimension of NMR spectroscopy to the second dimen-
and is known as the Larmor relationship (i.e. the angular frequency sion of spatial orientation being the foundation of MRI. Reflecting
of precession of the nuclear spins being proportional to the strength the fundamental importance and applicability of MRI in medicine,
of the magnetic field). This phenomenon was termed nuclear mag- Paul Lauterbur and Sir Peter Mansfield of the University of Notting-
netic resonance (NMR) as follows”: Nuclear” as only the nuclei of ham were awarded the 2003 Nobel Prize in Physiology or Medicine
certain atoms reacted in that way; “magnetic” as a magnetic field was for their “discoveries concerning MRI”. The Nobel citation acknowl-
required; “resonance” because of the direct frequency dependence edged Lauterbur’s insight of using magnetic field gradients to deter-
of the magnetic and radiofrequency fields. With this discovery NMR mine spatial localization, a discovery that allowed rapid acquisition
spectroscopy was born and soon became an important analytical of 2D images. Mansfield was credited with introducing the mathe-
method in the study of the composition of chemical compounds. For matical formalism and developing techniques for efficient gradient
this discovery Bloch and Purcell were awarded the Nobel Prize for utilization and fast imaging.
Physics in 1952. Interestingly, Dr Isidor Rabi, an American physicist In the late 70s and early 80s a number of groups, including
who was awarded the Nobel Prize for Physics in 1944 for his inven- manufacturers, in the US and UK showed promising results of MRI
tion of the atomic and molecular beam magnetic resonance method in vivo. In the UK these included the group from the Hammersmith
of observing atomic spectra, came across the NMR experiment in the (professor R Steiner and Dr (now professor) G Bydder) collaborating
late 1930s, but considered it to be an artefact of his apparatus and with Picker Ltd. (a subsidiary of GEC) at Wembley (Dr Ian Young),
disregarded its importance. two independent groups in Nottingham (professor P Mansfield and
During the 50s and 60s NMR spectroscopy became a widely used Dr W Moore), and in Aberdeen (professor J Mallard and Dr J Hutch-
technique for the nondestructive analysis of small samples. Many inson). The first commercial MR scanner in Europe (from Picker
of its applications were at the microscopic level using small (a few Ltd.) was installed in 1983 the Department of Diagnostic Radiology at
centimetres) bore high field magnets. In the 1950s, Herman Carr re- the University of Manchester Medical School (professor I Isherwood
ported on the creation of a one-dimensional MRI image.1 In the late & Professor B Pullen).
REFERENCES
1. Carr HY. “Field Gradients in Early MRI”. Physics Today (American Institute of Physics). 2004;57(7):83.
2. “The man who did not win” Sydney Morning Herald. 2003-10-17. Retrieved 2007-08-04.
3. “Scan and Deliver”. Wall Street Journal. 2002-06-14. Retrieved 2007-08-04.
4. Lauterbur PC. “Image formation by induced local interactions: examples of employing nuclear magnetic resonance”. Nature. 1973;242(5394):
190-1.
5. Filler AG. “The history, development, and impact of computed imaging in neurological diagnosis and neurosurgery: CT, MRI, DTI”. and-neurosur-
gery-ct-mri-and-dti.html Internet Journal of Neurosurgery. 2010;7(1).
6. Lauterbur PC. “Magnetic resonance zeugmatography”. Pure and Applied Chemistry. 1974;40:149-57.
63 History of Nuclear Cardiology
Mahapatra GN
In 1951, the rectilinear scanner was invented by Dr Benedict

INTRODUCTION
Cassen. His rectilinear scanning device dubbed the Scinti scanner
Clinical nuclear medicine began in 1960 with Louis G Stang and Powel was the talk of the first meeting of the society of nuclear medicine
Richards advertised radioactivity, i.e. Technetium-99m (Tc-99m) in Seattle, Washington during May 1954. Subsequently, this scanner
other generators for sale by Brookhaven National Laboratory, New was used in Cardiology to detect pericardial effusion and diagnose
York (United States of America). Slowly in mid-1960s, technologist pulmonary embolism. This device was capable of rendering static,
used radioactive materials to provide important information about life size images of organs which lacked resolution and did not yield
the anatomy and physiology of various organs and organ systems. quantitative measurements of volumetric data. Jeff Holter, the inven-
In the decades since, researchers and clinicians have used nuclear tor of the Holter monitor to detect cardiac arrhythmias in ambula-
medicine to detect and diagnose a host of diseases and disorders. In tory patients, had the idea to found the society of nuclear medicine
1925, Herman Blumgart and Utto Yens used bismuth-214 (radium-C) in 1954.
to determine the arm-to-arm circulation time in patients. In 1927, Hal Anger took Dr Cassen’s revolutionary work and made it even
Herman Blumgart used injectable solutions of radon gas and a better and more useful to practitioners through his landmark devel-
Geiger tube to measure the “velocity of the circulation”, the time it opment of the “Scintillation Camera” often called the “Anger Camera”.
took for the radioactivity to reach the heart in normal volunteers. Born in Denver in 1920, Anger’s immigrant family moved to Los
He subsequently studied patients with thyrotoxicosis, anemia, Angeles when Anger was five years old. Anger became an electrical
polycythemia vera, carcinoma and heart disease. engineer after building a television set from scratch, at home from
Since then radiotracers, external radiation detection instru- parts during the 1930s before TV was particularly well known by the
ments and sophisticated processing software have seen developed general public.
to give detailed quantitative information about cardiac function, re- Anger took his degree from the school of Engineering at the
gional myocardial blood flow, metabolism and innervation may be University of California at Berkeley in 1943 and immediately went to
measured noninvasively in individuals with or at risk of diseases of work for the government, developing useful applications of radar at
the heart. Harvard.
In 1936, John H Lawrence made the first clinical therapeutic In 1948, Anger came to the Donner Laboratory at Barkeley and
application of an artificial radionuclide when he used phosphorus-32 there developed and perfected his techniques that would lead to his
to treat leukemia. Subsequently Georg de Heresy used red blood invention of the scintillation camera.
cells labeled with phosphorus-32 to measure red blood cell volume Never one to hold the spotlight, Anger continued to develop and
inventing the “tracer principle”, the most fundamental in nuclear perfect his imaging system, eventually bringing to the field a camera
medicine. A major breakthrough was made by Werner Forssmann that could produce multiple exposures of suspected tumors from dif-
in Eberswald, Germany in 1929 when the human heart was first ferent depths, thus providing a composite image approaching a 3D
catheterized. In 1936, Paul Hahn used Iron-59 to measure total body effect as well as made it possible to conduct dynamic studies in 1958.
hematocrit. Research conducted during World War-II led to the However, Hans Geiger’s and Walther Muller’s radioactivity counter
introduction of sulfur-35 as a tracer of plasma proteins. In 1938, John found early use in radioisotope tracking. Unfortunately, its applica-
Livingood and Glenn Seaburg discovered Iodine-131 and cobalt-60. bility was eclipsed by the work of Benedict Cassen and Hal Anger.
Subsequently, Fein and Seligman invented the radioiodine method Finally, Hal Anger’s first scintillation camera which he displayed at
for measuring plasma volume. By 1943, radioiodinated bovine the 1958 society nuclear medicine annual meeting in Los Angeles.
albumin, the so called “first true radiopharmaceutical” was used Subsequently, the commercial development of Tc-99m in 1960, al-
in humans. Storaasli replaced bovine albumin with human serum lowed for the imaging of radiotracers circulating through different
albumin (HSA) among the earliest commercially available radio portions of the heart in real time. In 1964, Nuclear Consultants sold
pharmaceuticals, as radioactive tracers came to be known. the first commercial Tc-99m generator. Among the first cardiac uses,
this was the detection of intracardiac shunts soon followed by the fatty acid metabolism and autonomic innervation of the heart. O-15
measurements of regional myocardial perfusion and regional ven- water is the most widely used positron emitter worldwide in nuclear
tricular function. cardiology but requires a cyclotron at the site of the examination.
The first radiotracer used to measure regional myocardial blood 15N-ammonia is useful as a tracer of blood flow, but is not commer-
flow was potassium-43. Subsequently, Elliot Lebowitz introduced cially available. Rubidium-82 (Rb-82) with properties similar Tl-201
thallium-201 (Tl-201) for MPI, first proposed by Kawana in 1973. is beginning to be more widely used for examining myocardial perfu-
Again in the same year of 1973, H William Strauss and Barry L Zaret sion. Regional metabolic imaging with F-18-deoxyglucose is useful in
introduced the first noninvasive exercise stress MPI. This expanded detecting myocardial viability in patients being considered for surgi-
the world of nuclear medicine to include a new technology—Nuclear cal intervention.
Cardiology. Thallium-201 was first introduced for myocardial perfu The reported mortality of patients with CAD has been very high
sion imaging (MPI) in 1973 by Elliot Lebowitz, but it was not avail in the present day clinical practice. Nuclear imaging has been estab-
able commercially until 1977, when New England Nuclear received lished as one of the most popular noninvasive investigations com-
Food and Drug Administration (FDA) approval to distribute it for the monly used for the diagnosis, prognosis and guidance of therapy in
diagnosis and location of myocardial infarction (MI). Diagnosis was patients suffering from CAD. Nuclear cardiology procedures has dis-
the primary role of nuclear cardiology at that time. Today, advances in tinct advantages over other diagnostic imaging modalities, such as
technology and radiopharmaceuticals have made nuclear cardiology having a low radiation risk because low amounts of radioactivity are
an important tool for diagnosis, risk stratification and management used. It is being relatively painless and noninvasive. It provides both
of patients with known or suspected coronary artery disease (CAD). structural and functional information of the organ of interest. It is
In 1971, Gopal Subramanian and John McAfee introduced Tc- definitely superior to other noninvasive tests like routine electrocar-
99m labeled phosphates for bone imaging. Subsequently, Kulkarni diogram (ECG), stress ECG and 2-D-echocardiography with a sen-
and his associates used this Tc-99m labeled pyrophosphate (PYP) as sitivity of 93% and specificity of 95%. The various current concepts
“Hot-spot” (infarct avid) imaging methods for detecting acute MI. provide in a single noninvasive manner information about myocar-
During the mid-1970s, research and applications of nuclear dial function (systolic and diastolic), perfusion, viability (ischemic,
medicine took on a series of innovations. Chief among them was hibernating or stunned myocardium vs necrosed or scarred muscle),
in the arena of cardiology. “Nuclear cardiology stole the show” and metabolism and neuroreceptor activity. In addition to these, with the
was on the verge of becoming a major force that would bring nuclear introduction of newer radiopharmaceuticals and the improvement
medicine in to the mainstream of medicine, says Dr Henry Wagner in software by nuclear cardiology scientists have further made car-
as he reviewed the accomplishment of the society following the 1977 diovascular nuclear medicine a dynamic field. Every year new ap-
and 1978 annual meetings. plications are introduced and the old ones are refined.
In 1976, John Keyes developed the first general purpose single
photon emission computed tomography (SPECT) camera. Subse- VARIOUS NUCLEAR CARDIOLOGY
quently, Ronald Jaszczak developed the first dedicated head SPECT
PROCEDURES
camera. In 1979, Ronald Jaszczak developed the first general purpose
multihead SPECT camera. Myocardial function, systolic and diastolic: Global and regional:
In 1979, Berger examined the “first pass” of Tc-99m tracers • First pass radionuclide angiocardiography (FPRNA)
through the heart to evaluate left ventricular (LV) and right ventri • Stress multigated equilibrium radionuclide ventriculography
cular (RV) function in patients with coronary heart disease, chronic with nitroglycerin (NTG) intervention.
obstructive lung disease and congenital heart disease. Global ven Myocardial perfusion:
tricular function and regional contraction of the ventricles could be • Stress/Redistribution SPECT Tl-201 myocardial perfusion study
studied and quantitative measurements of stroke volume, ejection with reinjection protocols
fraction (EF), ventricular filling and emptying rates could be calcu • Rest-redistribution Tl-201 myocardial perfusion scintigraphy/
lated. rest and intravenous (IV) NTG/oral NTG study
Single photon emission computed tomography allowed us to • Stress gated SPECT Tc-99m sestamibi/tetrofosmin myocardial
electronically slice the LV into the short axis, horizontal long and ver- perfusion scintigraphy with rest IV/oral NTG gated SPECT study
tical long axis planes in order to evaluate regional perfusion. The ap- • Pharmacological stress perfusion imaging
plication of positron emission tomography (PET) offers better spatial • Rubidium-82 PET myocardial perfusion study
resolution. • Stress N-13 ammonia/O-15 labeled water
In 1974, a commercial PET imaging device was introduced by • F-18-fluorodeoxyglucose (FDG) PET myocardial ischemia imag-
Michael Phelps. The application of PET offers better spatial resolu- ing
tion than SPECT technology. Today there are a number of radiophar- Myocardial metabolism:
maceuticals useful in the study of myocardial perfusion, glucose and • F-18 FDG metabolic PET imaging
Chapter 63  History of Nuclear Cardiology 511
Myocardial stunning and hibernation defect (VSD), patent ductus arteriosus (PDA), etc. as well as valvu-
Myocardial infarct imaging lar heart disease. Detection and quantification of left to right and
• Tc-99m labeled pyrophosphate right to left shunts is possible before and after shunt repair surgery.
• Tc-99m labeled glucaric acid Since the number of cardiac cycles acquired is limited to six or
• Tc-99m labeled annexin seven cycles only, the global and regional LVEF or RVEF may be
• Indium-111 antimyosin antibody imaging underestimated. Inspite of its limitations this first pass study is con-
Myocardial innervation: Parasympathetic and sympathetic sidered as single most cost-effective and rapid screening procedure
• I-131 or I-123-metaiodobenzylguanidine (MIBG) planar/SPECT in cardiology.
myocardial neuronal imaging
Myocardial hypoxia imaging Stress Multigated Equilibrium Radionuclide
Myocardial apoptosis imaging.
Ventriculography with Nitroglycerin Intervention
Conventional planar nuclear imaging (gamma ray scintigraphy)
provides a two-dimensional (2D) display of a three-dimensional
[Gated Blood Pool (GBP) Imaging/Multigated
(3D) distribution of the tracer. Rotating gamma camera SPECT and Acquisition (MUGA) Scan Study)]
computer reconstruction of images provide a 3D view of the heart This method is a physiological, safe, noninvasive procedure, i.e. easy
and “slices” can be obtained in horizontal, vertical long axis and to perform and repeat without undesirable side effects or discomfort
short axis. This technique, called SPECT is particularly promising to patient. It is much less expensive than other cardiac catheteriza-
for accurate delineation of the extent and localization of CAD and tion or conventional X-ray contrast angiography. The more popularly
identification of culprit lesions among those seen on coronary known MUGA scan has been used for decades to evaluate global and
angiography. regional wall motion (RWM) of both ventricles, to calculate the ex-
In another technique, PET, ultra-short lived, cyclotron produced cursion of blood from LV or RV, determine ventricular volumes and
radionuclide like carbon-11, nitrogen-13, oxygen-15 and chlorine-18 to obtain a stroke volume ratio.
are used for imaging the heart with a special camera. Currently FDG In this MUGA or radionuclide ventriculography (RNV) proce-
PET imaging is the gold standard for viable myocardium. O-15 water dure using 20–25 mCi of TC-99m labeled RBCs, images of the blood
and N-13 ammonia PET provide absolute quantification of myocar- pool in the heart are acquired in a computer system synchronized
dial blood flow (ml/min/gm) and coronary flow reserve. They pro- with ‘R’ wave of patients’ ECG. Hence, it is called multigated acquisi-
vide quantitative evaluation of coronary endothelial dysfunction tion. This is done in three phases, i.e. rest, during stress and post-
and can monitor response to treatment strategies used to improve stress S/L NG intervention.
endothelial function. Ejection fraction, i.e. global and regional calculated by dividing
the stroke volume (ED-ES) by the background subtracted and end-
First Pass Radionuclide Angiocardiography diastolic (ED) volume is the most widely applied and accepted index
of global systolic ventricular function. Similarly, diastolic function
In first pass radionuclide angiocardiography (FPRNA), 15–20 mCi of can be calculated from LV volume curve and five important pa-
technetium pertechnetate (radiotracer) in a small volume of 0.2–0.4 rameters of ventricular relaxation and filling can be derived. These
mL is injected in the anticubital vein. Sequential images are recorded are peak filling rate (PFR), time to peak filling rate (TPFR), average
as bolus passes through the various chambers of the heart and finally filling rate (AFR), atrial contribution to LV filling and calculation of
to the aorta. The different timings of tracer appearance identify the first one-third filling fraction. Out of these parameters, the first one-
right ventricles and left ventricles. third filling fraction is the most sensitive parameter when the patient
Data can be acquired at rest or during exercise on a bicycle er- suffering from systemic hypertension is subjected to this MUGA
gometer. If the data collected or ECG gated where we can sum up to study where the first one-third filling fraction comes smaller and
six or seven cardiac cycles in each of the two phases/RV phase from is the important diagnostic criteria to label the patient as diastolic
bolus injection to lung, LV phase from left atrium to aortic visuali- dysfunction. As diastolic function abnormality occurs much earlier
zation. The software of computer provides right ventricular ejection than systolic function abnormality in all cardiac disorders including
fraction (RVEF) and left ventricular ejection fraction (LVEF) and wall CAD and congestive heart failure. The earliest changes in CAD are a
motion analysis. reduction in PFR with exercise and the expected increment in PFR
Computer derived time activity curves over the four chambers, is blunted.
aorta, pulmonary artery and the lungs provide useful information Imaging is possible which provides simultaneously accurate
about the presence as well as severity of various types of congenital LVEF and RVEF as well as ventricular volumes and quantitative
heart diseases such as atrial septal defect (ASD), ventricular septal RWM analysis in 3D.
Regurgitant fraction determined is also possible in valvular heart Planar imaging techniques are important to master even today.
disease. LV function and ventricular volumes are powerful, inde- Because of problem of overlapping structures of myocardium sup-
pendent, prognostic variables in cardiac patients. plied by two independent coronary arteries and soft tissue artifact,
Measurement of RVEF is important in evaluation of valvular nobody does this modality of imaging in the era of SPECT MPI unless
heart disease (mitral stenosis/regurgitation), ASD, chronic obstruc- and until the specific indications mentioned above.
tive pulmonary disease (COPD) and pulmonary hypertension.
Exercise induced RWM abnormalities is seen during this MUGA
study which may appear in patients in CAD before development of Stress/Redistribution Stress Thallium Myocardial
ECG changes or symptoms of ischemia. Perfusion Study
Normal range of global ejection fraction for the LV is 50–75%, Thallium-201 was the only isotope available for the clinician to im-
for RV is about 45%. Normal subjects increase their EF generally by age the myocardium from 1970 through about 1990. It is a cyclotron
at least 5% from rest to peak exercise. Patients with significant CAD produced radionuclide which decays by electron capture to mercu-
show no rise or marginal rise or an actual fall compared to the rest ry-201 with a half life of 73 hours, emitting mainly X-rays of 67/82
EF. Nitroglycerin given to normal person in the immediate postexer- KeV (88% abundance) and gamma photons of 135 KeV and 167 KeV
cise period does not evoke any further rise in peak exercise LVEF. But (12% abundance). It is supplied as thallous chloride and expires 7
in significant CAD (one vessel or more) under the same conditions, days after activity reference date and time. Due to excessive amount
NG produces a striking rise in LVEF over that peak exercise. Improve- of impurities, it should not be administered to patients after 7 days.
ment in RWM (resting or exercise induced) by NG study is an indica- Initially, used for planar imaging with a maximum dose 80 MBq
tor of viable, salvageable myocardium. (usually 1.5 mCi), SPECT imaging needs higher dose (2.5 to 3 mCi).
Radionuclide ventriculography or MUGA study with dobutamine The biological properties of thallium are similar to potassium. Be-
stress is superior to echocardiographic studies. RNV or MUGA stud- cause potassium is major intracellular cation in muscle and is es-
ies should be routinely employed for evaluation of cardiac fitness for sentially absent in scar tissue for which thallium which is potassium
major noncardiac surgery, for evaluation of cardiac status before and analog is well suited for differentiating viable from nonviable scarred
after during chemotherapy (i.e. doxorubicin) to monitor cardiotoxic- myocardium. Like potassium, thallium clashes the cell membrane
ity and thereby prevent sudden death. Following cardiac transplan- via the active Na+-K+-ATPase transport system and by facilitative dif-
tation RNV or MUGA can provide serial measurement of ventricular fusion.
function which noninvasively predict transplant rejection. Exercise It remained popular even after TC-99m based tracers became
LVEF more than 50% is the single most important determinant of low available for single day imaging protocols, viability studies or in con-
risk for the future cardiac events as compared to exercise LVEF 40% junction with Tc-99m tracers in “hybrid” dual-isotope protocols. It
predicts high risk group for future events (Figs 63.1A to F). was common to do resting thallium perfusion imaging followed by
Tc-99m sestamibi-gated SPECT stress imaging, combining the best
Myocardial Perfusion characteristics of both radiopharmaceuticals. Thallium imaging is
historically significant as the epitome of MPI for decades, becoming
Before SPECT technology became widely available, 2D planar was a short of gold standard for its time.
used for blood pool and MPI. Some of the early SPECT imaging ta- Thallium-201 scintigraphy is most often performed either at rest
bles would hold patient’s up to 350 pounds but often obese patients or in conjunction with exercise stress in patients of suspected CAD to
found planar techniques more easy to tolerate. In certain situations, diagnose myocardial ischemia or known to have CAD for diagnosing
planar imaging will be the only option for obtaining a nuclear myo- the site and extent of MI including impending ischemia leading to
cardial perfusion examination. Planar imaging may be acquired with risk stratification and prognosis following MI, assessment of throm-
gating, then summed to form composite images in three views. This bolytic therapy and assessment of myocardial viability.
is particularly useful for the morbidly obese patient, or a bed-ridden For stress imaging 3–4 mCi is administered at peak exercise and
individual who cannot tolerate a SPECT procedure. The morbidly then 1.5–2 mCi injection is given at least 30 minutes prior to redis-
obese patient will not always fit into the scan radians, even when a tribution imaging. First pass myocardial extraction is 60–70% after
circular orbit is chosen especially when short stretcher unable to lie stress injection and 80–90% after resting injection. The myocardium
flat, or unable to hold arms out of the way. The body habitus of these takes up around 5–15% of injected dose normally extracted by lungs
morbidly obese men prevented diagnostic SPECT imaging with our before reaching systemic circulation and the remainder distribution
dual head camera and in that case a gated planar examination may into skeletal muscle, gastrointestinal tract and kidneys. In patients
be completed successfully. Gating the images would enable our nu- with LV failure and raised left atrial pressure, pulmonary transit time
clear medicine physician to study the wall motion although we are is prolonged and greater quantity of tracer is deposited in lung, a
unable to quantitate an ejection fraction. finding predictive of a poor prognosis.
A B
C D
E F
Figures 63.1A to F: (A) Rest MUGA study showing almost normal left ventricular global ejection fraction (LVGEF = 49%); (B) Stress MUGA
study showing significant fall in left ventricular global ejection fraction (LVGEF = 44%) with definite hypokinesia involving anteroseptal segment; (C)
Nitroglycerin (NG) MUGA study showing significant further improvement in LVGEF = 69% with significant improvement in wall motion of anteroseptal
segment; (D) Resting MUGA study showing enlargement of left ventricular blood pool with poor LVGEF = 20% with global hypokinesia; (E) Stress
MUGA study showing no significant increase in LVGEF = 14% with no improvement in the wall motion abnormality pattern; (F) Nitroglycerin (NG)
study showing no further improvement in LVGEF = 15% without any improvement in the wall motion abnormality pattern
In normally perfused myocardium, 80–90% of peak activity is ages. However, after reinjecting a second dose of 1.5 mCi (55MBq) of
reached within 1 minute following IV injection of thallium, peaking Tl-201 at rest immediately after redistribution images and followed
within 10–20 minutes. Thallium injection is usually given at peak ex- by image acquisition 10–15 minutes later, 49% of the apparently ir-
ercise and exercise is continued for another minute longer to achieve reversible defects on 3–4 hours redistribution images demonstrated
maximum extraction in the myocardium. Imaging is initiated within improved or normal Tl-201 uptake. Moreover, in the subgroup of
5 minutes of injection and procedure is completed within 30 minutes patients who underwent coronary angioplasty, 87% of myocardial
because in this period the redistribution of tracer in myocardium is regions identified as viable by reinjection studies had normal Tl-201
relatively fixed, hence, this image reflects myocardial perfusion at uptake and improved RWM after coronary angioplasty. In contrast,
peak exercise. all regions with irreversible defects in reinjection imaging before an-
Over the subsequent hours, there is a washout proportional to gioplasty had abnormal wall motion as well as after coronary angio-
flow and slow equilibrium between thallium in the myocardial sys- plasty. Similar results were obtained subsequently in other medical
tole and systemic blood pool. This is independent of the flow rate but centers, as well as in a multicenter trial undertaken in Italy, involving
requires an intact myocyte cell membrane and is therefore a marker 402 consecutive patients with ischemic heart disease recruited from
of myocardial viability. 12 hospitals. In another series, Rocco et al. reported that Tl-201 rein-
Most redistribution occurs within 3–4 hours, hence, an image at jection identified only 38% viable myocardial segments compared to
this time reflects resting perfusion. In resin supplied by stenods ves- F-18 FDG imaging. Thallium-201 reinjection and 24 hours imaging is
sel, a stress perfusion defect is seen which improves in the distribu- more helpful for the detection of stunned/hibernating myocardium
tion image. A stress defect which fails to improve on redistribution a and is superior to 24 hours delayed imaging without reinjection of
fixed defect represents nonviable segment (infarct or old scar) most Tl-201 (Figs 63.3A and B).
of time, but hibernating myocardium may give the same appearance,
hence, importance of FDG PET imaging to differentiate viable hiber- Rest IV Nitroglycerin/Oral Nitroglycerin Tl-201
nating myocardium from scar (Fig. 63.2).
SPECT Myocardial Perfusion Scintigraphy
Reinjection of TL-201 Imaging Nitrates in the form of slow release NTG or slow IV infusion of NTG
is known to improve myocardial blood flow in severe CAD. This
In 1990, the author introduced the concept that reinjection of Tl-201 may enhance tracer uptake during resting MPI which helps to de-
at rest, after stress of 3–4 hours redistribution imaging improves the tect reversible ischemia in the patient group using Tl-201 SPECT
assessment of myocardial viability. Among 100 patients with CAD myocardial perfusion scintigraphy. This will help us to detect areas
studied using Tl-201 SPECT, 33% of abnormal myocardial regions of viable myocardium versus scarred myocardium in CAD patients
on stress appeared to be irreversible on 3–4 hours redistribution im- (Figs 63.4A and B).
Stress Gated SPECT Tc-99m Myocardial

Perfusion Imaging Agents
The Technetium labeled agents can be substituted for thallium in the
rest and stress evaluation of myocardial perfusion. These agents are
very different in behavior compared with thallouschloride. The tech-
netium labeled agent is lost slowly from the myocardium with com-
parable clearance from normal and ischemic tissue. Since, Tc-99m
labeled tracers are essentially fixed in the cells, separate injections
are required for the rest and stress study. Same day studies or sepa-
rate day studies are usually practised. Usually same day studies use
as little as 8–10 mCi for the stress study and up to 30 mCi for the rest
study. The second injection should contain 2.5–3 times the resting
dose. The doses are adjusted as per the weight of the patient. There
should be gap of at least 3 hours between the rest and stress study.
The advantage of using Tc-99m labeled agents gives useful ad-
Figure 63.2: Stress thallium myocardial perfusion scan showing a
large area of stress perfusion defect involving anterolateral myocardial ditional informations such as global ejection fraction, wall motion,
segments which shows fair amount of reperfusion in resting image wall thickening measurements in addition to pattern of myocardial
suggestive of anterolateral myocardial ischemia tissue perfusion. If the particular segment of myocardial region ap-
A B
Figures 63.3A and B: Reinjection of Tl-201 imaging
A B
Figures 63.4A and B: Rest and IV nitroglycerin tetrofosmin myocardial perfusion scan showing adequate amount of reperfusion involving
inferior and part of anterior segments which is suggestive of viable salvageable myocardium. Source: Reproduced with permission from Department
of Nuclear Medicine, KLES Hospital and MRC, Belgaum (India)
pears to have a fixed perfusion defect and it demonstrates relatively netium central core (Fig. 63.5). Sestamibi is cleared from blood very
preserved wall thickening and abnormal wall motion, it should be rapidly with T½ less than 3 minutes at stress and rest followed by a
viable and may be a candidate for coronary revascularization. This slow clearance phase. Less than 10% of injected dose remains in cir-
method can also detect the stunned/hibernating myocardium which culation at 5 minutes after injection. First pass myocardial extraction
is labeled as viable myocardium. It can also differentiate a fixed de- is about 40% after a stress injection and 60% after a rest injection.
fect in the stress and rest gated perfusion study in differentiating scar The myocardium takes up between 1.2–1.5% and retains it for hours.
from an attenuation artifact as one observes breast attenuation com- The myocardial distribution is proportional to blood flow up to about
monly in females and diaphragmatic attenuation in males. 2 ml/min/gram with a plateauing of extraction at higher flow rates
which are achieved with vasodilatation (4 ml/min/gram), but this
is not a constraint in detecting mild-to-moderate coronary stenosis
Sestamibi (50–70%). The most important clinical difference between Tl-201
Technetium-99m sestamibi is a lypophilic monovalent cation which and sestamibi is that the latter undergoes minimal (10–15%) redistri-
consists of six methoxy isobutyl isonitrile ligands surrounding a tech- bution from initial pattern of uptake.
Figure 63.5: Normal sestamibi myocardial perfusion scan Figure 63.6: Tetrofosmin after stress injection
Tetrofosmin pass extraction fraction is 90% and the myocardial clearance T1/2
is equal to 10 minutes only which indicates the rapid clearance by
It is lypophilic diphosphine cation which can be labeled with Tc- the myocardium. The shorter duration protocol can be used for
99m. It has been developed to replace the Tl-201 in MPI. Preparation stress where we inject around 25 mCi at peak exercise and around
takes about 20 minutes of incubation at room temperature (but no 60 minutes later resting perfusion can be evaluated. The advantage
boiling as required with sestamibi). The radiation dose is slightly less of Tc-99m teboroxime over other technetium labeled perfusion
than for sestamibi and less than half that associated with thallium. agents are that the rapid biological half life amounting to around 5.3
The blood clearance of tetrofosmin is very rapid with less than 5% minutes which allows studies to be completed in 60–90 minutes. It
residual activity by 10 minutes. Its first pass extraction is 45%, total redistributes into ischemic myocardium like Tl-201. Technetium la-
myocardial uptake is 1–1.2% of injected dose. Unlike thallium tetro- beled teboroxime can detect CAD patients having two or three vessel
fosmin is not potassium analog. disease. It can also detect one vessel disease to a great extent. The
Tetrofosmin enters myocyte via passive transport driven by the images can be compared with that of Tl-201 as an imaging. The injec-
negative membrane potential on the intact cell. The mitochondrial tion to imaging time at stress is very short varies from 0.1–2 minutes
membrane potential plays a major role in the myocardial uptake and compared to tetrofosmin 10–15 minutes or Sestamibi from 30–60
retention of tetrofosmin. Myocardial uptake is related to the meta- minutes. Because of the short duration of injection to imaging time
bolic status of the myocytes in particular the mitochondrial mem- as mentioned above, perfusion study should be completed within 10
brane and the plasma membrane potentials. Uptake is proportional minutes of administration due to rapid washout.
to blood flow.
Hepatic clearance of tetrofosmin is more rapid than sestamibi al- Clinical Applications of Myocardial
lowing to be started 15 minutes after stress injection (Fig. 63.6).
Perfusion Imaging
Teboroxime The following are the important clinical subset of patients having
suspected or proved CAD with or without history of heart attack in
Technetium-99m teboroxime is a myocardial perfusion tracer, i.e. the past to diagnose and advocate further treatment planning in-
highly extracted and rapidly cleared by the myocardium. The first cluding future risk stratification.
Suspected Patients Having Strong Family History segments resulting from MI, it can also detect the other impending
of Having One/Two Risk Factors (Hypertension, ischemic zones in the myocardium for future coronary events (fu-
Diabetes, Smoking, etc.) ture myocardial infarct) which warns the patient for the future and
also gives a clear cut guideline to the cardiologist to advocate his/her
In this particular subset of patients, if thallium stress test shows nor- treatment planning.
mal stress perfusion pattern with normal washout pattern in the
4-hour rest image (thallium has got a property to redistribute into the To Assess Borderline Lesions in Coronary
myocardium) it indicates that the suspected patient does not have
Angiography
any evidence of CAD which would save him or her to go for further
invasive test such as coronary angiography and the nuclear imaging Most of the coronary artery lesions are eccentric unless and until
is cost-effective as the thallium stress test is approximately one-third it is viewed in multiple projections during angiography one cannot
that of the cost of angiography. assess the lesions correctly (Figs 63.7A and B). In true sense, these
lesions are originally borderline where cardiologists very commonly
Known Case of CAD to Evaluate Ischemic/ underestimate or overestimate the same lesions. The borderline le-
sions are 40% or 50% or 60% on coronary angiography, which needs
Infarction Stratifying Impending Ischemia for
the stress thallium myocardial scintigraphy to assess to have whether
Future Coronary Events hemodynamic significant perfusion defect exists on the myocardial
Patient having a known history of previous MI or recovering from segments. In our experience, the authors always routinely give this
acute MI from the hospital, stress thallium myocardial scintigraphy information whether the coronary intervention is necessary for these
delineates the area of ischemic/infarcted myocardium by revealing a borderline lesions or nor by seeing a significant perfusion defect/
stress perfusion defect in the part of the myocardium with evidence normal on stress thallium test. This is considered to be an important
of redistribution (filling of the perfusion defect) in 4 hours image subset of patients which cardiologists are aware of.
indicates viable myocardium, where revascularization procedure
would convert completely the affected myocardium to its normal To Assess Myocardial Blood Flow in Significant
status/pattern. In an another group of patients fixed perfusion de-
Multi- or Single-Vessel Lesion on Coronary
fect at stress and rest and even with the resting reinjection of Tl-201
is likely to have scarred myocardium (dead) where further angiog-
Angiography
raphy/revascularization procedure would not help the patient as This is an important subset of patients where coronary angiography
the dead myocardium can not be recovered even if the circulation and stress thallium test do not match and it is called “mismatch
is re-established by angioplasty procedure. Tl-201 has got an unique pattern” (Figs 63.8A and B). In our experience of more than a decade
property of not only evaluating the extent and viability of the affected on stress thallium studies, the authors have found normal stress
A B
Figures 63.7A and B: Borderline lesions in coronary angiography, multiple projections
A B
Figures 63.8A and B: Myocardial blood flow in significant multi- or single-vessel lesion on coronary angiography
thallium pattern in the myocardium, where multiple significant that would definitely warrant redo coronary artery bypass graft
lesions are there in coronary angiography. This situation is due to the (CABG)/redo angioplasty procedure as the restenosis of the arterial/
establishment of sufficient collaterals, which has been opened up as venous graft has occurred. These types of patients even if they have
a result of significant lesion in coronary artery. The establishment undergone a routine treadmill stress test, literature review says if all
of these collaterals is resulted due to the change in the lifestyle of the grafts are closed, stress test does not show any significant positive
the patient pertaining to the regular exercise including yoga or changes. Certainly stress thallium myocardium perfusion has an up-
pranayam, diet restriction and control of risk factors (diabetes, per hand in this subset of patients.
hypertension, etc.)
Pharmacological Stress Perfusion Imaging
Equivocal or False Positive Treadmill Stress Test
The principle underlying MPI is to effect maximal exertion on the
Results
heart to attain maximum coronary blood flow. The purpose of stress-
Suspected patients having false positive ST-T depression less than 3 ing the heart is to create a disparity in blood flow between normal
mm or borderline ST-T changes or patients having left bundle branch and stenosed arteries. This stress can result from increased oxygen
block (LBBB) or female patients not able to perform the treadmill demand in response to exercise or by vasodilatory effects on a phar-
quite effectively, all these types of patients can be subjected for a macological stress agent such as dipyridamole, adenosine, dobu-
stress thallium test which clearly delineates, whether a stress per- tamine, arbutamine, etc.
fusion defect is existing in any part of the myocardium or not. De- Pharmacological stress perfusion imaging is useful for patient
pending on the stress thallium findings patient should be subjected who cannot exercise for various reasons including physical limita-
for further invasive test or else, the normal stress thallium test does tions, medications, lung diseases, peripheral vascular disease, severe
not indicate need for any further test such as angiography, etc. (Figs osteoarthritis, elderly aged persons and aortic aneurysm, etc.
63.9A to D). Pharmacological or physiologic stress is needed to detect CAD
when using MPI because even in the presence of high-grade stenosis,
Follow-up of Patients of Coronary Artery Bypass resting blood flow is typically normal since distal arterial resistance is
reduced to allow for a normal perfusion pattern. With dipyridamole/
Graft/Balloon Angioplasty/Thrombolytic Therapy
adenosine/dobutamine, myocardial regions supplied by normal or
Cardiac patients who have undergone triple/four vessel bypass graft near normal arteries will experience increasing blood flow due to
surgery or following postballoon angioplasty procedure complaints decrease coronary vascular resistance. In contrast, myocardium sup-
of shortness of breath, heaviness in the chest, transient short angina plied by stenosed vessels may have only a minimum reserve capacity
pain may be subjected to a stress thallium test to find out any signifi- to dilate and will therefore be unable to increase blood flow at same
cant perfusion defects at stress with evidence. Reversible ischemia rate seen in more normal territories.
There are three pharmacologic stress agents used today in cardi- or sitting in place. These interventions stimulate catecholamine
ovascular nuclear medicine viz. dipyridamole, adenosine and dobu- which reduces some splanchnic blood flow. This is an important
tamine/arbutamine. consideration when using Tc-99m labeled compounds because they
have more uptake in the splanchnic bed than Tl-201. The radiotracer
Dipyridamole myocardial perfusion imaging protocol: Dipyridamole either Tl-201/Tc-99m labeled agent is injected 7–9 minutes after
is administered in bolus, infusion with an optimal total dose of 0.56 dipyridamole infusion. The time for initiation or acquisition of image
mg/kg over a period of 4 minutes after stopping methyl xanthine is started within 15 minutes following the injection of Tl-201 or 30–40
medication and caffeine consumption for 24 hours before the study minutes following Tc-99m cardiolite/myoview injection.
is performed. During the cessation of dipyridamole infusion and Aminophylline is recommended as an antidote to any adverse
the resultant stress on the heart interventions where patient can be reactions to dipyridamole infusion such as fall of blood pressure, etc.
encouraged to perform low-level hand grip exercise and walking The routine use of this antidote is not recommended unless the side
B
Figures 63.9A and B
D Figures 63.9C and D
Figures 63.9A to D: Treadmill stress test showing significant ST-T depression in all chest leads; (B) Stress sestamibi myocardial perfusion scan
showing uniform stress perfusion pattern in all the defined myocardial segments; (C) Treadmill stress test shows no significant ST-T depression in
any of the chest leads; (D) Stresss-gated SPECT tetrofosmin myocardial perfusion scan involving anteroseptal segment with evidence of significant
reversible ischemia
A B
Figures 63.10A and B: Intravenous adenosine infusion gated myocardial perfusion scan reveals uniform stress perfusion pattern with good
systolic wall thickening is seen in all the defined myocardial segments
effect starts within 10–20 minutes after the infusion has been termi- – Ventricular tachycardia
nated. The patients should be supine and all the vital signs should be – Transient ischemic attack (TIA).
monitored during dipyridamole infusion.
Adenosine myocardial perfusion imaging: Adenosine myocardial
Mechanism of action of dipyridamole: As dipyridamole is infused, perfusion image is useful in evaluating patients with CAD who
it blocks the reabsorption and metabolism of adenosine normally cannot exercise. A review of clinical trials indicate that adenosine
produced in the body. At basal condition normal adenosine level are perfusion studies provide high sensitivity and specificity (80–90%)
relatively low. The biological half life of natural adenosine is normally for identifying CAD (Figs 63.10A and B).
15–30 seconds in the blood stream, increases with dipyridamole
infusion, tripling or quadrupling the level of circulating adenosine. Imaging protocol: Intravenous infusion of adenosine at a dose of
The increased level of natural adenosine actually produces the 140 mg/kg/min for 6 minutes procedure produces consistent
desired effect on the heart, i.e. coronary hyperemia with the increase hyperemia. The radiotracer is injected during adenosine infusion at
of 20–40% of the heart rate. Blood pressure and diastolic blood 3 minutes of 6 minutes infusion protocol) and then another 3 minutes
pressure drops slightly. infusion of adenosine is continued to have maximum vasodilatation
Patients on effective antianginal therapy such as beta blockers in the myocardium followed by initiation of myocardial imaging
and calcium blocker will still have a positive myocardial perfusion under SPECT gamma camera. Adenosine has a very short half-life
image with dipyridamole despite adequate therapy. of about 10 seconds and so the hemodynamic changes disappear
rapidly on completion of the injection. In the presence of coronary
Side effects: Following are the side effects: artery stenosis, regional flow differences are induced by adenosine
• Systemic vasodilatation, i.e. headache, light headedness or which are revealed as perfusion defects in the scan. Adenosine
symptoms like nausea, vomiting protocol gives accurate result as exercise SPECT. Adenosine SPECT
• Myocardial ischemia is a useful noninvasive test for the preoperative/intraoperative risk
• Bronchospasm in case of asthmatic patients assessment of myocardial infusion in patients undergoing major
• Patients with respiratory failure, severe COPD surgery like joint replacement, kidney transplantation, peripheral
• Major contraindication is allergy to dipyridamole or aminophyl- vascular surgery, abdomino-pelvic surgery, etc.
line
• Serious adverse reactions: Mechanism of action: It directly act on A-1 receptor on vascular
– Myocardial infarction endothelial cells and A-2 receptor on vascular smooth muscles that
– Bronchospasm result in vasodilatation.
Side effect: The commonest side effects are flushing, shortness of Various data from series of patients who have undergone this
breath and chest pain. About 70–80% of patients experience one dobutamine MPI indicated that an increase in heart rate is the most
or more of these reactions. The vast majority of these reactions is consistent effect of dobutamine. Systolic blood pressure increases,
transient and rarely requires a counter acting response. Interestingly peaking around 20 mg/kg/min, diastolic blood pressure decreases
older patients tolerate adenosine better than young patients. due to the peripheral (beta-2) vasodilator effect of dobutamine.
Recent PET studies using 13N-ammonia show that changes in
Serious adverse effects: The adverse effect that has generated the most blood flow after administration of dobutamine myocardial blood
attention is a high degree AV block. This has been reported in less flow with 40 mg/kg/minutes dose of dobutamine. The increase in
than 1% of patients. In general, it always occurs during the first 2–3 blood flow is significantly related to heart rate, a good correlation be-
minutes of adenosine infusion and is transient, first degree block tween increase in blood flow and oxygen demand. This result is ex-
(prolongation of PR interval) is more common occurring in 10% of pected because the primary cause of increased coronary blood flow
patients. A second degree block occurs in 4–5% of patients. Adverse with dobutamine has increased oxygen demand; the direct effect of
effects also occur in patients with bronchial asthma. coronary vasodilatation produced by dobutamine is secondary. With
dipyridamole and adenosine on the other hand, myocardial perfu-
Dobutamine myocardial perfusion imaging: Since dipyridamole and sion increases primarily because of the vasodilatory effect of drugs
adenosine work well to produce adequate hyperemia and causes on the coronary arteries.
maximal vasodilatation in the myocardium, one might ask why do
we need a third pharmacologic stress agent. The patients selected Side effects: Following are the side effects:
for dobutamine studies are those who cannot exercise and who • Palpitation due to patient’s awareness of increased heart rate
are not good candidates for dipyridamole or adenosine because of and force of contraction
history of COPD or asthma. These patients are prime candidates • Chest pain
for dobutamine stress perfusion imaging. Other candidates include • Headache, flushing and dyspnea
patients who drink coffee or use medication containing theophylline • Premature ventricular ectopic beats
(within 12 hours) before a scheduled dipyridamole or adenosine • Occasional ventricular tachycardia with atrial fibrillation.
myocardial perfusion study. Patients who use oral dipyridamole Dobutamine has a longer biological half life about 2 minutes
could attain dangerously high adenosine levels if adenosine is than adenosine. Many of its adverse effects are similar to those
administered intravenously as pharmacologic stress. These patients reported with adenosine and usually last only a few minutes. Rarely
are also candidates for dobutamine stress testing. In addition, do patients require medication such as a rapidly acting beta blocker,
patients with heart failure who are already receiving low dose of IV i.e. esmolol to neutralize the side effects of dobutamine.
dobutamine for ionotropic support are at times referred for stress
perfusion imaging. In these patients, it may be more reasonable to Sensitivity and specificity in detecting coronary artery disease:
perform dobutamine stress study by simply increasing its dose rather Dobutamine perfusion imaging detects CAD with a greater
than a dipyridamole or adenosine perfusion scan. accuracy in patients with multivessel disease (100%) than in
patients with single-vessel disease (84%). Another recent study
Protocol: The protocol used begins with a low dose of dobutamine using dobutamine-thallium SPECT in patient reported a sensitivity
10 ug/kg/min for 3 min and increases to maximum of 40 mg/kg/ of 97% and specificity of 80% for detecting CAD. Another two
min every 3 minutes. Thallium-201/Tc-99m sestamibi is injected 5 studies using dobutamine sestamibi imaging found sensitivities
minutes after starting the first dose of dobutamine with the infusion of 80% and 83% and specificities of 74% and 89% respectively. The
maintained for another 2 minutes. The infusion is stopped after 3 same studies reported sensitivities of 85% and 75% respectively for
minutes and image acquired followed by delayed (or rest) image echocardiography with dobutamine.
acquisition. Pharmacological stress perfusion imaging with low-level tread-
mill/bicycle exercise: It has been seen that only pharmacological stress
Mechanism of action: Dobutamine is a predominant beta-1 agonist perfusion imaging interferes with image interpretation particularly of
that increases heart rate and myocardial contractility at sufficiently inferior wall/segment of myocardium because of frequent occurrence
high dose. Dobutamine also increases systolic blood pressure. The of side effects with pharmacological stress such as the splanchnic
increases in three parameter results in increased myocardial oxygen pooling of tracer. This can be overcome with clubbing the former with
demand. Normal coronary arteries dilate to increase perfusion moderate or even low-grade exercise. The risk of brady-arrhythmias
in order to meet the demand, stenotic arteries may not be able to is minimized with combination of exercise to adenosine infusion
increase blood flow to the same degree as normal vessels creating protocol. The exercise could be on bicycle ergometer (at a workload
a perfusion defect based on a similar physiologic response as that of 25 to 50 watts) or on the treadmill following modified bruce or even
triggered by exercise stress. a flat low-grade demonstration level exercise (Fig. 63.11). Strict
The most commonly used radiopharmaceuticals for cardiac PET

imaging are F-18 FDG, Rubidum-82 chloride, N-13 ammonia and
O-15 water.
Injury to the myocardium is typically caused by decreased blood
flow, a consequence of arteriosclerosis. Such evaluations involve
monitoring regional coronary blood flow and ongoing active me-
tabolism. These procedures can help to identify potential viability of
injured myocardium, regions likely to benefit from revascularization
to facilitate its return to its normal function, e.g. PET study showing
increased glucose consumption (using F-18 FDG) in myocardial ar-
eas of decreased blood flow (using N-13 ammonia or Rb-82) would
indicate that restoration of cardiac function in those areas would be
possible. Impaired contractile function in response to chronic re-
duction of resting blood flow may mask myocardial viability in some
patients with severe CAD with the use of O-15 water, cardiologists
Figure 63.11: Intravenous adenosine infusion with low-level tread obtain images of artery walls, where live tissue is designated by areas
mill exercise images showing improvement in the perfusion pattern of illumination caused by high oxygen consumption.
particularly of the inferior myocardial segments
Tracers of myocardial perfusion: Positron emitting radionuclides
TABLE 63.1 Positron emitting isotopes used in cardiac positron emission used for assessment of regional perfusion can be classified into two
tomography groups:
Category/Compounds Function (Mechanism) 1. Tracers that are only partly extracted by the myocardium (Rb-82
chloride and N-13 ammonia), and
Tracers of blood flow
2. Tracers that are freely diffusible (O-15 water).
N-13 ammonia Metabolic trapping
82Rb Sodium-potassium pump
Rubidium-82 PET Myocardial Perfusion Study
150-water Diffusion
62 Copper PT SM Lipophilicity Myocardial perfusion imaging with positron emitter can be done
11C (gallium 68) albumin Capillary blockage without onsite cyclotron which is relatively complicated with an
microsphere onsite source of generator produced tracer, i.e. Rb-82.
Tracers of metabolism Rubidium-82 is a monovalent cation and has ultra-short half
life 75 seconds Sr-82 decays to an elution column. Rb-82 is eluted
11C- palmitate Fatty acid metabolism
with 25–50 mL of normal saline by a computer controlled elution
18-F-FDG Exogenous glucose metabolism
pump, connected by IV tubing to the patient. This generator has al-
11C-acetate Oxidative metabolism most no breakthrough of strontium and has useful life of 4–6 weeks.
150-oxygen Oxygen consumption Serial evaluations of regional myocardial perfusion can be made at
11C (13N) amino acid synthesis Amino acid and protein intervals as short as 5 minutes. The short half life of Rb-82 taxes the
metabolism performance limits of PET scanners; it facilitates the rapid comple-
Other tracers tion of a series of resting and stress myocardial perfusion studies.
Rb-82 is a very efficient imaging agent for routine clinical usage.
18F-misonidazole Hypoxic and ischemic tissue
Although the cost per patient at a low volume of studies per day is
11C-carbon monoxide Blood pool
high, the cost with 6–10 studies per day is competitive with SPECT
tracers.
monitoring of ECG for any arrhythmia, close watch on the blood pres- The first pass extraction of Rb-82 at rest is approximately 50–60%
sure and the patients symptoms is to be done. and it is via Na+/K+ ATpase pump. Myocardial extraction of Rb-82 is
similar to Tl-201 and slightly less than N-13 ammonia, decreasing
Positron emission tomography imaging: Positron emission during hyperemia. Rb- 82 extraction can be altered by severe acidotic
tomography techniques are employed to map myocardial perfusion hypoxia and ischemia. Thus, uptake of Rb-82 is a function of both
and detect ischemic response to stress in the presence of CAD, blood flow and of myocardial cell integrity. Rb-82 perfusion imaging
quantitate the regional coronary blood flow which can identify is usually performed before and after vasodilator stress rather than
diffuse atherosclerosis often undetectable on an angiogram and in with exercise. Infarcted myocardium doesn’t retain intravenously
the assessment of myocardial tissue viability (Table 63.1). administered Rb-82. After administration, it washes out rapidly from
damaged myocardial cells following the initial uptake phase. A mix- made direct comparisons of Tl-201 SPECT and PET MPI. In addition,
ture of reversible and irreversible myocardial tissue in the field of a survey of numerous studies of PET MPI in 1391 patients found ex-
view results in an intermediate level of Rb-82 washout that is propor- cellent sensitivity (92%: CI = 90% to 94%) and specificity (90% CI =
tional to the percentage of viable or infarcted tissue. 88% to 92%). Church well et al. has also shown greater accuracy in
a blinded analysis of the accuracy of 82-Rb. PET in 194 patients with
Imaging of Rb-82: Patient preparation for stress and rest myocardial new quantitative software developed in their laboratory. Patterson
PET perfusion imaging is identical to SPECT perfusion imaging. et al. has also shown significantly better results with 82-Rb PET than
Despite the short half-life of Rb-82, modern PET gamma cameras their own SPECT Tl-201 results. These comparisons and extensive
are able to obtain good quality images. The usual protocol takes clinical experiences of Emory University are over 30,000 SPECT Tl-201
approximately 15 minutes with a bismuth germinate Bi4Ge3O12 (BGO) and over 2000 MPI respectively. Though all patients with intermediate
crystal PET scanner and 35 minutes with lutetium oxyorthosilicate risk of CAD can undergo PET MPI, it is preferable to SPECT MPI in
[Lu2SiO5 (LSO)] crystals PET scanner. The proper positioning is done a subgroup of patients with attenuation problems, i.e. large patients,
with a low dose (20 mCi) injection of Rb-82 and short 3 minutes women, breast implants or left mastectomy, chest wall deformity and
scout acquisition and quick reconstruction. Subsequently, rest left pleural or pericardial effusion. However, it must be emphasized
transmission imaging, rest perfusion 2D imaging and rest gated 3D that attenuation problems in SPECT can not be predicted with con-
imaging were done sequentially. Stress imaging is also done in similar fidence from examination of body habitus. There is an incremental
manner. Transmission imaging is usually done with a germanium-68 benefit caused by greater specificity and sensitivity which gives rise
pin or rod source, which takes about 8 minutes. to incremental economic benefit caused by more accurate tests like
Tomographic data from Rb-82 images can be displayed using Rb-82 PET MPI.
polar maps utilizing the bulls eye approach with the apex located at During the last 10–15 years, both SPECT and PET imaging have
the center and the base at the rim. Both relative and absolute flow undergone significant improvements. A recent comparison between
reserve can be depicted on quantitative polar maps on Rb-82 activity. Tc-99m sestamibi SPECT and Rb-82 PET MPI revealed a significant
In this manner, the rest and stress images are functionally interrelat- margin of improvement for CAD detection accuracy with Rb-82 PET
ed. Three-dimensional topographic displays of Rb-82 cardiac activity compared to SPECT (Figs 63.12A and B). Given the proven value of
are more quantitative with respect to the polar maps. An automated PET MPI in the diagnosis of CAD, it is expected that the prognostic
quantitative analysis programmed may enhance accuracy and re- value of gated PET is also high, similar to SPECT imaging.
producibility of cardiac PET flow studies. Positron emission tomography-CT unit has become the pre-
The sensitivity and specificity of PET MPI are superior to other ferred approach for PET imaging in oncology. The potential benefits
noninvasive tests. Four studies involving a total of 342 patients have of PET-CT in cardiac imaging are reduction in acquisition time by
A B
Figures 63.12A and B: (A) Rubidium-82 PET myocardial perfusion image showing a fixed defect involving inferolateral segments; (B) Rubidium-82
PET myocardial perfusion image a fixed showing a reversible perfusion defect involving small part of anterior and inferolateral myocardial segments
10–12 minutes in comparison to a dedicated PET system. PET-CT thase. Despite back diffusion, the first pass trapping of N-13 ammo-
imaging holds challenges and solution for the attenuation correction nia at rest is high although decreasing with higher blood flow.
problem. N-13-ammonia allows good quality gated and ungated images,
taking full advantage of the superior resolution of PET imaging. Inter-
N-13 Ammonia/O-15 Labeled Water Positron estingly normal volunteers show mild heterogeneity or mild defect of
N-13-ammonia retention in the lateral wall of the LV compared with
Emission Tomography Perfusion Imaging
other segments. The mechanism of this is not known. This must be
N-13 ammonia has been used for most of the scientific investigation taken into account for both visual activity and increased lung activity
in cardiac PET imaging for the past 2 decades. Its 10 minutes half- in patient with lung congestion.
life requires an onsite cyclotron and radiochemistry synthesis capa-
bility. Imaging protocol from scout position to stress imaging takes Stress F-18-Fluorodeoxyglucose
100–120 minutes. Pharmacologic stress imaging usually follows rest-
Positron Emission Tomography
ing injection and imaging, after the initial activity has been allowed
to decay by staggering patients or using differential dose for rest and
Myocardial Ischemia Imaging
stress. Both rest and stress images can be gated. A dynamic acquisi- Direct myocardial ischemia imaging using FDG radionuclide MPI
tion is acquired for the quantification of blood flow. This can be ac- during exercise or pharmacological stress and at rest is the most
complished by performing separate dynamic and gated acquisition widely used noninvasive test for evaluation of known or suspected
with the same injection, or included list mode acquisitions. A third CAD. This technique relies on the demonstration of perfusion ab-
injection may be included for cold pressor testing. N-13-ammonia normalities on stress images which normalize on rest images in the
imaging is time cumbersome, needs logistic and coordination (Fig. presence of myocardial ischemia, but persist in the presence of scar
63.13). due to prior MI. Although, in extensive clinical use, this technique
In the blood stream, N-13-ammonia consists of neutral ammo- suffers from limitation inherent to cold spot imaging such as subop-
nia (NH13) in equilibrium with its charged ammonium ion (NH4). timal sensitivity and specificity due to limited resolution, partial vol-
The neutral NH3 molecule readily diffuses across plasma and cell ume effect, scatter and soft tissue attenuation. Availability of a radi-
membranes. Inside the cell, it re-equilibrates with its ammonium otracer with selective uptake in the ischemic myocardium (hot spot
form which is trapped in glutamine via the enzyme glutamine syn-
Figure 63.13: N-13 ammonia/O-15 labeled water positron emission tomography perfusion imaging
imaging), can potentially eliminate these limitations. However, cur- similar to glucose. However, unlike glucose-6-phosphate cannot be
rently no ischemic imaging agent is available for routine clinical use. phosphorylated further and because of its strong negative charge,
There is a need for the development of radiotracers targeted for is- 18FDG-6-phosphate is trapped intracellularly.
chemic myocardium. The feasibility and accuracy of exercise 18FDG imaging for hot
Myocardial ischemia results in a dramatic and sustained switch to spot imaging of exercise induced myocardial ischemia was studied
glucose uptake. At myocellular level, hypoxia results in an upregula- by performing simultaneous exercise perfusion and 18FDG imaging
tion and translocation of glucose transporters from cytosol to the cell in patient scheduled to undergo exercise and rest myocardial per-
membrane. Once activated, these transporters remain upregulated fusion imaging for suspected CAD. All patients underwent a symp-
for several hours. In contrast, normal myocardium is capable of utiliz- tom—limited exercise after an overnight fast. Tc-99m-sestamibi
ing a wide variety of substrates for its energy requirements, depending (25 mCi) and 18FDG (8–10 mCi) were injected IV at peak exercise.
upon their blood levels, insulin and catecholamine levels and or fast- The patients underwent imaging using a dual-head large field of view
ing status of individual. Fatty acids are normally the preferred sub- single-crystal SPECT imaging camera (Varicam, GE, Milwaukee, USA)
strate for energy production, with glucose contributing to less than equipped with ultra-high energy parallel-hole collimators and 5/8″
40% of total energy production. The differential uptake of glucose in thick sodium iodide crystal to optimize the detection of high-energy
ischemic and normal myocardium can help develop “hot spot” im- (511 KeV) 18F photons. Use of separate energy window of Tc-99m-
aging agent for myocardial ischemia. Fluorine-18 (18F) labeled 2-de- sestamibi (140% + 20%) and 18F (511 KeV + 30%) allowed simulta-
oxyglucose (18FDG) is a glucose analog, which tracks the initial steps neous imaging of Tc-99m-sestamibi and 18FDG (Figs 63.14A to C).
of glucose transport and uptake across the cell membrane. Once, in The results of exercise 18FDG imaging were compared with those of
the cell this is phosphorylated by hexokinase to 18FDG-6-phosphate standard exercise and rest MPI and coronary angiography.
A B
Figures 63.14A to C: (A) Intense F-18 FDG uptake in the lateral wall
of the myocardium in the stress ischemia imaging which is showing as a
fixed defect in the regular stress and rest myocardial perfusion imaging;
(B) Intense F-18 FDG uptake in inferior and lateral walls small fixed defect
in regular stress and rest myocardial perfusion imaging; (C) Stress F-18
FDG ischemia imaging showing intense F-18 FDG uptake in the inferior
and lateral walls of the myocardium which was showing a fixed defect in
C the regular stress and rest myocardial perfusion imaging
Myocardial Metabolism unlike the brain which mainly depends upon glucose metabolism.
The myocardium is an omnivore. There are three major circulating
A fundamental characteristic of the myocardium is its continuous substances which affect the myocardial metabolism: blood glucose,
requirement for oxygen and metabolic substrates to meet its energy free fatty acids (FFAs) and insulin. Many other factors, such as the
demands. This process largely occurs by oxidizing fatty acids and glu- fasting period and age, also affect the FDG uptake. Even hospitaliza-
cose. Under normal conditions, fatty acids are the preferred energy tion status (inpatient or outpatient) has an influence on the myocar-
source for overall oxidative metabolism. When blood flow is reduced dial FDG uptake.
to the heart muscle and ischemia ensues, fatty acids can no longer This complexity interferes with the interpretation of data ob-
be oxidized and glucose becomes the preferred energy source. This tained from FDG-PET imaging. To accommodate this complexity of
metabolic phenomenon is useful for the identification of myocar- metabolism, there are several different protocols for myocardial FDG
dium that is underperfused but still viable. Such tissue is often hy- PET imaging. These protocols can be divided into two major catego-
pokinetic or akinetic but returns to normal or near-normal function ries:
if blood flow is restored. Consequently, in patients with severely im- 1. One is imaging under low-myocardial glucose metabolism
paired ventricular function, combined with measurements of myo- which includes imaging under fasting conditions.
cardial perfusion and glucose metabolism have been advocated. It 2. The other protocol images the myocardium under high- to
may be noteworthy to mention that eating fat and protein shifts the maximum-myocardial glucose metabolism which includes oral
heart away from using glucose as an energy source. glucose loading and the euglycemic insulin clamp technique.
Under fasting conditions, the normal myocardium primarily uti-
Metabolic Tracers lizes fatty acids while glucose utilization and thus FDG uptake be-
comes minimal. Under this condition, ischemic myocardium with
Fluorine-18 FDG, C-11 palmitate and C-11 acetate are typical ex- enhanced glucose metabolism markedly takes up FDG, which is
amples of PET radiopharmaceuticals used for metabolic cardiac displayed on PET images as hot spots. The problem of imaging un-
studies. “Deoxyglucose” is an analog of glucose that can be labeled der fasting conditions is the heterogeneous distribution of FDG into
with F-18, a cyclotron produced radionuclide, to form F18-FDG. Its normal myocardium. Usually the lateral wall of the LV tends to show
myocardial uptake reflects overall myocardial utilization of glucose. higher FDG uptake than the septum. High-background activity with
Palmitate is a naturally occurring fatty acid that can be chemically low-tissue FDG uptake also leads to poor-image quality. For these
synthesized and labeled with C-11, a cyclotron-produced radio- reasons, FDG PET under fasting condition has recently not been rec-
nuclide with a physical half-life of approximately 20.4 minutes. Its ommended for clinical viability assessment.
myocardial uptake and clearance reflect the myocardial utilization The most commonly used protocol is oral glucose loading. Inges-
of fatty acids. tion of about 50–70 g of glucose stimulates insulin secretion and in-
The utilization of fatty acids and glucose by the heart is exqui- creases the FDG uptake into normal myocardium to near maximum.
sitely sensitive to the level of glucose, fatty acids and insulin in the This enhances the image quality with homogenous myocardial FDG
blood, as well as the level of blood flow to the myocardium. Con- uptake. Euglycemic insulin clamping is an alternative technique to
sequently, the substrate environment must be standardized when oral glucose loading and is slightly more complex but guarantees
these two tracers are used to study myocardial metabolism. FDG-6P more stable and controlled metabolic conditions. FDG uptake into
is the trapped form of the compound. Injected after the patient has normal and ischemic but viable myocardium is enhanced and nega-
fasted, insulin forces FDG into muscle cells, including myocardium. tive FDG uptake is considered to indicate scar tissue.
Acetate labeled with C-11 has emerged as a promising tracer of Thus, hibernating myocardium therefore would demonstrate
overall oxidative metabolism under diverse loading conditions levels increased FDG uptake in the fasting state unlike the surrounding
of blood flow. Unlike C-11 palmitate and FDG, the myocardial kinet- normal myocardium. But, in the postprandial state (with oral glu-
ics of C-11 acetate are relatively insensitive to changes in the sub- cose loading) hibernating myocardium would demonstrate FDG up-
strate environment. take. Therefore, either preserved or even enhanced FDG uptake in
dysfunctional myocardial regions represents presence of myocardial
Fluorine-18 FDG Metabolic Positron viability by the help of most popular criterion of flow-metabolism
mismatch methods (Figs 63.15A and B). However, using this crite-
Emission Tomography Imaging
rion requires a perfusion image preferably acquired either with PET
18F-FDG is a glucose analog which crosses the capillary and sar- or SPECT perfusion study.
colemmal membrane at a rate proportional to that of glucose. Regional dysfunction due to stunned myocardium may be mani-
Following myocardial uptake, FDG is phosphorylated to FDG phos- fested by normal blood flow and normal, enhanced or reduced glu-
phate and is then trapped in the myocardium unlike phosphorylated cose utilization using FDG and flow images. Only criterion to diag-
glucose. Regional myocardial uptake of FDG therefore reflects rela- nose this myocardium is the presence of regional myocardial wall
tive distribution of regional rates of exogenous glucose utilization, motion abnormalities.
A B
Figures 63.15A and B: Perfusion-metabolism mismatch using N-13 ammonia and F-18-FDG PET imaging tracer suggesting decreased
perfusion with adequate metabolism involved in the myocardium
Myocardial Stunning and Hibernation agents for imaging (Figs 63.16A and B). During the ischemia, there
is increased flux of Ca++ ions across the cell membrane. So, as the
In 1975, Heyndrickx et al. demonstrated in a concuss dog model that intracellular concentration of Ca++ ions increase, it damages the cell
a 15-minutes coronary occlusion (a period generally not associated irreversibility. So, this Ca++ ion provides the binding site for pyroph-
with cell death) followed by reperfusion produced a marked depres- osphate. Pyrophosphatase binds to the mitochondrial calcium com-
sion in regional contractile function that persisted for at least 6 hours plexes and proteins in region of necrotic myocardium.
after reperfusion. The term myocardial stunning was described this The maximal uptake of pyrophosphate is by 24–48 hours after
viability tissue that exhibits prolonged postischemic ventricular dys- injection and scan may remain positive for 6 days. Some patients
function even after the normal perfusion is restored. Stress-rest Tc- may show uptake by 12 hours. The scan to be positive in the uptake if
99m SPECT MIBI/tetrofosmin myocardial function and perfusion the suspected lesion should be more than uptake in ribs. Sometimes
study permits demonstration of stunning in patients with CAD after a “doughnut pattern” of uptake is seen in large infarcts as less tracer
exercise and dobutamine induced ischemia contractile dysfunction reaches to central necrotic zone. Other than the infarct increased
despite restoration of normal function shown in the rest study. pyrophosphate uptake is also seen in cardiomyopathy, pericarditis,
The concept that stunning and hibernation may be casually valvular calcification, amyloid heart, etc.
related is supported by PET quantitative myocardial blood flow and
flow reserved studies, which indicate that flow falls in chronically Tc-99m Labeled Glucarate
dysfunctional myocardium after a period of chronic stunning. Usu-
ally hibernating myocardium evident in FDG study has fair degree Glucaric acid, a six-cycle dicarboxylic acid sugar is a small molecule
of FDG uptake is usually seen in resting fixed myocardial perfusion which clears from the blood very rapidly and localizes in necrotic tis-
defects. Revascularization restores function in the functional hiber- sue by attachment to highly basic nuclear histones in the myocite.
nating state. Acute MI can be visualized within 1–2 hours of onset of pain in pa-
tients with or without thrombolytic therapy.
Myocardial Infarct Imaging Technetium labeled glucaric acid will have an important role
in the emergency room while evaluating the patient suffering from
Myocardial infarct imaging agents are classified as: acute coronary syndrome.
• Hot-spot infarct-avid agents
• Cold spot markers of hypoperfused tissue. Indium-111 Labeled Antimyosin Antibodies
Tc-99m Pyrophosphate Myosin is a larger intracellular protein present in abundance in

myocardial cells. When the cell membrane is disrupted, i.e. in acute
Tc-99m pyrophosphate planar imaging has been used for detec- MI these are exposed to outside. These antibodies are tagged with
tion of MI, but used less commonly today with availability of better Indium-111 and used for imaging infarct. Now-a-days fab fragments
A B
Figures 63.16A and B: Tc-99m pyrophosphate planar imaging
of these antibodies are used which is more specific thus pyrophos- cleavage of proteins and DNA. This is an energy dependent process.
phate in infarct imaging. Hence, the cell membrane integrity is maintained unlike necrosis.
Around 2 mCi of injection of Indium-111-antimyosin antibodies Subsequently, cell breaks into finger like processes, i.e. apoptotic bod-
immediately starts accumulating at the site of infarct. But, its blood ies which are cleared by phagocytosis by neighboring cells or scaven-
clearance is very slow (T1/2 = 6–12 hours). So, by 24 hours or later, ger cells resulting in inflammation or scar. As compared to the cell ne-
images are acquired which will give a good diagnostic yield. Antimy- crosis where the damage occurs to the cell membrane integrity which
osin antibodies have overall sensitivity of 92% in detection of acute results in denaturation of proteins and DNA damage. This results in
MI. False positive findings are also seen in patients with myocarditis release of intracellular contents and ultimately cell ruptures resulting
and idiopathic dilated cardiomyopathy. in disintegration or scar. Annexin is a protein having similar structural
Combined antimyosin and planar thallium imaging may pro- and functional characteristics that have an affinity to bind phospholip-
vide prognostic information for risk stratification for future coronary ids surfaces. It is a 34-kd protein binds to the phosphatidyl expose in
events. A matched defect, i.e. a fixed defect on thallium showing an the cell surface. Tc-99m labeled annexin V (22–30 mCi with 0.5–1.0 mg
area of antimyosin antibodies uptake confirm the irreversible dam- annexin) is injected and 4–6 hours following each injection imaging of
age to the area. myocardium can be initiated. Annexin accumulates in acute necrotic
An unmatched defect, i.e. absence of antimyosin uptake in thal- myocardium as a hot spot infarct-avid agent. The localization can be
lium defect or patchy uptake of antimyosin antibodies in thallium done by simultaneously doing a Tl-201 imaging (Figs 63.17A and B).
defect confirms the presence of hibernating myocardium which war-
rants immediate intervention. Dual Isotope Imaging Using Tl-201
It has also been observed that antimyosin antibodies are picked
and F-18 FDG Imaging
by patients of unstable angina. So it can be used for prognostication
in patients of unstable angina. Assessment of metabolism by PET provides the sensitive detection
In patients of receiving doxorubicin (a cardiotoxic drug), antimy- of tissue viability based on the integrity of cardiac substrate metabo-
osin antibodies can play a role in identifying cardiotoxicity in form of lism. The increased FDG uptake in the hibernating myocardium
intense accumulation of this radiotracer. appears to be an independent prognostic parameter identifying
Antimyosin antibodies can also be used in evaluation of heart ischemically compromised myocardium and thus high-risk clini-
transplant rejection and myocarditis or cardiomyopathy. cal conditions. This metabolic signal of jeopardized myocardium is
especially helpful in patients with advanced ischemic heart failure
Technetium-99m Labeled Annexin V because revascularization is associated with higher risk. The most im-
portant functional recovery following revascularization of the failing
Usually, cell death occurs through two very distinctive processes, ne- heart is the amount of hibernating myocardium present.
crosis or apoptosis. Apoptosis (programmed cell death/cell suicide) Metabolic imaging with PET offers a sophisticated means of as-
signal induced and result in progressive cell shrinkage and systemic sessing regional tissue viability in patients with advanced CAD and
A B
Figures 63.17A and B: Tc-99m labeled annexin myocardial infarct imaging showing a hot spot involving apical and lower-septal segment of
the myocardium which is showing a cold area in the regular thallium-201 myocardial perfusion imaging transaxial slices
impaired LV function. The assessment of relative and regional uptake Data Interpretation
covering the complete LV volume represents an advantage over com-
peting modalities. The classification of myocardial tissue into viable, Matching of perfusion and FDG uptake of normal viable myocardium,
hibernating or scarred can be performed with high sensitivity and which is not ischemic at rest whereas matched pattern of decreased
specificity. perfusion and metabolism are indicative for irreversible tissue injury
(scar). A mismatch pattern of reduced myocardial blood flow in pres-
Glucose Metabolism ence of increased FDG uptake identifies viable but ischemically com-
promised myocardium. This helps to emphasize the clinician the true
18F-fluorodeoxyglucose traces transmembranous transport as well extent of viability and the potential for recoverable tissue.
as phosphorylation of exogenous glucose. 18F-fluorodeoxyglucose Cardiac PET scan protocol (Figs 63.18A to C):
6-phosphate doesn’t enter any further metabolic pathways, but ac- • Thallium perfusion scan at 8.30 a.m.
cumulates in the myocardium, which is proportional to glucose • FDG PET scan at 12 noon (blood sugar level should not be > 130
transport and phosphorylation. mg/dl).
Patient Preparation Where do We Ask for FDG PET Imaging in the

Assessment of Myocardial Viability
Oral glucose loading is the most widely used approach for prepar-
ing patients for FDG imaging. FDG is administered 60–90 minutes One of the best-known disadvantages of PET is its low availability.
after 50 g of oral glucose load. This switches the primary substrate for PET scanners and on site cyclotron are too expensive for local hos-
myocardial metabolism from free acids to glucose. This is facilitated pitals. PET has only been available for a limited number of patients
by the release of insulin. Thus, viable myocardium will preferentially and researchers at least in the last century. Because of this problem
take up glucose and hence FDG. In patients with diabetes, supple- either stress-rest or rest-stress gated SPECT MPI with or without oral/
ment insulin is necessary. Even with glucose loading protocols with IV-augmented NG intervention with FDG SPECT imaging using ul-
bolus insulin, images are often suboptimal in diabetics. tra-high energy collimator or dual isotope simultaneous acquisition
Most cardiac FDG studies are acquired 40–60 minutes after injec- (DISA) by injecting FDG at photo peak (511 Kev) and Tc-99m perfu-
tion of tracer. This time period is required to reduce the FDG plasma sion tracers such as IV tetrofosmin or MIBI allows simultaneous flow
concentration to ensure high contrast between the blood pool and metabolism analysis with acceptable feasibility.
the myocardium. In patients with diabetes mellitus, a longer waiting The role of IV FDG PET with SPECT imaging should only be
period is advised to enhance myocardium-to-blood contrast. limited considering their higher cost to patients having fixed defects
Figures 63.18A and B

C
Figure 63.18C
Figures 63.18A to C: (A) Dual isotope myocardial imaging shows a stress perfusion defect involving part of anterior and apical myocardial
segments which shows adequate metabolism involving anterior segments only. However, apical segments seems to have no metabolism suggesting
scarred myocardium as evidenced from F-18-FDG metabolism study; (B) Stress myocardial perfusion imaging with thallium-201 showing an apical
defect which shows adequate metabolism with F-18-FDG metabolism study as evidenced from the bottom row of images; (C) Stress thallium
myocardial perfusion study shows a perfusion defect involving anteroseptal segments which seems to have absent metabolism using F-18-FDG
metabolic study
with stress-rest or rest-stress Tc-99m tetrofosmin or rest-IV NTG terpretation (mismatch/% uptake/metabolic rate) lacks standards.
intervention indicates a fixed defect which can be further confirmed In 2003, American Society of Nuclear Cardiology (ASNC) issued a
by F-18 FDG imaging a gold standard myocardial viable method. practice guideline for FDG/perfusion PET imaging. The requirement
for standardization was partially solved by this guideline. However,
FDG PET Versus FDG SPECT more studies especially large scale multicentric trials are needed to
establish the usefulness of FDG PET imaging in viability assessment.
A recent study by Sir Belink et al. compared the survival of patients One of the solutions for improving the accuracy of viability as-
randomized to PET-based or SPECT-based management. The au- sessment with PET comes from the technology commonly used in
thors found only a very small and nonsignificant difference between SPECT. Applying the gated SPECT analysis techniques to FDG PET,
these two management strategies. It seems from the result that it is evaluation becomes more precise. The big problem with this tech-
not necessary to perform PET to make a Go/No Go decision about nique is the reliability of the analysis program, such as QGS, 4D-M
coronary intervention in clinical practice. The PET cardiology com- SPECT or Emory cardiac tool box. These programs are all designed
munity must make FDG PET imaging more accurate and sophisticat- for clinical SPECT use. Thus, parameters such as gamma fitting for
ed. There are several problems that need to be solved to make FDG wall detection are not optimized for PET. For several reasons, it is
PET more reliable and useful. very hard for PET users to change and optimize such parameters.
The one major problem in viability assessment using FDG PET It is reported that ventricular volumes (EDV and ESV) measured by
is the absence of a standardized method. Both the imaging proto- gated FDG PET are higher than those measured with MIBI SPECT,
col (dynamic/static, loading/insulin clamp/ fasting) and data in- although there is a very good correlation between the former and
latter. Even with this limited methodology, gated FDG PET shows sig- of the chest and more than two detectors. In addition, it is neces-
nificant incremental value over viability diagnosis as assessed by the sary to use a collimator for low energy or I-123 only and to set the
perfusion-metabolism mismatch criterion. energy window to 159 KeV ± 10%. Planar images have been used in
Because of lower availability, increase cost and onsite cyclotron, many ways for the evaluation of cardiac sympathetic function, while
FDG PET has limited utility in the present day clinical practice. FDG SPECT images are advantageous for evaluating abnormalities in
SPECT has taken a front seat for decades. Using an ultra-high-energy local distribution in myocardium. Practically, both of the above
collimator, an FDG image could be obtained with routinely used images are used in combination.
relatively inexpensive gamma cameras, various studies have shown In the case of planar images, the anterior view is imaged for
comparable results to conventional PET scanners. However, there roughly 3–5 minutes, using a 128 × 128 or 256 × 256 matrix. If pos-
are also results raising questions about the reliability of FDG SPECT sible, further views in two directions are obtained at a left anterior
particularly absence of photon attenuation correction in the imaging oblique angle of 35–40° and at a 70° to the left lateral plane. The
of SPECT camera. However with the advent of CT containing (SPECT- SPECT images are collected using a 64 × 64 matrix over a 360° range
CT) Hawk eye, gamma-camera system, the photon attenuation or over 180° from the right anterior oblique plane to left posterior
correction can be tackled efficiently especially while interpreting oblique plane.
the inferior wall for viability assessment. Hence, FDG SPECT has
one major benefit over PET namely that it allow DISA. PET imaging Analysis and Interpretation of
uses only one photo peak (511 KeV) high-energy photon and thus
Metaiodobenzylguanidine Images
simultaneous dual-tracer acquisition is impossible. DISA using
FDG and Tc-99m perfusion tracer allows simultaneous flow and The most common indices are the heart to mediastinum ratio
metabolism imaging in one sitting with acceptable feasibility. (H/M ratio) and the washout rate obtained from the anterior planar
images. These indices represent simple semi-quantitative measures,
Cardiac Neuronal Imaging Using SPECT but have been widely used resulting in many reports which support
its usefulness in severity and prognosis evaluation for heart failure.
The heart is an organ with a dense distribution of sympathetic nerve. Regions of interest (ROIs) are set in the heart (H) and the mediasti-
The sympathetic nervous system plays important role in controlling num (M) to obtain the mean count in each ROI after which the H/M
the heart rate, blood pressure, capacity to cause myocardial contrac- ratio is calculated. Based on the resulting ratio the degree of accumu-
tion/dilatation and coronary tone. Hyperactivity of cardiac sympa- lation in the heart is evaluated. It is desirable to set the mediastinal
thetic nerves is known to cause exacerbation of myocardial ischemia, ROI as much as possible at an upper site that is unaffected by the
exacerbation of heart failure and induction of severe arrhythmia and thyroid gland and the cardiac ROI so as to surround the entire heart.
sympathetic functional disorder have important clinical significance The washout rate is an index that indicates the rate at which MIBG
in heart diseases. is washed out between the early image and the delayed image via
123I-metaiodobenzylguanidine myocardial scintigraphy is one of comparison with the cardiac count in the early image. In this calcu-
the few methods available for objective evaluation of cardiac sym- lation the mediastinal count is subtracted from the cardiac count as
pathetic function at the clinical level and provides an abundance of a background correction, in principle. A correction for decay due to
information useful for the evaluation of various heart diseases. the half-life of 123I may be performed, as required. The accumulation
on the early MIBG image reflects the distribution of cardiac sym-
Imaging Methods of Metaiodobenzylguanidine pathetic nerves and the uptake function at the nerve endings while
the washout rate is an index of the degree of sympatheticotonia. The
Metaiodobenzylguanidine, an analog of norepinephrine, was de- delayed image is a result of washout from the early image and thus
veloped as sympathetic nerve imaging agent. Before conducting the is considered to contain combined information regarding both the
examination, it is necessary to know whether the patient has taken accumulation on the early image and the washout rate.
drug that has an influence on accumulation of MIBG. Regarding re- Early image (H-M) – Delayed image (H-M)
serpine and tricyclic antidepressant agents, it is necessary to estab- Washout rate (%) = ___________________________________________________________ × 100
Early image (H-M)
lish drug withdrawal for an appropriate period taking into account
their blood half life. As I-123 has a short half-life of 13 hours and is a Regarding the SPECT images a method is available for visually
nuclide which emits only gamma rays, it does not necessarily require scoring the degree of accumulation by division into segments which
the blockage of thyroid accumulation. is similar to that used in MPI. The rate of uptake of MIBG in the myo-
Metaiodobenzylguanidine 111 MBq is intravenously adminis- cardium is as low as 1–2% and the image quality is inferior compared
tered at rest, and the early and delayed images are obtained 15–30 with Tl-201 images (Fig. 63.19). In some cases, substantial accumu-
minutes later and from 3 to 4 hours later, respectively. It is desirable lation of MIBG may occur in the liver which overlaps the myocardial
to prepare a gamma camera with sufficient visual field to cover most infero-posterior wall and scattering from the lung field to the lateral
high percentage shows increased washout in the region of the cul-

prit coronary artery on delayed images indicating a clearly abnormal
accumulation. In other words, delayed images are highly useful for
diagnosis. Taki et al. found the positive- and negative-accuracy rate
to be favorable at 83% and 81% respectively. Sakata et al. reported
MIBG to be more useful than stress myocardial perfusion SPECT in
the prediction of cardiac events in patients with vasospastic angina
having no dominant coronary stenosis.
Unstable Angina
A loading test is not indicated for unstable angina, although MPI at rest
is unable to diagnose this disease in many cases. MIBG makes it pos-
sible to identify culprit coronary artery with a high probability via find-
ings at rest and it is of diagnostic value. In a study by Tsutsui et al. MIBG
was demonstrated to have the ability to diagnose the culprit coronary
Figure 63.19: Interpretation of metaiodobenzylguanidine images artery in this disease with sensitivity of 71% and a specificity 78%.
Evaluation of Risk Areas in

Acute Coronary Syndrome
wall then exerts a considerable influence on the image, requiring
careful interpretation. Recently percutaneous coronary intervention (PCI) has been gener-
ally conducted for acute coronary syndrome in emergency situations.
Clinical Application Tc-99m agents are highly retained in the myocardium and exhibit al-
most no redistribution as is observed in the case of Tl-201. Thus, IV
MIBG in Ischemic Heart Diseases injection of such an agent prior to the practice of PCI enables evalua-
tion of the state myocardium perfusion before reperfusion treatment,
Sympathetic nerve ending are easily damaged by ischemia in even if the imaging is conducted after the completion of PCI (this is
comparison to myocardial cells and sympathetic function disorders referred to as freeze image). The defect range indicated on the image
are known to persist for a certain period even after alleviation of obtained via this method is called the risk area (i.e. the area at risk
ischemia. As a result, the potential exists for use of MIBG to detect of infarction if not treated appropriately) and is clinically important.
ischemia with extreme sensitivity providing images that memorize A second MPI procedure conducted in the subacute phase makes it
transient ischemia. MPI as a nuclear cardiological examination possible to quantitatively measure the infarcted myocardium. The
has been used in many ways for ischemic heart diseases and difference between the risk area and the infarcted area corresponds
sufficient evidence regarding the usefulness of this method has to the myocardium rescued by PCI.
been established. However in some cases, pathological conditions While evaluation of risk area by means of Tc-99m agents is an ex-
are difficult to evaluate precisely via perfusion imaging alone and cellent method with high objectivity, it is not necessarily easy to con-
MIBG may then be effective. In this group of patient, MIBG shows a duct nuclear medical examinations in emergency during the acute
decreased or reduced accumulation in the involved myocardium on phase. MIBG memorizes ischemia and thus reveals a wider range of
the delayed image and increased washout is usually observed in the defects compared with MPI if used in the subacute phase this results
involved regions of myocardium and the abnormal findings become in a mismatch between two methods. It has been reported that the
more marked. range of defects for MIBG corresponds more closely to the risk area
obtained using Tc-99m agents and that MIBG is useful in evaluating
Vasospastic Angina the risk area in acute coronary syndrome.
In vasospastic angina, the practice of MPI during nonseizure results

in normal accumulation and ordinary exercise loading rarely induc- Non-Q-Wave Myocardial Infarction
es coronary spasms. Accordingly, the ability of MPI to diagnose this Between 30% and 50% of cases MI are considered to be non-Q-wave
disease is not clinically satisfactory. infarction. In general, in such cases myocardial disorders are slight
According to a report by Taki et al. a small proportion of case and cardiac functions are maintained and compared with cases of
of vasospastic angina shows abnormal early MIBG images while a Q-wave infarction. However, no difference in prognosis has been re-
ported between these and non-Q-wave infarction has been reported 11C-Hydroxyephedrine (HED)
to have a rather high-risk of leading to sudden cardiac death.
For non-Q-wave infarction, the detection rate via MPI is regard- 11C-Hydroxyephedrine HED is most widely used PET tracer for cardi-
ed to be roughly 50%. While it is also reportedly possible to identify ac neuronal imaging. In healthy heart, there is an even distribution of
the culprit coronary lesions using MIBG in nearly all cases. Accord- HED over the LV making it a valuable tracer for detecting specific re-
ing to a reported comparative investigation into ‘Q’ wave infarction gional defects of presynaptic sympathetic system in disease. Dener-
and non-Q-wave infarction, Tc-99m-sestamibi (MIBI) myocardial vation studies in animal model and in human heart transplantation
perfusion SPECT and MIBG SPECT, MIBI defects in non-Q-wave patients have shown that HED has high affinity for the presynaptic
infarction were significantly smaller than those in Q-wave infarc- neuronal catecholamine transporter (NET also known as uptake-1)
tion, while MIBG defects showed no difference between these two and there exists negligible nonspecific binding. In addition, HED is
types of infarction. In addition, the size of MIBG defects in Q-wave not metabolized by monoamine oxidase (MAO) or catechol-O-meth-
infarction was proportional to that of MIBI defects while such a ten- yltransferase (COMT). Recently, it has been confirmed that HED re-
dency was not observed in non-Q-wave infarction. In other words, in tention is dependent on NET density of the heart. When desipramine
non-Q-wave infarction, a wide mismatch area is recognized between is used as a specific inhibitor of the uptake-1 system after HED ad-
perfusion SPECT and MIBG SPECT. This mismatch area is said to be ministration, gradual HED washout may be seen; thus, it has been
denervated but viable and is considered to be in an unstable state suggested that HED retention is actually dependent on continuous
which easily results in lethal arrhythmia. This situation may be one release and reuptake.
of reasons for many cases of cardiac sudden death in non-Q-wave
infarction. 11C-Ephinephrine (EPI)
11C-epinephrine also functions as true neurotransmitter but only
Heart Failure
to small extent. Epinephrine may be enzymatically labeled to 11C,
It has been reported that increased washout rate and the decreased producing 11C-epinephrine (EPI). Unlike HED is degraded by MAO;
heart/mediastinum ratio on delayed MIBG image become marked however, its storage in the vesicle is very efficient causing its slow
with an increase in hypofunction in LV in cases of heart failure, clearance from the heart. Therefore, EPI reflects the whole cascade
regardless of the underlying diseases. Similar results have been of uptake, metabolism and storage of neurotransmission while the
reported from studies on dilated cardiomyopathy (DCM). hyper- primary target for HED is the uptake-1 system. It has been suggested
trophic cardiomyopathy (HCM), valvular heart disease, pulmonary that these properties make it superior as a ligand truly tracing neu-
hypertension, amyloidosis and diabetes. As described above, the ronal dysfunction in heart.
relationship between cardiac hypofunction and abnormal MIBG in-
dices has been revealed in various diseases, and MIBG is thus useful 11C-Phenylephrine (PHEN)
for severity evaluation of heart failure.
Phenylephrine is commonly used as nasal decongestant. It may be
Cardiac Neuronal Imaging Using Positron labeled with 11C, thus making it a PET tracer, 11C-phenylephrine
(PHEN). It is metabolized by MAO forming radiolabeled metabolite
Emission Tomography
of PHEN, 11C-methylamine. The metabolite rapidly diffuses out of
Positron emission tomography is a highly specific tool for quanti- the nerve terminals. PHEN is gradually washed from myocardium
fying physiologic events. Compared with SPECT and conventional having a half-life of 60 minutes.
scintigraphy, it has higher spatial and temporal resolution, and at- The importance of vesicular leakage as a contributor to PHEN
tenuation correction is readily available and established. In addition, washout in addition to MAO metabolism has been emphasized.
many autonomic PET tracers more closely resemble the endogenous
neurotransmitter than 123I-MIBG used for SPECT imaging and the 18F-Flurodopamine
variety of available tracers may allow for more detailed analysis of
neuronal signaling. For practical application, specific activity and Dopamine may be labeled with 18F-fluroine to obtain 18F-flurodopa-
radiochemical purity are critical factors. These may expose myocar- mine which has been used in humans to assess cardiac and extracar-
dium to unlabeled catecholamine which compete with the labeled diac sympathetic innervation using PET. In humans, 18F-flurodopa-
tracer and may not only limit image quality but also cause pharma- mine scanning visualized sympathetic innervation in the heart, renal
cologic action via adrenoceptor activation. cortex, thyroid gland. Its early clinical application was mainly for the
identification of abnormalities in neuronal transmission in patients found that there are significant regional reductions in HED uptake
suffering from neurological diseases. The half-life of 18F-flurodopa- in apical and inferoapical segments in these patients. In another
mine is 110 minutes, which enables PET scanning for longer peri- study, patients with end-stage heart disease were scanned with HED
ods of time as compared with 11C-labeled compounds. After tracer before heart transplantation and after surgery the diseased heart
injection, sympathetic nerve terminals take up 18F-flurodopamine was investigated for uptake-1 density and NE content. They found
via uptake-1, after which it is rapidly internalized into vesicles and to have significant correlation of uptake-1 and NE content with HED
beta hydroxylated, forming radiolabeled NE. During sympathetic uptake, but not with uptake-1 affinity. According to these results,
neurotransmission, labeled NE is released similar to the endogenous they concluded that in dilated cardiomyopathy there is loss of neu-
NE. 18F-flurodopamine uptake may be blocked with desipramine. rons or downregulation of uptake-1 in humans; furthermore, in the
Owing to the nature of the radiolabel and the similarity of the meta- technical perspective they showed that PET imaging with HED is
bolic pathways compared with the endogenous NE, 18F-flurodopa- valid in human heart failure imaging.
mine may be used to assess the uptake and clearance of NE; however,
the production of 18F-flurodopamine is relatively difficult and, fur- Myocardial Hypoxia Imaging
thermore, owing to the complex fate of dopamine in plasma and the
heart, it is not widely used as the tracer of choice in assessing cardiac Tc-99m labeled nitroimidazoles are compounds which diffuse pas-
neuronal function. sively across normal cell membranes. Once in the cytoplasm of car-
diac myocite nitroreduction occurs with the formation of an RNO2
In Coronary Artery Disease radical ion which is oxygen independent step. In presence of no-
romoxia the radical interacts with oxygen to yield superoxide and
Myocardial ischemia and infarction result in nerve injury. This may noncharged nitroimidazole diffuses back out of the cell. Under the
be followed by sympathetic nerve sprouting and regional hyperin- hypoxic conditions, radical anion is decreased further and yields a
nervation, leading to environmental changes favorable to electrical nitroso compound which is trapped within the cell bound to intra-
imbalance. It has been observed that after MI beta-adrenoceptor cellular macromolecules. As a result, hypoxic or ischemic areas are
density is decreased as measured with 11C-CGP12177. In humans, visualized as zones of increased radionuclide uptake. It could offer a
chronic CAD caused reduction in HED uptake in patients with CAD new tool to assess ischemia and viability of myocardium. In addition,
but without MI. Furthermore, the decrease in HED uptake is most it will hold a promise of giving valuable information noninvasively
prominent in regions of significant coronary stenosis. After MI, defining a regional stimulus for angiogenesis.
there is an abnormal distribution of HED, showing impaired sympa- Besides technetium labeled hypoxic agents fluroinsonidazole is
thetic activity in the heart when compared with HED distribution in also used which can be labeled with F-18 and can be used as a hypox-
healthy subjects. These defects remained same after 8 months, show- ia imaging agent. With the advent of PET-CT and better attenuation
ing no reinnervation process in these patients. Thus, though there is correction of images, 18F MISO can be a promising tracer.
unarguable evidence of dysinnervation after ischemic insult, there is Similarly, Cu-60 ASTN is also another hypoxia imaging agent.
no clinical evidence as to whether this affects the prognosis of these
patients, and further studies are warranted to determine the clear cut CONCLUSION
clinical value of the innervation in ischemic heart disease.
Nuclear cardiology speciality is no doubt a state of art procedure in
In Heart Failure the present day clinical practice from its inception till date. Various
nuclear techniques have proved their superiority in the form of sen-
Heart failure as such is an end-stage form of several cardiac diseas- sitivity and specificity over other non-nuclear techniques such as CT
es. It is associated with neurohormonal activation causing impaired angiography, dobutamine stress echocardiography (DSE), cardio-
neurotransmission. Neuronal cardiac imaging with PET is attractive vascular MRI and contrast echocardiography in the detection and
method to study the failing heart since the sympathetic involve- further evaluation of patients suffering from CAD. In this context,
ment in heart failure is extensive. A study employing 11C-CGP12177 Tl-201 has been proved to be a potent radiotracer for the diagnosis
showed that in patients with idiopathic dilated cardiomyopathy, and for the treatment planning of patients having CAD for more than
there is significant reduction in amount of LV beta-adrenoceptor. 3 decades. The advent of various Tc-99m labeled perfusion agents,
These PET results were comparable with results obtained from car- particularly Tc-99m sestamibi (Cardiolite) or Tc-99m tetrofosmin
diac biopsies in the same study. Furthermore, Choudhary and as- (MYOview) have proved their increased specificity in detection of
sociates presented a similar reduction of beta-adrenoceptor den- CAD. The advantage of using technetium labeled perfusion imaging
sity in both primary and secondary LV hypertrophy with sustained agents has additional useful informations, such as global ejection
systolic function. Various other studies have also presented results fraction, RWM and systolic wall thickening of LV at rest/stress study.
of reduced HED uptake in heart failure caused by end-stage coro- Pharmacological stress MPI which is an unique technique to evalu-
nary disease or dilated cardiomyopathy. Hartmann and co-workers ate myocardial perfusion during maximal coronary vasodilatation.
In the early days of acute MI, pharmacological intervention study can Cardiovascular MRI imaging uses ultra-fast imaging sequence
be substituted as submaximal predischarge exercise testing which is using gadolinium-DTPA (Gd-DTPA) is a contrast agent itself and is
considered as a method for evaluating the extent of CAD and risk of expensive. Its rapid diffusion into interstitial space underestimates
future cardiac events. The role of Tl-201 reinjection and PET imag- the assessment of degree of myocardial viability. Additionally, there
ing particularly 18F-FDG, for myocardial viability has been used to is no quantitative assessment data is available till date and its ab-
correctly assess the amount of viable myocardium and would benefit sence availability of estimating simultaneous function and viability.
patients undergoing revascularization procedures. The presence of The cost of CMR test is phenomenal in present day clinical practice,
reversible defects on rest/reinjection Tl-201 myocardial scintigraphy e.g. it is almost double the cost of the gated SPECT myocardial perfu-
and PET pattern of perfusion metabolism mismatch are highly ac- sion scintigraphy.
curate for identifying the presence of hibernating myocardium and So, nuclear cardiology speciality is promising and cost-effective
thus predicting the potential for recovery of LV contractile dysfunc- in the assessment of cardiac function and its physiology and me-
tion following revascularization. The evidence of three important pa- tabolism. Every year newer radiopharmaceuticals are being invented
rameters of MPI (presence of transient defects, the number of tran- along with the improvement in the software as compared to other
sient defects and increased lung uptake of either Tl-201 or Tc-99m noninvasive modality of investigations, thereby keeping this modal-
agents) has emerged as strong predictors of future cardiac events in ity as the leader of noninvasive diagnostic modality in patients suf-
patients having postmyocardial infarction. fering from CAD.
BIBLIOGRAPHY
1. Bacharach SL, Bax JJ, Case J, et al. American Society of Nuclear Medicine Cardiology practice guidelines. J Nucl Cardiol. 2003;10:543-56.
2. Bateman TM, McGhie AL, Heller GV, et al. ECG-Gated rubidium-82 perfusion PET imaging. A multi-expert comparison with technetium-sestami-
bi SPECT. Circulation. 2004;110:111-611.
3. Bax JJ, Cornel JH, Visser FC, et al. Prediction of improvement of contractile function in patients with ischemic ventricular dysfunction after revas-
cularization by fluorine-18-fluorodeoxyglucose single photon emission computed tomography. J Am Coll Cardiol. 1997;30:377-83.
4. Berman DS, Kiat H, Van Train K, et al. Tc-99m sestamibi in the assessment of chronic artery disease. Semin Nucl Med. 1991;21:190-212.
5. Bodenheimer MM, Banka VS, Fooshee C, et al. Relationship between myocardial perfusion and the presences of severity and reversibility of a
synergy in patients with coronary heart disease. Circulation. 1976;53:792-800.
6. Brunken RC, Kottou S, Nienabar CA, et al. PET detection of viable tissue in myocardial segments with persistent defects at Tl-201 SPECT. Radiol-
ogy. 1989;172:65-73.
7. Burt RW, Perkins OW, Oppenheim BE, et al. Direct comparison of fluorine-18-FDG SPECT, fluorine-18-FDG PET and rest thallium-201 SPECT for
detection of myocardial viability. J Nucl Med. 1995;36:176-9.
8. Chen EQ, Maclntyre WJ, Go RT, et al. Myocardial viability studies using fluorine-18-FDG SPECT: a comparison with fluorine-18-FDG PET. J Nucl
Med. 1997;38:582-6.
9. Choudhury L, Rosen SD, Lefroy DC, et al. Myocardial beta adrenoceptor density in primary and secondary left ventricular hypertrophy. Eur Heart
J. 1996;17:1703-9.
10. Chua T, Kiat H, Germano GF, et al. Rapid back adenosine stress/rest technetium-99m teboroxime myocardial perfusion SPECT using a triple
detector camera. J Nucl Med. 1993;34:1485-93.
11. de Groot M, Meeuwis AP, Kok PJ. Influence of Blood glucose level, age and fasting period in nonpathological FDG uptake in heart and gut. Eur J
Nucl Med Mol Imaging. 2005;32:98-101.
12. DePuey EG, Parmett S, Ghesani M, et al. Comparison to Tc-99m sestamibi and Tl-201 gated perfusion SPECT. J Nucl Cardiol. 1990;6:278-85.
13. Forster T, McNeilt AJ, Alustri A, et al. Simultaneously dobutamine stress echocardiography and technetium-99m isonitrile single photon emission
computed tomography in patients with suspected coronary artery disease. J Am Coll Cardiol. 1993;21:1591-6.
14. Fukuchi K, Katafuchi T, Fukushima K, et al. Estimation of myocardial perfusion and viability using simultaneous 99mTc-tetrofosmin—FDG col-
limated SPECT. J Nucl Med. 2000;41:1318-23.
15. Gaemperli O, Schepis T, Koepfli P, et al. Accuracy of 64-slice CT angiography for the detection of functionally relevant coronary stenoses as as-
sessed with myocardial perfusion SPECT. Eur J Nucl Med Mol Imaging. 2007;34:1162-71.
16. Gianrossi R, Detrane R, Mulvihill D, et al. Exercise induced ST depression in the diagnosis of coronary artery disease. A meta-analysis. Circulation.
1989;80:87-98.
17. Goldstein RA, Mullani NA, Murani SK, et al. Myocardial perfusion with rubidium 82. II-Effects of metabolic and pharmacological interventions. J
Nucl Med. 1983;24:907-15.
18. Gracia E, Caake CD, Van Train KF, et al. Technetium-99m sestamibi. Am J Cardiol. 1990;6G:80E-90E.
19. Gutman J, Berman DS, Freeman M, et al. Time to complete redistribution of Tl-201 in exercise myocardial scintigraphy, relationship to the degree
of coronary artery stenosis. Am Heart J. 1983;106:989-95.
20. Hays JT, Manmarian JJ, Cochran AJ, et al. Dobutamine Tl-201 tomography for evaluating patients with suspected coronary artery disease unable
to undergo exercise or vasodilatory pharmacologic testing. J Am Coll Cardiol. 1993;21:1583-90.
21. Iskandrian AS, Heo J, Kong B, et al. Use of Tc-99m isonitrile (RP 30A) in assessing left ventricular perfusion and function at rest during exercise in
coronary artery disease and comparison with coronary arteriography and exercise Tl-201 SPECT imaging. Am J Cardiol. 1989;64:270-5.
22. Kiat H, Maddahi J, Roy LT, et al. Comparison of Technetium-99m methoxy isobutyl isonitrile and thallium-201 for evaluation of coronary heart
disease by planar and tornographic methods. Am Heart J. 1989;117:1-11.
23. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging-executive summary: a report
of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the
1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). J Am Coll Cardiol. 2003;42:1318-33.
24. Mabuchi M, Kubo N, Morita K, et al. Value and limitation of myocardial fluorodeoxyglucose single photon emission computed tomography using
ultra-high energy collimators for assessing myocardial viability. Nucl Med Commun. 2002;23:879-85.
25. Mabuchi M, Kuso N, Morita K, et al. Value and limitation of myocardial fluorodeoxyglucose single photon emission computed tomography using
ultra-high energy collimators for assessing myocardial viability. Nucl Med Commun. 2002;23:879-85.
26. Mahapatra GN, et al. Nuclear techniques in assessing myocardial viability. J Cardiol Today. 1998;2:39-41.
27. Marwick T, Willemart B, D’Hondt AM, et al. Selection of the optimal nonexercise stress for the evaluation of ischemic regional myocardial dys-
function and malperfusion. Comparison of dobutamine and adenosine using cardiography and Tc-99m MIBI single photon emission computed
tomography. Circulation. 1993;87:345-54.
28. Matsunari I, Kanayama S, Yoneyama T, et al. Electrocardiographic-gated dual-isotope simultaneously acquisition SPECT using 18F-FDG and
99mTc sestamibi to assess myocardial viability and function in a single study. Eur J Nucl Med Mol Imaging. 2005;32:195-202.
29. Matsunari I, Schricke U, Bengel FM, et al. Extent of cardiac sympathetic neuronal damage is determined by the area of ischemia in patients with
acute coronary syndromes. Circulation. 2000;101:2579-85.
30. Matsuo S, Nakamura Y, Tsutamoto T, et al. Impairments of myocardial sympathetic activity may reflect the progression of myocardial damage or
dysfunction in hypertrophic cardiomyopathy. J Nucl Cardiol. 2002;9:407-12.
31. Patterson RE, Horowitz SF, Eisner RL. Comparison of modalities to diagnose coronary artery disease. Semin Nucl Med. 1994;4:286-310.
32. Ritchie JL, Albro PC, Caldwell JH, et al. Tl-201 myocardial imaging: a comparison of the redistribution and rest images J Nucl Med. 1979;20:477-83.
33. Rocco T, Dilsizian V, Maltais F, et al. Tl-201 reinjection after delayed imaging demonstrates fill-in to region with “fixed” defect (abstract). J Nucl
Med. 1988;29:76.
34. Sakata K, Iida K, Kudo M, et al. Prognostic value of I-123 metaoidbenzylguanidine imaging in vasospastic angina without significant coronary
stenosis. Circ J. 2005;69;171-6.
35. Santana CA, Shaw LJ, Garcia EV, et al. Incremental prognostic value of left ventricular function by myocardial ECG-gated FDG PET imaging in
patients with ischemic cardiomyopathy. J Nucl Cardiol. 2004;11:542-50.
36. Schelbent HR, Beanlands R, Bengal F, et al. PET myocardial perfusion and glucose metabolism imaging: Part 2-guidelines for interpretation and
reporting. J Nucl Cardiol. 2003;10:557-71.
37. Schofer J, Spielmann R, Schuchert A, et al. Iodine-123-meta-iodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial
adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1988;12:1252-8.
38. Schwaiger M, Kalff V, Rosenspire K, et al. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomogra-
phy. Circulation. 1990;82:457-64.
39. Simula S, Lakka T, Laitinen T, et al. Cardiac adrenergic denervation in patients with non-Q-wave versus Q-wave myocardial infarction. Eur J Nucl
Med. 2000;27:816-21.
40. Slart RH, Bax JJ, van Valdhuisen DJ, et al. Prediction of functional-recovery after revascularization in patients with coronary artery disease and left
ventricular dysfunction by gated FDG-PET. J Nucl Cardiol. 2006;13:210-9.
41. Spyrou N, Rosen SD, Fath-Ordoubadi F, et al. Myocardial beta-adrenoceptor density one month after acute myocardial infarction predicts left
ventricular volumes at six months. J Am Coll Cardiol. 2002;40:1216-24.
42. Taillefer R, Lamberi R, Dupras G, et al. Clinical comparison between thallium-201 and Tc-99m methoxy-isobutyl isonitrile (sestamibi) myocardial
perfusion imaging for detection of coronary artery disease. Eur J Nucl Med. 1989;15:280-6.
43. Taki J, Yasuhara S, Takamatsu T, et al. Value of iodine-123 metaiodbenzylguanidine scintigraphy in patients with vasospastic angina. Eur J Nucl
Med. 1998;25:229-34.
44. Tamaki N, Yonekura Y, Mukai T, et al. Segmental analysis of stress Thallium of myocardial emission tomography for localisation of coronary artery
disease. J Nucl Med. 1984;9:99-105.
45. Tamaki N, Yonekura Y, Yamashita K, et al. SPECT Tl-201 tomography and positron tomography using N-13 Ammonia and F-18 FDG in coronary
artery disease. Am J Cardiac Imaging. 1989;3:3-9.
46. Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall motion abnormalities predicted by position tomography. N Engl J Med.
1986;314:884-8.
47. Tsutsui H, Ando S, Fukai T, et al. Detection of angina-provoking coronary stenosis by resting iodine-123 metaoidbenzylguanidine scintigraphy in
patients with unstable angina pectoris. Am Heart J. 1995;129:708-15.
48. Verzjibergen FJ, Vermeersch PHM, et al. Inadequate exercise leads to suboptimal imaging. Thallium-201 myocardial perfusion imaging after
dipyridamole combined with low level exercise unmasks ischemia in symptomatic patients with nondiagnostic Tl-201 scan who exercise sub-
maximally. J Nucl Med. 1991;32:2071-8.
64 Telemedicine and Cardiology
in India
Raju PK, Prasad SG
an equal value, because they cannot reach out to medical help, even
INTRODUCTION if, they want to.
In the last 4 or 5 years, telemedicine has generated immense interest
among users and medical professionals. It is actually a branch of sci HISTORY
ence that has been based upon the use of telecommunications.
Today, telecommunication has advanced gradually to a level The idea of performing medical examinations and evaluations
where audio, video and text are all possible at the same time. Simul through the telecommunication network is not new. Shortly after the
taneously with the growth of telecommunication, even the telemedi invention of the telephone, attempts were made to transmit heart
cine industry has been growing. However, telemedicine is not as new and lung sounds to a trained expert who could assess the state of the
an industry as people think and in fact, it has existed over 30 years in organs. Some historical milestones2 are mentioned below:
the medicine industry.1 National Aeronautics and Space Administra • 1906, electrocardiogram (ECG) transmission: Einthoven, the Fa
tion (NASA) had a big role to play in the popularity of telemedicine ther of electrocardiography, first investigated on ECG transmis
and they started using it when humans were being sent to space. sion over the telephone lines in 1906.
When scientists were sent to space on spaceships, their vital • 1920s, help for ships: Telemedicine dates back to the 1920s. Dur
statistics and other health conditions were monitored through tele ing this time, radios were used to link physicians standing, watch
medicine. This development came in as early as 1960s. However, at shore stations to assist ships at sea that had medical emergen
after that communication industry has developed by leaps and cies.
bounds and today, complicated satellites are used for transmitting • 1955, telepsychiatry: The Nebraska Psychiatric Institute was
life-like images and live ones too. After NASA used it efficiently for one of the first facilities in the country to have closed-circuit tel
their staff, telemedicine is still elusive. evision (TV) in 1955. In 1971, the Nebraska Medical Center was
The US armed forces have had a long-standing interest in mobile linked with the Omaha Veterans Administration Hospital and
health and telemedicine services. During the late 1980s and early veterans affairs (VA) facilities in two other towns.3
1990s, technological progress provided the military with the ability to • 1964: Under a grant from the US National Institute for Mental
establish an integrated healthcare delivery networks in many areas Health (NMH), the Nebraska Psychiatric Institute began using a
of the world. When Hurricane Hugo devastated the Virgin Islands in two-way closed-circuit TV link between the Institute itself and
March 1990, the Alabama Army National Guard mobile army surgi Norfolk State Hospital about 112 miles away. The link was used
cal hospital was deployed to St. Croix. They used the prototype Bat for education and consultations between specialists and general
tlefield computed radiography scanner, a digitizer, and an Interna practitioners.
tional Maritime Satellite (INMARSAT) terminal to transmit images • 1967: A medical station was established at Boston’s Logan Inter
acquired in the Virgin Islands via satellite to Walter Reed Army Medi national Airport and linked to Massachusetts General Hospital
cal Center (WRAMC) in Washington DC and to Dwight D Eisenhow (MGH), miles away within the city of Boston. Physicians at MGH
er Army Medical Center in Augusta, Georgia. This relief effort was the provided medical care to patients at the airport 24 hours a day,
first to demonstrate the value of deployable teleradiology systems in using a two-way microwave audio/video link.
times of crisis. • 1971: The US National Library of Medicine’s Lister Hill National
With the growing aging population and physical disabilities, Center for Biomedical Communication chose 26 sites in Alaska
the medical industry realized that the same concept can be used for to verify the reliability of telemedicine via satellite communica
the elderly and the disabled. The whole idea behind the concept is tions (SATCOM). National Aeronautics and Space Administra
to deliver medical help to a person where it is not possible to reach tion’s Applications Technology Satellite (ATS)-1 was used for this
them immediately. For an elderly, a space station or their home has experiment.4
• 1972: National Aeronautics and Space Administration began especially the SATCOM, combined with Information Technology, we
trial runs of its Space Technology Applied to Rural Papago Ad have means to benefit them from the advanced medical sciences to
vanced Health Care (STARPAHC) program for telemedical help reach even the remote and inaccessible areas.
for people living in remote locations with little or no medical The Government of India has been investing in telemedicine in
services, like Arizona’s Papago Indian Reservation.4 Engineered a bid to make healthcare more accessible to the country’s rural com
by NASA and Lockheed Missiles and Space Co. (now, Lockheed- munities. But skeptics are wary about the limitations of the technol
Martin), the system used two-way microwave transmissions to ogy when it comes to diagnosis, care and surgery. This chapter here
link paramedical personnel located in mobile (vans) and fixed deals with the current scenario of telemedicine and cardiology in
stations with medical experts at hospitals in Tucson and Phoe India with special emphasis on Telecardiology while highlighting our
nix. The program lasted until 1975. own experiences over the last one decade. It primarily focuses on the
• 1972: The Health Care Technology Division of the US Depart requirements in terms of technology, communication, infrastructure
ment of Health, Education and Welfare (HEW) funded seven tel and human resources to ensure a practical workable model, catering
emedicine research and demonstration projects: (1) the Illinois to the demands of our country.
Mental Health Institutes in Chicago, (2) Ohio’s Case Western
Reserve University in Cleveland, (3) Massachusetts’ Cambridge How Would We Want to Define Telemedicine?
Hospital, (4) Illinois’ Bethany/Garfield Medical Center in Chica
go, (5) Minnesota’s Lakeview Clinic in Waconia, (6) Dartmouth “Telemedicine has been defined as the use of telecommunications
Medical School’s INTERACT in Hanover, NH and (7) the Mount to provide medical information and services.” The actual practice of
Sinai School of Medicine in New York city. The next year, the US telemedicine can be defined as integration of medical, communica
National Science Foundation (NSF) funded two more telemedi tion and information technology to provide medical advice on the
cine projects: (1) the Boston Nursing Home project for geriatric basis of comprehensive information transferred from remote centers
patients and (2) the Miami-Dade project between Florida’s Dade to specialty centers.
County and Miami’s Jackson Memorial Hospital. If we were to talk from a layman’s point of view, we will not be
• 1977: Canada’s Memorial University of Newfoundland partici absolutely wrong if a patient calls up a doctor on account of a head
pated in a Canadian Space Program for distance education and ache and the doctor prescribes a medicine and define that as “Tel
medical care, using the joint Canadian/US Hermes satellite. emedicine”. However, the issue that comes up with this is the fact that
• 1984: The North-West Telemedicine project was set-up in Aus the transaction between the doctor and patient is not documented
tralia to pilot test the Australia Government’s Q-Network SAT and this piece of information cannot be retrieved for any further ref
COM network. The project’s goal was to provide healthcare to erence. It is therefore imperative that we ensure that telemedicine
people in five remote towns South of the Gulf of Carpentaria. services are used as judiciously as withdrawal of money from an au
• 1989: After a massive earthquake hit the Soviet Republic of Ar tomated teller machine (ATM) where everything is accounted.
menia, the US offered the Soviet Union, under the auspices of the Unlike our professionals in the West, where telemedicine is more
US/United States of Soviet Republic (USSR) Joint Working Group often used as a “second opinion tool”, the lack of medical expertise or
on Space Biology, use of a one-way international telemedicine specialists in centers even 100 km away from cities, suggests that we
network for consultations between Yerevan, Armenia and four more often need telemedicine services to ensure that patients living
medical centers in the US. The Space Bridge program was later here get their first opinion. So the whole perspective of the process of
extended to Ufa, Russia. telemedicine in India is distinctly different from the West.
The next question that comes to one’s mind before we go into the
INDIAN SCENARIO details of telemedicine is what is the actual need for this service?
Indian healthcare is very city centric and most of the healthcare
India is a nation of 1.3 billion people, populating a subcontinent services are highly skewed in favor of urban population which is 28%
sparsely in pristine landscapes or in a startling density in some of of the Indian population. Table 64.1 shows highlights some of the
the world’s largest cities. In today’s world with several advancements details5 to corroborate this fact.
made in the medical field still the benefits are available to the privi Healthcare today involves multiple work centers and interdisci
leged few, residing mainly in the urban areas. India with its vast pop plinary work cooperation. In addition to this the increasing mobility
ulation of which 70% are poor and live in difficulty to reach rural and of people and the actual time span between health episodes for pa
inhospitable terrain find themselves inaccessible to quality health tients have made it increasingly difficult for facilitating timely diag
care services. It must be noted that the average per capita spend on nosis. Moreover the lack of adequate infrastructure at district/rural
healthcare is 5.2% gross domestic product (GDP), one of the lowest hospitals and the unwillingness of people to travel to cities either due
in the world and various healthcare indicators are also lower than to lack of time or monetary constraints have left us with no choice,
the global average.5 With the advent of communication technology, but to evolve systems in a manner that quality healthcare services
Chapter 64  Telemedicine and Cardiology in India 541
TABLE 64.1 Health statistics in India by the World Health Organization (WHO), drawn mainly from this
Population deprived of healthcare services > 700 million source and for what they are worth, show a much higher prevalence
in India than in many other developing countries.
Specialists healthcare providers in urban areas 70%
Diseases of the circulatory system still are one of the top 10 caus
Allopathic doctors available per 1,000 of population 0.6
es of death in rural India.7 The subjects covered under “circulatory
Doctors available per 1,000 of urban population 2.97 diseases” include anemia, among others. Stroke, rheumatic heart
Doctors available per 1,000 of rural population 0.50 disease (RHD) and hypertension are not included. In another study
Relative cost of setting at 100 bed primary care hospital 1/10 conducted as a part of the Andhra Pradesh Rural Health Initiative
to a tertiary care super specialty hospital (APRHI) in 20 villages (size 4535), it was observed that 13.2% of them
Spend on healthcare as a percentage of gross domestic 5.2 suffered from diabetes, of which 6.4% were diagnosed and 6.8% un
product (GDP) diagnosed. There was also 15.5% of them in the prediabetic stage.8
Government spend on healthcare as a percentage of 0.9 Another study for the assessment of CVD and risk factors among 345
GDP adults in rural India, APRHI attributed 25.2% to smoking and 27%
to hypertension.9 Even though the number of open heart surgeries
performed (42 operations per million) is small as compared to 1,700
per million in the USA, it provides a clue to the enormous demand
can be delivered with the use of the information and communica in India. There are only 100 fully operational cardiac centers in India
tion technology (ICT) platform. Telemedicine finds its application in with surgical facilities.
various disciplines the most notable being in radiology, cardiology, Clinical impression alone suggests that there has been phenom
pathology, dermatology and ophthalmology.6 The latest application enal increase in ischemic heart disease (IHD) throughout India. The
of this technology has been in conducting robotic surgery; although, reasons, as in other developing countries, are obvious. Increase in
selection of patients followed with a robust communication network life expectancy (from 41 in 1961 to 65 for male and 67 for female in
are key factors to be considered. 2010), smoking, Western-style diet (with increase in saturated fat,
salt, calories and less intake of fiber) and decreased physical activ
Need for Telemedicine in Cardiology ity resulting in obesity are all responsible. Urbanization is on the in
crease and is responsible for many of these changes in lifestyle.
Among the many health predictions for the new millennium, the
most alarming is that of cardiovascular disease (CVD)—heart dis Risk Factors—Old and New
ease and stroke—topping the list for death and disability. While
there are undoubted regional differences between the developed The traditional risk factors, such as smoking, high blood pressure,
countries and other economies, the predictions for India by 2015 high serum cholesterol level and diabetes are applicable to the ma
show a steady increase since 1985. The projected rate per 100,000 jority of cases in India. The emerging risk factors, such as abdominal
for 1985 for all “circulatory diseases” was 145 males, 126 females; for obesity, high triglycerides, insulin resistance, the so-called metabolic
2000, 253 males and 204 females and for 2015, 295 males and 239 syndrome, elevated homocysteine levels, fibrinogen factors, etc.
females, which is higher than that for other causes such as cancer. In need not be invoked to explain the present high incidence of heart
a study that was conducted in 45 villages (population 180,162) dur attacks as they are yet to be proven as being causative in this era of
ing a 12-month period in 2003–2004 showed 32.6% of the population evidence-based medicine. Control of the traditional risk factors and
suffered from diseases of the circulatory system, of which 34.3% were use of proven preventive strategies should suffice in any preventive
males and 30.2% females.7 program. Keeping all of the above in mind, it has become imperative
that secondary and primary healthcare infrastructures have to now
BURDEN IN INDIA—CORONARY be empowered by making available the expertise from these tertiary
level centers located in the urban areas. This is where “telemedicine”
HEART DISEASE
plays a very significant role.
Mortality Statistics The greatest impact of telemedicine is on the patient, the family
and the community. By using telemedicine technologies, it reduces
Specific mortality data ideal for making comparisons with other travel time and related stresses to the patient. In many instances,
countries are not available in India. This is due to inadequate and patient movement would require travel by additional family mem
inappropriate death certification and multiple concurrent causes of bers, day care costs and time away from the job. This disruption in the
death. The annual surveys conducted by the Registrar General of In local community can be avoided when proper technologies are used
dia cover about 0.5% of rural deaths in India. The figures published to bring the consulting specialist to the patient.
Factors That Drive Telemedicine TABLE 64.2 Categories of Medical Information

Basic Categories Textual data
Telemedicine is driven by following:
Images
• Need to decrease costs of care through increased efficiency and
Audio and video
decreased provider time in travel
• Detect disease early Activity Categories Clinical consultations
• Need to increase access to care for underserved populations Doctor-patient interaction
• Convenience to patients and facilitate follow-up care Education and administration
• Desire to address new markets or new patient populations.
sion requires an uplink to the satellite and a downlink to the loca
TELEMEDICINE AS A PROCESS tion. The KU-Band satellite dish is relatively small and portable on
a truck compared to the C-band dish. However, the range and stur
Telemedicine essentially involves the integration of three technolo diness achieved with static dishes compared to the mobile dish
gies, which are following: is much higher. The advantage with satellite transmissions is that
• Medical technology (medical equipment) they have no boundary restrictions. It allows transmission of large
• Electronic patient records and clinical data (information tech amounts of information. It is ideal for sending visual information to
nology) multiple locations. However, the disadvantage is the cost. It is ap
• Mode of communication (communication technology). proximately eight times as expensive as terrestrial transmission. On
the other hand, terrestrial transmission is less expensive to operate
Medical Technology on an hourly basis, but is limited to areas that are linked to the ap
propriate line. Video transmission normally requires a bandwidth
This includes the medical equipment and the interfaces available in (carrying capacity) of 90 million bits per second (Mbps). A telephone
them to integrate with computer systems. Earlier days, all medical call requires 64,000 bits per second. The fastest speed available with
manufacturers had their own proprietary formats which meant that current digital technology is 1.54 Mbps. This requires a bandwidth
the images acquired in machines could be viewed only in the same commonly referred to as T1. T1 consists of 24 voice channels, which
systems. This raised issues of interoperability and consequently the may be combined with higher bandwidth as needed. The higher the
American Board of Radiology and national engineers manufacturing bandwidth, the better the image quality, however, increased cost is
association (NEMA)10 suggested that all medical equipment follow the tradeoff for better image quality. Fiber-optics is available from
a standardized format for imaging, digital imaging and communica long distance and local telephone companies. Optical fibers consist
tion system (DICOM). This ensured that all medical equipment gen of strands of hair-thin glass and use light to transmit telecommuni
erates an output, which can be viewed in any of the medical systems, cation signals. They may be leased as a dedicated line or on-demand
thereby solving the interoperability issue. basis. Optical fiber has a wide bandwidth allowing for choices of
transmission speed. Due to cost constraints, T1 line is not available
Information Technology in all areas. Today, with the advent of broadband internet technology
accessibility at an affordable cost, it has become a reality and most
This includes the kind of computer systems in terms of clients and applications are now based on web technology. One of the key pa
servers that are required. This varies from site to site based on the ac rameters to be assessed as described above is the “bandwidth factor”
tual modalities integrated for telemedicine. The system architecture whenever we talk of communication. A simple equation, which will
involves the operation and transfer of medical information in multi help us in determining this is given as:
ple categories, which are defined in Table 64.2. Bandwidth × Cost
Image resolution ∝ ___________________________
Transmission time
Communication Technology
Table 64.3 gives us an idea of bandwidth requirements for vari
The transmission mode may be transported via satellite or terrestrial ous applications.
media. Terrestrial modes include microwave, fiber-optic and con
ditioned copper cables. Satellite transmission allows a full-motion METHODOLOGIES
broadcast quality picture. Most satellites transmit analog signals,
which may be transported on C-Band or KU-Band. The transmit
Real Time
ted and received frequencies available with the C-Band (Tx -6 GHz;
Rx - 4 GHz) are much less than the respective frequencies available This typically includes transmission of dynamic images with mini
with the KU-Band (Tx - 14 GHz; Rx - 11 GHz). Satellite transmis mum delay. The bandwidth for such applications is important to
TABLE 64.3 Bandwidth requirements

Modality Bandwidth (kbps)
64 128 192 256 384 512 > 1000
Textual Information √
Images Transfer (like ECG, or jpg formats) √
Images (CT, MRI) DICOM format √ √√
Echocardiography (live) √ √√
Angiography √ √√
Surgical √ √√
Simple Video conferencing (for tele-consultation) √ √√
Key: √, Minimum requirement; √ √, Preferred requirement; Abbreviations: ECG, Electrocardiograph; CT, Computed tomography; MRI, Magnetic
resonance imaging; DICOM, Digital imaging and communication system
Source: Authors unpublished technical data
ensure that there is no compromise between video (of medical im

ages) and audio (voice). Typical applications are echocardiography
(ECHO), ultrasound and catheterization procedures. This would
involve direct interaction between the expert physician and patient
at the time of the investigation. Consequently, the best practice is to
have a prefixed scheduled time for this kind of methodology.
Near Real Time

This includes application like ECG wherein there is an acquisition
time involved for taking an ECG and then followed by transmission
through the appropriate port.
Store and Forward Figure 64.1: Application software architecture

This typically is used for static images, such as X-ray, computed
tomography (CT) scan and magnetic resonance imaging (MRI). The
advantage of this mode of communication is that one can archive all
the images and then forward all the cases simultaneously thereby • Expert or doctor who gives opinions and interacts with the pa
reducing usage time of connectivity between locations. tient.
A good telemedicine system should be designed to achieve the
APPLICATION SOFTWARE following:
The software design should provide a unique patient identification Precise Definition
numbers to archive records to be archived with necessary clinical
information and retrieved at any point of time. The basic architecture It gives a graphical user interface, provides an immediate, self-ex
(Fig. 64.1) should comprise of: planatory real-time access to all the available data of a single indi
The application software should be designed, keeping in mind vidual patient, as well as defined patient samples. It gives a precise
perspectives of five users, which are: description of the problem rather than part of the solution.
• Patient who would use the service
• Primary health center (PHC), which has trained medical person Logical Processing
nel
• Expert center/specialist involved in consultations This system creates an integrated patient’s record on a central func
• Medical administrator who administers the network and tion in the hospital context, the integration of a knowledge based on
this record, to develop testing facilities for clinical data’s processing • Facial recognition system helps the service providers to clearly
and for clinical support systems. It includes all patient-related data, identify the patients on the network, especially, in the case of
necessary administrative and organizational data from all involved video conferencing.
departments and also some decision support from those depart • Digital identity card is provided to the remote patients after iden
ments. tity verification by authorities. The encryption features and digi
tal signature of the patients in the card authenticates the users
The Medical Record and allows them to access online health services.
• The access to all the point-of-service computers should be user
The patient record consists of modules of a database which are con authenticated to ensure that only authorized personnel access
structed according to logical integrated complexes: modules for the system.
demographic data, scheduling, subjective complaints and physical • The computer network should be protected by firewall and
(SAP) findings exist: grouped data as the finding of a complex investi should be constantly monitored to detect any intrusion. There
gation or therapy exist as well as a problem list and a toll for the reim should be an audit system, which maintains a record of time, fre
bursement. Downloading of parts of the patient’s records both tex quency and nature of the hostile attacks made on the network.
tual and DICOM compatible images to intelligent terminals, where The security features in the network enable the health service
processing can be performed and uploading of updated data are the providers to provide quality healthcare services to remote patients
main principles on the system. in a safe and secure way. The patient health privacy is protected and
this is in line with HIPAA compliance norms thereby ensuring that
Clinical Workstations telemedicine can safely deliver customized health solutions to re
mote communities.
A cornerstone of this system is a problem list with a distinction be
tween active and inactive problems. The system uses relational data Retrieval and Archival
base technology. The system is one of the models of medical records,
which supports the medical user in the most advanced way with a In medical imaging, electronic picture archiving and communica
maximum amount of structured information in relation to the actual tion systems (PACS) have been developed in an attempt to provide
processed data of the individual patients. economical storage, rapid retrieval of images, access to images
acquired with multiple modalities and simultaneous access at mul
Security tiple sites.11 Digital medical images are typically stored locally on
a PACS for retrieval. It is important that facilities have a means of
Since information is exchanged over a great distance through a se recovering images in the event of an error or disaster. While each
ries of local and wireless networks, the remote settings of the patients facility is different, the goal in image back-up is to make it automatic
make the exchange of health information with health providers highly and as easy to administer as possible. The hope is that the copies
vulnerable to hostile intrusion. The Health Insurance Portability and won’t ever be needed, but as with other disaster recovery and busi
Accountability Act (HIPAA) compliance norms makes it mandatory ness continuity planning, they need to be available if needed. Ide
for all the covered entities, like hospitals, clinics, clearinghouses, ally, copies of images should be streamed off-site as they are cre
physicians, medical insurance companies and other health service ated. Depending on upload bandwidth and image volume, this may
providers to employ secure computer network systems, which follow not be practical if the backup system cannot be configured to tune
stringent security codes. The nomadic or remote settings of the pa bandwidth usage and frequency of backups. Other options include
tients make it a challenging task for the health providers to maintain removable media [hard drives, digital video discs (DVDs) or other
the privacy of patient health information. Further lack of proper vigi media that can hold many patients’ images] that is physically trans
lance at remote settings attracts hostile intrusion from both hackers ferred off-site. The content of these copies must be protected via en
and virus. To fortify the telemedicine network against unauthorized cryption from exposure to unauthorized personnel or stiff penalties
access, some stringent security features in the network can be incor can be assessed. Images may be stored both locally and remotely
porated as following: on offline media, such as tape or optical media, or partially or ex
• All the e-mail communications should be in encrypted form. The clusively on hard discs (“spinning”) media. The latter is becoming
e-mail content is encrypted into strings of codes and transmit more common. The hard drives may be configured and attached to
ted over the network. At the receiving end, the coded message the PACS server in various ways, either as direct attached storage
is assembled back into original form with the help of a key. Even (DAS), network attached storage (NAS) or via a storage area net
if, someone manages to access it illegally during the course of work (SAN). Today newer techniques, which employ cloud com
transmission, the coded message will make no sense. puting are being adopted to ensure that the healthcare provider
does not have the issue of worrying about storage or bandwidth for connecting the district hospital at Mahabubnagar to CARE hospital
transmission of high voluminous data. This quick retrieval of infor at Hyderabad. CARE was also the nodal agency for the pilot study
mation will help in research, educational and epidemiological work initiated by the Government of India as a part of the 54-nation Pan
apart from ensuring that a good comprehensive electronic medical African Network (PAN) (Figs 64.2A to C). The pilot study was associ
record (EMR) of the patient information is obtained. The availabil ated with Black Lion Hospital, Ethiopia for teleconsultations. Pres
ity of a good PACS system will eventually allow us to develop new ently, the link is used actively for providing continuous medical edu
structured reporting formats, which will lead to a drastic reduction cation (CME) for the medical fraternity across the connected nations
in the reporting time. of the network.
Real time methodology was adopted for viewing echocardio
OUR EXPERIENCES graphic images with a trained technician at Mahabubnagar provid
ing the views for the specialist at CARE. Store and forward method
Mooted by the inspiration of Bharat Ratna Dr APJ Abdul Kalam to ology was adopted for reporting of CT cases. The network operates
ensure accessibility of quality healthcare delivery systems to people on a 256 kbps leased line of point-to-point connectivity. Figure 64.3
living in remote centers, we have developed a telemedicine system illustrates our set-up at Mahabubnagar district hospital. We currently
under a public private partnership model with the Andhra Pradesh have a 2 Mbps broadband based internet connectivity on which most
Vaidya Vidhana Parishad (APVVP) (Government of Andhra Pradesh) of our telemedicine links work.
B C
Figures 64.2A to C: (A) Bharat Ratna Dr APJ Abdul Kalam addressing people about telemedicine projects in India to enable rural masses to
access medical facilities; (B) Former Chief Minister of Andhra Pradesh N Chandrababu Naidu interacting with telemedicine’s first patient on October
25, 2001; (C) Live echocardiography performed at district hospital, Mahabubnagar and read by cardiologist at CARE, Hyderabad
Figure 64.3: Telemedicine set-up at district hospital, Mahabubnagar.

Abbreviations: ECHO, Echocardiography; LAN, Local area network; DICOM, Digital imaging and communication system; ECG, Electrocardiograph
The link, which was inaugurated on October 25, 2001 by Shri N disease (HHD), 151 patients (13%) as having cardiomyopathy (CMP),
Chandrababu Naidu, former Chief Minister of Andhra Pradesh has 41 patients (3%) as having pulmonary arterial hypertension (PAH),
been operational till date and is one of the very few practicing centers 24 patients (1%) as having pericardial disease (PD) and four patients
of telecardiology. (0.3%) were diagnosed to be having cardiac masses (Fig. 64.4).
A total of 20,000 cases (includes CT, ECG and ECHO) have been Out of the 1,207 abnormal studies, 993 (82%) of them were med
done from the district hospital of Mahabubnagar as of July 2010. ically managed without them having to travel to city, 79 (7%) of them
From January 2002 to July 2007, a total of 2,068 cases12 (ECG and needed further evaluation for confirming treatment and 135 (11%)
ECHO) (994 males and 1,074 females) with average age of 40.56 ± of them needed immediate interventions. The patients of the first
20.27, were transmitted over the network for diagnosis. Of this group, category derived maximum benefits as they had necessary cardiac
1,696 (82%) of the patients were white card holders (below poverty care without having to come to any tertiary care center. The patients
line) while the remaining 372 (18%) belonged to the private catego and their attendees of the next two categories were benefited in that
ry, which suggests that this technology is assisted in reaching out to they were provided a complete picture of all the procedures and
the underprivileged population in the community. Out of the 2,068 outcomes that they were likely to go through. The level of mental
patients studied, 861 (41.6%) were classified as normal. The remain preparedness helps to buffer the patients both psychologically and
ing 1,207 (58.3%) were diagnosed as “abnormal”, and comprised of financially for any eventuality which would have been lacking if they
those with a past history of cardiac illness or abnormal findings in would have needed to travel to a distant tertiary center. The study
the present investigations. Of these shown, 292 patients (24%) were also revealed a cost benefit of 73% to the patients in these areas be
diagnosed as having RHD, 139 patients (11%) as having congenital cause of this technology as against getting these tests done at a pri
heart disease (CHD), 245 patients (21%) as having coronary artery vate center.
disease (CAD), 138 patients (11%) as having valvular (nonrheumatic) Some cases (Figs 64.5A and B) reported from the district hospi
heart disease (VHD), 173 patients (14%) as having hypertensive heart tal Mahabubnagar.
Figure 64.4: Disease-wise distribution of cases. Abbreviations: CAD, Coronary artery disease; CMP, Cardiomyopathy; PAH, Pulmonary arterial
hypertension; CHD, Congenital heart disease; HHD, Hypertensive heart disease; PD, Pericardial disease; RHD, Rheumatic heart disease; VHD,
Valvular (nonrheumatic) heart disease
Global System for Mobile Communication • Distance between the GSM transmitter and mobile and the kind
versus Landline Based Electrocardiograph of angulation used
Transmission • Additional noise interference (adverse signal-to-noise ratio)
from the surrounding while transmitting.
In collaboration with Cardguard (Hong Kong), we integrated an ECG
machine, which enabled acquisition and global system for mobile Multiparameter Device for
communication (GSM) transmission of ECG based on acoustics. The
Primary Health Center
device (Figs 64.6A and B) enabled acquisition of ECG and transmit
ted the same through a mobile phone to a hub station for diagnosis. A portable ruggedized simple cost-effective device (Fig. 64.7) inter
A pilot study was conducted to validate the quality of transmission grating five parameters namely ECG, blood pressure, temperature,
and the time take for transmission of the ECG through landline and stethoscope and oxygen saturation is currently being used as part of
mobile phone. Samples from 50 patients were taken and transmitted rural telemedicine project initiated by the Byrraju Foundation. The
through both landline and mobile phone (GSM enabled). device enables transmission of the data through broadband internet
The ECGs transmitted by both modes of communication were with a bandwidth as low as 64 kpbs.
graded and results are shown in Table 64.4. This makes it a very useful device to be used in remote areas
Our study suggested that 100% readability was achieved for all where communication and bandwidth are a challenge and handy for
ECG’s transmitted through landline as compared to 72% readability dealing with cardiopulmonary emergencies in remote rural and hilly
while transmitted through mobile. Some of the reasons for the lesser areas. It has practical application in managing the patients in transit
percentage readability through mobile could be following: and intra-ambulance prehospital care. We also had another study
• Motion artifacts for transmission of heart lung sounds through a digital stethoscope
Figures 64.5A and B: (A) Echocardiography; (B) Echocardiogram transmitted from Mahabubnagar
Complaints: Chest pain since 1 month
BP: 130/90 mm Hg
ECHO Report: Organic tricuspid valve (TV) disease with moderate tricuspid regurgitation (TR), Severe mitral stenosis, Moderate mitral regurgitation
(MR). No left atrial (LA) clot, Mild Pulmonary arterial hypertension (PAH)
Complaints: Chest pain since 4 days.

General Examination: Feeling uneasy
BP: 130/90 mm Hg
ECHO Report: Congenital heart disease, Large Patent ductus arteriosus (PDA) (5 mm) with left to right shunt. No Pulmonary arterial hypertension
(PAH). Dilated left ventricle (LV) and left atrium (LA). Atrial septal aneurysm. No coarctation, Ventricular septal defects (VSD), Atrial septal defect
(ASD)
B
Figures 64.6A and B: (A) Electrocardiograph device; (B) Global system for mobile communication based transmission
TABLE 64.4 Landline vs mobile transmission

Mode of Acceptability Diagnosability Non-
Transmission (%) (%) Diagnosable (%)
Landline 64 36 0
Mobile 24 48 28
(Littman), which was allowed for real-time transmission of sounds,

as well as through store and forward methodology. However, one of
the limitations was the cost associated with it and also the flexibility
of integrating the same with other application software, thereby rais
ing the issue of interoperability. Advances in the telecommunication
industry have made it possible for the evaluation of prosthetic valve
sounds and providing cardiac defibrillation transtelephonically. Figure 64.7: Multiparameter device
TABLE 64.5 Centers that are connected to CARE ECG machines, which were set-up in various smaller hospitals
Location Modalities - Telemedicine whereby a doctor based in the tertiary hospital could monitor his
patients from a distance. Simulations of teleconsultations between
Singareni Colleries, Kothagudem ECG, ECHO, X-ray
Apollo Hospitals, Hyderabad, Chennai and Dubai for cases specific
Singareni Colleries, Ramagundam ECG, ECHO, X-ray
to cardiology, neurosurgery and orthopedics were done. Apollo has
Mecure Diagnostic center, Nigeria X-ray, CT, MRI set-up over 45 telemedicine centers across the different locations in
CARE Byrraju Foundation (30 villages in ECG the country and many more are in the pipeline. It has worked with
the West Godavari district) different kinds of entities in the healthcare industry ranging from
Gurugovind Ballabh Pant Hospital, ECG, ECHO large corporate hospitals and Government hospitals to small clinics
Agartala, Tripura and information centers.
Fifty-four Nation Pan African Network Tele-education (CME)
(Government of India)
Narayana Hrudayalaya Heart Institute
Abbreviations: ECG, Electrocardiograph; ECHO, Electrocardiography;
CT, Computed tomography; MRI, Magnetic resonance imaging; CME, A center has been set-up in Brickfields to allow the poor who are suf
Continuous medical education fering from the heart ailments to seek free treatment at the Narayana
Hrudayalaya Heart Institute in Bangalore, South India. This collabo
ration was made possible through a tie-up between the Malaysian
Chapter of the institute, Global Organization of People of Indian
Other Centers Origin (GOPIO), the Malaysian Association of Indian Universities
Graduates (MAIUG) and the Asia Heart Foundation. A telecardiology
The other centers that are connected to CARE are listed in the Table unit had been set-up to enable the patients to communicate “face-
64.5. to-face” with the specialist providing expert advice from the heart
hospital in Bangalore, India.
Some Other Initiatives
Jivan Nirmaya Pradarshan
The Ministry of Communications and Information Technology, Gov
ernment of India, has classified “Telemedicine” as one of the thrust The first project of Jivan Nirmaya Pradarshan was implemented
areas for development in the country. In sync with the policy, the on May 1, 1998 for a period of 15-day. More than 550 numbers of
Government initiated a project called Development of Telemedicine patients’ data were transferred from Rajkot and Gandhinagar to
Technology. The three tertiary level hospitals of North India were Ahmedabad on simple telephone line. The telemedicine system was
linked up using Telemedicine Application developed by Centre for installed at Bhuj Military hospital and Ahmedabad Military hospital
Development of Advanced Computing.13 on December 20, 1999. The system works on simple telephone line
This included the following institutes: and working quite effectively.
• All India Institute of Medical Sciences at New Delhi
• Post Graduate Institute of Medical Education and Research Indian Defence Service
(Nehru Hospital) at Chandigarh
• Sanjay Gandhi Post Graduate Institute of Medical Sciences at In December 1999, telemedicine system was installed in the desert
Lucknow, Uttar Pradesh areas of Kutch, i.e. Military Hospital at Bhuj, which was connected
Some of the initiatives taken by players in this field are: with the receiving unit at the Main Military Hospital at Ahmedabad
and they are transferring the data and images for the different pur
Apollo poses. Data of several patients were transmitted successfully. This
was later extended to Air Force Hospital at Gandhinagar. Govern
The Apollo group of hospitals was a pioneer in starting a pilot pro ment of Gujarat funded this pilot project.
ject at a secondary level hospital in a village called Aragonda 16 km
away from Chittoor district (population 5,000, Aragonda project) in Indian Space Research Organization
Andhra Pradesh. Starting from simple web cameras and integrated
North-East Telemedicine Project
services digital network (ISDN) telephone lines, today, the village
hospital has a state-of-the-art video conferencing system and a very Online Telemedicine Research Institute along with ISRO started an
small aperture terminal (VSAT) satellite installed by Indian Space ambitious project in the North Eastern part of India on September 15,
Research Organization (ISRO). Apollo experimented with telecardi 2001 on permanent basis. The project was implemented by Online
ology more than 5 years back through the usage of transtelephonic Telemedicine Research Institute; Space Application Center; Sundari
District Hospital, Udayapur, Tripura and Rabindranath Tagore Inter there is still other medical equipment like the ECG, blood counters,
national Institute of Cardiac Sciences (IICS), Kolkata. The project was pathological equipment, etc. which need to generate outputs in
sponsored and funded by Space Application Center, Department of standard formats to be easily integrated to any application software.
Space, Government of India. In our study we did realize that the factor to be addressed through
this mode of technology is the “patient’s satisfaction” quotient as we
Asia Heart Foundation Southern India Project have the most important “feel factor” between the doctor and the
patient interaction missing. However, we do have good video confer
Asia Heart Foundation Southern India Project was installed in 2002 encing systems set in place to at least have good quality interactive
by Narayana Hrudayalaya, Bangalore, Karnataka, AJ Hospital and session between the patient and the doctor. Manpower continues
Research Center, Mangalore, K H Patil Hospital and Research Insti to be one more area of concern and setting up video conferencing
tute, Hulkoti and Vinaya Hospital, Kundapur. systems and providing continuous training sessions through this
link, which addresses this problem to some extent. Finally, a good
Teleradiology Solutions cost-effective system, which includes good application software,
hardware and communication mode to allow for the transfer of basic
Teleradiology Solutions was founded in 2002 by two Yale-trained medical information from anywhere to anywhere is the need of the
physicians, Dr Arjun Kalyanpur and Dr Sunita Maheshwari in Banga hour especially if we have to visualize telemedicine as good effective
lore, South India. It was initially set-up to provide hospitals in the US healthcare delivery system to remote areas.
with night shift radiology solutions. However, it grew rapidly and now
provides teleradiology to hospitals in Singapore and India with other CONCLUSION
countries on the anvil.
The advances made in communication technology have made it
Teleradiology and Cardiac Imaging Solutions possible to have effective healthcare delivery systems through tel
emedicine. Telemedicine has made it possible to have patients net
Teleradiology and Cardiac Imaging Solutions has just been estab worked always irrespective of their location. This has in fact also led
lished in Hyderabad to provide teleradiology and cardiology solu to remote monitoring and diagnosis for patients with various dis
tions with innovative and simple reporting mechanisms. A pilot ease conditions which include even patients with implantable de
study with the CT center in San Francisco for reporting cardiac CT’s vices. An invaluable advantage of telemedicine by having networked
is underway under the leadership of Dr Ravi Bathina at CARE hos patients is the availability of timely diagnosis.14 It is well-known that
pitals, Hyderabad. the distance decay effects, i.e. distance in terms of cost and distance
acting as a deterrent to people consulting is one important fac
OBSTACLES AND CHALLENGES tor that telemedicine overcomes. It cannot bring about cure to all
the problems existed in the rural areas, but sure, it will help in ad
One of the major challenges that we in India still face in spite of the dressing the vast range of problems. Telemedicine also ensures an
advances in communication technology is the reliability and acces increase in the general awareness of good health across the region
sibility of communication links to remote areas. While broadband in due to the availability of specialist opinions. Our initiatives have also
ternet technology has made great impact in the ways of life today, we brought into realization that the same network link serves as an ex
still have not reached that percentage of reliability. The other main cellent method for training of paramedics and nurses and in keep
concern that comes up is the integratability of medical devices (ap ing medical professionals at remote centers updated with the latest
propriate interfaces) with application software. While DICOM stand advances in medical sciences through continuous medical educa
ards have addressed most of these issues with imaging modalities, tion programs.
REFERENCES
1. Akselsen S, et al. Telemedicine and ISDN. IEEE Communication Magazine. 1993;31(1):46-51.
2. Katsilambros N. Telemedicine. Technology for medical diagnosis and patient care. http://users.forthnet.gr/ath/giovas/telemed.
3. Donglok K, et al. Networking requirements and the role of multimedia systems in Telemedicine. Technical Report, Image Computing Systems
Laboratory, Department of Electrical and Computer Engineering, University of Washington, 1995.
4. Lee W, Kim Y. Applications of a multimedia system in medical imaging. IEEE/EMB Magazine. 1996. (in press).
5. Bhargava A. (2010). Telemedicine: An opportunity in Healthcare. [online] Available from www.slideshare.net/bamit/telemedicine-an-opportuni
ty-in-healthcare-in-india. [Accessed July, 2012].
6. Ferrer-Roca O. Main telemedicine applications. In: Ferrer-Roca O, Sosa-Iudicissa M (Eds). Handbook of Telemedicine. Amsterdam: IOS Press;
1998. pp. 63-65.
7. Joshi R, Cardona M, Iyengar S, et al. Chronic disease now a leading cause of death in rural India–mortality data from the Andhra Pradesh Rural
Health Initiative. Int J. Epidemiol. 2006;35(6):1522-9.
8. Chow CK, Raju PK, Raju R, et al. The prevalence and management of diabetes in rural India. Diabetes Care. 2006;29(7):1717-8.
9. Chow C, Cardona M, Raju PK, et al. Cardiovascular disease and risk factors among 345 adults in rural India–the Andhra Pradesh Rural Health
Initiative. Int J Cardiol. 2007;116(2):180-5.
10. Perednia DA, Allen A. Telemedicine technology and clinical applications. JAMA. 1995;273(6):483-8.
11. Choplin RH. Picture archiving and communication systems: an overview. Radiographics. 1992;12(1):127-9.
12. Tiwari AK, Prasad SG, Sangma M, et al. Telemedicine: An assessment for delivery of quality healthcare. Health and Population: Perspectives and
Issues. National Institute of Health and Family Welfare. 2008;31(3)182-8.
13. GATS Report of India: Telemedicine Initiatives in India. pp. 96-101.
14. Hayes DL, Saxon LA. The value of the Networked Patient: Improving patient survival. CME released: 06/28/2010.
65 Echocardiographic Evaluation of
Tricuspid and Pulmonic Valve
Malhotra P
approach to the noninvasive quantification of both stenotic and

INTRODUCTION
regurgitant lesions of the tricuspid and pulmonic valves (PV).
Echocardiography, down the years, has historically and clinically
been shown to provide unique information about cardiac anatomy, TRICUSPID VALVE ANATOMY
physiology, hemodynamic and blood flow and is a noninvasive
monitor with a relative ease in performance. The right sided valves Situated in the crescentic, pyramid-shaped RV which supports the
have taken more time to develop on echocardiography than the left low-pressure pulmonary circulation, the tricuspid valve (TV) is in the
as they prove, elusive to view with echocardiography because of RV inlet chamber or sinus, while the PV is anterior and superior to
their complex anatomy and also because of their distance from the the TV in the RV outlet or conus (Figs 65.1A and B). Unlike the aortic
transducer probe.1 The importance of right ventricular (RV) and val- valves, the TV and PV are anatomatically discontinuous, separated
vular function should not be underestimated especially its role as a by myocardium. The TV is situated anterior, inferior and to the right
determinant of cardiac symptoms, exercise tolerance and survival in of the mitral valve. It is composed of three leaflets, the septal, the an-
patients. Historical development of the echocardiography technique terior, and the posterior (or inferior). Each leaflet is supported by a
has evolved by leaps and bounds from A-mode (amplitude based) to papillary muscle with the RV moderator band joining the septal and
B-mode (brightness based) to M-mode (motion based) ultrasonog- the anterior papillary muscles (Figs 65.1A and B). The TV has a large
raphy. Echocardiography evolved and was the principal technology orifice, usually greater than 7 cm2 and like its left-sided counterpart,
available as noninvasive diagnostic tool for over 10 years. Then a requires the coordination of multiple structures for proper function.
variety of two-dimensional (2D) approaches became available. Abnormalities affecting each of these components may in turn cause
Shortly thereafter, Doppler techniques for recording intracardiac TV regurgitation and/or stenosis. The normal tricuspid annular cir-
blood flow were described. The next development was displaying cumference in 12–14 cm with a diameter of 3 cm normally, the tricus-
the Doppler signal as a 2D image using color to denote the direction pid leaflet thickness is less than 3 mm. The PV is situated anterior and
and character of the flow. Doppler recordings reflect blood velocity, to the left of the aortic velocity (AoV). It has two posterior cusps (right
whereas M-mode motions of cardiac structures reflect volumetric and left) and one anterior cusp, in mirror image to the AoV cusps
blood flow. The two examinations are hemodynamically complemen- (Fig. 65.2). Proper PV function requires normal leaflet anatomy and
tary.2 Conventional 2D determination of RV function is often qualita- support from the pulmonary artery and RV outflow tract (RVOT).
tive. Doppler methods of tricuspid inflow and pulmonary artery flow
velocities, which are influenced by changes in preload and afterload, Tricuspid Leaflets
may not provide robust prognostic information for clinical decision
making. Recent advances in echocardiographic imaging of the RV, The normal tricuspid leaflets are delicate translucent structures that
such as Doppler tissue imaging and 3-dimensional (3D) imaging are have a scalloped appearance when closed. The name of the valve is
now available, which can be used for additional information beyond derived from the presence of three leaflets: anterior, septal and pos-
standard 2D measurements. Transesophageal echocardiography terior (Fig. 65.3). The anterior leaflet is the largest and the septal
(TEE) both 2D and 3D is now possible in the same modern machine. leaflet the smallest. The posterior leaflet is intermediate in size and
The lack of good quality evidence makes it difficult to recommend a is characterized by the presence of from one to three clefts. The clefts
validated quantitative approach, but expert consensus recommends in the posterior leaftet can be quite prominent, creating the illusion
a clinically useful qualitative approach. This chapter enumerates of multiple TV leaflets. The free edges of the three leaflets are longer
transesophageal probe placement, recommended cross-sectional than the circumference of the annulus, thereby providing a complete
views, flow patterns, quantitative equations including the clinical and unobstructed opening as the leaflets drop curtain like into the
A B
Figures 65.1A and B: Tricuspid valve seen from the right atrium. (A) The 0-900 echocardiographic planes are shown (1, septal leaflets; 2,
another leaflet; 3, inferior or posterior leaflets, 4, ventricular membranous septum; 5, atrial septum; 6, crista terminalis; 7, ostium of the right atrial
appendage; 8, anteroinferior commissure, 9, inferior commissure; 10, anterosuperior commissure); (B) Intraoperative aspect of the tricuspid valve
(PA, pulmonary artery)
Figure 65.2: The pulmonic valve seen from a right ventriculotomy Figure 65.3: Anatomic drawing of RV with
(1, pulmonary annulus; 2, septal leaflet of tricuspid valve; 3, right valves labeled anterior view
ventricle walls; 4, pulmonary cusps; 5, pulmonary commissures; 6, inter-
ventricular septum; 7, pulmonary artery)
Chapter 65  Echocardiographic Evaluation of Tricuspid and Pulmonic Valve 555
RV during diastole. In contrast to the other cardiac valves, the three Supporting Structure of Tricuspid Valve
thin membranous leaflets are not supported by a substantial fibrous
annulus. The leaflets are less distinct than those of the other cardiac The supporting structures of the TV tend to be more complex and
valves, separated more by indentations in a continuous sheet of tis- variable than those of the mitral valve. The anterior papillary mus-
sue rather than true commissures. This makes up the entire tricuspid cle is large and gives rise to the moderator band,5 a linear band of
apparatus.3 cardiac muscle that runs perpendicular to the papillary muscle, at-
taches to the septum near the apex of the RV, and may be mistaken
Chordae for an intracardiac mass. The posterior papillary muscle is frequently
small and at times even absent. The tricuspid annulus lies in a more
When the right heart is opened through the acute margin (Fig. 65.4), apical position than that of the mitral valve, with its inferior margin
the three largest fan-shaped chordae identify the three commissures. adjacent to the junction of the inferior vena cava and coronary sinus.
An average of 25 chordae tendineae attaches to the TV leaflets. In
contrast to mitral chordae, the chordae tendineae to the tricuspid TRANSESOPHAGEAL ECHO EXAMINATION
leaflets are quite variable. The scalloped appearance of the TV is due
OF THE TRICUSPID VALVE—
to the variability of the chordal attachments. Two interesting types
of chordae not seen in the mitral apparatus include the “free edge
DIFFERENT VIEWS
chordae”, which are long and attach to the free edge of the leaflets There are four standard SCA/ASE views and two modified views that
and the “deep chordae”, which are short and attach to the basal por- facilitate assessment of the TV apparatus.6 All six are not necessary if
tion of each leaflet.4 Of the greatest interest are the short chordae that upon initial inspection the TV looks normal and there is only mini-
arise directly from the muscle of the septum and posterior wall and mal tricuspid regurgitation (TR). However, look at all six during your
attach to the septal leaflet. This configuration limits the mobility of training so that obtaining the views becomes second nature.
the septal leaflet and may predispose the TV to incompetence. The
fixed small septal leaflet allows for little compensation should the View 1—Midesophageal Four-Chamber View
free wall of the RV dilate.
The assessment of the TV begins with the midesophageal (ME) four-
Papillary Muscle—Anterior and Medial chamber view (Fig. 65.5). The septal leaflet is seen medially. The
leaflet on the lateral aspect of the sector scan is either the anterior
The anterior papillary muscle supplies fan-shaped chordae to the or posterior leaflet, depending on the probe position. If the probe is
anterior and posterior leaflets, identifying the anteroposterior com- anteflexed (near the aortic valve) it will be the anterior leaflet. If the
missure. The medial papillary muscle supplies fan-shaped chordae probe is retroflexed (near the coronary sinus) it will be the posterior
to the posterior and septal leaflets and identifies the posteroseptal leaflet. Leaflet mobility and thickness should be assessed. Usually
commissure. The large fan-shaped chordae to the anterior and the the subvalvular apparatus is hypoechogenic in this view—if it is easy
septal leaflets arise from the septal wall. to see it may indicate fibrosis and thickening. Note the position of
the TV relative to the mitral valve in this view. The TV annulus can
be measured (at end-systole) and should not exceed 28 mm. The size
and function of the RV and right atrium (RA) should be evaluated as
part of the assessment.
Figure 65.4: The tricuspid valve as viewed after incision through

the acute margin of the right heart. The posterior, septal and anterior
leaflets are identified by the anteroposterior commissure. Fc, Fan-
shaped chordae; ms, membranous septum; apm, anterior papillary
muscle; ppm, posterior pappilary muscle; Small fan-shaped chordae
indentify clefts in the posterior leaflet. Figure 65.5: Midesophageal four-chamber
View 2—Midesophageal Right Ventricular View 4—Transgastric Right Ventricular

(ME RV) Inflow-Outflow View Inflow View
The second view is obtained by rotating the omniplane from 0° to With the TV essentially in the center of the sector scan, rotate the om-
approximately 30°–60° (keeping the TV in the scan plane) until niplane 90° (usually to 110°–130°) to obtain the transgastric RV (TG
the TV and the PV are visible simultaneously (Fig. 65.6). This view RV) inflow view (Fig. 65.9). This view provides excellent visualization
provides a view of the septal or anterior leaflet medially and the of the leaflets and the subvalvular apparatus. Typically, the anterior
posterior leaflet laterally. It usually provides better alignment for
Doppler assessment.
View 3—Transgastric Basal Short Axis View

The third view is obtained with the probe in the transgastric posi-
tion. After finding the transgastric (TG) basal short axis (SAX) view
(of the LV), rotate the probe rightward to identify the TV (Figs 65.8A
and B). The probe may need slight insertion to obtain the SAX TV
view—rotation of the omniplane 20°–30° may provide the best view
of the three TV leaflets. The commissures will not be as well defined
as those of the mitral valve. The anterior, septal, and posterior leaflets
A
are defined in Figure 65.7.
Figure 65.6: Midesophageal right ventricular inflow-outflow
Figures 65.8A and B: (A) Transgastric (TG) basal short axis;

(B) Modified TG basal
Figure 65.7: Midesophageal bicaval 110°–140° Figure 65.9: Transgastric right ventricular inflow
and posterior leaflets will be seen in this view. Rotation of the probe
to the left (counterclockwise) will provide a view of the septal leaflet
and its supporting apparatus.
View 5—Modified Midesophageal

Long Axis (ME LAX) View
This view can be obtained by starting at the ME RV inflow outflow
view and then rotating the omniplane another 90° to 120°–150° (Fig.
65.10). Alternatively, this view can be obtained by finding the ME
AV LAX view and rotating the probe to the patient’s right side (clock-
wise).
A
View 6—Modified Deep Transgastric View

The last view is a deep transgastric (TG) view. It is essentially the deep
TG LAX view with a slight adjustment in probe position (anterior
flexion to view more a more posterior aspect of the heart). This of-
ten provides the best alignment of the Doppler beam with TV inflow
or regurgitation (Figs 65.11A and B). It is particularly helpful when
there is prosthesis in the aortic position.
Mode—Normal Tricuspid Valve Motion

M-mode echocardiograms recorded in the parasternal short axis.
(Figs 65.12A and B)
• Right ventricular inflow tract
• Views demonstrate normal tricuspid valve motion. A, IVC, P, RA,
B
RV, RVOT.
Figures 65.11A and B: Deep transgastric.
Abbreviations: RV, Right ventricular; RA, Right atrium; TV, Tricuspid valve
Color Flow Doppler
Basic recommendations for use of color flow Doppler (CFD) include terest, minimum depth settings and maximal color scales (Nyquist
minimum gain just below the noise threshold, a small area of in- limit of 50–60 cm/sec). CFD imaging in the ME four-chamber, ME RV
inflow-outflow and the ME AV SAX views is a quick and useful meth-
od to determine severity, direction and other characteristics of the
regurgitant jet. The diameter of the vena contracta (VC), defined as
the narrowest part of the regurgitant jet distal to the regurgitant ori-
fice, is a simple, quantitative method which correlates well with the
effective regurgitant orifice area (EROA) and the regurgitant volume.7
Pulse Wave Doppler

Pulse wave (PW) Doppler is used in combination with the 2D
imaging to record the flow velocity by placing the sample volume (SV)
at the level of the tips of the open TV leaflets in the four-chamber view
or RV inflow-outflow view (Figs 65.13A and B). The SV axial length
is adjusted to 5–7 mm with low-respiratory cycles at a sweep speed
of 50 or 100 mm/s.8 Peak E and A velocities and E/A ratios, velocity-
time integrals and deceleration times of E wave can be determined.
Figure 65.10: Modified midesophageal long axis. The TV flow velocity is about 0.3–0.7 m/sec. The pressure half-time
Abbreviations: LA, Left atrium; RA, Right atrium; RV, Right ventricular method has not been as extensively validated for the calculation of
A B
Figures 65.12A and B: M-mode echocardiograms recorded in the parasternal short axis
A B
Figures 65.13A and B: Tricuspid and mitral inflow view
TV area as in case of the mitral valve. PW Doppler examination of the (TS) and the pulmonary artery systolic pressures (PASP). The maxi-
hepatic veins can be done by advancing the probe from the bicaval mal velocity of the TR jet is measured and PASP is calculated using
view to track the inferior vena cava into the liver. The sample volume the simplified Bernoulli equation: PASP = 4 (TR jet velocity) 2 + cen-
is placed 1–2 cm into the orifice of a central hepatic vein. The nor- tral venous pressure.
mal pattern of flow velocity consists of antegrade systolic (S wave),
transient flow reversal as the TV annulus recoils at the end of systole ABNORMALITIES OF THE TRICUSPID VALVE
(V wave), antegrade diastolic (D wave) and a retrograde A wave
caused by atrial contraction. Both the tricuspid and hepatic flow pat-
Tricuspid Regurgitation
terns are affected by respiration. Continuous wave Doppler (CWD)
in contrast to PW Doppler, CWD records the velocities of all the red Tricuspid regurgitation is mostly of rheumatic origin. It may be func-
blood cells moving along the path of the sound beam. The Doppler tional or organic. Functional TR may be seen in the elderly, athletes
beam should be oriented as parallel as possible to the flow, guided by and in patients with a pulmonary artery catheter or pacemaker
the 2D image, color flow imaging and the presence of a well-defined wires. Pathological TR is caused by annular or RV dilation secondary
envelope. CWD is used to estimate the severity of tricuspid stenosis to pressure or volume overload. Organic TR is caused by rheumatic
valvulitis, carcinoid disease, endocarditis, rheumatoid arthritis, 3.2 cm in systole or greater than 3.4 cm in diastole is associated with
endomyocardial fibrosis and radiation therapy. Congenital heart severe TR.12 In rheumatic disease, the TV leaflets and the subvalvular
disease such as Ebstein’s anomaly, atrioventricular defect, cleft structures are often thickened, shortened and retracted, leading to
TV and Marfan’s syndrome may cause TR as well.9 incomplete coaptation. In carcinoid disease, right atrial and ventric-
ular enlargement is present in up to 90% of cases.13 In myxomatous
Functional Tricuspid Regurgitation TV disease, billowing and prolapse of leaflets is seen. In endocardi-
tis, friable, mobile and destructive lesions can be observed. Ebstein’s
This commonly occurs secondary to left-sided valve lesions caus- anomaly is characterized by apical displacement of TV into the RV
ing pulmonary hypertension and RV dilatation. The normal TV causing “arterialization” of the RV. It is diagnosed when the distance
shortens during systole. When RV dilatation develops the tricuspid from the mitral annulus to the septal leaflet exceeds at least 8 mm/
annulus also dilates and fails to shorten during systole. This is most m2 body surface area.14
pronounced in the posterior part of the annulus, as the anterior part
is relatively fixed between the two trigones. This results in failure of Color Flow Doppler
leaflet coaptation and TR. Functional TR due to annular dilatation
is common in patients with severe rheumatic mitral stenosis. In the Overall, CFD mapping in various views using jet area correlates
series of 318 consecutive patients from the Massachusetts General well with clinical measures of regurgitant severity.10 Mild TR shows
Hospital reported by Sagie et al.10 associated TR was severe in 12% a small central color jet with minimal flow convergence in contrast
and moderate in 19%. In general, the more severe the functional to severe TR, which has very large flow convergence and jet area in
TR, the more severe the rheumatic mitral stenosis is. They found the the RA (Figs 65.14A and B). Color flow imaging may also be used to
functional TR improved only in a subset of younger (age less than 24 determine TR severity by the proximal is velocity surface area (PISA)
hours) patients with preoperative cardiomegaly (cardiothoracic ratio method or visualization of the vena contracta (VC) width, but there
greater than 60%) and significant pulmonary hypertension (pulmo- may be an underestimation of severe TR in 20–30% of patients.15
nary artery systolic above 50 mm Hg). PISA method is based on the continuity equation. PISA is the sur-
face area of a hemisphere at the aliasing region formed by layers of
M-Mode equal velocity caused by flow acceleration and convergence through
a small circular orifice in a flat plate. The PISA method has been vali-
The most prominent and consistent findings on M-mode or 2D echo- dated in small studies.16 The vena contracta width greater than 0.65
cardiography in TR are enlargement of the RV and RA. Additional cm identified severe TR with a sensitivity of 89% and a specificity of
findings include: the tricuspid annulus is often dilated. Septal move- 93%.17 Eccentric, wall-impinging jets may be underestimated.
ment may be paradoxical, reflecting the increased RV-volume over-
loaded pattern B “bump” or “notch” indicates increased RV end dias- Pulsed Wave Doppler
tolic pressure (≥ 9 mm Hg) within the RV (diastolic overload). Right
ventricular function may be hyperdynamic, normal or reduced, Pulsed Doppler echocardiography is a noninvasive method with high
reflecting the underlying cause of the TR. Tricuspid valve motion sensitivity and specificity for the assessment of TR. In patients with
may be normal or abnormal if there is a primary valvular abnormal- TR, pansystolic unusual Doppler signals are detected in the right
ity such an Ebstein’s anomaly, carcinoid, rheumatic valve disease, atrial cavity, which are interpreted as TR flow signals. They distrib-
prolapse, flail leaflet or endocarditis.11 The presence of pulmonary uted in a spindle-shaped area from the tricuspid orifice toward the
hypertension can be established by abnormalities of PV motion, right atrial posterior wall in parallel with the interatrial septum. The
especially an absence of the wave. orientation of the range where the regurgitant Doppler signals are
detected in the right atrial cavity shows the direction of the regurgi-
Two-Dimensional Echocardiography tant jet. However, such a result is determined mainly in patients with
functional TR. In regard to patients with organic tricuspid lesion, dif-
Significant TR may be associated with right atrial and annular dila- ferent considerations may be necessary. Semiquantitative grading
tation, RV dysfunction/enlargement, paradoxical ventricular septal of the severity of regurgitation is signals from the tricuspid orifice.
motion, ruptured chordae or vegetations on the valve caused by en- Tricuspid regurgitation is demonstrated also by contrast echocar-
docarditis. Since the RA is not allow always completely visualized on diography. The severity is graded based on the distance reached by
TEE in the same view as the maximum regurgitant jet area, absolute regurgitant curvilinear contrast echoes from the TV in the M-mode
areas have been used. Mild regurgitant is considered to be present echocardiography. If the ultrasound beam is adequately directed
when the maximum area is 4 cm2, moderate when the jet area is 4–8 through the tricuspid orifice, the grade estimated by the contrast
cm2 and severe when the jet is 8 cm2.11 In functional TR, secondary echoes are well correlated with that by the Doppler (Table 65.1).
to pulmonary artery hypertension, annular dilatation greater than However, if the M-mode is performed without the guide by the 2D
A B
Figures 65.14A and B: (A) Mild tricuspid regurgitation; (B) Severe tricuspid regurgitation
TABLE 65.1 Indications of severity of tricuspid insufficiency • PW Doppler examination of the hepatic veins show:
Method Indication of Severe TR – Blunting of the normally dominant systolic wave with
increasing severity of TR and finally culminate in flow rever-
Jet area > 10 cm2 (Ref 3)
sal with severe TR (sensitivity 80%)
Jet area/Right atrial area > 67%
• The hepatic vein flow patterns are also affected by:
Vena contracta width > 6.5 cm – Abnormalities in right atrial
Hepatic vein flow profile Systolic flow reversal – RV relaxation and compliance
TR jet intensity > 65% of antegrade flow – The phase of the respiratory cycle, preload and atrial fibrilla-
TR jet deceleration Rapid tion.
Continuous Wave Doppler

image, it may miss the most adequate beam direction for the obser- Continuous wave Doppler (CWD) may be used to evaluate the an-
vation, resulting in underestimating severity. The influences of TR are tegrade flow in the setting of TS or to evaluate the TR jet. Using the
generally seen in the flow pattern of the major veins. However, they TR jet, one can estimate of the RV systolic pressure: RVSP = 4 (TR
are more sharply reflected by the flow condition in the right atrial peak velocity) 2 + RAP. One can also assess the intensity and rate of
cavity than by the flows patterns in the major veins.18 Severe TR will deceleration of the TR jet to assist in the determination of TR severity
increase the early diastolic tricuspid E wave velocity (> 1.0 m/s). Dif- (see below). If the Doppler alignment is suboptimal, the CWD exam
ficulties in measuring the TV annulus preclude the measurement of should be performed in other views. In contrast to PW Doppler, CWD
TR volume. PW Doppler examination of the hepatic veins will show records the velocities of all the red blood cells moving along the path
a blunting of the dominant systolic wave with increasing severity of of the sound beam. The Doppler beam should be oriented as parallel
TR and finally culminate in flow reversal with severe TR (sensitivity as possible to the flow, guided by the 2D image, color flow imaging
80%).19 However, the absence of systolic flow reversal does not rule and the presence of a well-defined envelope. CWD is used to esti-
out severe TR. The hepatic vein flow patterns are also affected by ab- mate the severity of TS and the pulmonary artery systolic pressures
normalities in right atrial (RA) and RV relaxation and compliance.20 (PASP). The maximal velocity of the TR jet is measured and PASP is
calculated using the simplified Bernoulli equation: PASP = 4 (TR jet
Pulse Wave Doppler (Figs 65.15A and B) velocity) 2 + central venous pressure where PASP is the pulmonary
artery systolic pressure. Care must be taken to align the beam with
• Severe TR will increase the early diastolic tricuspid E wave veloc- the maximum TR jet, which may be more difficult in TEE then TTE. If
ity (> 1.0 m/s) the jet is not align the pressure will be underestimated.11
A B
Figures 65.15A and B: Pulse wave Doppler
Figure 65.16: Measurement of vena contracta. Figure 65.17: The Ebstein anomaly of the tricuspid valve
Abbreviations: RA, Right atrium; RV, Right ventricular
Measurement of the vena contracta: The narrowest width of ventricle (LV) may alter tricuspid annulus size and papillary muscle
the regurgitant jet that is immediately downstream to the flow
(PM) positions leading to TR. Alterations in ventricular geometry
convergence area—provides a more hemodynamically independent
estimate of the TR severity (Fig. 65.16). By TTE, this method has can lead to TR by altering both tricuspid annulus size and PM po-
been shown to correlate well with the effective orifice area. A VC sition. Understanding these geometric interactions with the aim of
greater than 6.5 mm indicates severe TR. correcting pathological alterations of the TV apparatus may lead to
The Ebstein anomaly of the tricuspid valve: The Ebstein anomaly of more robust tricuspid valve repairs. Spinner Em et al.21 correlated the
the TV (Fig. 65.17) is the marked distortion of RV and right atrial occurrence of TR on 3D Echo with variables like pulmonary artery
geometry. The approximate position of the mitral annulus is noted pressure, ventricular geometry, annular dilation and papillary mus-
by the broad arrow at the lower right. cles displacement. Using the GE Vivid 7 ultrasound system, they used
the end-diastolic area to classify ventricle geometry: GE EchoPAC
Three-Dimensional ECHO of TR was used to measure annulus area and position of the PM tips.
Patients with RV dilatation had significant (P ≤ 0.05) displacement
While it is understood that annular dilatation contributes to TR, oth- of all PMs apically and the septal PM and posterior PM away from
er factors are less clear (Fig. 65.18). The geometry of the RV and left the center of the RV toward the LV. Patients with LV dilatation had
by pacemaker catheters and metabolic or enzymatic abnormalities

such as Fabry’s or Whipple’s disease.22,23
Etiology
Rheumatic heart disease is the most common cause of TS. Less likely
causes include congenital malformation, carcinoid syndrome and an
obstructing mass.
M-Mode
Tricuspid stenosis almost never occurs as an isolated lesion; it gen-
erally accompanies mitral stenosis, so evaluate for mitral, aortic and
PV disease due to rheumatic fever more than M-mode of TV will
show thickened TV leaflets with restricted motion at the level of the
tips and chordate with a preservation of mobility at the midpoint of
Figure 65.18: 3D echo of tricuspid regurgitation the leaflets, in the real time imaging and a decreased diastolic slope
(EF slope). This alone may not indicate the presence of a TS. It is
important to correlate a decreased EF slope on M-mode Echo, with
significant (P ≤ 0.05) apical displacement of the anterior PM. Pulmo- a 2D echo simultaneously as was shown by Shimada R et al.24 who
nary arterial pressure (r = 0.66), annulus area (r = 0.51), apical dis- showed a diastolic doming in all patients with TS on a 2D echo in
placement of the anterior PM (r = 0.26), posterior PM (r = 0.49), and the apical four-chamber view. In contrast no patients without TS
septal PM (r = 0.40), lateral displacement of the septal PM (r = 0.37) who did have a decreased EF slope on the M-mode echocardiogra-
and posterior PM (r = 0.40), and tenting area and height (r = 0.54, phy showed diastolic doming more than these data suggest that a
0.49), were significantly (P ≤ 0.05) correlated to the grade of TR, in reduced Diastolic Excursion (DE)/ amplitude of less than or equal
their study. One goal of 3D imaging is to provide a more accurate as- to 10 mm associated with a decreased EF slope on the M-mode
sessment of the vena contracta, PISA calculations and jet volumes. echocardiogram and diastolic doming of the TV on the 2D echocar-
Live 3D TTE ad TEE color Doppler measurements of VC area can diogram are diagnosis of TS > thus 2D is complimentary to M-mode
be used for qualitative assessment of TR and its quantification. It is echo in TS. Also in M-mode for TS, one can visualize the anterior
evident that technology is growing by leaps and bounds and that 3D motion of the posterior tricuspid valve leaflets.
developers are getting closer to their goal of providing more accurate
quantitative information for the healthcare field (Table 65.2). Two-Dimensional Echocardiography
TRICUSPID STENOSIS Transthoracic Echocardiography

Tricuspid stenosis is infrequently encountered in both adults and As with all valve lesions, the initial evaluation starts with an anatomi-
children. Functional TS may occur with increased flow through the cal assessment of the valve by 2D echocardiography using multiple
right heart, caused by a left to right shunt such as an atrial septal windows, such as parasternal RV inflow, parasternal short axis, api-
defect. Organic TS is nearly always caused by rheumatic heart dis- cal four-chamber and subcostal four-chamber. One looks for valve
ease, congenital abnormalities, carcinoid disease and infrequently thickening and/or calcification, restricted mobility with diastolic
TABLE 65.2 Grading of tricuspid regurgitation

Parameter Mild Moderate Severe
Tricuspid valve Usually normal Normal/Abnormal Abnormal/Flail leaflet/Poor coaptation
RV/RA/IVC size Normal Normal or dilated Usually dilated
Jet area-central jets (cm2) <5 5–10 > 10
VC width (cm) Not defined < 0.7 > 0.9
PISA radius (cm) < 0.5 0.6–0.9 > 0.9
Jet density and contour—CW Soft and parabolic Dense, variable contour Dense, triangular with early peaking systolic reversal
Hepatic vein flow Systolic dominance Systolic blunting Systolic reversal
doming, reduced leaflet separation at peak opening and right atrial sence of significant TR, a mean pressure gradient of above 7 mm Hg
enlargement (Fig. 65.1).25 In carcinoid syndrome, one sees severe and pressure half-time greater than 190 msec are signs of severe TS.26
immobility of the leaflets, described as a “frozen” appearance (Fig.
65.2). Echocardiography also allows for the detection of valve ob- Color Flow Doppler
struction by atrial tumors, metastatic lesions or giant vegetations.
Using CFD one can appreciate narrowing of the diastolic inflow jet,
Transesophageal Echocardiography higher velocities that produce mosaic color dispersion and associ-
ated valve regurgitation (Figs 65.19A and B).
Two-dimensional echocardiography shows thickening of leaflets
with restricted motion, commissural fusion and doming of leaflets Estimation of Tricuspid Stenosis Severity
in diastole. There may be concomitant right atrial enlargement.
by Color Flow Doppler
The transvalvular gradients (peak and mean) are very dependent
on flow—thus significant TR may be associated with a high gradi- Although the diagnosis of TS generally can be made by 2D exam
ent even in the absence of any stenosis. CWD of the tricuspid inflow (since the most common cause is rheumatic), Doppler studies are
shows an increased peak E wave velocity (> 1.5 m/sec). In the ab- used to quantify the severity (Fig. 65.20). The transvalvular gradi-
Figures 65.19A and B: Color flow Doppler in TR. (A) Turbulent diastolic color flow through the TV CW Doppler—mean gradient > 6 mm Hg with
proximal flow acceleration; (B) Tricuspid valve exposed through a right atriotomy with an annuloplasty ring. Ring is seen at 0o ME view
averaged. Whenever possible, it is best to assess the severity of TS at

heart rate 100 bpm, preferably between 70 bpm and 80 bpm. As with
MS, faster heart rate makes it impossible to appreciate the decelera-
tion time (or pressure halftime). The hallmark of a stenotic valve is
an increase in transvalvular velocity recorded by CWD. Peak inflow
velocity through a normal TV rarely exceeds 0.7 m/s. Tricuspid
inflow is normally accentuated during inspiration; consequently, with
TS, it is common to record peak velocities 1.0 m/s that may approach
2 m/s during inspiration. As a general rule, the mean pressure gra-
dient derived using the 4v2 equation is lower in tricuspid than in
MS, usually ranging between 2 mm Hg and 10 mm Hg, and averag-
ing around 5 mm Hg. Higher gradients may be seen with combined
stenosis and regurgitation.28-29 The primary consequence of TS is
elevation of right atrial pressure and development of right-sided
congestion. Because of the frequent presence of TR, the transval-
vular gradient is clinically more relevant for assessment of severity
Figure 65.20: Tricuspid stenosis and decision-making than the actual stenotic valve area. In addition,
• Most commonly of rheumatic etiology, other causes are congenital, because anatomical valve orifice area is difficult to measure (not
endocarditis, carcinoid heart disease, endomyocardial fibrosis. withstanding future developments in 3D), and TR is so frequently
• 2D-examination: Doming and thickening of leaflets, restricted leaf- present, the typical CWD methods for valve method (T1/2) has been
let motion and commissural fusion applied in a manner analogous to MS. Some authors have used the
• Doppler: Peak velocities (E waves >1.5 m/sec) same constant of 220, while others have proposed a constant of 190
Abbreviations: RA, Right atrium; RV, Right ventricular; PV, Pulmonic with valve area determined as: 190/T1/2. Although validation studies
valve with TS are less than those with MS, valve area by the T1/2 method
may be less accurate than in MS. This is probably due to differences
in atrioventricular compliance between the right and left side, and
the influence of RV relaxation, respiration, and TR on the pressure
ents (peak and mean) should be obtained from two different views. half-time. However, as a general rule, a longer T1/2 implies a greater
Importantly, the gradients are very dependent on flow—thus signifi- TS severity with values 190 frequently associated with significant (or
cant TR may be associated with a high gradient even in the absence critical) stenosis. In theory, the continuity equation should provide a
of a stenotic orifice. In the absence of significant TR, a mean gradient robust method for determining the effective valve area as SV divided
of above 7 mm Hg indicates severe TS and a gradient of 2–6 mm Hg by the tricuspid inflow VTI as recorded with CWD.30 The main limita-
indicates moderate TS. Calculation of the valve area with the pres- tion of the method is obtaining an accurate measurement of the inflow
sure half time method has been described using a constant of 190 volume passing through the TV. In the absence of significant TR, one
(TVA = 190/PHT) rather the 220 used for the MV.26 An area of 1 cm2 can use the SV obtained from either the left or RV outflow; a valve
or less is severe. area of 1 cm2 is considered indicative of severe TS. However, as
severity of TR increases, valve area is progressively underestimated
How to Assess Tricuspid Stenosis? by this method. Nevertheless, a value 1 cm2, although it is not
accounting for the additional regurgitant volume, may still be indica-
The evaluation of stenosis severity is primarily done using the tive of a significant hemodynamic burden induced by the combined
hemodynamic information provided by CWD. Although there are lesion.
reports of quantification of orifice area by 3D echocardiography, the
methodology is neither standardized nor sufficiently validated to be How to Grade Tricuspid Stenosis?
recommended as a method of choice. The tricuspid inflow veloc-
ity is best recorded from either a low parasternal RV inflow view or From a clinical standpoint, the importance of an accurate assess-
from the apical four-chamber view. For measurement purposes, all ment of TS is to be able to recognize patients with hemodynamically
recording should be made at sweep speed of 100 mm/s.27 Because significant stenosis in whom a surgical or catheter-based procedure
tricuspid inflow velocities are affected by respiration, all measure- may be necessary to relieve symptoms of right-sided failure. In the
ments taken must be averaged throughout the respiratory cycle or presence of anatomic evidence by 2D echo of TS, the findings listed
recorded at end-expiratory apnea. In patients with atrial fibrillation, in Table 65.3 are consistent with significant stenosis with or without
measurements from a minimum of five cardiac cycles should be regurgitation.
TABLE 65.3 Finding indicative of hemodynamically significant tricuspid dedicated computer (Tom-TEC, Echo-view) for measurements. The
stenosis valve area is then measured.
Specific Findings
Mean pressure gradient ≥ 5 mm Hg PULMONARY REGURGITATION
Inflow time-velocity > 60 cm
Anatomy and Function of the Pulmonary Valve
T1/2 ≥ 190 ms
Valve area by continuity equationa ≤ 1 cm2 The pulmonary valve is a three-leaflet structure, anatomically similar
Supportive Findings to the aortic valve, the PV structure is however thinner because of the
Enlarged right atrium ≥ moderate lower pressures in the right than in the left heart system.
Dilated inferior vena cava
Echocardiography of Pulmonic Valve
Evaluation of the pulmonary valve, RVOT morphology and the pres-
TABLE 65.4 Grading of TS ence and severity of PR can be performed with echocardiography.
Normal Severe The complex RV geometry further distorted by previous surgery may
Mean pressure drop (mm Hg) -- ≥5 limit complete assessment, however. The presence of retrograde
color flow from the distal main pulmonary artery, or its branches,
Valve area > 7.0 < 1.0
and a high regurgitant fraction calculated with pulsed Doppler34
have been used until recently as echo markers of severe PR and oth-
ers recently reported good agreements between duration of pulmo-
Pacemaker Lead-induced Severe nary regurgitant flow (expressed as a percentage of the total diastolic
Tricuspid Valve Stenosis time on continuous wave Doppler) and CMR-derived pulmonary
regurgitant fraction35,36 (Figs 65.21A to C). The size and function of
Severe tricuspid valve stenosis due to pacemaker leads is uncom- the RV should also be evaluated. RV systolic function in the presence
mon. Tricuspid valve stenosis secondary to transvenous leads are of severe PR can be maintained, but ultimately deterioration occurs
reported to be treated with surgical replacement,31,32 surgical val- following prolonged exposure to volume overload. Interventricular
vuloplasty or percutaneous balloon valvuloplasty.33 Cardiac CT can
provide supportive evidence of the anatomic mechanism of valve
dysfunction and planning of treatment strategy (Table 65.4).
Three-Dimensional Echocardiography
Three-dimensional echocardiography can provide better anatomical
detail of the relation of the three leaflets to each other and assess-
ment of the orifice area.27 Tricuspid stenosis is a rare clinical condi-
tion with rheumatic disease accounting for about 90% of all cases.
Two-dimensional echocardiography permits definitive diagnosis
showing thickening and shortening of the valve leaflets. Neverthe- A B
less, unlike evaluation of mitral stenosis, short axis 2D imaging of the
valve orifice is rarely feasible, but an image of TV area is very easily
obtained using 3D transthoracic echocardiography. A transthoracic
three 3D echocardiography examination can be performed using
a Philips Sonos 7500 (Phillips MEDICAL Systems, Eindhoven, the
Netherlands) and a new 4 MHz, 4X matrix transducer capable of
providing real time 2D and live 3D transthoracic images. Pyramidal
shaped full volume 3D images are acquired with ECG gating by ask-
ing the patient to hold his breath for a few seconds. The image is then
cropped using an elevational cutting plane to obtain the profile of C
the TV area viewed from the apex perspective. Three-dimensional Figures 65.21A to C: Two- and 3D echo recordings of the pulmonic
images are then digitally stored on optical disk and transferred into a valve. PT-SAX, parasternal short-axis view
septal motion is usually paradoxical in these patients, again reflect- TV, Myxomatous valve is rare, resulting in thickening, redundancy,
ing volume overload. and sagging of the pulmonary valve leaflets. As for AR, examining
the anatomic abnormalities associated with PR may help define the
Two-Dimensional Echo mechanisms of regurgitation and yield clues to its severity. TTE, TEE
or 3D echo could provide useful information regarding anomalies of
With 2D echo, typically only one or two leaflets can be simultaneous- cusp number (bicuspid or quadricuspid valves), motion (doming or
ly visualized (Figs 65.22A and B), On occasion, the pulmonary valve prolapse) or structure (hypoplasia, dysplasia, absence of pulmonary
can be seen in a short-axis view. In adults, visualization of the pul- valve).
monary valve is obtained from the parasternal short-axis view at the
level of the aortic valve or from a subcostal approach. Evaluation of Assessment of Pulmonary
the pulmonary valve anatomy is however more difficult than for oth-
Regurgitation Severity
er valves (limited by POOR-acoustic access), in pulmonary hyperten-
sion, the dilatation of pulmonary artery allows better assessment of Determination of the PR severity has been less validated than deter-
the valve. The role of TEE in PR is limited since the pulmonary valve mination of AR degree.
is more difficult to image with TEE (far from the probe). The views
that maximize visualization of the pulmonary valve include horizon- Color Flow Doppler
tal (0°) plane imaging at 25–30 cm from the incisors and a deep gas-
tric view in 120° imaging plane. Color Flow Imaging: Detection of PR relies almost exclusively on color
flow imaging. PR is diagnosed by documenting a diastolic jet in the
2D Echo PR may be: RV outflow tract directed toward the RV, pathological PR is distin-
• Congenital anomalies prolapse or hypoplasia of the pulmonary guished from physiological PR by a longer duration of flow (holodias-
valve tolic) and a wider jet as the regurgitant jet crosses the PV.” Functional
• Dilatation of the pulmonary artery; size and function of the RV PR jets are usually)’ small, central, and spindle-shaped—in severe PR,
provide an indirect indicator to the significance of PR where equalization of diastolic pulmonary artery and RV pressures
• Limited in role of assessing severity of PR. occurs early in diastole, the color jet area can be brief and inaccurate
(dependency on the driving pressure).37 The assessment of PR
Etiology and Mechanisms severity is usually estimated by the diameter of the jet at its origin.38
The maximum color jet diameter (width) is measured in diastole
Pulmonary regurgitation may be caused by congenital anomalies immediately below the PV (at the junction of the RV outflow tract
(quadricuspid or bicuspid valves), hypoplasia, post-repair of tetra and pulmonary annulus) in the parasternal short-axis view or from
logy of Fallot or prolapse of the pulmonary valve; other causes include the subcostal view. Although this measurement suffers from a high
infective endocarditis, carcinoid syndrome, and rheumatic heart inter-observer variability, a jet width that occupies more than 65% of
disease. Carcinoid syndrome results in shortening and thickening the RV outflow tract width measured in the same frame is in favor of
of the pulmonary valve leaflet. Similar to the involvement of the severe PR.
A B
Figures 65.22A and B: 2D echo of pulmonary regurgitation

Vena Contracta Width of regurgitatlon.41 In mild PR, there is a slow deceleration of the jet
velocity. A rapid deceleration rate with termination of flow in mid to
Although the vena contracta width is probably a more accurate late diastole is not specific, but compatible with severe regurgitation.
method than the jet width to evaluate PR severity by color Doppler, Grading of PR severity remains difficult since standards for quantifi-
it lacks validation studies. As for other regurgitations, the same cation of PR are less robust than for AR (Table 65.5). The vena con-
limitations are applicable. The shape of the vena contracta is complex tracta is probably the most accurate approach. If possible the PISA
in most cases. The 3D vena contracta is correlated with the 20 vena method could provide quantitative evaluation of PRo. In all cases, the
contracta, but provides more quantitative assessment of PR.39 The experts recommend corroborating the results of these methods with
EROA values of less than 20, 21–115 and more than 115 mm2 have the other available parameters.
been proposed to serve as cut-offs for PR grade mild, moderate,
and severe. By multiplying the 3D vena contracta with the spectral Consequences of Pulmonary Regurgitation
Doppler-derived velocity integral of the PR jet, the R Vol can be
obtained. The regurgitant volume values of less than 15, 15–115 and Evaluation of the size and function of the RV in the absence of pul-
more than 115 ml have also been proposed to serve as cut-offs for monary hypertension provides indirect clues to the severity of PR.
PR grade mild, moderate and severe. These values require further Evidence of RV dilatation is however not specific for severe PR. Nev-
validation since they are from a single study. Values are relatively ertheless, its absence suggests milder degree of PR. As for TR, the RV
high and could reflect some technical drawbacks. function is classically evaluated by the RV ejection fraction. The utility
of the new indices deriving from tissue Doppler imaging has not been
extensively examined in the context of PR unrelated to congenital
The Flow Convergence Method heart disease. In the tetralogy of Fallot, the severity of PR has a nega-
In some patients the flow convergence zone can be assessed. How- tive influence on RV functional parameters and there is significant re-
ever, no studies have examined the clinical accuracy of this method lation between RV functions and exercise capacity. In this disease, the
in quantifying the severity of PR. myocardial acceleration during the isovolumic contraction is a new
emerging index of RV function. The assessment of RV function in the
Pulsed Doppler setting of congenital heart disease is not the scope of this document.
Theoretically, PW Doppler assessment of the forward and the reverse

flows at the pulmonary annulus and in the pulmonary artery can Role of Exercise Echocardiography
been used to calculate R Vol and regurgitant fraction. The pulmonary Latent RV dysfunction and impaired functional response to stress
annulus should be measured carefully during early ejection (2–3 can be unmasked by exercise echocardiography. Except in the set-
frames after the R wave on the ECG), just below the valve. This tech- ting of congenital heart disease, the value of exercise testing in pa-
nique is subject to errors in measurement and is not well validated.40 tients with PR has not been examined.42
Continuous Wave Doppler Integrating Indices of Severity

There is no clinically accepted method of quantifying PR using CW Echocardiographic assessment of PR includes integration of data
Doppler. The density of the CW signal provides a qualitative measure from 20/30 imaging of the pulmonary valve and RV, as well as
TABLE 65.5 Grading of pulmonary regurgitation

Parameter Mild Moderate Moderate
Pulmonic valve Normal Normal or abnormal Abnormal
RV size Normal Normal or dilated Dilated
Jet size by color Doppler* Thin (usually < 10 mm in length with a Intermediate Usually large, with a wide origin;
narrow origin may be brief in duration
Jet density and deceleration rate CW Soft, slow deceleration Dense, variable deceleration Dense; steep, deceleration of
diastolic flow
RVOT VTI ↑ ↑↑ ↑↑↑
LVOT VTI (PW)
* At a Nyquist limit of 50-60 cm/s adapted from Masani N, Wharton G, Allen J, Chambers J, Graham J, Jones R, et al. Echocardiography: Guidelines for
Valve Quantification. British Society of Echocardiography Education Committee. [Online] Available from http://www.bsecho.org/Guidelines%20for%20
Valve%20Quantification.pdf.
Doppler measures of regurgitant severity. In the absence of extensive vena contracta (VC) precluding accurate assessment of its shape or
data on quantitation of PR, the experts recommend to assess the PR size. This limitation would be expected to be obviated by 3D trans
severity by using the different approaches available and to corrobo- thoracic echocardiography, which could provide a more accurate
rate each other. quantitative assessment of PR severity. A study done by Pothineni
KR et al.43 evaluated those 82 adult patients with PR using 2D and
Pulmonic Regurgitation 3D. PR VC area by 3D was obtained by planimetry by positioning the
cropping plane exactly parallel to the VC, which was viewed en face
Most patients will have a small degree of PR, especially if the patient by cropping of the 3D data set. Regurgitant volumes were calculated
has a PA line. Significant PR is most often due to dilation of the pul- by 2D (assuming a circular VC) and by 3D as a product of the VC and
monary artery in patients with pulmonary hypertension. Endocar- velocity time integral obtained by color Doppler-guided convention-
ditis, carcinoid syndrome and congenital heart disease (residual or al Doppler interrogation of the PR jet. The 3D VC area correlated with
unrepaired defects) can also cause PR (Fig. 65.23). Estimation of the 2D jet width (JW)/RV outflow tract (RVOT) width (r = 0.71) and 2D
severity of PR typically relies on the size and depth of penetration of VC area (r = 0.79). 3D JW/RVOT width correlated with 2D JW/RVOT
the PR jet. Although somewhat speculative, the use of the jet height (r = 0.87). 3D regurgitant volumes also correlated with 2D regurgitant
relative to the RVOT height (similar to the method used to assess AI) volumes (r = 0.76). The 3D VC values of < 0.20, 0.20-0.45, 0.46–1.15,
as a means to assess the severity of PR makes intuitive sense (and and > 1.15 cm (2) and regurgitant volumes of < 15 ml, 15–50 ml, 51–
that is what I use). Alternatively, if the CWD jet has high intensity and 115 ml, and > 115 ml were effective as cutoffs for grades 1, 2, 3, and
decays fast, then the PR is severe. 4 PR, respectively. In conclusion, quantification of 3D VC area and
regurgitant volumes correlate reasonably well with the current 2D
Three-Dimensional ECHO methods for measurement of PR. Since 3D visualizes PR VC in three-
dimensions, it would be expected to provide a more accurate and
in Pulmonic Regurgitation
more quantitative assessment of PR severity as compared to 2D.43
There is no gold standard for the measurement of pulmonary regur-
gitation (PR) severity. Two-dimensional transthoracic echocardio PULMONARY STENOSIS
graphy is most commonly used to quantify PR severity using color
Doppler criteria for aortic regurgitation. However, this method is Pulmonary stenosis (PS) is diagnosed almost exclusively by Doppler
limited by visualization of only 1D or 2D of the proximal PR jet or echocardiography, although the diagnosis may be suggested from
the M-mode and 2D echocardiogram.
Echo of the Pulmonic Valves
M-Mode Recording of the Pulmonic Valve

Valve: The PV is sometimes considered to be the forgotten valve. It
is not the easiest valve to record with M-mode or 2D echocardiog-
raphy, especially in adults. We frequently merely rely on the easier
to record Doppler PV velocity for the valve evaluation. Even in those
laboratories where M-mode echocardiography is still a part of the
examination, the PV is frequently not interrogated. The diagram in
Figure 65.24 shows some of the diagnostic findings of an M-mode
recording of the PV.47 Because of the orientation of the valve to the
M-mode beam, only the motion of one of the leaflets is usually
recorded. The normal valve has a small “a”-wave secondary to atrial
contraction. The valve then opens and stays open throughout sys-
tole. Figure 65.25A illustrates an M-mode recording of a normal PV.
Figure 65.23: Pulmonic regurgitation
The most important use of the M-mode recording of the PV today is
• CFD analysis is used to map the extent of PR jet into the RVOT. for those few patients who have pulmonary hypertension and may
• Definitions: not have a good enough TR jet to fully appreciate the severity of the
- Mild PR: PR jet < 1 cm pulmonary hypertension. In these patients, the pulmonary artery is
- Pathologic PR: Pandiastolic jet of > 1–2 cm frequently dilated and the recording of the PV is technically easier.
- Significant PR: Jet extends > 2 cm in the RVOT or within 1 cm of TV With pulmonary hypertension one will see an absence of the “a”
and PWD velocity > 1.5 m/sec wave.43-46 However, the “a” wave might reappear if the RV diastolic
pressure becomes elevated. The more striking finding is that in sys- mild, peak 40–75 mm Hg = moderate, peak above 75 mm Hg = severe.
tole there is mid-systolic closure and then reopening of the valve The continuity equation can be used to calculate the PV area—the
before diastole (Fig. 65.25B). This pattern is sometimes referred to as deep transgastric view often works best for this calculation. RVH is
the “flying W” sign. It is a fairly specific finding of severe pulmonary present if the wall thickness is greater than 5 mm. Pulmonic stenosis
hypertension and usually elevated pulmonary vascular resistance. is categorized as valvular, subvalvular or peripheral (supravalvular).
The M-mode PV finding of PS with its exaggerated "a" wave (Fig. Ninety percent of the lesions are valvular in nature and the majority
65.24) is hardly used anymore. We rely almost entirely on a Doppler of PS in the adult population is from untreated or recurrent congeni-
gradient for that diagnosis. tal disease, such as tetralogy of Fallot. Pulmonary stenosis is more
commonly seen as individuals with complex congenital heart dis-
ease increasingly survive into adulthood. Pressure gradients using
M-mode Echocardiogram in PS
CW Doppler across the stenotic valve allow the quantification of PS
M-mode echocardiographic findings in PS are usually limited to the as follows: peak gradients below 30 mm Hg are associated with mild
occurrence of an exaggerated “A wave” during diastole although, stenosis, peak gradients between 30 mm Hg and 65 mm Hg indicate
with aging, a congenitally abnormal valve may exhibit findings as- moderate stenosis, and gradients >65 mm Hg are seen with severe
sociated with thickening or calcification. The A wave is due to a pow- PS. The continuity equation can be used to determine the area of the
erful right atrial contraction that, because of low diastolic pulmo- pulmonary valve to further assess disease severity.
nary artery pressure, is able to open or at least to dome the stenotic
pulmonary valve in late diastole. The A wave is most pronounced
during inspiration and accounts for the disappearance of the
Two-Dimensional ECHO in PS
pulmonary ejection sound at that point in the respiratory cycle. This The valve leaflets may be thickened, dysplastic and fused forming a
behavior makes the pulmonary ejection sound the only right sided conical or domed pulmonary valve.47 Two-dimensional imaging may
event that diminishes with inspiration. shows restricted motion of thickened leaflets, flattening of the inter-
ventricular septum, RV hypertrophy/enlargement and post-stenotic
GRADING PULMONIC STENOSIS dilatation of the pulmonary artery.
In adults, the majority of PS will be congenital disease, either un- Color Flow Doppler
treated or recurrent. Patients with tetralogy of Fallot may return for
RVOT revision. Importantly, valvular stenosis must be differentiated Color flow Doppler will demonstrate aliasing and turbulent flow
from subvalvular or supravalvular stenosis. Rheumatic heart disease across the valve. Pulmonary stenosis is accurately quantified by
and carcinoid are the other important causes of PS. The pressure gra- calculating peak instantaneous and mean pressure gradients from
dient may be used to define the severity: peak below 40 mm Hg = Doppler signals obtained from the pulmonary valve orifice.48 Quan-
A B
Figure 65.24: Relationship between the M-mode recording of the Figures 65.25A and B: (A) M-mode examination of a normal
pulmonic valve and the pressures in the right ventricle and pulmonary pulmonic valve. Only 1 of the leaflets is usually recorded; (B) M-mode
artery pulmonic valve recording from a patient with pulmonary hypertension.
The "a" wave is absent, and there is mid-systolic closure (n) in mid-
systole. This finding has been called the "flying W" sign
tifying of the pulmonary valve area by continuity equation has not

been well standardized.49
Three-Dimension of PS
The 3D examination of the TV may add clinically relevant informa-
tion to the standard 2D assessment. Since traditional 2D imaging
cannot provide a real-time view of the entire valve, an anterior to
posterior sweep of the TEE transducer is required for the echocar-
diographer to mentally envision valve anatomy. A 3D en face view of
the TV eliminates the need for probe manipulation and mental re-
construction of valve anatomy and provides a simultaneous view of
the anatomical relationship between three valve leaflets, their points
of coaptation, movements during the cardiac cycle (Fig. 65.26). The
3D imaging may reduce interobserver variability and may allow the
diagnosis of unusual TV variants, such that increase a bileaflet TV. Figure 65.26: The 3D face view of the TV from the atrial perspective.
Other reports highlight the incremental value of real-time 3D tran- Abbreviations: A , anterior leaflet; S, septal leaflet; P, posterior leaflet;
sthoracic and TEE over the 2D technique in carcinoid disease, Eb- PAC, pulmonaryartery catheter
stein’s anomaly, chordal rupture, rheumatic tricuspid disease, pro-
lapsing Chiari network, and other uncommon valvular pathology.
Although also technically challenging, 3D examination of the PV echocardiography. These are now standard in cardiologic examina-
has been reported to provide additional information in some cases. tions.
The morphology of the TV and PV leaflets and annuale is generally Echocardiography is now the most rapidly growing medical im-
best assessed using the real-time 3D zoom mode. The 3D full volume aging technique, projected by many to become more important than
mode images may provide additional information regarding the RV the X-ray itself.
walls and papillary muscles, and the 3D color full volume mode may Edler’s pioneering work has prolonged and improved the lives
be useful to assess TE jets. In spite of these reported benefits, 3D of millions of patients. The echocardiogram is the true stethoscope,
examination of the right-sided valves remains difficult with current for it permits us to see what occurs beneath the surface of the skin.50
ultrasound technology, likely due to the anterior location and thin Today, more than 25 millions echocardiograms are performed each
leaflets of these values. In one recent report, optimal visualization year throughout the world.
of the tricuspid leaflets from both the atrial and ventricular perspec- Hand-held ultrasonographic devices are becoming smaller and
tives was only possible in 11% of cases. smaller and have highly superior image qualities and functions; there
are new methods to study ventricular function with very high tem-
HISTORICAL ASPECTS OF poral resolution, which far exceed the capabilities of cardiac mag-
netic resonance imaging; contrast echocardiography is now used
ECHOCARDIOGRAPHY OF TRICUSPID
worldwide for myocardial perfusion studies and may soon become
AND PULMONARY VALVE a means of drug delivery and 3D echocardiography is now a reality.
The clinical detection and quantification of tricuspid valve disease, Academic echocardiologists are now devoting their time to teaching
although important, is not entirely accurate. Diagnostic evaluation and research in the rapidly expanding field. Although Edler’s original
is based on echocardiography and color flow Doppler is useful for M-mode technique has largely been replaced by new and improved
quantifying tricuspid regurgitation. Echocardiography provides in- imaging modes, it remains an important part of the complete ultra-
formation on heart chamber dimensions, right ventricular function sonic examination of the heart—its superior local-target sensitivity
and the degree of pulmonary hypertension. enables better detection of small pericardial effusions and its higher
The original description of M-mode echocardiography in 1953, effective sampling rate (in comparison with 2D echocardiography) is
by Inge Edler (1911–2001) and his physicist friend Hellmuth hertz, useful for the precise timing of cardiac events.
marked the beginning of a new diagnostic noninvasive technique. The recent development of percutaneous valve replacement
Edler used this technique primarily for the preoperative study of is a major advance and 3D echocardiography has in recent times
mitral stenosis and diagnosis of mitral regurgitation and it was later become the essential monitoring modality for this advanced mini-
adapted for the right sided valves—the tricuspid and pulmonary mally invasive procedure.51
valve. His work was carried forward by cardiologists all over the Echocardiographic assessment of the right ventricle has been
world, who developed Doppler, 2D, contrast and transesophageal largely qualitative, primarily because of the difficulty with assessing
RV volumes because of its unusual shape. Hence there are minimal in cases of congenital left ventricular-right atrial communication as-
quantitative data overall on RV size and function in normal controls sociated with a defect involving the tricuspid valve. They suggested
and in disease states. A gradual shift to more quantitative approaches that systolic segments of the tricuspid valve should be carefully stud-
for the assessment of the right ventricle across laboratories and al- ied for the presence of tricuspid valve flutter in all patients with clini-
low clinicians to better incorporate assessment of the right heart into cal evidence of ventricular septal defect to exclude this anomaly.53
an echoardiographic evaluation. Improvements in 3D imaging will
result in increased use and have the potential to help in the clinical Live 3D ECHO
assessment of RV size and function particularly of the tricuspid and
pulmonary valve.52 Live 3D Echo is a significant new advancement in ultrasound that is
changing the way in which cardiology in practiced from the clinic all
Echocardiographic Study of the Tricuspid the way to the operating room. As a result, live 3D Echo is advanc-
ing the level of care provided to patients, which will ultimately have a
Valve is of Value in the Recognition of the
positive impact on an patients right heart function on RV, TV and PV
Congenital Left Ventricular-Right Atrial as much as left heart.54
Communication
Nanda, Gramiak et al. showed that systolic flutter of the tricuspid
valve is a rare echocardiographic finding which is of diagnostic value
REFERENCES
1. Prabhu MR. Trans-esophageal echocardiography for tricuspid and pulmonary valves. Ann Card Anaesth. 2009;12(2):167.
2. Figenbaum H. Role of M-mode technique in today’s echocardiography. J Am Soc Echocardiogr. 2012;01:240-57.
3. Silver MD, Lam JH, Ranganathan N, et al. Morphology of the human tricuspid valve. Circulation. 1971;43:333-48.
4. Wafae N, Hayashi H, Gerola LR, et al. Anatomical study of the human tricuspid valve. Surg Radiol Anat. 1990;12:37-41.
5. Lamers WH, Virαgh S, Wessels A, et al. Formation of the tricuspid valve in the human heart. Circulation. 1995;91:111-21.
6. Shanewise JS, Cheung AT, Aronson S, et al. ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal echo-
cardiography examination: Recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and
the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography. Anesth Analg.
1999;89:870-84.
7. Quιrι JP, Tribouilloy C, Enriquez-Sarano M. Vena contracta width measurement: Theoretic basis and usefulness in the assessment of valvular
regurgitation severity. Curr Cardiol Rep. 2003;5:110-5.
8. Quirones MA, Otto CM, Stoddard M, et al. Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American
Society of Echocardiography. Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task
Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr. 2002;15:167-84.
9. Waller BF, Howard J, Fess S. Pathology of tricuspid valve stenosis and pure tricuspid regurgitation-part III. Clin Cardiol. 1995;18:225-30.
10. Shapira Y, Porter A, Wurzel M, et al. Evaluation of tricuspid regurgitation severity: Echocardiographic and clinical correlation. J Am Soc Echocar-
diogr. 1998;11:652-9.
11. Nanda NC, Domanski MJ. TEE of tricuspid and puolmonary valves—chapter 4. Atlas of Transesophageal Echocardiography. Volume 2.
Lippincott: Williams & Wilkins; 2007. pp. 191-2.
12. Fisher EA, Goldman ME. Simple, rapid method of quantification of tricuspid regurgitation by two-dimensional echocardiography. Am J Cardiol.
1989;63:1375-8.
13. Abi-Saleh B, Schoondyke JW, Abboud L, et al. Tricuspid valve involvement in carcinoid disease. Echocardiography. 2007;24:439-42.
14. Attenhofer Jost CH, Connolly HM, Dearani JA, et al. Ebstein's anomaly. Circulation. 2007;115;277-85.
15. Grossmann G, Stein M, Kochs M, et al. Comparison of the proximal flow convergence method and the jet area method for the assessment of the
severity of tricuspid regurgitation. Eur Heart J. 1998;19:652-9.
16. Yamachika S, Reid CL, Savani D, et al. Usefulness of color Doppler proximal isovelocity surface area method in quantitating valvular regurgitation.
J Am Soc Echocardiogr. 1997;10:159-68.
17. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, et al. Quantification of tricuspid regurgitation by measuring the width of the vena contracta with
Doppler color flow imaging: A clinical study. J Am Coll Cardiol. 2000;36:472-8.
18. Nimura Y, Miyatake K, Okamoto M, et al. Pulsed Doppler echocardiography in the assessment of tricuspid regurgitation. Ultrasound Med Biol.
1984;10(2):239-47.
19. Pennestrn F, Loperfido F, Salvatori MP, et al. Assessment of tricuspid regurgitation by pulsed Doppler ultrasonography of the hepatic veins. Am J
Cardiol. 1984;54:363-8.
20. Nagueh SF, Kopelen HA, Zoghbi WA. Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right
ventricular function. Circulation. 1996;93:1160-9.
21. Spinner EM, Lerakis S, Higginson J, et al. Correlates of tricuspid regurgitation as determined by 3D echocardiography: pulmonary arterial pres-
sure, ventricle geometry, annular dilatation, and papillary muscle displacement. Circ Cardiovasc Imaging. 2012;5(1):43-50.
22. Waller BF, Howard J, Fess S. Pathology of tricuspid valve stenosis and pure tricuspid regurgitation—Part I. Clin Cardiol. 1995;18:97-102.
23. Taira K, Suzuki A, Fujino A, et al. Tricuspid valve stenosis related to subvalvular adhesion of pacemaker lead: A case report. J Cardiol. 2006;47:
301-6.
24. Shimada R, Takeshita A, Nakamura M, et al. Diagnosis of tricuspid stenosis by M-mode and two-dimensional echocardiography. Am J Cardiol.
19841:53(1):164-8.
25. Pearlman AS. Role of echocardiography in the diagnosis and evaluation of severity of mitral and tricuspid stenosis. Circulation. 1991;84(3 Sup-
pl):193-7.
26. Assayag P, Thuaire C, Benamer H. Partial rupture of the tricuspid valve after extraction of permanent pacemaker leads: Detection by transesopha-
geal echocardiography. PACE. 1999;22:971-4.
27. Pothineni KR, Duncan K, Yelamanchili P, et al. Live/real time three-dimensional transthoracic echocardiographic assessment of tricuspid valve
pathology: incremental value over the two-dimensional technique. Echocardiography. 2007;24:541-52.
28. Hatle L. Noninvasive assessment of valve lesions with Doppler ultrasound. Herz. 1984;9:213-21.
29. Fawzy ME, Mercer EN, Dunn B, et al. Doppler echocardiography in the evaluation of tricuspid stenosis. Eur Heart J. 1989;10:985-90.
30. Karp K, Teien D, Eriksson P. Doppler echocardiographic assessment of the valve area in patients with atrioventricular valve stenosis by application
of the continuity equation. J Intern Med. 1989;225:261-6.
31. Heaven DJ, Henein MY, Sutton R. Pacemaker lead related tricuspid stenosis: a report of two cases. Heart. 2000;83:351-2.
32. Krishanan A, Moulick A, Sinha P, et al. Severe tricuspid valve stenosis secondary to pacemaker leads presenting as ascites and liver dysfunction: a
complex problem requiring a multidisciplinary therapeutic approach. J Interv Card Electrophysiol. 2009;24:71-5.
33. Hussain T, Knight WB, Mcleod KA. Lead-induced tricuspid stenosis successful management by ballon angioplasty. Pacing Clin Electrophysiol.
2009;32:140-2.
34. Goldberg SJ, Allen HD. Quantitative assessment by Doppler echocardiography of pulmonary or aortic regurgitation. Am J Cardiol. 1985;56:131-5.
35. Li W, Davlouros PA, Kilner PJ, et al. Doppler-echocardiographic assessment of pulmonary regurgitation in adults with repaired tetralogy of Fallot:
comparison with cardiovascular magnetic resonance imaging. Am Heart J. 2004;147:165-72.
36. Silversides CK, Veldtman GR, Crossin J, et al. Pressure half-time predicts hemodynamically significant pulmonary regurgitation in adult patients
with repaired tetralogy of Fallot. J Am Soc Echocardiogr. 2003;16:1057-62.
37. Kobayashi J, Nakano S, Matsuda H, et al. Quantitative evaluation of pulmonary regurgitation after repair of tetralogy of Fallot using real-time flow
imaging system. Jpn Cric J. 1989:53:721-7.
38. Williams RV, Minich LL, Shaddy RE, et al. Comparison of Doppler echocardiography with angiography for determining the severity of pulmonary
regurgitation. Am j Cardiol. 2002;89:1438-41.
39. Pothineni KR, Wells BJ, Hsiung MC, et al. Live/real time three-dimensional transthoracic echocardiograph assessment of pulmonary regurgita-
tion. Echocordiography. 2008:25:911-7.
40. Goldberg SJ, Allen HD. Quantitative assessment by Doppler echocardiography of pulmonary or aortic regurgitation. Am J Cardiol. 1985;56:131-5.
41. Lei MH, Chen JJ, Ko YL, et al. Reappraisal of quantative evaluation of pulmonary regurgitation and estimation of pulmonary artery pressure by
continuous wave Doppler echocardiography. Cardiology. 1995;86:249-56.
42. Marx GR, Hicks RW, Allen HD, et al. Noninvasive assessment of hemodynamic responses to exercise in pulmonary regurgitation after operations
to correct pulmonary outflow obstruction. Am J Cardia. 1988;61:595-601.
43. Weyman AE, Dillon JC, Feigenbaum H, et al. Echocardiographic patterns of pulmonic valve motion with pulmonary hypertension. Circulation.
1974;50:905-10.
44. Nanda NC, Gramiak R, Robinson TI, et al. Echocardiographic evaluation of pulmonary hypertension. Circulation. 1974;50:575-81.
45. Shiina A, Yaginuma T, Matsumoto Y, et al. Echocardiographic analysis of pulmonic and aortic valve motion by simultaneous recordings of flow ve-
locity and intravascular pressure: genesis of mid-systolic semi-closure of the pulmonic valve in patients with pulmonary hypertension. J Cardiogr.
1977;7:599.
46. Marin-Garcia J, Moller JH, Mirvis DM. The pulmonic valve echogram in the assessment of pulmonic hypertension in children. Pediatr Cardiol.
1983;4:209-14.
47. Koretzky ED, Moller JH, Korns ME, et al. Congenital pulmonary stenosis resulting from dysplasia of valve. Circulation. 1969;40:43-53.
48. Lima CO, Sahn DJ, Valdes-Cruz LM, et al. Noninvasive prediction of transvalvular pressure gradient in patients with pulmonary stenosis by quan-
titative two-dimensional echo Doppler studies. Circulation. 1983;67:866-71.
49. Richards KL. Assessment of aortic and pulmonic stenosis by echocardiography. Circulation. 1991;84:182-7.
50. Feigenbaum H. Evolution of echocardiography. Circulation. 1996;93:1321-7.
51. Pravin M Shah. Tricuspid and pulmonary valve disease evaluation and management. Rev Esp Cardiol. 2010;63(11):1349-65.
52. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society
of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and
the Canadian Society of Echocardiography.. J Am Soc Echocardiogr. 2012;23:685-713.
53. Nanda NC, Gramiak R, Manning JA.. Echocardiography of the tricuspid valve in congenital left ventricular tight atrial communication. Circula-
tion. 1975;51:268-72.
54. Nanda NC, Chopra HK. Live 3D Echo—delivering realtime benefits to cardiologists. Business briefing global healthcare. 2003.
66 History of Interventional Cardiology
Bhatia V, Kaul U
catheters to first record intracardiac pressures accurately.5 He also

INTRODUCTION
coined the term “Catheterization”. Refinements continued and the
The history of interventional cardiology is as intriguing as the dis- experience and information grew.
cipline itself. The discipline today and the comforts of the cardiac An excellent breakthrough that changed the future course of in-
patients in the present times is the result of years of perseverance, vasive cardiology was the discovery of X-ray by Roentgen6 in 1895.
research, dedication of several genius minds. Some spectacular events followed like the production of fluoroscopic
images of the beating heart by Williams in 1896, cadaveric angio-
THE DEVELOPMENT OF RIGHT AND grams of brachial artery by Haschek and Lindenthal and subsequent
coronary angiograms by Baumgarten in 1899 in cadaveric hearts.7
LEFT HEART CATHETERIZATION
During the initial years of the 28th century Alexis Carrel of France
In ancient times dating to as early as 3000 BC the Egyptians, Greek carried out experimental bypass surgery, stenting and cardiac trans-
and Romans performed bladder catheterizations using bronze, gold plantation in dogs. He won the Nobel Prize in 1912 for the same.8 In
and silver pipes1 and also delivered catheter tipped enemas into the 1912, James Herrick in Chicago described clinical features of sudden
rectum using animal bladders as a bag and a quill or metal tube as coronary obstruction (clots?) and resultant myocardial infarction
the catheter.2 As centuries passed gradually information stated trick- (MI).8
ling in and the concepts of the cardiovascular systems anatomy and Then came the spectacular experiments of Werner Forssmann.
physiology were formulated. Harvey catheterized the cadaveric infe- Born in Berlin in 1904, he worked in Eberswald Germany at the Au-
rior vena cava in 1651.3 In 1667, Major became the first to deliver an gustine Victoria Home. In 1929, his interests in delivering drugs di-
intravenous injection into a living human subject while Lower used rectly into the cardiac chambers during resuscitation led him to cut
the first vascular catheter (silver pipes connected by a quill) to trans- down his own basilic vein, insert a ureteral catheter to its full length
fuse blood from the carotid artery of sheep to the jugular vein of a of 65 cm. He then walked across to the radiology department and
human. These success stories led to greater confidence and Hales4 radiographed the catheter tip position in the right atrium.9 What
in 1711 performed the first cardiac catheterization by inserting brass Forssmann had done was a remarkable achievement which years
pipes into the venous and arterial system of a horse to reach the ven- later would fetch him the Nobel Prize. However, he received wide-
tricles. The brass pipes were connected to a long glass tube for pres- spread criticism for what he did and he was forced to quit his post.
sure measurements and the trachea of a goose was used as a flexible He repeated and refined his technique by cannulating himself some
connector. Stephen Hales in fact undertook in Tordington in 1710 27 times, but in face of the criticism he faced he quit cardiology and
the first precise definition of the capacity of a heart. He bled a sheep moved to urology. He joined the army and subsequently worked in
to death and then led a gun-barrel from the neck vessels into the small hospitals in villages until in 1956, when in light of work carried
still-beating heart. Through this, he filled the hollow chambers with out by Cournand and Richards he was once again in the limelight.7
molten wax and then measured from the resultant cast the volume of Not all ridiculed Forssmann. In 1930, Klein reported 11 right heart
the heartbeat and the minute-volume of the heart, which he calcu- catheterizations, including passage to the right ventricle and meas-
lated from the pulse-beat. Besides this, Stephen Hales was also the urement of cardiac output using the Ficks principle. The cardiac out-
first, in 1727, to determine arterial blood pressure when he measured puts were 4.5 and 5.6 L/min in two patients without heart disease.
the rise in a column of blood in a glass tube bound into an artery. The Andre Cournand and Dickinson Richards10 at Columbia University
fact that these contributions were acknowledged by Forsmann in his and Bellevue Hospital in New York began in 1941, the systematic ex-
Nobel Prize acceptance speech in 1956 goes to show the pioneering ploration of normal and abnormal hemodynamics. They recorded
vision of Hales and how he influenced the future of invasive cardiol- intracardiac pressures and cardiac output in normal subjects and in
ogy. It was in 1844 that the French physiologist Claude Bernard used patients with many forms of congenital and acquired heart disease.
576 Section 3  Interventional Cardiology
These investigators established cardiac catheterization as the basis was entered. This technique was also used by Fischer (1955) and by
for defining normal and disordered function of the cardiac pump Brock et al.14 however due to complications faced especially when
and as a premier diagnostic technique in cardiology. In fact they were the left atrium was small sized, the procedure was abandoned. This
applauded for their rediscovery of the “cardiac” catheter. Cournand technique was simple when the LA was enlarged as in patients with
in fact suggested that “the catheter was the key to the lock”.11 In 1956, mitral stenosis. This is now replaced by the technique of trans-septal
Forssmann shared the Nobel Prize for medicine for discovery and puncture. The trans-septal puncture was developed by Ross, Braun-
development of the cardiac catheter with Cournand and Richards. wald and Morrow at the National Heart Institute (now the National
This really set the ball rolling for invasive cardiology. Heart, Lung, and Blood Institute), Bethseda in the late 1950s to allow
Some other vital achievements were as those by Warren who left heart catheterization, principally for the evaluation of valvular
carried out catheterization in a patient with atrial septal defect. In heart disease. Early problems were difficulty in cannulating the LV,
1946, Dexter et al.12 placed the catheter in the wedge position and injecting sufficient volume of contrast for imaging, and inadvertent
measured the oxygen saturation while Bing et al.13 reported the first aortic puncture. Brockenbrough made some important refinements
coronary sinus catheterization. Refinements were also made in the in the needle, catheter and technique. So, perfect were these changes
material used in catheters such that rubber catheters were replaced that since, 1962 there has been little if any change in the technique.
by synthetic polymer polyethylene. The radiopaque version became Mullins developed a combined catheter and dilator set designed
available in 1956. Charles Dotter in Portland developed the first precisely to fit over the Brockenbrough needle, which gives a smooth
balloon-tipped angiographic catheter in 19517 and in 1953 Lategola taper from the tip of the needle, over the dilator to the shaft of the
and Rahn devised the soft, flow directed pulmonary artery catheter.7 sheath. The terms Brockenbrough needle and Mullins sheath are
These laid the foundation for the subsequent development of the often used by operators generically when referring to trans-septal
flow directed and balloon-tipped catheters as the Swan Ganz cath- needles and sheaths, respectively; however, there is a range of equip-
eter (Edwards Laboratories) so widely used all over the world even ment available from several manufacturers, often designed for spe-
today. Until this time the focus had largely been on right heart cath- cific applications—for example, catheter ablation of atrial fibrillation
eterization and having nearly perfected the techniques soon focus (AF).
shifted toward unraveling the mysteries of the left side of the heart. Some other advances were in the hemodynamic arena. Gorlin
Initial attempts at left heart catheterization were largely in the and Gorlin in 1951 devised the formulas to help calculating stenotic
form of percutaneous ventricular needle puncture using the ante- valve orifice areas through the use of cardiac output and pressure re-
rior parasternal, subxiphoid and apical approaches. Nuvoli in 1936 cordings during right and left heart catheterizations.17 In 1954, Felger
performed the first left ventricular (LV) puncture in man by the left devised the thermodilution technique for calculating cardiac output.
parasternal route in order to outline an aortic aneurysm. The patient A vital breakthrough in 1953 was achieved by a Swedish radiolo-
developed temporary syncope and bradycardia.14 Smith, Wilson, gist Dr Sven-Iver Seldinger of the Karolinska Institute in Stockholm.
Cregg, and Klassen (1954) performed the LV puncture on six patients He introduced a new technique to achieve vascular access which was
by subxiphoid route for cardioangiography. They encountered extra simple, safe and associated with very few complications. Seldinger
systoles in all cases; one patient developed asystole and another ven- first published this technique in Acta Radiologica.18 This has been
tricular fibrillation, but it seemed that these complications were at- described as a “substantial refinement” of a procedure first described
tributable to the effects of the injected material rather than the punc- by Farinas in 1942. In 1975, the New York Academy of Medicine
ture itself. The apical approach by Brock et al.14 was introduced in awarded Seldinger the Valentine award. The Swedish Association
1956 while they tried to investigate patients with aortic valve disease of Medical Radiology and the German Roentgen Association both
prior to surgery. They made a puncture using an 18 gauge needle awarded him an honorary membership to their organizations. Seld-
from the apical position as in most cases the apex of the LV seems inger died at home in Dalecarlia, Sweden, on February 21, 1998. The
almost subcutaneous and simultaneously obtained brachial artery pigtail catheter was introduced in 1960.
pressures to obtain the gradient across the valve. This was later re-
placed by the technique of retrograde catheterization of the LV as UNRAVELLING THE CORONARY
described by Zimmerman et al.15 and Limon-Lason et al.16 in 1950.
VASCULATURE
Zimmerman while at the Cleveland clinic carried out retrograde LV
catheterization using a catheter introduced via the ulnar route in pa- The ideas of visualizing the coronaries tickled many minds, but sev-
tient with aortic regurgitation. They performed hemodynamic stud- eral fears were associated, primarily of inducing life-threatening
ies, intracardiac electrocardiogram (ECG) and left heart pullback. arrhythmias. The coronaries were first selectively accidentally can-
Bjork, Malmstörm and Uggla (1953) developed a technique for nulated by Sones; a pediatric cardiologist at the Cleveland Clinic
left atrial puncture through the right hemithorax in which, by pass- in 1958. While carrying out his experimental work in patients with
ing a fine catheter down the needle through the mitral valve, the LV valvular heart disease the catheter accidentally engaged the right
Chapter 66  History of Interventional Cardiology 577
coronary ostium. Before Sones could recognize the catheter position Then came the time when two geniuses Charles Dotter and An-
he had already made the injection and some 30 ml of dye entered dreas Gruentzig made some startling inroads into revascularization
the artery opacifying it. This led Sones to develop special catheters to of peripheral and coronary vessels. In 1963, Charles Dotter inadvert-
cannulate the coronary vasculature.19 This was a giant leap forward ently recanalized an occluded right iliac artery while he was trying to
and would open the gates to coronary interventions. He published introduce a catheter so as to do a renal angiogram.21 Having tested
his work in 1962.20 This technique remained the favorite for the next the success he inadvertently carried out cadaveric studies and went
few years. The disadvantage with the Sones catheter was that it used onto dilate arteries using gradually larger sized dilators, construct-
the normal curvature of the aorta to be directed to the coronary os- ing balloon mounted catheters and then went on to develop endo-
tia. These lead to difficulties in cannulating the coronaries in patients luminal stents. He was closely assisted in his feats by Judkins. In fact
with dilated aortas. This drove other workers to develop better cathe- both performed the first formal elective peripheral angioplasty of the
ters namely the Judkins and Amplatz catheters, developed by Melvin popliteal artery in 1964. They successfully salvaged a limb which was
Judkins at the University of Oregon and Kurt Amplatz of the Univer- gangrenous and would have led to amputation.22 The drawback was
sity of Minnesota. Judkins initial work involved shaping stiff wires the rigid equipments available. This too was worked upon by several
and comparing those shapes to radiographs of the ascending aorta workers including the duo and smaller, more flexible, latex balloon-
to determine if the shape appeared promising. Then he would place tipped catheters then became available. Mylert and Portsmann were
the stiff wire inside a flexible catheter and use a heat fixation method also instrumental in improving upon the balloon dilatation catheter
to permanently shape the catheter. In the first use of these catheters designs.
in humans, each catheter was specifically shaped to match the size One individual who influenced interventional cardiology the
and shape of the aorta of the subject. His work was documented in most was Dr Andreas Gruentzig, a German. He worked under Ebe-
1967 and by 1968 the Judkins catheters were manufactured in a lim- hart Zeitler in Nuremberg and learned from him Dotter’s technique.
ited number of fixed tip shapes. Catheters in these shapes carry his He subsequently, relocated to The University Hospital, Zurich in
name and are still used to this day for selective coronary angiogra- 1970. His interests in cardiology grew and he used his kitchen table
phy. Judkins also played a vital role along with dotter in developing as the workplace where he would design and produce balloon cath-
the J tipped guide wire and equipment for angioplasty. Dr Kurt Am- eter designs. He developed the double lumen fitted with the polyvi-
platz (born 1925) is a retired Austrian radiologist and medical device nyl chloride balloon in 1975 which could be termed as a revolution-
inventor.7 He developed the Amplatz series of catheters, guide wires, ary advancement. He presented the results of animal studies with
inferior vena cava filter, the CO2 power injector and an early Nitinol the balloon at the American Heart Association meeting in 1976 and
wire stent. His other best known invention is the “amplatzer septal was met with skepticism, although a few individuals saw the poten-
occluder” as well as the amplatzer cribriform occluder”, which is tial of his work.23 Dr Richard Myler of Saint Mary’s Hospital in San
used for closing atrial septal defect. He founded the AGA Corpora- Francisco suggested and collaborated the first human coronary an-
tion, a device company. gioplasty intra-operatively during bypass surgery in San Francisco.
Some other heroic feats of this period were:7 In September 1977, in Zurich Switzerland, Gruentzig performed the
• 1968: Schoonmaker and King—devised the multipurpose cath- first coronary angioplasty on an awake human.24 Shortly thereafter
eter Gruentzig with Kaltenbach and Kober performed another successful
• 1969: Damato et al. and Scherlag et al.—first His Bundle record- procedure. A year later, when he presented the results of his first four
ings. They set the ball rolling for electrophysiological studies. angioplasty cases to the American Heart Association (AHA) meeting
• 1970: Swan et al.—balloon-tipped flow directed catheter for right in 1977, the audience burst into applause, acknowledging his break-
heart and pulmonary capillary wedge pressure (PCWP) moni- through with a standing ovation.
toring. In January 1978, a small group met in Zurich to discuss plans of
• 1974: Endomyocardial bioptome developed. introducing the technique in the United States. On March 1, 1978
• 1979: Routine use of sheath with hemostatic valve for maintain- Myler in San Francisco and Stertzer in New York introduced Coro-
ing access during multiple catheter exchanges. nary angioplasty.7 The first percutaneous transluminal coronary an-
gioplasty (PTCA) registry was initiated by the National Heart Lung
MOVING INTO THE PERIPHERAL and Blood institute. Though largely self-funded by the participat-
ing 73 centers it generated immense interest, wealth of information
AND CORONARY TREE
which was widely published and discussed and helped accelerate
Rentrop et al. made some path breaking findings in 1978–1980 when interest and acceptance of angioplasty.8
they showed that in acute myocardial infarction (AMI) clots in coro- Sadly Gruentzig met with a tragic end in October 1985 when a
nary arteries could be successfully treated with guide wire, catheter private plane he was piloting crashed in Georgia with his wife beside
manipulation and intracoronary streptokinase. him. That same year some other greats as Dotter, Sones and Judkins
passed away. A golden era seemed to have come to a sudden end, ogy also led to the recognition of better drug regimens which helped
but the inspiration derived from them led others to carry the flame decrease bleeding complications and decrease stent thrombosis
forward and achieve newer heights. In 1987, Gruentzigs first patient rates.
traveled to Emory for an angiogram. Demonstration of a patent ves- Despite all the success restenosis remained the Achilles heel of
sel drew a heartfelt applause from the gathered audience. angioplasty. In order to overcome this several conceptual designs
Simpson in 1985 developed the atherectomy catheter to cut were developed such as heparin-coated stents, but they failed to live
through plaques in peripheral vessels.25 The cardiac adaptation was up to their expectations.
used in 1986 and the Simpson Atherocath received the US Food and Vascular brachytherapy was applied to prevent restenosis in
Drug Administration (FDA) approval in 1991 for use in coronary 1992. The concept was derived from work in oncology and initial
interventions. This device uses the concept of excision and tissue work that dated back to 1965, before the angioplasty and restenosis
removal called directional coronary atherectomy (DCA). Several era. Freidman et al. reported the use of iridium-192 at 14 Gy deliv-
other modifications were developed such as the Rotablater (Heart ered intraluminally to the injured aorta of cholesterol fed rabbits and
Technology, Inc. Bellevue, Wash.), Transluminal extraction catheter demonstrated inhibition of smooth muscle cell (SMC) proliferation
(TEC; Interventional Technologies, Inc. San Diego, Cal.), Rotational and intimal hyperplasia in irradiated atherosclerotic arteries. Based
atherectomy device (Bard CR), Kensey catheter (Theratek Interna- on results of several well-designed clinical trials the US FDA ap-
tional, Miami, Fla.). The transluminal extraction catheter (TEC) de- proved vascular brachytherapy for in-stent restenosis in November
vice developed by Stack and based on concept of cutting and aspira- 2000.28
tion of thrombus obtained the US FDA approval in 1989 or peripheral In 1995, Johnson & Johnson set-up the Stent Therapeutics Team.
interventions and in 1992 for revascularization of saphenous vein Over the next 5 years, this team collaborated with internal and
grafts and native coronary arteries. Even in high volume centers their external Johnson & Johnson partners to develop a therapeutic strat-
average use is in less than 5% of interventions.8 egy for the prevention and treatment of restenosis. They identified a
number of promising drug candidates and examined a wide variety
THE STENT ERA—STENTS of polymeric materials and stent coating processes. They discovered
that antineoplastic drugs used in small amounts could fine tune
AND OTHER DEVICES
neointimal proliferation the basis of in-stent restenosis. Extensive
Some of the problems that plagued plain balloon angioplasty were preclinical testing and safety data eventually led to the creation of the
abrupt vessel closure (which occurred in up to 1% of cases and polymer coating for the Cypher stent that slowly releases Sirolimus
required urgent bypass surgery), vessel dissection and restenosis into the artery wall over 90 days. In 2000, the Cypher stent team be-
which occurred in up to 30% cases. To overcome these, the concept gan the RAVEL trial, the first multicenter, double-blind, randomized
of a scaffold at site of intervention seemed compelling. This gave trial in history for drug-eluting stents. Results from the trial surpassed
birth to the concept of the “stent”. Several prototypes were developed, expectations, and 2 years later the Cypher stent was introduced in
but the first stents to be used in coronary interventions were the self- Europe. Further trials with the Cypher stent revealed that restenosis
expanding wallstent which were spring loaded stents developed by did occur in some individuals with high-risk features (such as long
Sigwart et al. in 1986.26 The use of intracoronary stents was quickly lengths of stenosis or a history of diabetes); but that the restenosis
identified as a method to treat some complications due to PTCA and rate was significantly lower than with bare metal stents (3.2% com-
that their use could decrease the incidence of emergency bypass pared to 35.4%). About a year after approval in Europe, the US FDA
surgery for acute complications post balloon angioplasty. The next approved the use of the Cypher stent as the first drug eluting stent
generation of stents, were balloon mounted and balloon expand- (DES) for use in the general population in the United States.29 The
able such as the Palmaz-Schatz7 (Johnson & Johnson Interventional initial success led to a situation when company was not able to pro-
Systems, Warren, NJ) and the Gianturco-Roubin stent27 (Flex-stent, duce the number of stents in demand. Boston scientific at nearly the
Cook) introduced in 1989. The US FDA initially approved the use of same time developed the Taxus stent on the express 2 platform. This
stents in abrupt and threatened closure. Then arrived the concept of stent was approved for use in Europe in 2003 and in USA in March
using stents electively after balloon angioplasty. This practice was to 2004.29 By the end of 2004 about 80% of interventions used DES. The
change the future of coronary interventions in the face of robust data era of “DES for all” seemed to have come until the issue of ST espe-
from two landmark trials: (1) BENESTENT and (2) STRESS in 1993.8 cially late and very late ST emerged. The magnitude of the problem
Both trials noted better luminal gain and significantly reduced clini- of late and very late ST was worked out to be 0.2% per year in patients
cal end points. However, both also noted an excess of vascular site with on label use and up to 0.6% per year for patients with off label
complications after stenting, resulting from the associated excessive use based upon the data from randomized studies and large regis-
anticoagulation regimen. By 1999 about 85% cases of balloon angio- tries. This led to a heated debate within the community of cardiolo-
plasty were followed by stenting. Significant advances in pharmacol- gists and it is now largely believed that one should restrict oneself
Chapter 66  History of Interventional Cardiology 579
to on label use of DES. Better stent technologies have been devel- incidence of stent thrombosis. These observations were made by
oped such as safer stent-polymer combinations, inert polymers, sur- Colombo in 1995.35 Intravascular ultrasound usage has shown a
face modification for drug delivery without polymer, bioengineered steady growth and greater application in the future will help to
stents; Biodegradable stents that will help overcome these issues and achieve technically better results.36
provide better long term results. Refinements continue to happen
and are bound to improve success rate such that generations con- Ultrasound Angioplasty
tinue to be benefited from these technological marvels.
In 1965, Anscheutz and Bernard37 put forward the concept of using
HISTORY OF SOME OTHER DEVICES ultrasound energy to ablate atherosclerotic plaques. Human Cadav-
eric coronaries were subject to this technique successfully in 1965.
AND CONCEPTS
The same principles were used to achieve clot lysis by Trubestein in
Transmyocardial Revascularization 1976. Siegel et al. in 1989 and 1994 presented the first series of periph-
eral and coronary ultrasound angioplasties.38,39 Rosenchein expand-
The concept of myocardial revascularization emerged in 1930s ed this technique for AMI, unstable angina, and to treat thrombosed
when Wearn et al. demonstrated myocardial sinusoids and arterio- saphenous vein bypass grafts (SVBGs). The technique is still in evolu-
sinusoidal vessels that connected the coronary arteries to LV cham- tion and it could be while before its use becomes common.
ber in human cadaveric heart akin to amphibian hearts.30 Based
on these observations, attempts were made to enhance myocardial Lasers
supply or create new sinusoidal channels. In 1935, Beck31 used my-
opexy and omentopexy, and later Vineberg and Kato implanted the The lasers possess the advantage of that they help evaporate and
distal end of the internal mammary artery into the myocardium in debulk tissues. The intial class of lasers used in interventional cardi-
canine hearts and subsequently in patients, reporting symptomatic ology were, the continuous wave lasers. The first clinical applications
and angiographically apparent myocardial blush. In 1982, Mirho- involved the neodymium (Nd): yttrium aluminum garnet (YAG)
seini et al. applied surgical transmyocardial revascularization (1,060 nm) laser in Europe and the argon (500 nm) laser in Europe in
(TMR) technique using CO2 laser to create myocardial channels 1984. However, it was soon realized that these continuous wave lasers
as an adjunct to coronary artery bypass graft (CABG) in patients caused excess thermal damage that lead to thrombosis, vasospasm,
who could not be completely revascularized using saphenous vein and high restenosis rates. These lead to their discontinuation. In the
grafts.32 Based on such data from several pivotal studies the US mid-1980s Grundfest et al. pioneered the delivery of excimer laser
FDA approved the commercial use of surgical TMR in early 1999 energy through optical fibers. These second generation lasers were
in patients on optimal medical treatment or in those when options associated with fewer complications, caused lesser thermal damage
of surgical or percutaneous interventions were exhausted. Subse- and better plaque vaporization. Deckelbaum et al. also reproduced
quently catheter based devices were also introduced. Despite this similar gratifying results with these pulse wave second generation
the technique remains surrounded by controversy and larger and lasers. Today the laser is a niche device utilized ford debulking and
better planned studies are needed if this therapy is to be used in thrombolysis in complex lesions considered unsuitable for standard
the future. balloon angioplasty.40
The rapid pace of developments in this field has been exempla-
Intravascular Ultrasound ry. The field of electrophysiology, ablation of arrhythmias, pediatric
interventions including closure of defects, valvuloplasties, aorto-
The intravascular ultrasound (IVUS) imaging is a method used to iliac interventions and carotid angioplasty all followed the bold and
obtain high definition images of the blood vessels and even look courageous innovation started by Andreas Gruentzig. This decade
beneath their surfaces. The first ultrasound imaging catheter system is going to be remembered for the advances in percutaneous valve
was developed by Bom et al. in Rotterdam in 1971 for intravascular replacement, a field pioneered by Alain Cribier.
imaging of cardiac chambers and valves.33 Subsequently in 1980s The cardiac catheterization laboratory has clearly transformed
several; catheter systems were developed to image plaques and from a diagnostic facility to a place for providing definitive treat-
facilitate balloon angioplasty and other interventions. The first im- ment—“The Heart of a Cardiology Unit”.
ages of the human vessels were obtained in 1988 by Yock et al.34 with So fascinating is the history of interventional cardiology. One of
coronary images being obtained a year later by Honda et al. and the best narrations of the same goes the credit of Mueller and San-
Hodgson et al. The IVUS was instrumental in establishing the pivotal born.7 Many surprises are bound to come as gifted minds toil night
concept of high pressure inflation that helped significantly reduce and day to make this world a better place with less suffering.
REFERENCES
1. Shepherd RFJ, Vliestra RE. The history of balloon angioplasty. In: Vliestra RE, Holmes DR (Eds). PTCA: Percutaneous Transluminal Coronary
Angioplasty. Philadelphia: FA Davis; 1987. pp. 1-17.
2. Geddes LA, Geddes LE. The catheter introducers. Chicago: Mobium Press; 1993. pp. 38-39.
3. Miller SW. Cardiac angiography. Boston: Little, Brown; 1984. pp. 3-20.
4. Hales S. Statistical essays, containing hemastaticks. In: Innys W, Manby R, Woodward T (Eds). London: 1733.
5. Cournand A. Cardiac catheterization: development of the technique, its contributions to experimental medicine, and its initial applications in
man. Acta Med Scand. 1975;579(Suppl):3-32.
6. Fye WB. Coronary arteriography: it took a long time! Circulation. 1984;70(5):781-7.
7. Mueller RL, Sanborn TA. The history of interventional cardiology: cardiac catheterization, angioplasty, and related interventions. Am Heart J.
1995;129(1):146-72.
8. Myler RK. Coronary and peripheral angioplasty: historical perspective. In: Topol EJ (Ed). Textbook of Interventional Cardiology, 4th edition. Phila-
delphia: Saunders; 2003. pp. 141-161.
9. Forssmann W. The catheterization of the right side of the heart. Klin Wochenschr. 1929;8:2085-7.
10. Cournand A, Riley RL, Breed ES, et al. Measurement of cardiac output in man using the technique or catheterization of the right auricle or ventri-
cle. J Clin Invest. 1945:24(1):106-16.
11. Liljestrand G. Le prix Nobel en 1956. Stockholm: Nobel Foundation; 1957.
12. Dexter L, Haynes FW, Burwell CS, et al. Studies of congenital heart disease: the pressure and oxygen content of blood in the right auricle, right
ventricle, and pulmonary artery in control patients, with observations on the oxygen saturation and source of pulmonary capillary blood. J Clin
Invest. 1947;26(3):554-60.
13. Bing RJ, Vandam LD, Gregoire F, et al. Catheterization of coronary sinus and middle cardiac vein in man. Proc Soc Exp Biol Med. 1947;66:239.
14. Brock R, Milstein BB, Ross DN. Percutaneous left ventricular puncture in the assessment of aortic stenosis. Thorax. 1956;11(3):163-71.
15. Zimmerman HA, Scott RW, Becker NO. Catheterization of the left side of the heart in man. Circulation. 1950;1(3):357-9.
16. Limon Lason R, Rubio Alvarez V, Bouchard F. El cateterismo intracardico: cateterizacion de las cavidades izquierdas en el hombre—registro simul-
taneo de presiony electrocardiograma intracavetarios. Arch Inst Cardiol Mex. 1950;20(3):271-85.
17. Gorlin R, Gorlin SG. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves, and central circulatory shunts:
I. Am Heart J. 1951;41(1):1-29.
18. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography: a new technique. Acta Radiol. 1953;39(5):368-76.
19. Hurst JW. History of cardiac catheterization. In: King SB III, Douglas JS (Eds). Coronary Arteriography and Angioplasty. New York: McGraw-Hill;
1985. pp. 5-6.
20. Sones FM, Shirey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis. 1962;31:735-8.
21. Dotter CT. Presented at the 1963 Czechoslovak Radiological Congress. 1963.
22. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction: description of a new technique and a preliminary report of its ap-
plication. Circulation. 1964;30:654-70.
23. Gruentzig A, Turina MI, Schneider JA. Experimental percutaneous dilatation of coronary artery stenosis. Circulation. 1976;54:81.
24. Hurst JW. The first coronary angioplasty as described by Andreas Gruentzig. Am J Cardiol. 1986;57(1):185-6.
25. Simpson JB, Selmon MR, Robertson GC, et al. Transluminal atherectomy for occlusive peripheral vascular disease. Am J Cardiol. 1988;61(14):96-
101.
26. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med.
1987;316(12):701-6.
27. Roubin GS, Robinson KA, King SB, et al. Early and late results of intracoronary arterial stenting after coronary angioplasty in dogs. Circulation.
1987;76(4):891-7.
28. Waksman R. Radiation for restenosis. In: Topol EJ (Ed). Textbook of Interventional Cardiology, 4th edition. Philadelphia: Saunders; 2003. pp. 725-
45.
29. Müller DWM. Coated stents and local drug delivery for prevention of restenosis. In: Topol EJ (Ed). Textbook of Interventional Cardiology, 4th edi-
tion. Philadelphia: Saunders; 2003. pp. 649-73.
30. Wear JT, Mettier SR, Klumpp TG, et al. The nature of the vascular communications between coronary arteries and the chambers of the heart. Am
Heart J. 1933;9:143.
31. Beck CS. The development of new blood supply to the heart by operation. Ann Surg 1935;102(5):801-13.
32. Kornowski R, Leon MB. Percutaneous transmyocardial revascularization. In: Topol EJ (Ed). Textbook of Interventional Cardiology, 4th edition.
Philadelphia: Saunders; 2003.
33. Bom N, ten Hoff H, Lancée CT, et al. Early and recent intraluminal ultrasound devices. Int J card Imaging. 1989;4(2-4):79-88.
34. Yock P, Linker D, Saether O, et al. Intravascular two-dimensional catheter ultrasound: initial clinical studies. Circulation. 1988;78:21.
35. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance.
Circulation. 1995;91:1676-88.
36. Honda Y, Fitzgerald PJ, Yock PG. Intravascular Ultrasound. In: Topol EJ (Ed). Textbook of Interventional Cardiology, 4th edition. Philadelphia:
Saunders; 2003. pp. 893-917.
37. Topaz O. Laser. In: Topol EJ (Ed). Textbook of Interventional Cardiology. 4th edition. Philadelphia: Saunders; 2003. pp. 675-703.
38. Anscheuutz R, Bernard HR. Ultrasonic irradiation and atherosclerosis. Surgery. 1965;57:549-53.
39. Siegel RJ, Cumberland DC, Newman CMH, et al. Ultrasound angioplasty. In: Topol EJ (Ed). Textbook of Interventional Cardiology, 4th edition.
Saunders: Philadelphia; pp. 705-23.
40. Trübestein G. Entferung intravasaler Thromben durch Ultraschall. Fortschr Med. 1978;96(14):755-60.
67 History of Saphenous Vein
Grafts Intervention
Kumar V, Rastogi V, Seth A
INTRODUCTION AND INTERESTING FACTS Approximately 75% of the SVG graft stenoses are today treated by
devices other than just PTCA, allowing more patients with advanced
Aortocoronary saphenous vein graft (SVG) is used in a significant age, left ventricular dysfunction and more extensive coronary artery
number of coronary artery bypass graft (CABG) operations and is disease being treated with PCI without increasing the complications.
a good choice of myocardial revascularization procedure but ironi- Stent placement is the treatment of choice today for most non
cally SVG failure is its limitation. These thin-walled grafts begin to fail degenerated grafts and selective poorly degenerated grafts too.
with intimal hyperplasia, thrombosis and progressive atherosclerosis Numerous studies have now shown a vein graft stenting accomplish
when exposed to an abrupt increase in wall stress imparted by sys- 95–100% success rate, lower incidence of stent thrombosis (0–3%),
temic arterial pressure. Approximately, 50% of the SVGs get occluded emergency CABG (0–2.8%), MI (0–2%) and restenosis to be (17–35%)
between 5 years and 10 years after the CABG.1 In patients presenting in grafts and emergence of new lesions resulting in target vessel failure.
with acute coronary syndrome more than 5 years after CABG, 85% of This review focuses on the historical evolution of the present day SVG
them have one of the SVGs as the culprit vessel. The optimal treat- intervention.
ment for the old degenerated graft is still not known. Redo CABG sur-
gery is not an ideal option because of higher morbidity and mortality NATURE OF VEIN GRAFT DISEASE AND
(2-4 fold) than the first CABG, as well as less symptom improvement,
ITS PATHOPHYSIOLOGY
compared to the first surgery. It carries significant risk to the patient
and existing patent internal thoracic artery grafts. Atherosclerosis, thrombosis and neointimal hyperplasia are the
Percutaneous transluminal balloon angioplasty had been used three distinctive processes believed to contribute to its disease and
since the beginning of the technique as an alternative to the repeat 50% of venous conduit may occlude at 10 years. Graft atheroma is
CABG in selected patients with recurrent ischemia from SVG disease. diffuse, friable, soft and lipid-rich. The fibrous cap is usually poorly
Several variables have been associated to the problems encountered developed or absent and marked calcification is rare. Saphenous
in percutaneous coronary interventions (PCIs) of stenotic SVG. Fre- vein grafts atherosclerosis is characterized by a larger proportion
quent association of soft and friable, degenerated vein graft lesions, of foam cells and inflammatory cells compared with native lesions,
superimposed thrombus on critical graft stenoses, provide unique prone to fragmentation and distal embolization during PCI. In late
challenges due to the propensity for distal embolization resulting graft occlusions, thrombus formation superimposed on diffuse
in slow or no-reflow phenomena with periprocedural myocardial atherosclerosis is frequently observed (Fig. 67.1).
infarction (MI). The distal embolization during percutaneous trans-
luminal coronary angioplasty (PTCA) of the SVG occurs in 2–15% Initial Injury to Vein Graft
cases of SVG older than 3 years. Independent predictors of distal em-
bolization are diffuse degeneration and large plaque volume within After 1 month, diffuse intimal hyperplasia is a universal finding
the site of stenosis. Another major limitation of PTCA was restenosis caused by systemic arterial pressure inducing wall stretch. Between
(23–73%) within 6 months. However multiple nonrandomized stud- 1 month and 1 year, intimal fibroplasias develop with a concentric,
ies comparing redo CABG versus PTCA have showed high success as hypercellular proliferative response. This seldom results in graft
well as lower death rate and MI following PTCA. occlusion and is more amenable to stenting than the degenerated
A number of pharmaceutical and device-based approaches vein graft lesion. Perioperative vein graft occlusion is often caused
spawned for the above problems of restenosis and distal emboliza by endothelial disruption with superimposed thrombus formation
tion. Stents to embolic protection devices (EPDs) have evolved very and tends to be related to excessive operative trauma, anastomotic
fast with good features and have been used with varied success. compromise or poor distal run-off.
Percutaneous Saphenous Vein

Grafts Intervention
A strategy for avoiding redo CABG is sensible because reoperation
carries a significantly higher perioperative mortality (3–7%) and MI
incidence (3–11%), with less symptomatic benefit compared with
the initial operation.3 Patients requiring redo CABG are more likely
to be of advanced age with significant comorbidities, have smaller
substrates of myocardial ischemia and fewer available conduits. Fur-
thermore, resternotomy carries a risk to existing functional grafts,
particularly patent internal mammary arteries. Long-term patency is
poor in this patient population, irrespective of the treatment modal-
ity. Percutaneous SVG intervention is associated with high restenosis
rates, distal embolization and significant new lesion frequency. The
likelihood of recurrent ischemia due to restenosis or development of
a new lesion is greater than 50% at one1 year.4
Balloon Angioplasty
Figure 67.1: Degenerated venous graft with filling
defect due to thrombus It is a poor strategy for treating significant stenoses in the aged vein
grafts.5 In the Venestent trial, which was a randomized comparison
of balloon angioplasty versus Wiktor stent implantation, 6-month
Accelerated Atheroma
target vessel revascularization was 25% with balloon angioplasty
This begins after approximately 3 years and is diffuse, circumferential compared with 11.5% in the stent group (p = 0.03). There was a 35.6%
and, because it is not contained by a fibrous cap, it is extremely fri- restenosis rate in the balloon angioplasty group and 21.9% in the
able. group with stenting (p = 0.09).6 The multicenter, prospective, ran-
domized SAVED trial also compared balloon angioplasty (n = 110)
Established Vein Graft Disease with stenting (n = 110), using Palmaz-Shatz7 stents. Restenosis rate
in the balloon angioplasty group was 47% and 36% in the stent group
The nature of established vein graft disease is one of the complex, (p = 0.11). Restenosis was more common in diabetics (p = 0.07) in
bulky atheromatous plaques with similar morphology to that seen smaller vessels, if there was complex, ulcerated atheroma and when
in native coronary arteries. It is frequently associated with throm- postprocedural minimal luminal diameter was smaller.
bus formation with a high incidence of atheroembolism occurring
spontaneously or during percutaneous intervention.2 This is a diffuse Stenting of Saphenous Vein Grafts
process resulting in multiple stenoses with a paucity of calcification.
Stenting significantly improves event-free survival when compared
Differential Impact of Baseline Patient Risk with balloon angioplasty, despite similar rates of restenosis.7 SAVED
and Venestent trials did not show a significant reduction in binary
Profile and of the Intervention on Outcomes
angiographic restenosis (the primary end point of both studies) of
Patients with SVG disease requiring revascularization have greater bare metal stents (BMS) versus balloon angioplasty. The results of
risk profile than their counterparts undergoing native coronary BMS in SVGs are less favorable than those in native vessels, with
artery intervention. The former are usually older and have more restenosis rates exceeding 30%.7,8
comorbidity, such as prior MI, diabetes, hyperlipidemia, hyper Drug-eluting stents (DES) have reduced the rate of restenosis
tension, stroke, heart failure and peripheral vascular disease. and repeat revascularization with respect to BMS in de novo native
Patients undergoing PCI of a bypass graft have higher death coronary artery lesions in selected patient population. Drug-eluting
rates and more nonfatal cardiac events than patients undergoing stents appear to be superior to BMS in the treatment of SVG lesions.
native coronary intervention. Although partially explained by the In the only randomized trial to date comparing DES and BMS in the
increased prevalence of high-risk characteristics among the patients treatment of SVG disease, sirolimus-eluting stents (SES) significantly
undergoing graft intervention, it has been demonstrated that the reduced late loss at 6-month angiographic follow-up.9 Thirty-eight
procedure per se is associated with worse outcomes compared with patients received 60 SES for 47 lesions and 37 patients received 54
interventions of the native circulation. BMS for 49 lesions. Binary in-stent and in-segment restenosis were
Chapter 67  History of Saphenous Vein Grafts Intervention 583
reduced: 11.3% versus 30.6% (p = 0.024) and 13.6% versus 32.6% (p = soft, acellular atheromatous particles, 80–200 m in diameter.19 With
0.031), respectively. Target lesion and vessel revascularization rates atheroembolization, distal (arteriolar) myocardial microcirculation
were significantly reduced: 5.3% versus 21.6% (p = 0.047) and 5.3% is compromised resulting in the “no-reflow” phenomenon compli-
versus 27% (p = 0.012), respectively. Death and MI rates did not differ. cating 10–15% of vein graft interventions.20 By definition, thromboly-
DES implantation showed the potential to be superior to bare metal sis in myocardial infarction (TIMI) flow is grade 0–1 in the absence of
stenting in SVGs.10,11 In reducing late lumen loss when compared epicardial vessel dissection, spasm, thrombus or high-grade residual
with BMS, SES tacitly inhibits neointimal hyperplasia, a pathologi- stenosis at the original target lesion. Lesser degrees of impaired flow
cal forerunner of in-stent restenosis.12 Randomized trial performed (TIMI grade 2) are generally referred to as “slow-flow.” No-reflow is
in de novo SVG lesions has shown significant angiographic benefit more likely if there is thrombus, the patient has an acute coronary
for DES (SES) over BMS. Some studies have proposed superiority of syndrome, the graft is degenerated or the plaque is ulcerated.21
DES in SVG lesions when compared to BMS in short and midterm Throughout the 1990s, when it was thought that microcirculatory
follow-up. Increased late mortality after SES versus BMS in diseased spasm was responsible for no-reflow, intragraft vasodilators, such
SVGs. Results from the randomized, delayed RISC Trial is the only as verapamil, adenosine and sodium nitroprusside, were given with
study, which reported unfavorable clinical outcomes with DES com- limited success. Multiple and rapid intragraft boluses of adenosine
pared to BMS in long-term (> 3 years) follow-up.13 Short- and long- have been demonstrated to be safe and effective in reversing no-re-
term clinical outcomes of paclitaxel-eluting stents (PES) and SES in flow in observational studies.22,23 Platelet aggregation was naturally
the treatment of SVG lesions are similar.13 The results showed that targeted as a possible cause of no-reflow phenomenon, however, ad-
both DES are effective and safe in real world patient with diseased junctive use of platelet glycoprotein IIb/IIIa inhibitors do not appear
SVGs. All clinical outcomes at 30 days, 6 months and 1 year after to reduce myonecrosis or improve survival in SVG intervention.24,25
the interventions were similar in both groups. Early stent thrombo- Periprocedural MI occurs in up to 28% of all SVG percutaneous
sis was detected in one patient (2.2%) of PES group (p = 0.65). Late coronary interventions26 and is associated with higher morbidity
stent thrombosis was not observed in both groups. The rate of major and mortality.27 Although several pharmacologic [administration of
adverse cardiac events (MACE) at 1 year was 8.7% in the PES group calcium channel blockers,28 nitrates,22 adenosine,29 thrombolytics30
and 16% in the SES group (p = 0.44.).13 and glycoprotein IIb/IIIa inhibitors31 and mechanical (direct stent-
High restenosis rates and distal embolization of atheromatous ing,32 use of undersized stents33 or covered stents34 to trap debris
debris, itself a strong predictor of late mortality, provide the rationale against the SVG wall and EPDs27)] strategies have been evaluated
to develop a membrane-covered stent to trap plaque material against over the last 2 decades to address this problem, only EPDs have been
the graft wall and so limit the microembolization and reduce reste- shown to decrease periprocedural MI in SVG interventions.
nosis by preventing proliferating plaque from protruding through the No-reflow is more likely with PCI of diffusely diseased SVGs,
stent cells. The Jostent coronary stent graft was thus developed and but can also occur in PCI of focally diseased SVGs.35 A degeneration
utilized a biocompatible polytetrafluoroethylene membrane sand- score was developed to quantify the extent of lumen irregularity and
wiched between two stainless steel stents. These so-called “covered” ectasia (> 20% of the reference normal segment) within the SVG. The
stents were evaluated in a German multicenter registry and were cumulative length (in millimeters or mm) of SVG luminal irregu-
found to be a safe and efficient treatment strategy for obstructed larities or ectasia is divided by the length of the entire SVG and pre-
SVGs with restenosis rates of approximately 17%.14 However, data sented as a percent. If the ratio is less than 25%, an SVG degenera-
from the multicenter, randomized Stents IN Grafts trial, comparing tion score of 0 is assigned; a degeneration score of 1 is assigned for a
the Jostent coronary stent graft with BMS demonstrated that stent ratio between 26% and 50%, 2 for 51–75%, and 3 for more than 75%.
grafts deliver no benefit over BMS with respect to restenosis or clini- Along with SVG plaque volume, the SVG degeneration score has
cal events, with no evidence of reduced distal embolization.15 These been shown to be the strongest predictor of 30 days MACE follow-
covered stents are stiff, commonly causing difficulty in crossing le- ing an SVG PCI.36 Although SVGs with a higher degeneration score
sions and steering ability. The lack of evident embolic protection, late have a higher risk of post-PCI myocardial infarction, the use of an
loss of 1.17 mm and a high restenosis rate of 29% (one half (16%) of EPD provided a similar relative risk reduction (approximately 40%)
which represented late occlusion), make stent graft use disappoint- in all categories of the SVG degeneration score.
ing.16,17
Distal Embolic Protection Devices and Embolic
Distal Embolization Protection Device Trials in SVG Intervention
The propensity for distal atheroembolization and periprocedural MI Prevention of distal embolization has to be anticipated before hand
in SVG intervention is a significant one indeed. Periprocedural MI is and points to be kept in mind while performing an SVG PCI. Phar-
associated with a significantly higher 1-year mortality.18 The compo- macological agents, technique of deployment and, very importantly,
sition of collected particulate debris resulting from vein graft lesion the EPDs have all been modes of preventing or treating the slow flow
manipulation has been studied. Material predominantly consists of or no-reflow situation. Various devices have evolved till date with
refinement of hardwares today that are very easy to use and also 30-day MACE rate has remained unchanged.36 This may represent
consistently shown to protect against distal embolization in SVG the complexity and high risk associated with SVG PCI, limitations of
intervention. This growing importance of EPDs has been echoed in current EPDs, an alternate mechanism of SVG disease progression,
many studies although its use has not been greatly done routinely in and may call for operator experience along with consistent use of
all SVG interventions because of cost issues and its cost-effectiveness both pharmacological and mechanical embolic protection strategies
especially where thrombus burden is less. The devices have been during SVG PCI.
evaluated based on features of deployment, position of the device, Deployment of EPDs except for the ProxisTM (St. Jude Medical,
flow preservation, pore size, optimization, embolic protection time Maple Grove, Minnesota) may be challenging across severely sten-
line and deliverability. The evidence base for use of EPDs during SVG otic lesions, and may either prevent device delivery or the need for
PCI is compelling, and its use is a Class I indication by the American predilatation with an undersized balloon, which may itself lead to
College of Cardiology and American Heart Association guidelines. distal embolization. Although the proximal balloon occlusion device
Table 67.1 shows different EPDs in use and related trials. or Proxis allows embolic protection of body and distal anastomotic
Although EPDs are the only clinical, trial proven therapy for pre- SVG lesions, it does not provide protection of ostial lesions.37
venting periprocedural MI during SVG interventions, they are cur-
rently used in only a small proportion of eligible patients. Five EPDs Distal Occlusion
are currently FDA-approved for use in the US: one proximal occlu-
sion device, three filters and one distal occlusion device. Most SVG The PercuSurge GuardWire utilizes an aspiration thrombectomy
lesions are located in the midbody of the graft (38%), followed by catheter that removes atherothrombotic material prior to balloon
proximal (30%) and distal graft (23%) locations.36 Ostial and anasto- deflation. The long distal occlusion balloon serves to protect the
motic lesions account for less than 7% of SVG lesions.36 The impact of microcirculation during lesion manipulation. The SAFE registry was
the size of the filter pore, the ability to provide protection from small the first to report on EPDs in SVG intervention.38 The PercuSurge
particle (< 60 µm) embolization and its clinical impact remain con- distal occlusion GuardWire 801-patient, randomized SAFER trial
troversial.36 hence evolved and demonstrated a significant reduction in 30-day
Before providing individual device descriptions, it is important adverse events (from 17% to 9.6%) and no-reflow (from 8.3% to 3.3%)
to point out that none of the devices can be universally used for all compared with stenting over a conventional guidewire.26 This trial
SVG lesions. Apart from the technical factors associated with device established embolic protection as the standard of care for SVG stent-
selection, familiarity of the primary operator and catheterization lab- ing. Since then, the PRIDE trial utilizing the TriActiv system, demon-
oratory staff with one or more of these EPDs are crucial for technical strated noninferiority to the established GuardWire distal protection
success and procedural safety. The use of EPDs may be associated device with respect to 30-days MACE.39
with unique risks and complications such as intragraft entrapment.
Ischemia induced during the use of balloon-occlusive EPDs may re- Distal Filtration
sult in significant patient discomfort and associated hemodynamic
and electrical instability. The use of EPDs reduces the 30-day MACE The FilterWire EPD followed the GuardWire and a comparison
rate by about 40%, however, despite their use; the approximate 10% of the two in the FIRE study showed equivalence.39 The FilterWire
TABLE 67.1 Embolic protection device trials in saphenous vein grafts intervention
Type Trial Device 30-Day MACE (%) P Result
Distal occlusion device SAFER GuardWire 9.6 0.004 GuardWire superior
Conventional guidewire 16.5
PRIDE TriActive 11.2 0.02 TriActive system not inferior
GuardWire 10.1
Distal filter device FIRE FilterWire EX 9.9 0.0008 FilterWire EX not inferior
GuardWire 11.6
CAPTIVE CardioShield 11.4 0.57 CardioShield not non inferior
GuardWire 9.1
SPIDER SPIDER/SpideRX 9.1 0.012 SPIDER/SpideRX not inferior
GuardWire or FilterWire EX/EZ 8.4
Proximal occlusion device PROXIMAL Proxis 9.2 0.006 Proxis not inferior
FilterWire or GuardWire 10
system consists of a windsock-shaped, nonocclusive filter (100 m Plaque Trapping

pore size)38 mounted on a self-expanding nitinol loop positioned
distal to the lesion. Intervention is performed over the wire and the New plaque-trapping41 devices including a nitinol stent with integral
device is captured using a retrieval sheath. Subgroup analysis in the nitinol mesh have evolved and are under study. These aim to keep
FIRE trial suggested an advantage of the FilterWire over the Guard- potentially embolic debris at the treatment site. Early pilot testing
Wire in small vessels and eccentric lesions. Whilst the FilterWire may shows promise. As yet, none of the above EPDs successfully eliminate
be more difficult to maneuver and malapposition of the nitinol loop distal embolic risk and reduce the current 6–10% MACE rate in this
within the graft, it may lead to an incomplete seal, preserve coronary challenging patient group. Future plaque-trapping stent grafts with
blood flow and retrieves most debris (80% of particles collected are antiproliferative compounds may prove to be the ultimate solution. If
smaller than 100 m diameter) (Fig. 67.2). large luminal thrombi are present, mechanical thrombectomy cath-
eters such as the X-sizer are useful, particularly if thrombus burden is
Proximal Occlusion/Flow Reversal overwhelming for filter protection or if protection devices cannot be
used (distal SVGs, bifurcation sites). Hydrodynamic thrombectomy
In addition to distal occlusion (GuardWire) and distal filtration (Fil- systems (Angiojet, Pronto) that create a Venturi effect and fragment
terWire), proximal occlusion and flow reversal utilizing the Proxis thrombus are also available.
system are the most studied members of yet another family of EPDs.
This allows suspended debris to be aspirated via a guiding catheter. Spider, Interceptor
The PROXIMAL trial compared the Proxis device in SVG intervention
with distal protection devices and demonstrated noninferiority in Embolic protection devices that can be delivered simultaneously with
preventing 30-day MACE.40 The Proxis device may be advantageous stent deployment (Spider, Interceptor), thereby eliminating the re-
during PCI of SVG lesions where balloon or stent delivery is difficult, quirement for a delivery catheter, have emerged. The Spider RX™ (ev3,
as it often provides superior support after anchoring. However, the Inc., Plymouth, Minnesota) allows the operator to choose any 0.014
delivery of cutting balloons, rotational atherectomy and thrombecto- inch guidewire, and the Interceptor® PLUS (Medtronic Vascular, Santa
my (Angiojet XMITM, Possis Medical, Inc., Minneapolis and Minne- Rosa, California) obviates the need for a dedicated re-retrieval device.
sota) devices through the Proxis is not possible. Yet, Proxis is the only
device that provides the ability for protected crossing of the lesion, MGuard
and along with the GuardWire® (Medtronic Vascular, Santa Rosa,
California), allows confirmation of embolic protection and a real- A new approach to embolic protection16,17 in which an attempt
time road map for balloon or stent delivery with suspended con- to block the debris at its source itself done and thus, preventing it
trast material within the SVG. The Proxis and GuardWire devices from entering the bloodstream in the first place has evolved. It is a
theoretically offer protection from small particulate embolization. BMS covered by an ultrathin polymer mesh sleeve on its external
surface, designed to reduce embolization (Fig. 67.3). During stent
deployment, the net stretches and slides over the expanding stent
struts, creating custom-designed pores of less than or equal to 200
microns in diameter (pores created by stent struts have a 5–40-
fold larger diameter, translating into 25–1,600-fold larger cross
Figure 67.2: Magnified image of a FilterWire embolic protection Figure 67.3: MGuard device on an expandable bare metal stent
device containing atheromatous debris
TABLE 67.2 Efficacy of different strategies in percutaneous intervention of vein grafts
Therapy Efficacy Comments
Stents Likely Not prospectively addressed in large-scale randomized trials
Majority of SVG PCI performed are stent-based
Covered stents Failed Lack of efficacy demonstrated in a randomized trial
Preliminary data on new-generation covered stents promising
Drug-eluting stents Unknown Safety/efficacy not assessed in graft interventions
GP IIb/IIIa inhibitors Failed No efficacy in a pooled analysis
Not recommended in unprotected SVG PCI
Combination with distal emboli protection devices requires investigation
Emboli protection devices Highly effective Efficacy demonstrated in randomized trials
Distal balloon occlusion and filter devices equally effective
Ultrasound thrombolysis Failed Tested in a randomized trial
Atherectomy devices Unknown Insufficient safety and/or efficacy data
Brachytherapy Highly effective Efficacy demonstrated in randomized trials of in-silent restenosis
Abbreviations: SVG = saphenous vein graft; PCI = percutaneous coronary intervention.
sectional area) parallel to the arterial wall. The microfiber net (string death. The major breakthrough has been the use of distal protection
diameter 20 microns) has minimal effects (< 0.1 mm) on the stent’s devices, a strategy associated with a dramatic reduction in adverse
crossing profile and deliverability. By trapping the thromboembolic events. More studies are needed to assess the impact of DES, new
debris underneath the fiber net and isolating the prothrombotic generation covered stents and the EPDs. At present, the optimum
subintimal components. Once in place, MGuard captures embolic treatment for stenotic, degenerated SVGs is DES placement with
debris between the fiber net and the arterial wall and isolates the distal embolic protection device. Table 67.2 shows the efficacy and
prothrombotic intima components from the bloodstream. Side safety of different options in the treatment of SVG PCI. Stents can be
branch compromise and mesh issues are its limitations but first-in- deployed directly without an embolic protection device only when
man studies have been encouraging. graft and lesion anatomy are favorable with little or no thrombus
burden, thereby avoiding undue plaque manipulation. Saphenous
Current and Future Directions in Saphenous vein grafts intervention is still fraught with challenges such as distal
embolization and restenosis, which may result in periprocedural MI
Vein Grafts Intervention
and target vessel failure, respectively.
Percutaneous coronary intervention of SVG is associated with worse The challenges of SVG intervention remain obstinate and, whilst
outcomes compared with procedures involving the native circula- progress is being made, the complete and best solution(s) have yet to
tion. In addition to baseline risk features carried by SVG patients, be found. Research should focus on the still badly understood patho-
the endovascular treatment of a graft per se is more frequently as- genesis of graft atherosclerosis and mechanisms of disease progres-
sociated with periprocedural MI, subsequent revascularization and sion.
REFERENCES
1. Campeau L Lespérance J, Hermann J, et al. Loss of improvement of angina between 1 and 7 years after aortocoronary bypass surgery. Circulation.
1979;60:1-5.
2. Fitzgibbon GM, Leach AJ, Kafka HP, et al. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5065 grafts related and
reoperation in 1388 patients during 25 years. J Am Coll Cardiol. 1996;28:616-26.
3. Cameron A, Kemp HG, Green GE. Reoperation for coronary artery disease: 10 years of clinical follow-up. Circulation. 1998;78:1158-62.
4. Le May M, Labinaz M, Marquis JF, et al. Predictors of long-term outcome after stent implantation in a saphenous vein graft. Am J Cardiol.
1999;83:681-6.
5. de Feyter P, van Suylen RJ, de Jaegere PJ, et al. Balloon angioplasty for the treatment of lesions in saphenous vein bypass grafts. J Am Coll Cardiol.
1993;2:1539-49.
6. Hanekamp C, Koolen J, den Heijer P, et al. A randomized comparison between balloon angioplasty and elective stent implantation in venous
bypass grafts; the Venestent study. Cathet Cardiovasc Interv. 2003;60:452-7.
7. Savage MP, Douglas Jr JS, Fischman DL, et al. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. N Engl J
Med. 1997;337:740-7.
8. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. Task Force for Percutaneous Coronary Interventions of
the European Society of Cardiology. Guidelines for percutaneous coronary interventions. Eur Heart J. 2005;26:804-47.
9. Vermeersch P, Agostini P, Verheye S, et al. Randomised double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation
in diseased saphenous vein grafts: six month angiographic, intravascular ultrasound and clinical follow-up of the RRISC Trial. J Am Coll Cardiol.
2006;48(12):2423-31.
10. Ge L, Iakovou I, Sangiorgi GM, et al. Treatment of saphenous vein graft lesions withdrug-eluting stents. J Am Coll Cardiol. 2005;45:989-94.
11. Lee MS, Shah AP, Aragon J, et al. Drug-eluting stenting is superior to bare metal stenting in saphenous vein grafts. Cathet Cardiovasc Interv.
2005;66:507-11.
12. Kereiakes DJ, Kuntz RE, Mauri L, et al. Surrogates, sub-studies and real clinical end points in trials of drugeluting stents. J Am Coll Cardiol.
2005;45:1206-12.
13. Chu W, Kuchulakanti P, Wang B, et al. Efficacy of sirolimus-eluting stents as compared to paclitaxel-eluting stents for saphenous vein graft inter-
vention. J Interv Cardiol. 2006;19(2):121-5.
14. Baldus S, Köster R, Elsner M, et al. Treatment of aortocoronary vein graft lesion with membrane-covered stents: a multicentre surveillance trial.
Circulation. 2000;102:2024-7.
15. Schachinger V, Hamm CW, Munzel T, et al. A randomized trial of polytetrafluoroethylene membrane-covered stents compared with conventional
stents sub-studies and real clinical end points in trials of drug eluting stents. J Am Coll Cardiol. 2005;45:1206-12.
16. Preliminary Experience with the Novel MGuardTM Stent System Containing a Protection Net to Prevent Distal Embolization - Results From a
Prospective, Non-Randomized, Single Center Study. Circulation. 2008;118:S_745.)
17. Kaluski E, Hauptmann KE, Müller R. Coronary Stenting with MGuard: first-in-man trial. J Invasive Cardiol. 2008;20:511-5.
18. Hong M, Mehran R, Dangas G, et al. Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated
with late mortality. Circulation. 1999;100:2400-5.
19. Webb J, Carere R, Virmani R, et al. Retrieval and analysis of particulate debris after saphenous vein graft intervention. J Am Coll Cardiol.
1999;34(2):468-75.
20. Leopold J, Berger C, Cupples L. No-reflow during coronary intervention: observations and implications. Circulation. 2000;102:II-644.
21. Sdringola S, Assali A, Ghani M, et al. Risk assessment of slow or no-reflow phenomenon in aortocoronary vein graft percutaneous intervention.
Cathet Cardiovasc Interv. 2001;54(3):318-24.
22. Sdringola S, Assali A, Ghani M, et al. Adenosine use during aortocoronary vein graft interventions reverses but does not prevent the slow-no reflow
phenomenon. Cathet Cardiovasc Interv. 2000; 51(4):394-9.
23. Kern MJ. Adenosine boluses: a cure for “no-reflow”? Cathet Cardiovasc Diagn. 1998;45(4):366-7.
24. Ellis S, Linkoff A, Miller D, et al. Reduction in complications of angioplasty with abciximab occurs largely independently of baseline lesion mor-
phology. J Am Coll Cardiol. 1998;32:1619-23.
25. Mathew V, Grill DE, Scott CG, et al. The influence of abciximab use on clinical outcome after aortocoronary vein graft interventions. J Am Coll
Cardiol. 1999;34:1163-9.
26. Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein
aorto-coronary bypass grafts. Circulation. 2002;105:1285-90.
27. Michaels AD, Appleby M, Otten MH, et al. Pretreatment with intragraft verapamil prior to percutaneous coronary intervention of saphenous vein
graft lesions: results of the randomized, controlled vasodilator prevention on no-reflow (VAPOR) trial. J Invasive Cardiol. 2002;14:299-302.
28. Zoghbi GJ, Goyal M, Hage F, et al. Pretreatment with nitroprusside for microcirculatory protection in saphenous vein graft interventions. J Invasive
Cardiol. 2009;21:34-9.
29. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic
drugs. Circulation. 2000;101:125-30.
30. Roffi M, Mukherjee D, Chew DP, et al. Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment
for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials. Circulation. 2002;106:3063-7.
31. Leborgne L, Cheneau E, Pichard A, et al. Effect of direct stenting on clinical outcome in patients treated with percutaneous coronary intervention
on saphenous vein graft. Am Heart J. 2003;146:501-6.
32. Iakovou I, Dangas G, Mintz GS, et al. Relation of final lumen dimensions in saphenous vein grafts after stent implantation to outcome. Am J Car-
diol. 2004;93:963-8.
33. Stankovic G, Colombo A, Presbitero P, et al. Randomized evaluation of polytetrafluoroethylene-covered stent in saphenous vein grafts: the Rand-
omized Evaluation of polytetrafluoroethylene covered stent in Saphenous vein grafts (RECOVERS) Trial. Circulation. 2003;108:37-42.
34. Lim MJ, Young JJ, Senter SR, et al. Determinants of embolic protection device use: case study in the acceptance of a new medical technology.
Catheter Cardiovasc Interv. 2005;65:597-9.
35. Coolong A, Baim DS, Kuntz RE, et al. Saphenous vein graft stenting and major adverse cardiac events: a predictive model derived from a pooled
analysis of 3958 patients. Circulation. 2008;17:790-7.
36. Mauri L, Cox D, Hermiller J, et al. The PROXIMAL trial: proximal protection during saphenous vein graft intervention using the Proxis Embolic
Protection System: a randomized, prospective, multicenter clinical trial. J Am Coll Cardiol. 2007;50:1442-9.
37. Grow P, Rab ST. Percutaneous saphenous vein graft intervention with sequential embolic protection devices: complementing lesion anatomy with
embolic protection device. Catheter Cardiovasc Interv. 2008;72:636-40.
38. Grube E, Schofer J, Webb J, et al. Evaluation of a balloon occlusion and aspiration system for protection from distal embolization during stenting
in saphenous vein grafts. Am J Cardiol. 2002;89:941-5.
39. Carrozza J, Mumma M, Breall J, et al. Randomized evaluation of the TriActiv balloon-protection flush and extraction system for the treatment of
saphenous vein graft disease. J Am Coll Cardiol. 2005;46:1677-83.
40. Stone G, Rogers C, Hermiller J, et al. Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspira-
tion system during percutaneous intervention of diseased saphenous vein aortocoronary bypass grafts. Circulation. 2003;108:548-53.
41. Rogers C. A prospective randomized comparison of proximal and distal protection in patients with diseased saphenous vein grafts [abstract].
Presented at Transcatheter Cardiovascular Therapeutics; 2005.
68 History of Left Main Percutaneous
Coronary Intervention
Mishra S, Bahl VK
Charles Dotter (Fig. 68.1), working with Melvin Judkins was the In 1974, Andreas Gruentzig, a young German physician working
first to introduce the concept of transluminal angioplasty in 1976. at University Hospital in Zurich, Switzerland, performed the first pe-
He used multiple catheters of increasing diameter to open blocked ripheral human balloon angioplasty. Subsequently, he presented his
arteries and improve blood flow in patients with arteriosclerosis in results of animal studies of coronary angioplasty at American Heart
peripheral arteries. Association (AHA) meeting in 1976 (Fig. 68.2).
In 1977, first human coronary artery angioplasty was performed
intraoperatively by Gruentzig, Myler and Hanna in San Francisco
(Fig. 68.3).
Andreas Gruentzig was also the first to perform first cath lab per-
cutaneous coronary intervention (PCI) on awake patient in Zurich.
Since then there has been a rapid advance in the field of interven-
tional cardiology from introduction of better balloon catheters, to
stents and now DES. So much so, that angioplasty is currently the
most favored revascularization procedure for patients of stenotic
coronary artery disease. However, until recent past, unprotected left
main coronary artery (LMCA) disease requiring revascularization has
remained the final frontier for the surgeons at most institutions. The
reason for this was symptomatic atherosclerotic disease of the LMCA
managed conservatively (without revascularization) portends a dire
prognosis, with up to a 20% 1-year and 50% 7- to 10-year mortality.1-5
Numerous registries and two randomized trials have demonstrated
Figure 68.1: Charles Dotter a marked survival advantage of coronary artery bypass graft (CABG)
Figure 68.2: Andreas Gruentzig in American Heart Association Meeting 1976

Chapter 68  History of Left Main Percutaneous Coronary Intervention 589
Figure 68.3: First human coronary balloon angioplasty performed Figure 68.5: Dr James O’Keefe, preventive cardiologist for
intraoperatively cardiovascular consultants of the St Luke’s Mid America Heart
Figure 68.4: Trials of coronary artery bypass graft for left main
revascularization. Abbreviations: VACSS: Veterans Administration
Cooperative Surgery Study; CASS: Coronary Artery Surgery Study;
ECASS: European Cooperative Acute Stroke Study
B
surgery over medical therapy in most subsets of patients with LMCA

disease (Fig. 68.4).3-5
On the other hand, O’Keefe and colleagues at St Luke’s Hospital
in Kansas City exposed the limits of 1980s technology, documenting
a high rate of procedural death (9.4%) and mortality at 3 years (64%)
after LMCA balloon angioplasty, with restenosis often manifesting as
sudden cardiac death (Fig. 68.5).6
C
To a beginner, the LMCA might be considered an attractive tar-
get for PCI; lesions in the LMCA are proximally located, and thus Figures 68.6A to C: First percutaneous coronary intervention of
readily crossable with a guidewire and balloon. Moreover, many of left main artery disease done more than 30 years ago
these lesions are short and, therefore, easily tackleable. Indeed, the
first left main angioplasty was performed by Andreas Gruentzig him- Generally, left main angioplasty was limited by risk of acute pro-
self as one of the first five angioplasty procedures (Figs 68.6A to C).7 cedural complications like dissection and abrupt closure and poor
long-term durability because of restenosis and risk of sudden cardiac

death.6 With the implantation of the coronary stents by Jacques Puel
on March 28th 1986 in Toulouse, the acute problems associated with
PCI were successfully addressed. Moreover, there was some reduc-
tion even in rates of restenosis.8 The Unprotected Left Main Trunk In-
tervention Multicenter Assessment (ULTIMA) registry conducted by
Steve Ellis in 279 patients with unprotected LMCA lesions (between
1993 and 1998 at 25 hospitals) demonstrated that procedural mortal-
ity was reduced to 13.7%. Furthermore in 89 low-risk patients, there
were no periprocedural deaths, and survival at 1 year was 96.6%.9
Other centers also demonstrated favorable results in stable patients A
with preserved left ventricular function.10-12 Subsequently, evolu-
tion of interventional techniques in terms of availability of invasive
imaging, such as intravascular ultrasound (IVUS) and availability of
debulking devices and devices used for hemodynamic support, like
intra-aortic balloon counter-pulsation (IABP) and now Impella de-
vice have also contributed improvement in acute results (Figs 68.7A
to C, Table 68.1).13-20
Nonetheless, long-term outcomes were still not favorable. In
ULTIMA registry, 1-year mortality was 24%. In other studies too,
restenosis rates remained high, especially with involvement of the B C
distal bifurcation, and therefore direct comparisons with CABG were
Figures 68.7A to C: Use of intravascular ultrasound in
avoided (Fig. 68.8).
left main stenosis
The next step in evolution of LMCA PCI was development of
drug eluting stents (DES). Although LMCA lesions were excluded TABLE 68.1 Outcome after improved strategy
from the initial pivotal randomized trials with DES, their use in this Strategy In-hospital Mortality 1-Year Mortality
indication was cautiously explored.21-28 The studies showed that with Plain old balloon angioplasty 12 17
use of DES even 6–12 month outcomes were somewhat acceptable, (POBA)
mortality ranging from 0% to 11% and restenosis rate varying from Stent + IVUS + Debulking 0 2
7% to 44%. The first randomized controlled study by Erglis and device
Figure 68.8: Mortality at follow-up in percutaneous coronary intervention series in unprotected left main stem stenosis
co-workers comparing bare metal stents (BMS) with DES, employing Thus, after introduction of DES, PCI has emerged as a viable
the best of available technology (utilizing cutting balloon predila- alternative to CABG, especially in low-risk patients (with preserved
tion and IVUS guidance to optimize procedural results) also demon- LV function), and those with a suitable anatomy (such as discrete ste-
strated that while acute results were good in both the groups, i.e. no nosis in ostium or shaft) and the only option in patients high risk for
in-hospital death in either group, even subacute results were reason- CABG (multiple co-morbidities).
able: only two deaths (1.9%, 1 in each group) at 6 months, with no However, the moot question at this point of time is that do these
episodes of stent thrombosis.29 However, repeat revascularization for results justify considering DES as a valid alternative to CABG for the
recurrent angina or ischemia at 6 months was 16.0% in BMS group majority of patients with LMCA disease? The Left Main Coronary Ar-
versus 1.9% in DES group, p = 0.01, probably attributable to a marked tery Stenting (LE MANS) trial comparing (BMS or DES) versus CABG,
reduction in angiographic restenosis with the DES (22.0% vs 5.7%, p the resting left ventricular ejection fraction (LVEF) rose from similar
= 0.02) (Fig. 68.9). baseline values to a higher level in the PCI group at 12 months (60.3 ±
12.6% vs 54.0 ± 9.1%, p = 0.037). At 40-month follow-up, the survival
and angina status were similar in both groups, with no occurrences
of stent thrombosis reported (Table 68.2).30
Lee and colleagues also compared the clinical outcomes of con-
secutive, selected patients treated with CABG or PCI with DES for un-
protected left main coronary artery (ULMCA) disease. The estimated
major adverse cardiac or cerebrovascular events (MACCE)-free sur-
vival at 6 months and 1 year was 83% and 75% in the CABG group
versus 89% and 83% in the PCI group (p = 0.20). By multivariable Cox
regression, Parsonnet score, diabetes, and CABG were independent
predictors of MACCE. They found that the short-term and interme-
diate-term outcome with PCI were at least equivalent to CABG if not
superior (Fig. 68.10).31
TABLE 68.2 Outcomes of LE MANS trial

Outcomes CABG (%) PCI (%) P
Any major adverse cardiac events 20.7 3.8 0.028
(MACE) (< 30 days)
Any major adverse events (MAE) (< 30 35.8 5.8 0.0001
days)
Figure 68.9: Andrejs Erglis: Chief, Latvian Center of Cardiology Any MACE (30 d–12 m) 20 21 NS
Figure 68.10: Direct comparison of best of coronary artery bypass graft with best of percutaneous coronary intervention.
Abbreviations: MI, Myocardial infarction; TLR, Target lesion revascularization; LM, Left main
Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX)

was a unique trial in that all-comers were invited to participate pro
spectively (instead of a highly selected patient population). The du
ration of follow-up was 1 year at which time there was a significantly
higher rate of revascularization in the PCI group (13.7 vs 5.9%
p < 0.0001) and a significantly higher rate of cerebrovascular accident
(CVA) in the CABG group (2.2 vs 0.6% p = 0.003). There was, however,
no difference in the occurrence of all cause death, myocardial infarc
tion and CVA among patients who underwent CABG and stenting
(7.7% vs 7.6% p = 0.98).32
However, in patients with isolated left main disease or those with
left main disease with single vessel disease, the 1-year outcome of
PCI actually appeared superior (Fig. 68.11).
Figure 68.11: One-year outcome in SYNTAX trial. Abbreviations: LM, The current status is that while LMCA PCI has become an
Left main; SVD, Single vessel disease; DVD, Double vessel disease; acceptable alternative to CABG in Europe, other countries are still
TVD, Triple vessel disease following a cautious “wait and watch” policy applying it on patients
who are contraindicated for CABG or those having a suitable anato-
my like discrete stenosis at ostium or shaft.
REFERENCES
1. Edmond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) registry.
Circulation. 1994;90:2445-57.
2. Campeau L, Corbara F, Crochet D, et al. Left main coronary artery stenosis: the influence of aortocoronary bypass surgery on survival. Circulation.
1978;57:1111-5.
3. Caracciolo EA, Davis KB, Sopko G, et al. Comparison of surgical and medical group survival in patients with left main coronary artery disease
long-term CASS experience. Circulation. 1995;91:2325-34.
4. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group Eleven-year survival in the Veterans Administration ran-
domized trial of coronary bypass surgery for stable angina. N Engl J Med. 1984;311:1333-9.
5. European Coronary Surgery Study Group Long-term results of a prospective randomized study of coronary artery bypass surgery in stable angina
pectoris. Lancet. 1982;2:1173-80.
6. O’Keefe JH, Hartzler GO, Rutherford BD, et al. Left main coronary angioplasty: early and late results of 127 acute and elective procedures. Am J
Cardiol. 1989;64:144-7.
7. Grüentzig A. Transluminal dilatation of coronary artery stenosis (letter). Lancet. 1978;1:263.
1987;316:701-6.
9. Tan WA, Tamai H, Park SJ, et al. Long-term clinical outcomes after unprotected left main trunk percutaneous revascularization in 279 patients.
Circulation. 2001;104:1609-14.
10. Park SJ, Hong MK, Lee CW, et al. Elective stenting of unprotected left main coronary artery stenosis: effect of debulking before stenting and intra-
vascular ultrasound guidance. J Am Coll Cardiol. 2001;38:1054-60.
11. Silvestri M, Barragan P, Sainsous J, et al. Unprotected left main coronary artery stenting: immediate and medium-term outcomes of 140 elective
procedures. J Am Coll Cardiol. 2000;35:1543-50.
12. Black A, Cortina R, Bossi I, et al. Unprotected left main coronary artery stenting: correlates of midterm survival and impact of patient selection. J
Am Coll Cardiol. 2001;37:832-8.
13. Mishra S, Chiu W, Wolfram R, et al. Role of Prophylactic Intra-aortic Balloon Pump in High-risk Patients Undergoing Percutaneous Coronary
Intervention. Am J Cardiol. 2006;98(5):608-12.
14. Sousa EJ, Serruys PW, Costa MA. New frontiers in cardiology: drug-eluting stents. Circulation. 2003;107:2274-9.
15. de Feyter PJ, Kay P, Disco C. Reference chart derived from post-stent-implantation intravascular ultrasound predictors of 6-month expected reste-
nosis on quantitative coronary angiography. Circulation. 1999;100:1777-83.
16. Fujii K, Mintz GS, Kobayashi Y, et al. Contribution of stent underexpansion to recurrence after sirolimus-eluting stent implantation for in-stent
restenosis. Circulation. 2004;109:1085-8.
17. Sonoda S, Morino Y, Ako J. An optimal diagnostic threshold of minimum stent area to predict long-term stent patency following sirolimus-eluting
stent implantation: Serial intravascular ultrasound analysis from the SIRIUS trial. J Am Coll Cardiol. 2003;41:80A.
18. Curzen N. Percutaneous coronary intervention in unprotected left main stem disease: the state of play. Heart. 2005;91:iii39-41.
19. Mishra S, Bahl VK. The Choice of Guiding Catheter. Indian Heart J. 2009;61:80-8.
20. Mishra S, Bahl VK. Coronary hardware—Part II. Guidewire selection for coronary angioplasty. Indian Heart J. 2009;61:175-85.
21. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J
Med. 2003;349:1315-23.
22. Stone GW, Ellis SG, Cox DA, et al. A polymer-based paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350:
221-31.
23. Valgimigli M, van Mieghem CA, Ong AT, et al. Short- and long-term clinical outcome after drug-eluting stent implantation for the percutaneous
treatment of left main coronary artery disease: insights from the Rapamycin-Eluting and Taxus Stent Evaluated At Rotterdam Cardiology Hospital
registries (RESEARCH and T-SEARCH). Circulation. 2005;111:1383-9.
24. Park SJ, Kim YH, Lee BK, et al. Sirolimus-eluting stent implantation for unprotected left main coronary artery stenosis: comparison with bare
metal stent implantation. J Am Coll Cardiol. 2005;45:351-6.
25. Chieffo A, Stankovic G, Bonizzoni E, et al. Early and mid-term results of drug-eluting stent implantation in unprotected left main. Circulation.
2005;111:791-5.
26. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circu-
lation. 2004;109:1244-9.
27. Lee MS, Kapoor N, Jamal F, et al. Comparison of coronary artery bypass surgery with percutaneous coronary intervention with drug-eluting stents
for unprotected left main coronary artery disease. J Am Coll Cardiol. 2006;47:864-70.
28. Price MJ, Cristea E, Sawhney N, et al. Serial angiographic follow-up of sirolimus-eluting stents for unprotected left main coronary artery revascu-
larization. J Am Coll Cardiol. 2006;47:871-7.
29. Erglis A, Narbute I, Kumsars I, et al. A randomized comparison of paclitaxel-eluting stents versus bare-metal stents for treatment of unprotected
left main coronary artery stenosis. J Am Coll Cardiol. 2007;50:491-7.
30. Buszman P, Kiesz RS, Peszek E, et al. LEMANS. A prospective, randomized trial of stent implantation vs bypass graft surgery in patients with left
main coronary artery disease. TCT 2005. Washington DC; 2005.
31. Lee MS, Kapoor N, Jamal F, et al. Comparison of coronary artery bypass surgery with percutaneous coronary intervention with drug-eluting stents
for unprotected left main coronary artery disease. J Am Coll Cardiol. 2006;47:864-70.
32. Ong ATL, Serruys PW, Mohr FE, et al. SYNTAX Committees and Investigators SYNergy between percutaneous coronary intervention with TAXus
and cardiac surgery (SYNTAX): Main Results. As presented at ESC 2008.
69 History and Future of Coronary
Angioplasties by Radial Approach
Sengottuvelu G
In 1995, Kiemeneij et al.4 conducted a study on transradial artery

INTRODUCTION angioplasty using 6F sheaths with new 6F guiding catheters. The use
There have been numerous advances in coronary angioplasty since of smaller percutaneous transluminal coronary angioplasty (PTCA)
Andreas Gruentzig performed the first angioplasty in mid-1970s. guiding catheters made the radial artery a suitable access site for
Coronary angioplasties may be associated with discomfort and loss PTCA. In 100 patients with collateral blood supply to the right hand,
of productivity afterwards related to access site issues. Vascular PTCA was attempted using 6F guiding catheters on 122 lesions. Cor-
access influences ambulation and subsequent patient care, hospital onary cannulation was successful in 94 patients. The six unsuccessful
length of stay, costs and postprocedure quality of life. Femoral access interventions had successful PTCA through the femoral or the bra-
is widely used for cardiac catheterization, but often requires post- chial artery. The authors reported that withdrawal of the sheath im-
procedure bed rest to achieve hemostasis that may lead to signifi- mediately after the angioplasty and aggressive anticoagulation may
cant morbidity, longer hospital stay, higher costs including higher be important factors in the prevention of radial artery thrombosis.
complication rates.1,2 The transradial approach to coronary inter- They showed the radial artery was a low risk entry site for angioplasty
vention is now recognized as being associated with lower vascular despite radial artery occlusion, provided the ulnar artery was patent.
complication rates, earlier mobilization, less patient discomfort and In a follow-up study of 100 consecutive patients,5 after an-
lower procedural costs.1 There is sufficient evidence to warrant more gioplasty, the sheath was withdrawn, intense anticoagulation and
wide-spread use of the radial approach to angioplasty in appropriate mobilization was initiated, and the radial artery puncture site was
patients. studied by Doppler. Successful stenting through the radial artery was
achieved in 96 patients. None of the four patients with radial artery
HISTORY occlusion postprocedure showed any sign of hand ischemia. Aver-
age length of hospital stay was 5.2 ± 4.1 days. Despite heparinzation,
During the early 1980s, the transbrachial and femoral routes were the early major entry site related complications were rarely encountered.
most commonly used entry sites for angiography and angioplasty. The authors concluded that by combining 6F guide catheters and low
However, complications including hematomas, psuedoaneurysms, profile dilatation catheters with bare Palmaz Schatz stents, smaller
arteriovenous fistulae, neuropathies and limb ischemia were seen vessels, such as the radial artery, could be selected as the entry site
with these approaches.3 and that transradial artery Palmaz-Schatz coronary stenting was
In 1989, Lucien Campeau attempted the first radial artery feasible and safe.5
approach to cardiac catheterization, postulating that this approach Kiemeneij et al. also noted similar rates of procedural success
would prove free of significant vascular complications, primarily and suboptimal result when they compared angioplasty via the
because the hand has collateral circulation and the cannulation site radial, brachial and femoral approaches.2 Additionally, artery
is devoid of nerves or veins of significant size. Campeau studied this occlusion rates at the time of discharge were 5% in the radial artery,
approach in 100 patients using 5F sheaths and preshaped catheters.3 no occlusions in the brachial and femoral groups and the length of
Although radial artery puncture and cannulation were difficult, these hospital stay was similar in all three groups.
impediments were overcome with experience and improved equip- In1995, ultrasound imaging of the radial artery following cath-
ment. Once the learning curve was crossed, problems such as radial eterization was studied to check the incidence of the radial artery
artery spasms, loops and hematoma were overcome, providing evi- occlusion and it was concluded that radial artery occlusion was
dence that benefits far outweigh risks. In the early period the radial uncommon and results in no ischemic sequelae in the setting of a
approach was used in patients in whom the femoral approach was patent ulnar artery.6
difficult or contraindicated because of advanced arteriosclerosis or In more recent years, indications for transradial approach have
tortuosities. broadened significantly. Radial approach has been used successfully
Chapter 69  History and Future of Coronary Angioplasties by Radial Approach 595
in peripheral angioplasty and renal artery angioplasty, particularly

in patients with unfavorable femoral artery anatomy.7,8 Further, Gil-
FUTURE
christ et al. reported on the safety and feasibility of left and right heart Radial access is associated with a near elimination of local complica-
catheterization by transradial and transbrachial approach, respec- tions, such as hematomas that extend hospital stays, to bleeding re-
tively.9 quiring transfusion, bleeding or ischemic complications that require
In 2006, Lo and colleagues subsequently reported on the safety surgical repair. Specifically in contemporary interventional practice
of transradial right and left heart catheterization in 28 consecutive greater use of antiplatelet and anticoagulant therapies magnifies
patients who were anticoagulated to an international normalized the bleeding risk that is attenuated with radial access as shown in
ratio (INR) of 2.5, showing low bleeding and thromboembolic risk.10 analysis of the “synergy” trial.22 Moreover, as the compendium of
Also in 2006, Sanmartin et al. described the safety and feasibility of risk increases in a patient including female gender, acute coronary
transradial coronary bypass graft catheterization in 280 patients, syndrome, use of glycoprotein 2b/3a agents and older age the advan-
when compared to the transfemoral approach.11 tage of radial access in regards to bleeding complications is further
Finally, multiple studies since 2003, have demonstrated safety realized.23 Azamendi et al. recently observed that transradial PCI was
and efficacy of the transradial approach for primary coronary angio- associated with a fourfold reduction in major bleeding and a lower
plasty in the setting of acute myocardial infarction. Recently Heth- rate of major adverse events out to 1 year compared with the trans-
erington et al.12 reported that in patients with ST-segment elevation femoral approach.24
myocardial infarction (STEMI), a transradial approach to primary Finally, further refinements in transradial interventions are con-
percutaneous coronary intervention (PCI) is safe and reduces vas- tinuing such as the use of 5Fr sheaths and guiding catheters, improv-
cular complications compared with a transfemoral approach. In ad- ing patient comfort.25 Currently the 0.014-inch guidewire is com-
dition, procedural success and short-term outcomes are comparable monly used for coronary intervention and all devices are 0.014-inch
between the two techniques. Philippe reported on safety and efficacy compatible. Recently, 0.010-inch guidewires applicable for the kiss-
of transradial access in 119 consecutive patients undergoing primary ing balloon technique (KBT) using a 5F guiding catheter and 0.010-
angioplasty during acute myocardial infarction who were also treat- inch guidewire-compatible balloons have been developed in Japan,26
ed with glycoprotein IIb/IIIa inhibitors.13 and a 3F angiography catheter has also been developed referred as
Radial approach to angioplasty is becoming increasingly popular the “slender system”, and this system has been used for treatment of
since its initial use in 1989 due to its relative safety, cost-effectiveness bifurcation lesions and chronic total occlusion (CTO). Motomaru
and less patient burden than other approaches. In our own experi- Masutani et al.27 described angiography using a 3F catheter, the KBT
ence we have reported both efficacy and safety of transradial access using a 5F guiding catheter and 0.010-inch guidewires, and treat-
for complex coronary angioplasties including bifurcation, chronic ment of CTO using a 5F catheter and 0.010-inch guidewires. For CTO
total occlusions, bypass grafts and primary angioplasty.14-16 We have treated using the slender system, the transradial arterial approach
also shown the feasibility of radial approach in difficult anatomies was used in 96% of cases, treatment using the slender system alone
like arteria lusoria and in dealing with complications such as radial succeeded in 68%, and the overall success rate was 89%. Their results
artery perforation.17,18 A recent review of registry data suggests that show that complex lesions may be treatable using the slender system,
percutaneous coronary intervention (PCI) via the radial artery is saf- and that not all complex lesions require a 6F or larger guiding cath-
er than the standard femoral approach and should be more widely eters, a femoral arterial approach, or bilateral guiding catheters. How-
adopted. PCI success was equivalent between the two groups. After ever, further modification of the devices is necessary and only a few
adjustment, rates of bleeding complications were significantly lower devices are applicable for the slender system and development of
among patients receiving radial PCI compared to those receiving slender system-related products by manufacturers are awaited.
femoral PCI.19 Therefore the transradial procedures are only going to further
increase as more and more operators switch to this patient friendly
LIMITATIONS OF THE RADIAL APPROACH approach and with availability of newer equipments and devices.
The transradial artery route is suitable usually only with for 6F cath- CONCLUSION
eters, thereby limiting the choice of devices available for coronary in-
terventions.2 Although some speculate no relative increase in radia- The radial artery has been increasingly accepted as a reasonable
tion exposure to the operator,20 Lange and von Boetticher reported alternative route for angioplasty. The safe and immediate mobiliza-
an increase in radiation exposure to the operator by radial approach tion of patients following transradial intervention would allow more
in a randomized comparison to femoral approach.21 However, one outpatients coronary angioplasty techniques. Radial access for car-
could surmise that with increasing operator experience, fluoroscopy diovascular procedures is associated with favorable postprocedural
time by radial approach would decrease, ultimately limiting overall quality of life, presumably due to the near absence of required bed
exposure. rest and the rapid return to normal levels of function. Due to the
avoidance of bleeding and ischemic complications and the ability during acute myocardial infarction, it is likely the indications for ra-
to rapidly discharge patients, radial access is oftentimes more cost- dial artery access to coronary angioplasty will continue to grow. Fur-
effective than other modes of vascular access. Certainly in settings ther, various new methods and materials have been introduced over
where vascular complications are more likely, radial access becomes the years which would make the technique more operator friendly.
a dominant strategy due to the ability to improve postprocedural To conclude, transradial approach to cardiac catheterization and
quality of life. percutaneous coronary intervention is promising, with many advan-
Given data being presented recently on the safety and efficacy of tages that seemingly outweigh the relatively few limitations when
the transradial approach for more complex (e.g. bifurcation) lesions, employed in the appropriate patient population. This approach car-
peripheral disease, coronary bypass graft angiography, as well as po- ries the potential to be the standard approach in the setting of elec-
tentially right and left heart catheterization and primary angioplasty tive angioplasty, with increasing use in the emergency setting as well.
REFERENCES
1. Choussat R, Black A, Bossi I, et al. Vascular complications and clinical outcome after coronary angioplasty with platelet IIb/IIIa receptor blockade:
comparison of transradial and vs. transfemoral arterial access. Eur Heart J. 2000;21:662-7.
2. Kiemeneij F, Laarman GJ, Odekerken D, et al. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial,
branchial and femoral approaches: the access study. J Am Coll Cardiol. 1997;29:1269-75.
3. Slogoff S, Keats AS, Arlund C. On the safety of radial artery cannulation. Anesthesiology. 1983;59:42-7.
4. Kiemeneij F, Laarman GJ, de Melker E. Transradial artery coronary angioplasty. Am Heart J. 1995;129:1-7.
5. Kiemeneij F, Laarman GJ. Transradial artery Palmaz-Schatz coronary stent implantation: results of a single-center feasibility study. Am Heart J.
1995;130:14-21.
6. Hall JJ, Arnold AM, Valentine RP, et al. Ultrasound imaging of the radial artery following its use for cardiac catheterization. Am J Cardiol.
1996;77(1):108-9.
7. Scheinert D, Bräunlich S, Nonnast-Daniel B, et al. Transradial approach for renal artery stenting. Catheter Cardiovasc Interv. 2001;54(4):442-7.
8. Galli M, Tarantino F, Mameli S, et al. Transradial approach for renal percutaneous transluminal angioplasty and stenting: a feasibility pilot study.
J Invasive Cardiol. 2002;14(7):386-90.
9. Gilchrist IC, Moyer CD, Gascho JA. Transradial right and left heart catheterizations: a comparison to traditional femoral approach. Catheter Car-
diovasc Interv. 2006;67(4):585-8.
10. Lo TS, Buch AN, Hall IR, et al. Percuatenous left and right heart catheterization in fully anticoagulated patients utilizing the radial artery and fore-
arm vein: a two-center experience. J Interv Cardiol. 2006;19(3):358-63.
11. Sanmartin M, Cuevas D, Moxica J, et al. Transradial cardiac catheterization in patients with coronary bypass grafts: feasibility analysis and com-
parison with transfemoral approach. Catheter Cardiovasc Interv. 2006;67(4):580-4.
12. Hetherington SL, Adam Z, Morley R, et al. Primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction:
Changing patterns of vascular access, radial versus femoral artery. Heart. 2009;95:1612-8.
13. Philippe F, Larrazet F, Meziane T, et al. Comparison of transradial vs. transfemoral approach in the treatment of acute myocardial infarction with
primary angioplasty and abciximab. Catheter Cardiovasc Interv. 2004;61(1):67-73.
14. Sengottuvelu G, et al. Bifurcation angioplasty using Transradial approach. Indian Heart J. 2005;57:410.
15. Pinto B, Shah M, Sengottuvelu G, et al. Technical tips for transradial approach in post CABG interventions. Indian Heart J. 2008;60(1Suppl A):A38-
41.
16. Raghu C, Sengottuvelu G, Mss M, et al. Transradial primary angioplasty. Indian Heart J. 2008;60(1 Suppl A):A72-5.
17. Sengottuvelu G, Kallarakkal JT, Thanikachalam S. Percutaneous transluminal coronary angioplasty by right transradial approach in a patient with
arteria lusoria. Indian Heart J. 2006;58(4):365-7.
18. Sengottuvelu G, Cherukupalli R. Radial artery perforation and its management during PCI. J Invasive Cardiol. 2009;21:E24-6.
19. Rao SV, Ou F-S, Wang TY, et al. Trends in the prevalence and outcomes of radial and femoral approaches to percutaneous coronary intervention.
J Am Coll Cardiol Inv. 2008;1:379-86.
20. Geijer H, Persliden J. Radiation exposure and patient experience during percuatneous coronary intervention using radial and femoral artery ac-
cess. Eur Radiol. 2004;14(9):1674-80.
21. Lange HW, von Boetticher H. Randomized comparison of operator radiation exposure during coronary angiography and intervention by radial or
femoral approach. Catheter Cardiovasc Interv. 2006;67(1):12-6.
22. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive manage-
ment can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv. 2007;69:73-83.
23. Pristipino C, Pelliccia F, Granatelli A, et al. Comparison of acces-related bleeding complications in women versus men undergoing percutaneous
coronary cathterization using the radial versus femoral artery. Am J Cardiol. 2007;99:1216-21.
24. Azamendi D, Ly HQ, Tanguay JF, et al. Effect on bleeding, time to revascularization, and one-year clinical outcomes of the radial approach during
primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction. Am J Cardiol. 2010;106:148-54.
25. Dahm JB, Vogelgesang D, Hummel A, et al. A randomized trial of 5 vs. 6 French transradial percutaneous coronary interventions. Catheter Cardio-
vasc Interv. 2002;57:172-6.
26. Yoshimachi F, Masutani M, Matsukage T, et al. Kissing balloon technique within a 5 Fr guiding catheter using 0.010 inch guidewires and 0.010 inch
guidewire-compatible balloons. J Invasive Cardiol. 2007;19:519-24.
27. Masutani M, Yoshimachi F, Matsukage T, et al. Use of slender catheters for transradial angiography and interventions. Indian Heart J. 2008;60
(1 Suppl A):A22-6.
70 History of Cardiac Interventions
and Future Directions
Upasani PT, Lal P
INTRODUCTION The Era of Forssmann and Cournand

(1929–1949)—Unlocking the Right Heart
Among the greatest achievements in cardiovascular medicine in the
past century have been the advent, development, and refinement of The target of Unger’s wrath was a 25-year-old German surgical resi-
the invasive diagnostic and therapeutic modalities of cardiac cath- dent named Werner Forssmann. Newly graduated from medical
eterization, angioplasty and related catheter-based interventions. school and embarking on a surgical residency at the Augusta Victoria
These techniques, which have evolved sequentially through long Home in Eberswalde in 1929, Forssmann became interested in car-
pathways over the past century, have unleashed a torrent of basic sci- diac arrest and was struck by how intracardiac injections of resusci-
ence and physiologic information on the cardiovascular system and tation medications were avoided, until patients were beyond help,
have permitted the accurate diagnosis of practically all major cardiac because of well-founded fears of causing pneumothorax, tamponade
diseases and the safe and effective treatment of coronary artery dis- or coronary artery laceration. Deciding to research better ways to
ease (CAD) and other cardiac conditions by percutaneous routes. inject drugs for cardiac resuscitation, he deduced that catheteriza-
Certainly the development and maturation of cardiac catheterization tion of the right heart via the venous system would be a far safer and
and angioplasty have revolutionized the diagnosis and management thus more applicable method of access to the cardiac chambers.
of cardiovascular disease in almost every way. Given the enormous Wanting to test his theory, Forssmann suggested the project to his
toll CAD takes on the developed world, the advent of these tech- superior, who was aghast and refused to allow the studies. However,
niques and the surgical treatment of coronary disease are among the Forssmann was aware of reports of foreign bodies accidentally enter-
most important and plainly spectacular developments in medicine. ing the heart without any sequelae and of Chauveau and Mary’s work
The history of these techniques is an exciting and instructive in animals. Emboldened by these reports, Forssmann successfully
testament to the scientific spirit and method. Like those of most performed right heart catheterization on cadavers by passing ureteral
medical discoveries, the stories of the innovations and innovators catheters into the right ventricle and confirming the tip position by
involved are marked by charismatic and independent personalities, autopsy. He then convinced a colleague to pass a catheter into For-
their perseverance despite failure and ridicule, the wise and timely ssmann right basilic vein via a percutaneous approach. Forssmann
exploitation of serendipitous observations, and several lag periods then passed the catheter to 35 cm, at which point his colleague pan-
during which technology and scientific peers caught up slowly with icked and pulled the catheter out despite Forssmann’s protests.2
those ahead of their time. These pioneers came from Europe, South Undeterred, Forssmann decided he would have to pursue his
America, and North America, and were of diverse backgrounds: they work alone. He gained the trust of the surgical nurse Gerda Ditzen,
included a theologian scholar, physiologists, a veterinarian, a physi- manipulating her to gain access to the necessary venesection instru-
cist, a surgical intern, radiologists and a pediatric cardiologist. ments. A week later, in July 1929, the persistent surgery resident man-
aged to get Ditzen to volunteer for another attempt.2-4 Tying her to
CARDIAC CATHETERIZATION the table while his colleagues slept during their afternoon naps, he
quickly anesthetized his own left antecubital fossa while turned away
During his Nobel Lecture in 1956, Cournand stated simply but el- and then prepared her elbow for a cut down. When the anesthetic
egantly that “the cardiac catheter was the key in the lock”.1 In doing took effect on Forssmann, he quickly performed a venous cut down
so, he summarized the powerful influence that the development of on his own left elbow and inserted a ureteral catheter to its full length
cardiac catheterization has had on the diagnosis and treatment of of 65 cm inside. He then released the deceived and angry nurse and
coronary disease and of valvular and congenital heart disease. The ordered her to follow him to the X-ray room in the basement, where
cardiac catheter has uniquely fostered basic science understanding he documented the catheter’s position in his right atrium and made
of the anatomy and physiology of the heart and circulatory system in medical history. Exhilarated, he claimed he would have advanced
ways that noninvasive methods never could. the catheter further into the heart, but the length of the catheter had
not allowed further advancement. Although he was never engaged In 1951, the father-and-son team of Gorlin and Gorlin13 reported
in cardiac research after 1931 or ever held any faculty appointments, their adaptation of hydraulic formulas to the calculation of stenotic
he was awarded a Nobel Prize that year, along with fellow catheteri- valve orifice areas through the use of cardiac output and pressure
zation pioneers Cournand and Richards. At that point, the reluctant recordings during right and left heart catheterization. In 1953 Sven
and overwhelmed country surgeon accepted a faculty appointment I Seldinger,14 of the Karolinska Institutet in Stockholm, invented a
in Dusseldorf, commenting, “I feel like a village person who has just technique for the percutaneous replacement of an access needle
learned that he has been made bishop.5 with catheters over guide wires, and this technique became widely
At Bellevue Hospital, Cournand and Richards began their classic applied for virtually all catheterization techniques within the next
studies of right heart physiology in 1936. Beginning in 1941, by us- decade.
ing modified urethral catheters this team6,7 issued a series of papers In 1960, a loop-end (“pigtail”) catheter with multiple side
on simultaneous right heart pressure measurements and oximetry- holes, designed to avoid myocardial trauma and catheter whip
based studies of cardiac output; in 1942 they catheterized the right and dislodgement during high-pressure contrast injection, was in-
ventricle and in 1944 the pulmonary artery.6 They also introduced troduced for ventriculography in animal15 application in humans
double-lumen right heart catheters, similar to those used by Chau- followed.
veau and Marey, and radiopaque catheters.6 This team shared a 1956
Nobel Prize with Forssmann for their landmark work.1 The Era of Sones and Judkins—Unlocking the
Coronary Arteries (1958 to Present)
The Era of Unlocking the Left Heart by Direct,
The unlocking of the left heart by the 1950s rounded out the under-
Anterograde and Retrograde (1949–1957)
standing of cardiac physiology and led to the pursuit of the next goal,
In 1933 Reboul and Racine8 performed the first percutaneous ven- that of imaging the coronary arteries. For several years numerous
tricular needle puncture by using an anterior parasternal approach workers described partial, nonselective opacification of the coro-
to both ventricles in dogs for the injection of contrast. Ponsdomene- nary vessels.16-18 These methods, clever and ambitious, were wholly
ch and Beato Nunez9 used the subxiphoid approach, across the right inadequate and only of historical and physiologic and not clinical
ventricle and interventricular septum, to access the left ventricle for interest.
contrast ventriculography in 1951. In 1954, Smith et al.10 used the F Mason Sones, a pediatric cardiologist at the Cleveland Clinic, is
technique for right and left ventriculography. Brock et al.11 reported credited with performing the first and meaningful coronary angiog-
the apical approach to left ventricular puncture in humans in 1956. raphy. He began by performing semiselective coronary angiography
Most of the studies that involved aortic catheterization used in dogs, in which the aortic catheter was precisely positioned in either
the hazardous and cumbersome access technique of direct needle of the coronary sinuses of Valsalva to place contrast dye closer, but
puncture into the thoracic or abdominal aorta, which was first not into the coronary ostia. After performing a left ventriculogram in
described by Rousthoi. However, in 1941 Farinas became the first a patient with valvular disease, Sones pulled the catheter back and
to perform aortography via catheters introduced by femoral artery set up for an aortogram, but neglected to verify the catheter position
cut down access. Gradually other investigators abandoned direct by fluoroscopy before proceeding. Just before the injection, Sones
needle access of the aorta in favor of retrograde catheterization via began cineangiography and was horrified to see that the catheter had
the brachial, radial, ulnar, or femoral arteries, first by cut down and accidentally intubated the ostium of the right coronary artery. Before
later by percutaneous access. Retrograde left heart catheterization he could pull the catheter out, 40 ml of contrast was injected directly
was an outgrowth of early arterial access experiments such as those into the vessel. Certain that the patient’s heart would fibrillate and
by the 19th century workers and Bleichroeder’s group. By 1950 lacking knowledge of the yet-to-be-described closed chest cardiac
aortic catheterization for pressure measurement, oximetry and massage and direct current defibrillator, Sones grabbed a scalpel in
angiography was established. Until then, however, it was thought to anticipation of having to perform open chest massage. Asystole de-
be too dangerous to pass a catheter retrograde across the aortic valve. veloped instead, and Sones resuscitated him via coughing, which
Zimmerman et al.12 reported successful human retrograde left heart converted the rhythm to sinus bradycardia.19 The patient recovered
catheterization in 1950; Zimmerman, working at Cleveland City fully and Sones soon developed the new technique of selective coro-
Hospital, passed a catheter into the aorta via an ulnar artery cut down nary angiography with specially formed catheters supplied in April
and then into the left ventricle of a patient with aortic regurgitation. 1959 by the US. Catheter and Instrument Company (now a division
They then performed a left heart pullback while recording pressures of C R Bard, Inc., Billerica, Mass), by using brachial artery cut down
and without performing ventriculography; later they recorded access. These specially shaped catheters permitted selective cannu-
intracardiac electrograms from the left ventricle and, like Chauveau lation of the coronary ostia and did not occlude the ostia completely,
and Marey, placed catheters in both ventricles simultaneously. thereby reducing the risk of ventricular fibrillation.
Chapter 70  History of Cardiac Interventions and Future Directions 599
The Sones technique remained the standard until it was chal-

ANGIOPLASTY AND RELATED
lenged by separate reports in 1967 from radiologists Judkins20 of the
CATHETER INTERVENTIONS
University of Oregon and Amplatz (Wilson et al.21) of the University
of Minnesota of a more practical and advanced group of preformed Angioplasty and related catheter interventions have revolutionized
catheters for percutaneous use via femoral artery access. Judkins’ the treatment of atherosclerosis in a variety of vascular beds includ-
impetus for developing his coronary seeking catheters was his frus- ing the coronary, peripheral and renal circulations. Angioplasty and
tration with using Sones’ catheters in patients with dilated aortas; related methods have made nonsurgical coronary revascularization
because they were guided to the coronary ostia by the normal cur- a viable alternative in the treatment of obstructive vascular disease,
vature of the aorta. In patients with dilated aortas this guidance was even for frontier applications such as chronic total occlusions and
uncertain. Judkins went on to devise a set of catheters that would acute MI. The growth in use of catheter-mediated revascularization
seek the coronary vessels innately, regardless of aortic structure. Cur- methods since their advent in the 1960s and 1970s has been explo-
rently most catheterization laboratories use the Judkins technique, sive. The history of angioplasty and related catheter methods is only
although many still prefer Sones’ method and catheters. 35 years old, but has been marked by a steady stream of intellectual
Working with Boijsen in Sweden in 1966, Judkins also introduced and technological advances. The promise of nonsurgical revasculari-
the “hooktail” catheter for ventriculography, aortography, and right zation has led to unbridled enthusiasm for these devices despite the
and left heart catheterization followed by his own pigtail catheter in relative lack of long-term or randomized data on safety and efficacy.
1968; he also introduced the nickname “pigtail” which Boijsen found Because of this almost unrestrained enthusiasm, these devices are
too demeaning. In 1968, Schoonmaker and King22 devised their finding an ever widening circle of indications and applications in
“multipurpose” catheter, a single catheter with which an entire left acute and chronic vascular disease.
heart and coronary catheterization study could be performed percu-
taneously. Damato et al.23 opened an entirely new avenue of invasive The First Era (1963–1976)—The Dotter
cardiac investigation in 1969 when they described the first His bun-
Technique and Gruentzig’s Balloon
dle recording in humans, leading quickly to the advent of modern
cardiac electrophysiology. Swan et al.24 revolutionized coronary care In 1963 Dotter28 inadvertently recanalized an occluded right iliac
in 1970 by introducing a balloon tipped, flow-directed catheter that artery by passing a percutaneously introduced catheter retrogradely
made right heart and pulmonary capillary wedge pressure monitor- through the occlusion to perform an abdominal aortogram in a pa-
ing possible at the bedside without the use of fluoroscopic guidance. tient with renal artery stenosis. Dotter immediately recognized the
Meanwhile, Chazov et al.25 in 1976 and Rentrop et al.26 in 1979 therapeutic potential of his finding, and after studies on cadaveric
showed that immediate revascularization by intracoronary strep- peripheral arteries he conceived of dilating obstructions gradually
tokinase or streptokinase combined with guide wire and catheter with sequential dilators, constructing balloon-mounted dilating
recanalization respectively, was feasible and safe in patients with catheters and placing endoluminal stents to augment recanaliza-
myocardial infarction (MI). DeWood et al. demonstrated in 1980 that tion. Several investigators attempted to improve on Dotter’s method.
immediate diagnostic coronary angiography was safe during MI and Staple29 modified the technique in 1968 by using sequentially larger
that most of these patients have occlusive acute coronary thrombi.27 single dilators with tapered ends; Van Ande130 used a single tapered
This fundamental reassessment of the pathophysiologic cause of catheter.
acute infarction led to a revolution in its therapy by stimulating the A critical turning point occurred as a remarkable and charismat-
rediscovery of intravenous thrombolytic therapy in the 1980s. ic figure stepped to the fore. Andreas R Gruentzig, a young German
Thus the introduction of selective coronary angiography in the trained in epidemiology and social medicine and then in internal
1960s fostered the revolutions that quickly followed in coronary medicine learned the Dotter technique of transluminal angioplasty
artery surgery and presaged the critical transition from diagnostic from Zeitler in 1969 and 1970. Relocating to University Hospital in
catheterization to therapeutic intervention by catheter methods. The Zurich, Switzerland in 1970, Gruentzig used these techniques for
history of cardiac catheterization is filled with charismatic person- peripheral and renal arterial recanalization and in 1972 began con-
alities of near mythic stature who pursued their observations and ceiving of adding a balloon to the Dotter catheters. In 1973, now a
theories with relentless disregard for prevailing thought and criti- cardiology fellow, Gruentzig performed peripheral balloon angio-
cism, thereby unlocking one by one the basic science and diagnostic plasty on animals with his first catheter, a single lumen prototype.
secrets of the heart. In so doing they set the stage for another set of On February 12, 1974, he used the single lumen device to perform
charismatic tinkerers who, by standing on the shoulders of their fore- the first of numerous human balloon peripheral angioplasties on
runners, would move beyond documentation of coronary disease to a patient’s superficial femoral artery.31 The single lumen catheter’s
work inside the artery. balloon was inflated through the central lumen after an occluder
wire was inserted through it. All of Gruentzig’s catheters were made The catheter shafts were of high profile, with poor pushability and
at night or on weekends in Gruentzig’s kitchen until 1976, when the steerability. In 1979, the ends of the double lumen catheters were
Schneider (Minneapolis, Minn.) and Cook companies took over pro- tipped by a soft, fixed guide wire that could not be retracted, maneu-
duction. This catheter contained a distal lumen that allowed for pres- vered or moved independently from the catheter.
sure monitoring and contrast injection; the proximal lumen inflated In 1980, a team of workers, including Amplatz reported evidence
the rigid balloon, which assumed a fixed diameter at balloon pres- that established the mechanism of angioplasty as a combination
sures below or equal to 6 atm. Besides the innovative balloon design, plaques splitting, “limited” or “beneficial” intimal dissection and
the catheter represented a major advance in 1975 because of its small arterial stretching. The new theory helped explain the sobering and,
profile and flexibility compared with the Dotter dilators. to this day, limiting phenomena of primary procedural failure, even
when the lesion can be crossed, and of abrupt closure, elastic recoil,
The Second Era (1977–1985)—Gruentzig and deep intimal injury leading to a proliferative response and cul-
minating in restenosis.
and Coronary Angioplasty
Gruentzig and Myler performed the first human coronary angioplas- The Third Era (1985 to Present)—
ty in May 1977 at St. Mary’s Hospital in San Francisco intraoperatively
Devices beyond the Balloon
during bypass surgery. The angioplasty was performed by retrograde
passage of the balloon catheter through the arteriotomy made in the From its inception coronary angioplasty has witnessed rapid strides
native left anterior descending coronary artery distal to the stenosis with ever increasing cases being performed annually worldwide.
before placement of the bypass graft. After balloon deflation and With time more and more lesion types considered to be unamenable
removal of the catheter, a cannula was introduced, the coronary ves- to dilation have yielded to the balloon. Angioplasty was soon applied
sel flushed, and the effluent collected on filter paper. Of importance, to acute MI. Gruentzig’s bold forays into multivessel angioplasty
they found no evidence of distal embolization of debris. Subsequent have culminated in several randomized trials comparing it to bypass
angiography revealed patent grafts and improvement in the native surgery.
lesion dilated.32 Several other adjunctive devices and techniques followed. These
The first coronary angioplasty in an awake human was per- were Simpson’s atherocath for directional coronary atherectomy
formed by Gruentzig, in Zurich, on September 16, 1977. The patient (wherein a motor driven cutter advances and shaves off plaques that
was a 37-year-old (the same age as Gruentzig at the time) insurance bulge through the window into a conical nose cone collection hous-
salesperson with an isolated proximal left anterior descending artery ing at the end of the catheter),34 Rotablator (a high-speed rotational
stenosis.32 The patient consented to angioplasty even after being in- pulverizing device capped by a diamond-studded conical end, devel-
formed that he would be the first patient so treated. With the chief oped by D Auth),35 transluminal extraction catheter [(TEC), contain-
of cardiology, a cardiac surgeon, an anesthesiologist, and numerous ing a low-speed rotating cutting head connected to a vacuum sys-
cardiology and radiology fellows in attendance, the lesion was quickly tem that aspirates shaved fragments back into the shaft, developed
dilated with two balloon inflations. The distal lumen of the catheter by Stack],36 Kensey catheter (a high-speed rotational system that
recorded a prompt normalization of the distal coronary pressure and creates a pulverizing vortex in front of the tip, Medrad (Pittsburgh,
angiography revealed a marked reduction in stenosis. The only com- PA) atherolytic reperfusion guide wire and the rotational angioplasty
plication was a transient right bundle branch block. To Gruentzig’s catheter system (ROTAC) low-speed rotational angioplasty wire,37
horror, the patient promptly notified a reporter of the successful pio- which are pulverizing bare wire devices. Only the Atherocath and
neer procedure from his hospital bed, but Gruentzig was able to con- TEC devices remove plaque from the vessel wall into the catheter;
vince the press to remain silent until he published a report on his first the other devices remove plaque from the vessel wall but grind and
five cases in a letter to the editor of Lancet in February 1978.33 disperse the atheromata, allowing the particles to microembolize
Recognition of Gruentzig’s triumph was immediate and wide- rather than drawing them into the catheter.
spread; the medical community was ready to embrace percutane- Several other novel catheter-based revascularization devices
ous revascularization, perhaps because in the interim the benefits of have been developed in recent years. The only FDA approved coro-
surgical revascularization had become recognized. However, coronary laser angioplasty device is the xenon chloride excimer laser (Dy-
nary angioplasty was still in its infancy. Early equipment was cum- mer 200 + laser, AIS, Inc., Irvine, California approved in 1992; and the
bersome and primitive; guiding catheters were 9.4F and solid teflon, CVX-300 laser, Spectranetics Corp., Colorado Springs, Colorado ap-
with resultant low torqueability and poor memory, causing frequent proved in 1993), which ablates plaque by photochemical rather than
inability to cannulate the target vessel. Likewise, the early balloons thermal mechanisms. Thus thermal injury is avoided, and ablation of
were of high profile and were made of polyvinyl chloride, which was tissue occurs with less diffusion and greater precision; in addition, ex-
noncompliant and had a low rupture pressure threshold of 6 atm. cimer lasers have the ability to ablate calcified plaque components.
A variety of endoluminal stents have been applied to the periph-

HIGH-RISK ANGIOPLASTY AND
eral and coronary arterial trees, among other vascular beds and or-
RELATED PROCEDURES
gan ducts, to provide a scaffolding to enhance procedural success,
to prevent restenosis, or to treat threatened or acute vessel closure Several devices or products have been developed as adjuncts to
resulting from balloon angioplasty. Sigwart et al.38 innovators of the high-risk angioplasty procedures to support systemic blood pressure
spring-loaded self-expanding stainless steel Wall stent (Medinvent or to protect distal vessels supplying ischemic myocardium during
SA, Lausanne, Switzerland), reported the first use of coronary stents balloon inflation in patients with severe left ventricular dysfunction
in humans in 1987. The next generation of stents was balloon mount- or in those whose target vessel supplies the majority of viable myo-
ed and balloon expandable; examples include the Palmaz-Schatz cardium. As for global hemodynamic support during high-risk angi-
(Johnson & Johnson interventional systems, Warren, NJ) slotted oplasty, devices that have been used include the intra-aortic balloon
articulated stainless steel device and the Gianturco-Roubin flexible pump, percutaneous cardiopulmonary bypass systems and a cathe-
stainless steel, coil stent (Flex-Stent, Cook, Inc.). ter-mounted blood pump placed in the left ventricle (Hemopump,
Regular stents are still widely in use but drug eluting stents are Johnson & Johnson Interventional Systems, Warren, NJ) that oper-
being implanted in great numbers. Drug eluting stents consist of ates by the Archimedes screw principle. As for distal vessel perfusion
three principle components: (1) the stent backbone itself, (2) the during balloon inflation, several autoperfusion catheters use passive
pharmacologic agents intended to reduce neointimal hyperplasia or active means of delivering arterial blood through the catheter
and sometimes other adverse effects and (3) a polymer designed beyond the occluding balloon and into the distal vessel. The most
to slow the release of the pharmacologic agent such that it remains widely used of the passive devices, the Stack perfusion catheter (Ad-
at a sufficient concentration for long enough to interdict relevant vanced Cardiovascular Systems, Inc., Santa Clara, California) was
biological process. The albatross around the neck of the stent era of described in 1987 and 1988;39 by ensuring distal vessel perfusion,
coronary intervention was in-stent restenosis, an aggressive healing long inflations can be carried out. Erbel et al. described an earlier
response to the arterial injury which occurs with both balloon an- passive autoperfusion device in 1986; other devices infuse oxygen-
gioplasty and stent implantation. This process results in renarrow- carrying fluorinated hydrocarbon emulsions through the catheter or
ing of the stented segment over the course of the first 6–9 months use active autoperfusion by pumping femoral artery blood into the
of follow-up. Restenosis generally presents as recurrent angina. The catheter.
risk of restenosis is related primarily to the presence of diabetes, and Another technique for myocardial preservation during occlu-
the length and diameter of the stent implanted. The arrival of drug sion is coronary sinus retroperfusion; this technique is reminiscent
eluting stents has greatly diminished the risk of patients developing of the abandoned Beck II surgery for coronary disease (performed in
restenosis and thereby requiring repeated procedures and suffering the 1950s), which entailed arterial grafting to the coronary sinus to
recurrent symptoms. Drug eluting stents have encouraged a more perfuse the myocardium from the venous end of its circulation.
aggressive percutaneous approach to the treatment of CAD disease In 1976, Meerbaum et al. pioneered active synchronized coro-
in patients who would have previously been directed toward surgical nary sinus retroperfusion in animals by using a catheter with a bal-
revascularization. When only bare metal stents were available, it was loon that occluded the sinus during diastole, during which time arte-
hard to justify pursuing an angioplasty that would almost certainly rial blood was actively pumped through the catheter lumen into the
result in restensosis. sinus. As systole begins, the R-wave-gated balloon deflates, allowing
Drug eluting stents have been implicated in an increased risk of for normal venous drainage. The technique has since been applied in
stent thrombosis (a much more deadly acute occlusion of a stented humans; in 1986 Weiner et al.40 treated patients with unstable angina
segment) late after the index procedure. Drugs are likely to delay en- and several workers reported use during angioplasty in 1990.
dothelialization of the stents by blocking the intense healing response
which causes restenosis. A prolonged duration of dual antiplatelet ADJUNCTIVE EQUIPMENT AND
therapy with aspirin and clopidogrel, longer than 3–6 months rec-
THERAPIES USED IN ANGIOPLASTY
ommended in the initial trials of these therapies, has been suggested
by most interventional practitioners and is thought to be protective. A number of devices have been developed to aid in the evaluation
The most recent analyses have suggested no increased risk of drug of arteries, in selection of therapies and in performance of the pro-
eluting versus bare metal stents in up to 4 years of follow-up after cedures. Prominent among these is intravascular ultrasound, which
a coronary intervention. They have also shown no difference in the can give an image of the arterial wall that is not available by angi-
rate of death or death/MI in these two groups calling into question ography. Characteristics, such as lumen size and contour, amount
the cost-effectiveness of drug eluting stents, which are three to four of plaque, the true size of the external dimension of the artery, and
times the cost of bare metal stents. the presence and distribution of calcium deposits within the artery
are readily ascertained. This technique is used in selecting patients to identify the relation between operator activity and outcomes.45,46
for devices such as rotary ablation when calcium is present, for siz- New recommendations are being generated based on this and other
ing balloons and stents and when evaluating the result of therapy to evidence in an effort to improve outcomes. However, credentialing
decide whether further interventions are necessary. Although used to perform interventional procedures is entirely a local matter to be
extensively in some centers, ultrasound remains an expensive addi- determined by the hospital in which one practices. Many have dis-
tion to the armamentarium. Fiberoptic angioscopy can give accurate covered that consolidation of experience among smaller numbers of
information regarding the presence of thrombus but is seldom used operators within groups has been an effective strategy. This achieves
clinically. a higher level of experience, which is necessary as interventional
Two methods of assessing the physiology of coronary flow have procedures become more and more complex and the knowledge of
been developed: (1) the Doppler flow wire, which can record the new innovations becomes critical. The participation in the selection
velocity of blood flow in the coronary artery and thereby establish of interventional procedures by colleagues who do not perform these
whether lesions are impeding the flow of blood. Measurements techniques can also be helpful in diffusing the concern about self-
across lesions can show increased velocity and turbulence and, in referral. A quick solution to the problem of an oversupply of opera-
combination with measurements of the arterial dimension, can lead tors performing angioplasty is not immediately attainable, but there
to assessment of flow. This technique has been validated against an- is pressure to consolidate and improve quality. Undoubtedly, height-
giography and ultrasound examinations and has a potential future in ened surveillance of performance of all medical procedures would
assessing borderline lesions and guiding therapy, (2) direct coronary be part of our future and it is crucial that the professionals partici-
pressure measurement can be performed with balloon catheters, but pate to the greatest extent possible in developing rational guidelines.
the bulk of the catheter adds artifact to the measurement. Results Much of the expanding knowledge base in interventional cardiology
have shown that the gradient was an important predictor of acute is being developed through the mechanism of ongoing randomized
results and restenosis. Small-bore fluid-filled guidewires have been clinical trials. Some of these will be structured to look at surrogate
developed, and catheter tipped manometers on guidewires as small endpoints, such as restenosis rates. However there is an increasing
as 0.014 inch allow accurate measurements of pressure across coro- emphasis on clinical outcomes, which is appropriate. Topol et al.47
nary stenoses. The use of direct pressure measurements and velocity emphasized some of the problems in clinical trial design in an ex-
determinations during maximal pharmacologic vasodilation allow cellent review. They stressed the importance of death and MI as a
assessment of the degree of coronary flow impairment, which may robust endpoint for these trials. However, one should remember that
not be obtained by angiography alone. coronary interventions only occasionally result in death, but often
Finally, several invasive imaging devices have been recently de- produce creatine kinase (CK) elevations recorded as infarction. The
veloped as adjuncts to catheter-based interventions. Several groups evidence regarding the prognosis of CK elevations in the moderate
reported the development and use in humans of intravascular ultra- range without Q waves, documented vessel reclosure or emergency
sound catheters that produced two-dimensional echocardiographic surgery is still controversial, and much more information is needed
images of great vessels, cardiac chambers, and coronary arteries.41 before combining these events with death as the reference standard.
Another adjunctive imaging tool developed to guide catheter-based Carefully designed and executed randomized trials will be necessary
revascularization is the fiberoptic angioscope, first used in living hu- to answer many questions and carefully controlled registries will be
man coronary arteries by Spears et al.42 in 1983 during bypass sur- appropriate for others. The challenge will be to thoughtfully judge
gery and then in 1985 during cardiac catheterization and in 1986 dur- which method is sufficient and cost-effective.
ing unstable angina.
FUTURE DIRECTIONS
THE DISCIPLINE OF INTERVENTIONAL
Interventional cardiology has changed dramatically for the good
CARDIOLOGY
over past 2 decades. Almost every balloon angioplasty is now being
Initially, balloon angioplasty was available only to those who would followed by the implantation of the stent, which has been shown
commit to recording data and cooperating with national registries. to improve the immediate and long-term results of interventional
Later, the technique became available to all cardiologists who wished therapy. Similar rapid advancements have taken place regarding
to apply it in their patients. In 1988 and again in 1993, the American antiplatelet therapy so essential after any coronary angioplasty.
College of Cardiology issued guidelines on indications for coronary Angioplasty equipments have also improved with better, less bulky
interventions.43,44 Included in those guidelines were recommenda- balloons that allow for smaller caliber guiding catheters and arterial
tions for approximate activity levels considered necessary to achieve access; the latter is associated with decreased vascular complication.
and maintain competence. These recommendations have been con- Newer stents have been developed with a particular aim to reduce
troversial and recently a number of studies have been performed to try restenosis; notable mention in this regard would be drug eluting
stents which are now being increasingly implanted in great numbers plored and the merits of conventional surgery versus a catheter inter-
so as to reduce restenosis vis-à-vis bare metal stents. Drug eluting vention are discussed overtly with the patient.
stents have encouraged a more aggressive percutaneous approach to
the treatment of CAD in patients who would have previously been CONCLUSION
directed toward surgical revascularization.
Coronary interventions have been compared to coronary artery As Cournand suggested so eloquently, the cardiac catheter and its
bypass surgery in many populations both with bare metal stents and soon to be innumerable derivations have been the keys to the lock
with drug eluting stents. In summary, there is really no evidence of guarding the heart’s secrets. The saga of invasive cardiology since its
mortality benefit of one of these treatments versus the other. The inception by Hales almost 3 centuries ago has been a series of new
angioplasty patients generally require repeat procedures versus the keys, fashioned by distinctive pioneers and used ingeniously to un-
surgical patients. Despite an apparent advantage of surgery, most lock each of the heart’s diagnostic and therapeutic challenges. These
patients who have been given a full informed consent choose angio- investigators and their innovations relentlessly opened the heart to
plasty for its less invasive properties and the shorter recovery time diagnosis and therapy by nonsurgical routes, beginning with the
required. right heart and the pulmonary circulation, followed by the left heart
Structural heart disease is an explosive area of cardiovascular in- and the aorta, and then by the diagnostic conquest of the coronary
terventional cardiology and can be alternatively defined as noncoro- tree and its therapeutic challenges. The diagnostic and therapeutic
nary cardiac intervention. Nowadays noncoronary interventions, use of catheters in invasive cardiology will undoubtedly continue at
such as transcatheter atrial septal defect and patent foramen ovale an accelerated pace, as the yet unimagined keys of tomorrow unlock
closures, transcatheter patent ductus arteriosus closure and tran- today’s forbidden cardiac realms by nonsurgical means.
scatheter valve therapies (percutaneous aortic valve replacement,
transcatheter repair of mitral regurgitation with Evalve MitraClip, SUMMARY
transcatheter pulmonary valve replacement) are also being increas-
ingly performed. The histories of cardiac catheterization, angioplasty and other cath-
eter interventions are spectacular journeys marked by undeterred
A NOTE OF CAUTION genius, serendipity and the vindication of the scientific method.
Cardiac catheterization began with Hales’s equine biventricular
The success of transcatheter structural heart disease therapies has catheterization in 1711 AD, other early experimental catheteriza-
been the ability to repair intracardiac defects that once required sur- tions in the 19th century, and Forssmann’s dramatic 1929 right heart
gery in a minimally invasive fashion. In high-risk patients these ther- self-catheterization. Cournand, Richards, and others finished un-
apies are readily accepted. In patients of low operative risk we must locking the right heart in the 1940s; Zimmerman, Cope, Ross, and
constantly re-examine and be critical of transcatheter therapies with others unlocked the left heart in the 1950s and the coronary arteries
the availability of excellent surgical therapies with long-term track were inadvertently unlocked by Sones in 1958, leading to the advent
records. A healthy respect for the complications of new and innova- of percutaneous femoral coronary angiography by Judkins and by
tive therapy is critical for interventionalists. Careful evaluation, mon- Amplatz in 1967. Dotter’s accidental catheter recanalization of a pe-
itoring and reporting of outcomes of these new therapies are critical ripheral artery in 1963 ushered in the era of intervention, crowned
for further advancement and insight into ideal patient selection. A by Gruentzig’s balloon angioplasty in the mid-1970s and leading to
referral to a structural heart disease interventionalist should be a true today’s panoply of devices used percutaneously to revascularize the
consulting process where the relative indications for therapy are ex- coronary arteries in a variety of clinical settings.
REFERENCES
1. Liljestrand G. Le prix Nobel en 1956. Stockholm: Nobel Foundation; 1957.
2. Splittgerber F, Harken DE. Catheterization of the right heart, by Werner Forssmann. Cardiac Chronicle. 1991;4:13-5.
3. Steckelberg JM. Vlietstra RE, Ludwig J, et al. Werner Forssmann (1904-1979) and his unusual success story. Mayo Clin Proc. 1979;54(11):746-8.
4. Warren JV. Fifty years of invasive cardiology: Werner Forssmann (1904-1979). Am J Med. 1980;69:10-2.
5. Forssmann W. Experiments on myself: memoirs of a surgeon in Germany. New York: St. Martm’s Press; 1974. pp. 84-5.
6. Cournand A. Cardiac catheterization; development of the technique, its contributions to experimental medicine, and its initial applications in
man. Acta Med Scand Suppl. 1975;579:3-32.
7. Cournand AF, Ranges HS. Catheterization of the right auricle in man. Proc Soc Exp Biol Med. 1941;46:462-6.
8. Reboul H, Racine M. La ventriculographie cardiagque experimentale. Presse Med. 1933;1:763-7.
9. Ponsdomenech ER, Beato Nunez V. Heart puncture in man for diodrast visualization of ventricular chambers and great arteries. Am Heart J.
1951;41(5):643-50.
10. Smith PW, Wilson CW, Cregg HA, et al. Cardioangiography. J Thorac Surg. 1954;28(3):273-80.
11. Brock R, Milstein BB, Ross DN. Percutaneous left ventricular puncture in the assessment of aortic stenosis. Thorax. 1956;11(3):163-71.
12. Zimmerman HA, Scott RW, Becker NO. Catheterization of the left side of the heart in man. Circulation. 1950;1(3):357-9.
13. Gorlin R, Gorlin SG. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves, and central circulatory shunts.
I. Am Heart J. 1951;41(1):1-29.
14. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography; a new technique. Acta Radiol. 1953;39(5):368-76.
15. Littmann D, Starobin OE, Hall JH, et al. A new method of left ventricular catheterization. Circulation. 1960;21:1150-5.
16. Nordenstrom B, Overfors CO, Tornell G. Coronary angiography in 100 cases of ischemic heart disease. Radiology. 1962;78:713-24.
17. Arnulf G, Chacornac R. Methodical coronary arteriography with acetylcholine; experimental & clinical findings. Lyon Chir. 1958;54(2):212-22.
18. Bellman S, Frank HA, Lambert P, et al. Coronary arteriography: I. Differential opacification of the aortic stream by catheters of special design-
experimental development. N Engl J LV normal in size with marked hypokinesis of basal and basal anterior septum, basal anterior and basal
lateral LV free walls, akinesia of mid and apical septum, mid and apical lateral LV free walls. 1960;262:325-8.
19. Hurst JW. History of cardiac catheterization. In: King SB III, Douglas JS (Eds). Coronary Arteriography and Angioplasty. New York: McGraw-Hill;
1985. pp. 5-6.
20. Judkins MP. Selective coronary arteriography. I. A percutaneous transfemoral technic. Radiology. 1967;89(5):815-24.
21. Wilson WJ, Lee GB, Amplatz K. Biplane selective coronary arteriography via percutaneous transfemoral approach. Am J Roentgenol Radium Ther
Nucl Med. 1967;100(2):332-40.
22. Schoonmaker FW, King SB. Coronary arteriography by the single catheter percutaneous femoral technique. Experience in 6,800 cases. Circula-
tion. 1974;50(4):735-40.
23. Damato AN, Lau SH, Berkowitz WD, et al. Recording of specialized conducting fibers (A-V nodal, His bundle, and right bundle branch) in man
using an electrode catheter technique. Circulation. 1969;39(4):435-47.
24. Swan HJ, Ganz W, Forrester J, et al. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J Med.
1970;283(9):447-51.
25. Chazov EI, Matveeva LS, Mazaev AV, et al. Intracoronary administration of fibrinolysin in acute myocardial infarct. Ter Arkh. 1976;48(4):8-19.
26. Rentrop KP, Balnke H, Karsch KR, et al. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase. Clin Cardiol.
1979;2(5):354-63.
Med. 1980;303(16):897-902.
28. Dotter CT. Presented at the 1963 Czechoslovak Radiological Congress, June 10; 1963.
29. Staple TW. Modified catheter for percutaneous transluminal treatment of atherosclerotic obstructions. Radiology. 1968;91(5):1041-3.
30. Van Andel GJ. Percutaneous transluminal angioplasty: the Dotter procedure. Amsterdam: Excerpta Medica; 1976.
31. Gruntzig A, Hopff H. Perkutane rekanalisation chronischer arterieller verschlusse mit einem neuen dilatationskatheter modifikation der Dotter-
Technik. Dtsch Med Wochenschr. 1974;99(49):2502-10.
32. Hurst JW. The first coronary angioplasty as described by Andreas Gruentzig. Am J Cardiol. 1986;57(1):185-6.
33. Gruntzig A. Transluminal dilatation of coronary-artery stenosis. Lancet. 1978;1(8058):263.
34. Simpson JB, Zimmerman JJ, Selmon MR, et al. Transluminal atherectomy: initial clinical results in 27 patients [Abstract]. Circulation. 1986;74:203.
35. Zacca NM, Raizner AE, Noon GP, et al. Treatment of symptomatic peripheral atherosclerotic disease with a rotational atherectomy device. Am J
Cardiol. 1989;63(1):77-80.
36. Greenfield JC. An explosion of technology. Am J Cardiol. 1988;62(10 Pt 2):1F-2F.
37. Valbracht C, Liermann D, Prignitz I, et al. Results of low speed rotational angioplasty for chronic peripheral occlusions. Am J Cardiol.
1988;62(13):935-40.
1987;316(12):701-6.
39. Stack RS, Quigley PJ, Collins G, et al. Perfusion balloon catheter. Am J Cardiol. 1988;61(14):77G-80G.
40. Gore JM, Weiner BH, Benotti JR, et al. Preliminary experience with synchronized coronary sinus retroperfusion in humans. Circulation.
1986;74(2):381-8.
41. Mallery JA, Tobis JM, Griffith J, et al. Assessment of normal and atherosclerotic arterial wall thickness with an intravascular ultrasound imaging
catheter. Am Heart J. 1990;119(6):1392-400.
42. Spears JR, Spokojny AM, Marais HJ. Coronary angioscopy during cardiac catheterization. J Am Coll Cardiol. 1985;6(1):93-7.
43. Ryan TJ, Faxon DP, Gunnar RM, et al. Guidelines for percutaneous transluminal coronary angioplasty: a report of the American College of Car-
diology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures. J Am Coll Cardiol.
1988;12:529-45.
44. Ryan TJ, Bauman WB, Kennedy JW, et al. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of
Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on
Percutaneous Transluminal Coronary Angioplasty). J Am Coll Cardiol. 1993;22(7):2033-54.
45. Hannan EL, Racz M, Ryan TJ, et al. Coronary angioplasty volume-outcome relationships for hospitals and cardiologists. JAMA. 1997;277(11):892-8.
46. Ellis SG, Weintraub W, Holmes D, et al. Relation of operator volume and experience to procedural outcome of percutaneous coronary revasculari-
zation at hospitals with high interventional volumes. Circulation. 1997;95(11):2479-84.
47. Topol EJ, Califf RM, Van de Werf F, et al. Perspectives on large-scale cardiovascular clinical trials for the new millennium.The Virtual Coordinating
Center for Global Collaborative Cardiovascular Research (VIGOUR) Group. Circulation 1997;95(4):1072-82.
71 History of Catheter Ablation
Chen FC, Tester GA, Bisco SE, Gard JJ, Asirvatham SJ
Abbreviations HISTORY OF THE PREREQUISITES:

AC Alternating current SETTING THE TABLE
AF Atrial fibrillation
No work on the history of catheter-based ablation would be com-
AV Atrioventricular
pleted without mentioning the early pioneers who ushered in the era
AVNRT Atrioventricular nodal reentrant tachycardia of invasive EP. Although no one individual can claim responsibility
DC Direct current for this era, much of the foundation was laid by the late Dr Anthony
EP Electrophysiology N Damato.3 In the early 1960s, Dr Damato became the deputy chief
IVC Inferior vena cava of the cardiopulmonary laboratory at the United State Public Health
Science Hospital (USPHS) in Staten Island, New York. Dr Damato,
RF Radiofrequency
along with his colleagues, Dr Sun Hing Lau and Emanuel Stein began
SVT Supraventricular tachycardia
to train a highly gifted group of cardiac fellows who would form the
UCSF University of California at San Francisco cornerstone of modern clinical cardiac EP.4 Across town, in New York
USPHS United State Public Health Science Hospital City, Dr Brian Hoffman in the 1960s had accepted the David Hosack
VF Ventricular fibrillation Professorship and Chair in Pharmacology at Columbia University.
VT Ventricular tachycardia The interaction and in some ways a positive rivalry between Dr Hoff-
man’s Laboratory and Dr Damato’s group resulted and propelled
what we now know were many revolutionary ideas in EP. From Dr
Hoffman’s Laboratory would arise a stream of significant discoveries
INTRODUCTION
involving the basis of the normal cardiac impulse, cardiac conduc-
The history of catheter ablation is a modern history. In many ways, tion, theories of arrhythmogenesis, importance of slow conduction,
the basis for the multiple discoveries that allow us to treat patients summation and cancellation of impulses, promoting re-entry and
with arrhythmia successfully via percutaneous catheter manipula- among the first ideas and techniques for cardiac mapping. An exam-
tion grew on a foundation of general cardiology and neuroelectro- ple of the synthesis between two leading pioneering groups in EP is
physiology. Cardiac electrophysiology (EP) itself has a fascinating Dr Benjamin J Scherlag who had worked both in Dr Brian Hoffman’s
history that includes the fields of varied molecular channelopathies, Laboratory and Staten Island.
cardiac resynchronization devices, microelectrode studies, implant- Perhaps more important than the groundbreaking work in
able cardiac defibrillators, lead extraction, and all of the invasive developing clinical cardiac EP, Dr Damato’s contribution was his
therapeutic catheter techniques. vision to devise a structured and rigorous fellowship training pro-
While an entire book could be devoted to any of these, especially gram which allowed EP to become a distinct, vital, and to this day,
momentous are breakthroughs in how we manage patients today growing branch of cardiology. Of the multinational cadre of young
(Michel Mirowski and the ICD)1 and the advent of resynchronization cardiac electrophysiologists he trained, almost all subsequently took
therapy.2 Here, we focus on the history of catheter ablation. We will prominent positions and themselves broke new ground and pushed
first examine nontherapeutic catheter interventions and then dis- the frontiers of both basic and clinical EP research. In addition, many
cuss in approximate chronological order the major breakthroughs in of these individuals have dedicated themselves to the training of
catheter ablation that allow the present effective and safe manage- subsequent generations of electrophysiologists. Some of the USPHS
ment of complex cardiac rhythm disorders. History is a relative term. laboratory trainees are “household” names in invasive EP, includ-
Thus, we briefly review the remote history and what in the future will ing Dr Masood Akhtar,5 William Batsford,5 David Cannom,6 Stafford
be historical landmarks in this varied, complex and fascinating sub- I Cohen,7 Marcelo Elizari,8 John Gallagher,9 J Anthony Gomes,10,11
specialty of cardiology. Richard Helfant,12 Mark E Josephson,9 Michel Mirowski,13 J Bimbola
Ogunkelu,5 Eric N Prystowsky,14 Kenneth M Rosen,15 Jeremy Ruskin,5 conduction disturbances, concealed conduction33,34 and create
Benjamin Scherlag,12 Andres Ticzon,16 Guillermo Vargas,5 Melvin new concepts including electrophysiological gap, post extra-systolic
Weiss,17,18 Andrew Wit17,18 and Melvin Young.7 Another individual potentiation and demonstrate concealed His extra-systoles. For
who would later play a major role in the evolution and knowledge example, Ken Rosen would prove conclusively, using intracardiac
of catheter ablation also had a brief stint in the Damato Laboratory. recordings, theories on the genesis of AV node re-entry proposed by
Dr Melvin Scheinman19 would later himself lead an innovative, prac- Langendorf and Pick and demonstrate the existence of dual AV node
tical and leading EP division at the University of California at San physiology and its role in the creation of typical AV node re-entrant
Francisco (UCSF).20-24 tachycardia.
Internationally, innumerable observations and advances in
cardiac EP can be traced to the work and mind of Dr Hein J Wellens.25 SURGERY AND CATHETER ABLATION
Dr Wellens wrote the first “book” of intracardiac EP which to this day
remains a starting point for complex invasive electrogram analysis. If electrophysiological is parent to catheter ablation, then surgical
Dr Wellens’ plethoric pioneering efforts and the longevity of his crea- ablation is the elder sibling. As electrophysiologists probe further in
tive ideas and input into the field of cardiac EP, as well as device- unlocking the mysteries behind the mechanism of various arrhyth-
based therapy (which continues to this day) are legendary. He is also mias, a better understanding of what arrhythmogenic substrate can
considered one of the foremost educators in EP with heads of various be targeted to potentially effect arrhythmia cure was emerging. This
international laboratories having been trained through his program. led to a natural interest in techniques employed to disrupt abnormal
Beyond the actual work and teaching of Dr Wellens, perhaps like no circuitry and destroy arrhythmia foci. One of the earliest works in this
other electrophysiologist, he has provided an example and role mod- field remains a classical example of surgical proof of concept that led
el for generations of future electrophysiologists that creativity, intel- to routine catheter ablation. At Mayo Clinic in 1967, Harold Burchell,
lectual pursuit, tempered with practicality, sincere effort and honest Robert L Frye and Dwight McGoon35 used epicardial open chest
reporting of data leads to meaningful discovery.26-29 cardiac surgical mapping to localize accessory pathway conduc-
Thus, the table was set in the 1960s for the birth and flourishing tion intraoperatively. Burchell had recently returned after learning
growth of catheter ablation. It is said that just about any contributing mapping techniques using epicardial electrodes at Professor Dirk
electrophysiologist today can often trace their EP heritage to Staten Durrer’s36 Laboratory in Amsterdam. A 43-year-old patient with
Island. For example, Frank C Chen, Samuel J Asirvatham, Douglas L Wolff-Parkinson-White syndrome underwent successful termination
Packer, Warren Jackman, Eric Prystowsky, John J Gallagher, Benja- of circuit movement reentrant tachycardia with temporary loss of
min J Scherlag and Anthony Damato. preexcitation when 1% procaine was directly injected into a visualized
and mapped Kent bundle (accessory pathway). Although preexcita-
THE HIS BUNDLE ELECTROGRAM tion was to return later, this was the definitive proof of concept that
pathways could be disrupted and potentially eradicated.
Diagnosis is both mother and father to therapy. In the early 1960s the The next phase of invasive catheter EP concepts arising from
culmination of various basic cardiac physiology and EP, and cardiac joint research and intervention with surgical colleagues progressed
pharmacology gave rise to detailed speculation on the mechanism rapidly. Much of the work was carried out at Duke University by
of arrhythmia. The major enabling breakthrough in invasive EP took a team of outstanding insightful electrophysiologists (Dr John J
place in this environment when in 1969 Drs Scherlag,30 Kosowsky Gallagher and cardiac surgeons Sealey WC and Wallace AG).37 The
and Damato performed the first reliable recording, as well as stimu- team, utilizing epicardial mapping to isolate and surgically divide
lation of the human His bundle potential with a catheter electrode. accessory pathways, experimented with alternate technology,
This seminal work formed the premise upon which organized sys- including cryothermia to ablate Kent bundles (accessory pathways),
tematic approaches for arrhythmia diagnosis was established. Pre- as well as the atrial ventricular junction.38 This flurry of exciting
vious elegant conjecture on arrhythmia mechanisms were based on and quickly recognized to be groundbreaking EP research at Duke
the electrocardiogram where atrial (P wave) and ventricular (QRS attracted talented EP trainees and the Duke University would now
complex) depolar activations were visualized. In that one instant become the hub to train future leaders of cardiac EP, including
when the His bundle was recorded, a third layer was added to what George Klein,39 Douglas Zipes,40-45 David Benditt,46 Stephen C Ham-
was available over the prior decades. In many instances, the vision- mill,47 Kenneth Ellenbogen,48,49 Douglas L Packer,50 Neal Kay G,51
ary theories of the great electrocardiologists (Alfred Pick and Rich- Gust H Bardy52 and Peng-Sheng Chen.53,54
ard Langendorf and others) would simply be proven,31 yet this proof,
what was needed, to allow a true furthering of intellectual pursuit in SUPRAVENTRICULAR TACHYCARDIA
EP and gave rise to catheter intervention.32 Successive Damato and
Scherlag acolytes would use this newly found intracardiac technique Although surgical approaches were providing insight and being clin-
to shed light on various arrhythmias, including atrioventricular (AV) ically used, the highly invasive nature of these methods was a major
Chapter 71  History of Catheter Ablation 607
limitation. For example, up to this point, ablation of the AV junction Hiroshi Nakagawa, Kenichi Otomo and Dr Warren Jackman in
for supraventricular tachycardia (SVT) and rate control in atrial fibril- Oklahoma.67-71 Radiofrequency catheters were then equipped with
lation (AF) involved open thoracotomy, right atriotomy and endo- saline irrigation for cooling that allowed for higher power delivery
cardial mapping of the His bundle for its surgical destruction. A leap and deeper lesions without compromising safety.69
forward occurred in 1978 at Dr Melvin Scheinman’s Animal Labora- With the additional understanding afforded by invasive EP, the
tory at UCSF. Here, initial attempts for ablating the AV junction were true nature of slightly misrepresented arrhythmia mechanisms with
done using the radiofrequency (RF) energy with alternating current accessory pathways was rapidly outlined. The true nature of Mahaim
(AC), but were abandoned because several dogs developed ventricu- fibers, fasciculoventricular tracts, etc. was much better understood.
lar fibrillation (VF) during RF ablation. Dr Scheinman then visited Mr The detailed and meticulous studies performed with closely spaced
Beazell in Los Angeles, California, who was working for a pacemaker electrodes from Jackman’s and Lazzara’s Laboratory introduced
company and had developed a technique of AV junction ablation us- major new concepts that facilitated ablation of pathways including
ing high energy direct current (DC) shocks.55 Dr Rolando Gonzalez parahisian pacing,72 the pathway potential,72 and pathway slant.73
working with Dr Scheinman at that time perfected the technique of The evolution of RF ablation to treat AV nodal re-entry is an
identifying His bundle recordings and appreciating the ideal loca- even more fascinating journey. Building on the original work of Dr
tion for applying DC energy to induce heart block and implanting a Tawara74,75 and Professor Aschoff, more than a 100 years ago, Inoue
pacemaker in dogs.32 Much of the important histological characteri- and Anton Becker rediscovered detailed anatomy of the AV nodal
zation of AV node/His bundle post ablation specimens was done by extensions.76 Dr Jackman’s team combined this knowledge with
Saroja Bharati and Maurice Lev in Chicago.56,57 The first DC ablation electrophysiological data that showed AV node re-entry could be
in humans was done by Scheinman’s team on an oil refinery worker reset at significant distances from the compact AV node and safely
who had developed pulmonary edema whenever paroxysms of AF ablated a large number of patients with AV nodal reentrant tachy-
with rapid ventricular rates happened.21 The patient was deemed to cardia (AVNRT) without AV block or pacemaker need. This revisiting
be too high a risk for open thoracotomy. The procedure took place in of anatomy and classic EP conclusively won within raging debate as
March 1981 and the patient developed complete AV block after just to whether or not AV node re-entry was a circuit within the AV node
one shock. Riding on this initial success of DC ablation, the Schein- and could be ablated only by creating AV block, a major supposition
man team, which included present leaders in EP (Fred Morady and at that time. The debate was won by demonstrating that the inferior
Larry Epstein), extended the technique to treat other arrhythmias, atrial perinodal extensions, the so-called “slow pathway region,” can
including posteroseptal accessory pathways, ventricular tachycardia be targeted for ablation at significant distances from the compact AV
(VT), and AV nodal re-entry.58,59 Contemporaneous experiments on node with very low occurrence of AV conduction damage.72 Although
DC ablation were also being conducted by Dr Gallagher’s team at great success has occurred with ablating AVNRT, to this day the exact
Duke.60 Although considered somewhat primitive by today’s stand- circuit and variants in unusual cases has not been fully worked out
ards, DC shock proved beyond any doubt the feasibility of destroying and remains a challenge for cardiac anatomists and electrophysiolo-
arrhythmic targets without open heart surgery and truly revolution- gists today.
ized percutaneous catheter-based therapies for cardiac arrhythmia.
Later in the 1980s, several groups, including Stephen Huang SK TYPICAL ATRIAL FLUTTER
and Frank Marcus in the United States and Dr Budde’s team in Ger-
many, were reinvestigating RF energy as an alternative to DC shock Another classical arrhythmia that had baffled cardiologists for close
for ablative intervention.61,62 Earlier work by Dr Jonathan Langberg at to a century involved defining the circuit for typical atrial flutter. Vari-
UCSF demonstrated that a 4 mm sized electrode was optimal for RF ous and at times conflicting theories for the primary circuit had been
generators with a 50-Watt capacity.63 Based on this, one of the earli- proposed, but a simple and comprehensive explanation that would
est successful RF ablations in humans was performed by Dr Marcus’ allow targeted ablation remained elusive. Classical concepts of in-
group, ablating the AV junction for refractory SVT. vasive entrainment analysis was outlined and taught by Dr Albert L
It should be emphasized that many of the breakthroughs in cath- Waldo,77 and building on these principles and animal data, Francis-
eter intervention for arrhythmia are based on advances in under- co G Cosio78 and Gregory K Feld79 were credited with discovering the
standing the biophysics of ablation. Leaders who helped us under- arrhythmogenic substrate for atrial flutter being the cavotricuspid
stand how to effectively and safely ablate using RF and other energy isthmus.80 Successful termination and lack of reducibility of typical
sources include Dr David Haines64 and the Laboratory of Dr Ralph atrial flutter was done by ablating in a linear fashion from the tricus-
Lazzara in Oklahoma City.65,66 As RF energy use became widespread, pid valve to the inferior vena cava (IVC).81
further advances arose from understanding the biophysics of RF Atrial flutter is also an excellent example of how one historical
lesion formation with varying power, the concepts of thermal laten- discovery leads to the need and eventual fulfillment of further inno-
cy, and the relationship of active electrode cooling, versus lesion size, vative clarification. Cavotricuspid isthmus ablation was sometimes
as was elegantly proposed and worked out by Drs Fred Wittkampf, challenging and recurrences were observed initially. Anatomical
clarification of the circuit and causes for difficulty were made with the way in the search for anatomic approaches for this seemingly too
worked by S W Ho, Jose Cabrera and Damian Sanchez Quintana.82,83 complex arrhythmia.98 Taking this approach further, Frank March-
Perhaps even more importantly, understanding the history of the linski, Hiroshi Nakagawa, and others advanced the concept that
errors made and eventual success in describing the typical atrial substrate mapping (mapping in sinus rhythm or without necessar-
flutter circuit has allowed real time intraprocedural analysis of ily VT induced) and identifying abnormal, but not scarred areas of
numerous atypical flutters in contemporary EP. myocardium (the putative channels for VT circuits) often existing
between electrically inert structures (scars, valves, etc.) could be
ATRIAL FIBRILLATION targeted for ablation, have all provided major historical advances
that lead to the present ablation approach for VT. The pioneering
The most recent of historical advances in catheter ablation involves work of Dr Edwardo Sosa and colleagues in Sao Paolo Brazil created
targeted ablation to prevent, minimize and occasionally cure AF. an entirely new vantage point (the pericardial space) for attacking
Once again, the breakthrough occurred when investigators stood on the three-dimensional substrate.99
the shoulders of decades of insightful reported insights into the anat- More recently, a fourth dimension for VT, namely the endo-
omy and EP of AF.84,85 With the help of work from multiple investiga- cavitary structures (papillary muscle, moderator band and false
tors and laboratories, it became largely accepted that AF was in fact tendons), has allowed an even more comprehensive approach to this
two diseases, with abnormal atrial substrate being the prominent difficult arrhythmia.100-103
arrhythmogenic culprit for persistent and chronic forms of the dis- Ventricular fibrillation for years thought to be beyond the realm
ease and possibly automatic triggers inciting the arrhythmia being of catheter intervention has had some recent advances and insights
paramount for paroxysmal AF. What exactly the trigger was, however, for both the triggers and substrate responsible for this complex
was not easy to identify, and the work of Michel Haissaguerre, Pier arrhythmia that in some cases has allowed successful catheter
Jais, Dipen Shah and Jacque Clementy showed the importance of the ablation.104,105
pulmonary veins in triggering AF.86 Subsequent work identified other
triggers often in thoracic veins, such as the superior vena cava.87,88 PAST HISTORY
Another important breakthrough was appreciating that an elec-
trical signature existed for arrhythmogenic pulmonary veins, even Although we have reviewed here the history of catheter ablation,
when the patient was not in AF, thus allowing an electrical endpoint the dynamic nature of what history represents can be understood
for ablation in sinus rhythm.89,90 These advances facilitated the abla- when we appreciate that the true historical origins for the origins
tion procedure, moving from prolonged hospitalizations waiting for described above began with a group of astute, insightful electrocardi-
patients to go in and out of AF to in turn allow mapping to what is ologists, including Professors Gaskell, Einthoven, Winckebach and the
now an elective procedure that is largely anatomically-based.91,92 redoubtable Sir Thomas Lewis from the classical era. These investiga-
Further advances that have enabled the widespread use of cath- tors paved the way for the next generation of insightful electrocar-
eter ablation as an effective and safe option for managing paroxys- diology and microelectrophysiologists, including Pick, Langendorff,
mal AF have included advances in cardiac imaging, navigation, and Katz, Scherf, Leo Schamroth, Charles Fisch, Augustine Castellanos
combined mapping and imaging technology.93-95 and Rosenbaum. These cardiologists’ uncanny ability to deduce
complex interaction and substrates for various arrhythmias based
VENTRICULAR TACHYCARDIA on surface electrocardiography alone has been proven with present
invasive techniques. However, as emphasized above, it was this
There were early breakthroughs with VT intervention, largely stem- proof, enabled by Dr Scherlag and coworkers’ discovery of the His
ming from the work of Dr Mark Josephson and colleagues96 and DC bundle electrogram, that truly set the stage for catheter ablation.
ablation mentioned above. The challenges, however, of percutaneous
catheter ablation for VT appeared for some years to be insurmount- FUTURE HISTORY
able. The three-dimensions of electrical substrate (endocardium,
mid myocardium and epicardium), hemodynamic instability during The history of catheter ablation written 20 years from now will reflect
VT and multiplicity of VT circuits, all seemed to create improbably the advances we would have made in the present frontiers of cardiac
success with catheter ablation for this arrhythmia. EP, namely chronic AF and VF. Holding us back now is the lack of un-
Dr William G Stevenson97 elegantly showed both in computer derstanding of the diagnosis. That is, what these arrhythmias truly
models and in vivo arrhythmia that classical entrainment concepts represent. Are they focal, reentrant, or both? Are there substrates be-
appropriately modified was a powerful tool for real-time diagnosis yond what we consider (diseased myocardium), such as the smooth
of arrhythmogenic substrate in patients with VT. Dr David Wilber muscle of the great arteries and thoracic veins and the heterogene-
showed an equivalent to an atrial flutter isthmus occurring in some ity of the tissues in the cul-de-sacs of the heart that we need to un-
patients with inferior wall myocardial infarction and VT. That paved derstand further.106,107 Recent appreciation of the complex gross and
microscopic anatomy of VT that arises in structurally normal hearts, Prystowsky, Warren Jackman and Ralph Lazzara), have been able to
as well as the electrophysiological manifestations of channelopathies, maintain the ability to provide landmarks in the history of catheter
may provide further insights.83,108 We may potentially be at this mo- ablation over decades. These and other individuals serve not only as
ment on the threshold of a historical advance in catheter ablation. beacons in the understanding of what catheter ablation can be based
This involves the hypothesis that the cardiac autonomic nervous sys- on what cardiac EP is, but also as role models for present electrophysi-
tem is as or more important a substrate for atrial and possible VF and ologists, for what he or she can achieve in their own career.
thus can be targeted for ablation. Once again, the combined work of
pioneering anatomists and physiologists has led to what appears to be SUMMARY—BACK TO THE FUTURE
near-definitive animal studies and early human work to support this
hypothesis. A leader in this field is surprisingly Dr Benjamin Scherlag. Dr Scherlag’s work with autonomic physiology and recent re-interest
The fact that he and his group make groundbreaking discoveries at in DC ablation and resurgence of interest in anatomic physiological
the very threshold of catheter ablation advances 40 years after his dis- correlation109,110 show us that in many ways we borrow from the past
covery of the His bundle electrogram is a testament to the resilience to get to the future. Every present innovator and contributor to in-
and longevity of human innovation when founded on careful, hon- terventional cardiac EP jumps on this circuit of discovery, gradually
est and incrementally important observations. Scherlag and Wellens, widening it to a fascinating spiral. We are all grateful that we can help
along with very few other electrophysiologists (Douglas Zipes, Eric our patients while enjoying the ride.
REFERENCES
1. Kastor JA. Michel Mirowski and the automatic implantable defibrillator. Am J Cardiol. 1989;63(15):1121-6.
2. Lattuca JJ, Cohen TJ, Mower MM. Biventricular pacing to improve cardiac hemodynamics. Clin Rev. 1990;38:882.
3. Anthony M Damato. Pacing and Clinical Electrophysiology. 2001;24(5):914.
4. Lau SH, Cohen SI, Stein E, et al. P waves and P loops in coronary sinus and left atrial rhythms. Am Heart J. 1970;79(2):201-14.
5. Akhtar M, Damato AN, Batsford WP, et al. Demonstration of re-entry within the His-Purkinje system in man. Circulation.1974;50(6):1150-62.
6. Cannom DS, Goldreyer BN, Damato AN. Atrioventricular conduction system in left bundle-branch block with normal QRS axis. Circulation.
1972;46(1):129-37.
7. Cohen SI, Lau SH, Stein E, et al. Variations of aberrant ventricular conduction in man: evidence of isolated and combined block within the special-
ized conduction system. An electrocardiographic and vectorcardiographic study. Circulation. 1968;38(5):899-916.
8. Varghese PJ, Elizari MV, Lau SH, et al. His bundle electrograms of dog. Correlation with intracellular recordings. Circulation. 1973;48(4):753-60.
9. Josephson ME, Caracta AR, Lau SH, et al. Effects of lidocaine on refractory periods in man. Am Heart J. 1972;84(6):778-86.
10. de Paola AA, Gomes JA, Miyamoto MH, et al. Transcoronary chemical ablation of ventricular tachycardia in chronic chagasic myocarditis. J Am
Coll Cardiol. 1992;20(2):480-2.
11. Gomes JA. Ode to the electrophysiologist. J Am Coll Cardiol. 1992;19(1):234.
12. Helfant RH, Scherlag BJ, Damato AN. Diphenylhydantoin prevention of arrhythmias in the digitalis-sensitized dog after direct-current cardiover-
sion. Circulation. 1968;37(3):424-8.
13. Mirowski M, Lau SH, Bobb GA, et al. Studies on left atrial automaticity in dogs. Circ Res. 1970;26(3):317-25.
14. Prystowsky EN, Pritchett EL, Gallagher JJ, et al. The natural history of cardiac conduction system disease in myotonic muscular dystrophy as de-
termined by serial electrophysiology studies. Trans Am Neurol Assoc. 1979;104:18-21.
15. Wu D, Amat-y-leon F, Denes P, et al. Demonstration of sustained sinus and atrial re-entry as a mechanism of paroxysmal supraventricular tachy-
cardia. Circulation. 1975;51(2):234-43.
16. Ticzon AR, Damato AN, Caracta AR, et al. Interventricular septal motion during preexcitation and normal conduction in Wolff-Parkinson-White
syndrome: echocardiographic and electrophysiologic correlation. Am J Cardiol. 1976;37(6):840-7.
17. Wit AL, Weiss MB, Berkowitz WD, et al. Patterns of atrioventricular conduction in the human heart. Circ Res. 1970;27(3):345-59.
18. Wit AL, Damato AN, Weiss MB, et al. Phenomenon of the gap in atrioventricular conduction in the human heart. Circ Res. 1970;27:679-89.
19. Scheinman MM. NASPE Plenary Lecture 2001. Catheter ablation: a personal perspective. J Cardiovasc Electrophysiol. 2001;12(9):1083-8.
20. Lesh MD, Van Hare GF, Epstein LM, et al. Radiofrequency catheter ablation of atrial arrhythmias. Results and mechanisms. Circulation.
1994;89(3):1074-89.
21. Scheinman MM, Morady F, Hess DS, et al. Catheter-induced ablation of the atrioventricular junction to control refractory supraventricular ar-
rhythmias. JAMA. 1982;248(7):851-5.
22. Scheinman MM. Nonpharmacologic management of supraventricular tachycardia. Am J Geriatr Cardiol. 2000;9(3):159-61.
23. Scheinman MM. NASPE survey on catheter ablation. Pacing Clin Electrophysiol. 1995;18(8):1474-8.
24. Scheinman MM, Bharati S, Wang YS, et al. Electrophysiologic and anatomic changes in the atrioventricular junction of dogs after direct-current
shocks through tissue fixation catheters. Am J Cardiol. 1985;55(1):194-8.
25. Wellens HJ, Schuilenberg RM, Durrer D. Electrical stimulation of the heart in patients with Wolff-Parkinson-White syndrome, type A. Circulation.
1971;43(1):99-114.
26. Wellens HJ, Lie KI, Durrer D. Further observations on ventricular tachycardia as studied by electrical stimulation of the heart. Chronic recurrent
ventricular tachycardia and ventricular tachycardia during acute myocardial infarction. Circulation. 1974;49(4):647-53.
27. Wellens HJ, Bär FW, Farré J, et al. Initiation and termination of ventricular tachycardia by supraventricular stimuli. Incidence and electrophysi-
ologic determinants as observed during programmed stimulation of the heart. Am J Cardiol. 1980;46(4):576-82.
28. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998;98(21):2334-51.
29. Wellens HJ. Electrical Stimulation of the Heart in the Study and Treatment of Tachycardias. Baltimore: University Park Press; 1971.
30. Scherlag BJ, Lau SH, Helfant RH, et al. Catheter technique for recording His bundle activity in man. Circulation. 1969;39(1):13-8.
31. Langendorf R. Concealed A-V conduction; the effect of blocked impulses on the formation and conduction of subsequent impulses. Am Heart J.
1948;35(4):542-52.
32. Gonzalez R, Scheinman M, Margaretten W, et al. Closed-chest electrode-catheter technique for His bundle ablation in dogs. Am J Physiol.
1981;241(2):283-7.
33. Damato AN, Lau SH. Concealed and supernormal atrioventricular conduction. Circulation. 1971;43(6):967-70.
34. Igarashi M. Wedensky phenomena in bundle branch system. Am J Cardiol. 1972;30(1):105.
35. Burchell HB, Frye RL, Anderson MW, et al. Atrioventricular and ventriculoatrial excitation in Wolff-Parkinson-White syndrome (type B). Tempo-
rary ablation at surgery. Circulation. 1967;36(5):663-72.
36. Durrer D, Roos JP. Epicardial excitation of the ventricles in a patient with wolff-Parkinson-White syndrome (type B). Circulation. 1967;35(1):15-21.
37. Svenson RH, Gallagher JJ, Sealy WC, et al. An electrophysiologic approach to the surgical treatment of the Wolff-Parkinson-White syndrome. Re-
port of two cases utilizing catheter recording and epicardial mapping techniques. Circulation. 1974;49(5):799-804.
38. Gallagher JJ, Sealy WC, Anderson RW, et al. Cryosurgical ablation of accessory atrioventricular connections: a method for correction of the pre-
excitation syndrome. Circulation. 1977;55(3):471-9.
39. Klein GJ, Guiraudon GM, Kerr CR, et al. “Nodoventricular” accessory pathway: evidence for a distinct accessory atrioventricular pathway with
atrioventricular node-like properties. J Am Coll Cardiol. 1988;11(5):1035-40.
40. Kaseda S, Zipes DP. Supersensitivity to acetylcholine of canine sinus and AV nodes after parasympathetic denervation. Am J Physiol. 1988;255
(3 Pt 2):534-9.
41. Kaseda S, Zipes DP. Contraction-excitation feedback in the atria: a cause of changes in refractoriness. J Am Coll Cardiol. 1988;11(6):1327-36.
42. Martins JB, Zipes DP. Epicardial phenol interrupts refractory period responses to sympathetic but not vagal stimulation in canine left ventricular
epicardium and endocardium. Circ Res. 1980;47(1):33-40.
43. Zipes DP, Prystowsky EN, Miles WM, et al. Future directions: electrical therapy for cardiac tachyarrhythmias. Pacing Clin Electrophysiol. 1984;7
(3 Pt 2):606-10.
44. Zipes DP. Interpretation and significance of supraventricular arrhythmia with abnormal QRS complex. Nurs Clin North Am. 1972;7(3):491-508.
45. Zipes DP, Heger JJ, Miles WM, et al. Early experience with an implantable cardioverter. N Engl J Med. 1984;311(8):485-90.
46. Benditt DG, Brignole M. Syncope: is a diagnosis a diagnosis? J Am Coll Cardiol. 2003;41(5):791-4.
47. Hammill SC, Packer DL, Stanton MS, et al. Termination and acceleration of ventricular tachycardia with autodecremental pacing, burst pac-
ing, and cardioversion in patients with an implantable cardioverter defibrillator. Multicenter PCD investigator group. Pacing Clin Electrophysiol.
1995;18(1 Pt 1):3-10.
48. Martin RE, Ellenbogen KA, Lau YR, et al. Phased-array intracardiac echocardiography during pulmonary vein isolation and linear ablation for
atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13(9):873-9.
49. Ellenbogen KA, Wood MA. Ablation of atrial fibrillation: awaiting the new paradigm. J Am Coll Cardiol. 2003;42(2):198-200.
50. Chan RC, Johnson SB, Seward JB, et al. The effect of ablation electrode length and catheter tip to endocardial orientation on radiofrequency lesion
size in the canine right atrium. Pacing Clin Electrophysiol. 2002;25(1):4-13.
51. Kay GN, Ellenbogen KA, Giudici M, et al. The ablate and pace trial: a prospective study of catheter ablation of the AV conduction system and per-
manent pacemaker implantation for treatment of atrial fibrillation. APT investigators. J Interv Card Electrophysiol. 1998;2(2):121-35.
52. Anderson J, Bardy GH. Key clinical insights from the sudden cardiac death in heart failure trial. J Cardiovasc Nurs. 2006;21(6):463-8.
53. Weiss JN, Chen PS, Qu Z, et al. Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol. 2002;13(3):292-5.
54. Chen PS, Wu TJ, Hwang C, et al. Thoracic veins and the mechanisms of non-paroxysmal atrial fibrillation. Cardiovasc Res. 2002;54(2):295-301.
55. Beazell J, Tan K, Criley J, et al. The electrosurgical production of heart block without thoracotomy. Clin Res. 1976;24:137.
56. Gonzalez R, Scheinman M, Bharati S, et al. Closed chest permanent atrioventricular block in dogs. Am Heart J. 1983;105(3):461-70.
57. Scheinman MM. Catheter electrocoagulation of serious cardiac arrhythmias. Cardiovasc Clin. 1985;16(1):167-75.
58. Morady F, Scheinman MM. Transvenous catheter ablation of a posteroseptal accessory pathway in a patient with the Wolff-Parkinson-White syn-
drome. N Engl J Med. 1984;310(11):705-7.
59. Winston SA, Morady F, Davis JC, et al. Catheter ablation of ventricular tachycardia. Circulation. 1984;70(suppl II):11-412.
60. Gallagher JJ, Svenson RH, Kasell JH, et al. Catheter technique for closed-chest ablation of the atrioventricular conduction system. N Engl J Med.
1982;306(4):194-200.
61. Huang SKS, Lee MA, Bazgan ID, et al. Radiofrequency catheter ablation of the atrioventricular junctional for refractory supraventricular tachyar-
rhythmia. Circulation. 1988;78(suppl II):II-156.
62. Budde T, Borggrefe M, Martinez-Rubio A, et al. Acute and long-term results of radiofrequency ablation of the conduction system. Circulation.
1989;80(suppl II):II-44.
63. Epstein LM, Scheinman MM, Langberg JJ, et al. Percutaneous catheter modification of the atrioventricular node. A potential cure for atrioven-
tricular nodal reentrant tachycardia. Circulation. 1989;80(4):757-68.
64. Haines DE. The biophysics of radiofrequency catheter ablation in the heart: the importance of temperature monitoring. Pacing Clin Electro-
physiol. 1993;16(3 Pt 2):586-91.
65. Jackman WM, Wang XZ, Friday KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofre-
quency current. N Engl J Med. 1991;324(23):1605-11.
66. Jackman WM, Friday KJ, Scherlag BJ, et al. Direct endocardial recording from an accessory atrioventricular pathway: localization of the site of
block, effect of antiarrhythmic drugs, and attempt at nonsurgical ablation. Circulation. 1983;68(5):906-16.
67. Nakagawa H, Wittkampf FH, Yamanashi WS, et al. Inverse relationship between electrode size and lesion size during radiofrequency ablation
with active electrode cooling. Circulation. 1998;98(5):458-65.
68. Otomo K, Yamanashi WS, Tondo C, et al. Why a large tip electrode makes a deeper radiofrequency lesion: effects of increase in electrode cooling
and electrode-tissue interface area. J Cardiovasc Electrophysiol. 1998;9(1):47-54.
69. Wittkampf FH, Hauer RN, Robles de Medina EO. Control of radiofrequency lesion size by power regulation. Circulation. 1989;80(4):962-8.
70. Wittkampf FH, Nakagawa H, Yamanashi WS, et al. Thermal latency in radiofrequency ablation. Circulation. 1996;93(6):1083-6.
71. Wittkampf FH, Nakagawa H, Foresti S, et al. Saline-irrigated radiofrequency ablation electrode with external cooling. J Cardiovasc Electrophysiol.
2005;16(3):323-8.
72. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal re-entry, by radiofre-
quency catheter ablation of slow-pathway conduction. N Engl J Med. 1992;327(5):313-8.
73. Otomo K, Gonzalez MD, Beckman KJ, et al. Reversing the direction of paced ventricular and atrial wavefronts reveals an oblique course in acces-
sory AV pathways and improves localization for catheter ablation. Circulation. 2001;104(5):550-6.
74. Tawara S. Das reilzeitungssystem des saugetierherzens. London: Imperial College Press; 2000.
75. Suma K. Sunao Tawara: a father of modern cardiology. Pacing Clin Electrophysiol. 2001;24(1):88-96.
76. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular node: a neglected anatomic feature of potential clinical signifi-
cance. Circulation. 1998;97(2):188-93.
77. Waldo AL, MacLean WA, Karp RB, et al. Entrainment and interruption of atrial flutter with atrial pacing: studies in man following open heart
surgery. Circulation. 1977;56(5):737-45.
78. Cosio FG, Arribas F, Palacios J, et al. Fragmented electrograms and continuous electrical activity in atrial flutter. Am J Cardiol. 1986;57(15):1309-
14.
79. Feld GK, Fleck RP, Chen PS, et al. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter. Identification of a critical zone
in the reentrant circuit by endocardial mapping techniques. Circulation. 1992;86(4):1233-40.
80. Wells JL, MacLean WA, James TN, et al. Characterization of atrial flutter. Studies in man after open heart surgery using fixed atrial electrodes.
Circulation. 1979;60(3):665-73.
81. Cosio FG, López-Gil M, Goicolea A, et al. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am
J Cardiol. 1993;71(8):705-9.
82. Cabrera JA, Ho SY, Sánchez-Quintana D. How anatomy can guide ablation in isthmic atrial flutter. Europace. 2009;11(1):4-6.
83. Gami AS, Noheria A, Lachman N, et al. Anatomical correlates relevant to ablation above the semilunar valves for the electrophysiologist: a study
of 603 hearts. J Interv Card Electrophysiol. 2011;30(1):5-15.
84. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circula-
tion. 1995;92(7):1954-68.
85. Nathan H, Gloobe H. Myocardial atrio-venous junctions and extensions (sleeves) over the pulmonary and caval veins. Anatomical observations
in various mammals. Thorax. 1970;25(3):317-24.
86. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J
Med. 1998;339(10):659-66.
87. Asirvatham SJ. Anatomy of the vena cava: an electrophysiological perspective. In: Chen SA, Haissaguerre M, Zipes DP (Eds). Thoracic Vein Ar-
rhythmias: Mechanisms and Treatment. Blackwell Future; 2004. pp. 54-65.
88. Macedo PG, Kapa S, Mears JA, et al. Correlative anatomy for the electrophysiologist: ablation for atrial fibrillation. Part I: pulmonary vein ostia,
superior vena cava, vein of Marshall. J Cardiovasc Electrophysiol. 2010;21:721-30.
89. Asirvatham SJ. Pulmonary vein-related maneuvers: part I. Heart Rhythm. 2007;4(4):538-44.
90. Asirvatham SJ. Pacing maneuvers for nonpulmonary vein sources: part II. Heart Rhythm. 2007;4(5):681-5.
91. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: a new anatomic approach for curing
atrial fibrillation. Circulation. 2000;102(21):2619-28.
92. Cha YM, Friedman PA, Asirvatham SJ, et al. Catheter ablation for atrial fibrillation in patients with obesity. Circulation. 2008;117(20):2583-90.
93. Gurevitz OT, Glikson M, Asirvatham S, et al. Use of advanced mapping systems to guide ablation in complex cases: experience with noncontact
mapping and electroanatomic mapping systems. Pacing Clin Electrophysiol. 2005;28(4):316-23.
94. Asirvatham SJ, Bruce CJ, Friedman PA. Advances in imaging for cardiac electrophysiology. Coron Artery Dis. 2003;14(1):3-13.
95. Seward JB, Packer DL, Chan RC, et al. Ultrasound cardioscopy: embarking on a new journey. Mayo Clin Proc. 1996;71(7):629-35.
96. Josephson ME, Harken AH, Horowitz LN. Endocardial excision: a new surgical technique for the treatment of recurrent ventricular tachycardia.
Circulation. 1979;60(7):1430-9.
97. Stevenson WG, Khan H, Sager P, et al. Identification of re-entry circuit sites during catheter mapping and radiofrequency ablation of ventricular
tachycardia late after myocardial infarction. Circulation. 1993;88(4 Pt 1):1647-70.
98. Wilber DJ, Kopp DE, Glascock DN, et al. Catheter ablation of the mitral isthmus for ventricular tachycardia associated with inferior infarction.
Circulation. 1995;92(12):3481-9.
99. Sosa E, Scanavacca M, D’Avila A, et al. Nonsurgical transthoracic epicardial approach in patients with ventricular tachycardia and previous car-
diac surgery. J Interv Card Electrophysiol. 2004;10(3):281-8.
100. Liu XK, Barrett R, Packer DL, et al. Successful management of recurrent ventricular tachycardia by electrical isolation of anterolateral papillary
muscle. Heart Rhythm. 2008;5(3):479-82.
101. Abouezzeddine O, Suleiman M, Buescher T, et al. Relevance of endocavitary structures in ablation procedures for ventricular tachycardia. J Car-
diovasc Electrophysiol. 2010;21(3):245-54.
102. Chen FC, Asirvatham SJ. Tachycardia and the AV nodal region: guilt by association? Circ Arrhythm Electrophysiol. 2010;3(1):2-6.
103. Yamabe H, Tanaka Y, Morihisa K, et al. Analysis of the anatomical tachycardia circuit in verapamil-sensitive atrial tachycardia originating from
the vicinity of the atrioventricular node. Circ Arrhythm Electrophysiol. 2010;3(1):54-62.
104. Srivathsan K, Gami AS, Ackerman MJ, et al. Treatment of ventricular fibrillation in a patient with prior diagnosis of long QT syndrome: impor-
tance of precise electrophysiologic diagnosis to successfully ablate the trigger. Heart Rhythm. 2007;4(8):1090-3.
105. Haissaguerre M, Warin JF, Lemetayer P, et al. Closed-chest ablation of retrograde conduction in patients with atrioventricular nodal reentrant
tachycardia. N Engl J Med. 1989;320(7):426-33.
106. Kapa S, Asirvatham SJ. Atrial fibrillation: focal or reentrant or both?: a new autonomic lens to examine an old riddle. Circ Arrhythm Electro-
physiol. 2009;2(4):345-8.
107. Niu G, Scherlag BJ, Lu Z, et al. An acute experimental model demonstrating 2 different forms of sustained atrial tachyarrhythmias. Circ Arrhythm
Electrophysiol. 2009;2(4):384-92.
108. Chu AF, Zado E, Marchlinski FE. Atrial arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and ventricular
tachycardia. Am J Cardiol. 2010;106(5):720-2.
109. Lim B, Venkatachalam KL, Jahangir A, et al. Concurrent application of charge using a novel circuit prevents heat-related coagulum formation
during radiofrequency ablation. J Cardiovasc Electrophysiol. 2008;19(8):843-50.
110. Kapa S, Venkatachalam KL, Asirvatham SJ. The autonomic nervous system in cardiac electrophysiology: an elegant interaction and emerging
concepts. Cardiol Rev. 2010;18(6):275-84.
72 Cardiac Resynchronization
Therapy
Rao BH
The next milestone was the report by Cazeau from France of

INTRODUCTION
four-chamber pacing in a patient with Class IV New York Heart As-
Cardiac resynchronization therapy (CRT) has proven to be a defini- sociation (NYHA) heart failure.4 Standard pacing leads were placed
tive therapy for some patients with congestive heart failure (CHF) in RA and RV, coronary sinus lead was used for LA, and LV lead was
where symptoms persist despite optimal medical therapy includ- paced epicardially.
ing diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta Resynchronization of both atria and ventricles was achieved by
blockers and digoxin. Clinical data gathered in the last decade has a regular dual chamber pacemaker resulting in clinical improvement
decisively placed this therapy in the algorithm of heart failure man- in the patient. This study heralded the era of LV pacing with positive
agement with an established role in alleviation of symptoms, reduc- results reported from several acute studies in achieving an increase
tion in hospitalizations and mortality. in femoral arterial pressures and a decrease in pulmonary capil-
lary wedge pressures. A prospective randomized study proved that
PACING FOR HEART FAILURE direct left ventricular (LV) activation with a temporary pacing sys-
tem results in a significant improvement in cardiovascular function
From the Past to the Present in patients with CHF and conduction system disease.5 It was further
shown in this study that acute hemodynamic results of LV pacing
Pacemakers evolved principally as life-saving devices for patients alone were similar to biventricular pacing. Insync was an observa-
with complete heart block and for a long time it was uncertain if they tional study which confirmed the effectiveness of atrio biventricular
would aid in alleviating symptoms, if heart failure co-existed.1 In pacing in about a hundred patients.6 This was followed by the report
1992, a publication from Austria introduced a new concept in heart of the first randomized study–pacing therapies (PATH)-CHF, where
failure treatment by implantation of dual chamber pacemakers with a LV epicardial lead was placed by thoracotomy.7 Pacing in the VDD
a short atrioventricular (AV) delay in a few heart failure patients, [ventricle, dual (A+V), dual (T+I)] mode replicated the results of the
but with no indication for pacing.2 The short-term benefits were en- acute study in showing similarity of benefit between univentricular
couraging and resulted in increased left ventricular ejection fraction LV pacing and biventricular pacing and also demonstrating a sus-
(LVEF), and a decrease in echocardiographic dimensions. Though tained clinical improvement over a period of 1 year. PATH-CHF II
only 3 patients out of 17 survived the 5 years follow-up period, there study evaluated the effect of LV pacing in patients stratified by the
were no heart failure related hospitalizations. Despite few other duration of wide QRS. 25 of the 86 patients in this study received LV
reports showing similar benefits, subsequent prospective follow-up lead by transvenous route.8 Though clinical improvement was seen
studies showed that these short-term clinical or echocardiographic in the whole cohort, maximum benefit was experienced in those
benefits were neither consistent nor long lasting. A randomized trial with QRS greater than 150 msec. Though subsequent CRT trials were
involving 12 patients conclusively demonstrated lack of hemody- focused on biventricular pacing, it is interesting to note that a recent
namic, clinical or echocardiographic improvement in heart failure trial B-LEFT HF study with 176 heart failure patients showed nonin-
patients receiving dual chamber pacemakers.3 This put to rest specu- feriority of LV pacing to biventricular pacing with respect to clinical
lations on the benefit of this strategy in the management of heart fail- and echocardiographic parameters.9
ure. Dual chamber pacing with short AV delay, no doubt increased
LV filling time and enhanced atrial contribution to the cardiac out- THE ERA OF RANDOMIZED TRIALS
put, but negated these beneficial effects by the deleterious effect of
right ventricular pacing worsening the inter ventricular dyssynchro- Large data of evidence from randomized trials has established CRT
ny thus accounting for overall lack of improvement in heart failure. as an effective therapy in heart failure. Salient aspects of landmark
TABLE 72.1 Cardiac resynchronization therapy trials

MUSTIC MIRACLE PATH-CHF COMPANION CARE-HF MADITCRT
Year 2001 2002 2002 2004 2005 2009
N= 67 453 41 1520 813 1820
NYHA class III III/IV III/IV III/IV III/IV I/II
Mean LVEF (%) 23 ± 7 22 ± 6 21 ± 6 22 25 24 ± 5
QRS (ms) ≥ 150 ≥ 130 ≥ 120 ≥ 120 ≥ 120 ≥ 130
Exercise capacity Improved Improved Improved Improved Improved Not assessed
QOL improved Yes Yes Yes Yes Yes Not assessed
LVEF improved Not assessed Yes Not assessed Not assessed Yes Yes
NYHA improved Yes Yes Yes Yes Not assessed
Hospitalizations for HF Decreased Decreased Decreased Decreased Decreased Decreased
Mortality benefit Not assessed Not assessed Not assessed Yes Yes None
Abbreviations: NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; QOL, quality of life; HF, heart failure; MUSTIC, multisite
stimulation in cardiomyopathies; MIRACLE, multicenter insync randomized clinical evaluation; PATH-CHF, pacing therapies in congestive heart failure;
COMPANION, comparison of medical therapy, pacing and defibrillation in chronic heart failure; CARE-HF, cardiac resynchronization-heart failure; MADIT-
CRT, multicenter automatic defibrillator implanting trial-cardiac resynchronization therapy.
TABLE 72.2 Recommendations for cardiac resynchronization therapy in patients with severe systolic heart failure45
Class I
1. For patients who have LVEF less than or equal to 35%, a QRS duration greater than or equal to 0.12 seconds, and sinus rhythm, CRT with or without
an ICD is indicated for the treatment of NYHA functional Class III or ambulatory Class IV heart failure symptoms with optimal recommended medical
therapy.
Class IIA
1. For patients who have LVEF less than or equal to 35%, a QRS duration greater than or equal to 0.12 seconds, and AF, CRT with or without an ICD is
reasonable for the treatment of NYHA functional Class III or ambulatory Class IV heart failure symptoms on optimal recommended medical therapy.
2. For patients with LVEF less than or equal to 35% with NYHA functional Class III or ambulatory Class IV symptoms who are receiving optimal
recommended medical therapy and who have frequent dependence on ventricular pacing, CRT is reasonable.
Class IIB
1. For patients with LVEF less than or equal to 35% with NYHA functional Class I or II symptoms who are receiving optimal recommended medical therapy
and who are undergoing implantation of a permanent pacemaker and/or ICD with anticipated frequent ventricular pacing, CRT may be considered.
Class III
1. Cardiac resynchronization therapy is not indicated for asymptomatic patients with reduced LVEF in the absence of other indications for pacing.
2. Cardiac resynchronization therapy is not indicated for patients whose functional status and life expectancy are limited predominantly by chronic
noncardiac conditions.
trials are summarized in Table 72.1. Current guidelines which largely Trials of Cardiac Resynchronization
influence clinical therapeutic decisions on the use of these devices Therapy Without a Defibrillator
have evolved from the outcomes of patients included in these trials
(Table 72.2). It is to be noted that as these studies predominantly
Multisite Stimulation in Cardiomyopathies
included symptomatic patients with systolic heart failure in sinus
rhythm and with a broad QRS, the outcome data with CRT pertain to The multisite stimulation in cardiomyopathies (MUSTIC) was a
this patient population. single-blinded, randomized, crossover trial evaluating effectiveness
Chapter 72  Cardiac Resynchronization Therapy 615
of CRT.10 Forty-seven patients were randomized to active cardiac apy decreased mitral regurgitation, increased ejection fraction and
resynchronization or no pacing and then crossed over to the alter- improved symptoms and QOL. These benefits were seen both in
native study assignment. The primary end point was the change in patients with ischemic and non-ischemic cardiomyopathy.
distance walked in 6 minutes, and secondary end points included
change in quality of life (QOL), NYHA class, peak VO2, hospital ad- Trials of Cardiac Resynchronization
missions, worsening heart failure, and patient preference for pacing
Therapy with a Defibrillator
mode. Significant improvement was shown in all of these end points
which were sustained over 1 year. Mortality was 7.5% however the Heart failure and propensity for sudden cardiac death are coexisting
trial was small with short follow-up not powered to assess survival clinical problems. As implantable cardioverter defibrillators (ICD)
benefit. have an established role in primary and secondary prevention of
sudden cardiac deaths in patients with severe LV dysfunction; there
Multicenter InSync Randomized is a logical ground for a role for incorporating this therapy in the CRT
devices. The effectiveness of this combination (CRT-D) can be in-
Clinical Evaluation
ferred from three of the CRT trials where it was used.
Multicenter insync randomized clinical evaluation (MIRACLE) was
the first prospective randomized, double-blind, parallel-controlled Ventak-Congestive Heart Failure/Contak-Cd
clinical trial designed to validate the results from previous cardiac
resynchronization studies.11 Primary end points were NYHA class, The CONTAK CD study examined the safety and effectiveness of
QOL score and 6 minute hall walk distance. Secondary end points in- CRT when combined with an ICD.13 This trial included 490 patients
cluded assessments of a composite clinical response, cardiopulmo- with NYHA II–IV, LVEF less than 35%, QRS greater than and equal
nary exercise performance, neurohormone and cytokine levels, QRS to 120 msec and with an existing indication for ICD. Patients were
duration, cardiac structure and function, and a variety of measures implanted with a device capable of providing CRT and ICD therapy
of worsening heart failure and combined morbidity and mortality. In and were then randomized to CRT or no CRT. Patients were followed
this trial which was completed late in the year 2000, four hundred fif- for up to six months. The primary end point was progression of heart
ty-three patients with moderate to severe symptoms of heart failure failure, defined as all-cause mortality, hospitalization for heart fail-
associated with LVEF less than 35% and a QRS duration greater than ure, and ventricular tachycardia/ventricular fibrillation requiring
130 msec were randomized to cardiac resynchronization (n=228) intervention. A 15% (statistically nonsignificant) reduction in heart
or to a control group (n=225) for 6 months. Patients randomized failure progression was observed. However, CRT improved peak
to cardiac resynchronization demonstrated a significant improve- oxygen consumption, 6 minutes walking distance (MWD) and LV
ment in functional capacity, clinical status and QOL. These patients dimensions and function.
demonstrated an overall improvement in broad range of measures
of cardiac function with a reduction in heart failure hospitalizations Miracle Implantable Cardioverter Defibrillator
and these benefits were incremental to those achieved by standard
pharmacological therapy. The MIRACLE ICD trial examined the efficacy and safety of com-
bined CRT and ICD therapy in heart failure patients with NYHA class
Cardiac Resynchronization-Heart Failure III or IV despite optimal medical management and who had LVEF
less than 35% and QRS greater than and equal to 130 msec.14 Three
Cardiac resynchronization-heart failure (CARE-HF) was the first hundred sixty nine patients received a device with combined capa-
CRT trial to show a survival benefit. Eight hundred thirteen patients bility of CRT and ICD and in the control group the CRT was off. At the
with NYHA Class III and IV with an ejection fraction less than 35% six month follow-up, patients in the CRT group achieved significant
and a QRS time greater than 120 msec were randomly assigned to improvement in their QOL score, peak oxygen consumption and
either CRT or continuation of their standard medical therapy.12 functional capacity. However, there was no significant improvement
Direct measures of dyssynchrony were used in this trial and neu- in 6 MWD, heart failure hospitalization and LV size or function.
rohormonal measures (e.g. N-terminal pro-brain natriuretic pep-
tide) were shown to improve dramatically with CRT. Patients were Comparison of Medical Therapy, Pacing and
followed up for a mean of 29.4 months. CRT therapy was associated
Defibrillation in Chronic Heart Failure
with a 36% decrease in mortality or hospitalization for cardiovascular
symptoms [55% in the medically treated patients compared with 39% Comparison of medical therapy, pacing and defibrillation in chronic
in the CRT patients; hazard ratio (HR) = 0.63; p < 0.001], and a 36% heart failure (COMPANION) was a randomized trial comparing CRT
decrease in death from any cause (30% in medically-treated patients P (pacing only) and CRT-D (pacing with a defibrillator) with standard
vs. 20% in CRT patients; HR= 0.64; p < 0.002). In addition, CRT ther- medical therapy in 1,520 patients with advanced heart failure (NYHA
Class III-IV) with QRS duration of greater than 120 msec.15 Patients NYHA I to 50% in NYHA IV. AF and heart failure have a mutual
were in normal sinus rhythm, had an ejection fraction less than 35% cause and effect relationship and synergistically contribute to mor-
and were all well treated with ACE inhibitors, beta blockers and bidity and mortality. Patients having either AF or heart failure and
spironolactone. The mean follow-up of the study was approximately developing the other have a poor prognosis.18 Adverse hemodyna
15 months, and data was available for 3 years. The results of COM- mic consequences of AF are accentuated in the presence of impaired
PANION demonstrated that CRT therapy alone led to a 19% decrease LV function and contribute to worsening of heart failure. The issue of
in death and hospitalization for any cause compared with medi- AF in CRT recipients is clinically relevant as AF can exist at the time
cal treatment (68% in medically-treated patients vs 56% in the CRT of implant or develop over the course of time as seen in CARE-HF
group; HR=0.81; p < 0.014). CRT-D decreased the same end point by trial where 155 of the 813 patients developed AF over a mean follow-
20% (HR=0.80; p < 0.01). Death from or hospitalization due to car- up of 29.4 months.19 In patients with CRT devices, with the advent
diovascular disease was decreased by 25% in the CRT alone group, of AF there is a loss of coordinated AV pacing precluding program-
and by 28% in the CRT-D treated patients. Furthermore, CRT alone ming of optimal AV delay, existence of fast and irregular ventricular
reduced the risk of death from any cause by 24% and CRT-D resulted rates causing in consistent biventricular capture. Fusion and pseu-
in a decrease in all cause mortality by 36% compared with standard do-fusion beats resulting from an interaction between intrinsically
medical therapy. conducted and paced beats may be responsible for ineffective pac-
Based on the large randomized trials, the current indications for ing. Device data logs may inaccurately overestimate the percentage
the CRT devices are summarized in Table 72.2. of ventricular pacing and in this situation despite delivery of pacing,
biventricular capture is suboptimal. The efficacy of CRT heart failure
DO ALL HEART FAILURE PATIENTS patients with AF was examined in a number of small observational
studies and MUSTIC trial. This trial showed a similar improvement in
NEED CARDIAC RESYNCHRONIZATION
6 minute walk test of patients in sinus and with AF.20 It is notable that
THERAPY-D? in this trial all patients in AF had a slow ventricular rate trial achieved
The practical clinical issue that arises from the COMPANION trial is through either spontaneous or induced AV block. Achieving a
whether all patients who merit a CRT device should have a CRT-D controlled ventricular rates hence form an effective strategy to
device implanted. There has been no trial directly comparing these optimize efficacy of CRT in patients with AF.
therapies, hence inferences can be drawn from the published stud- There are four ways of achieving this endpoint
ies. One third of all deaths in the CARE-HF trial were sudden which 1. Use of rate control drugs
was similar to that seen in the CRT-P arm of the COMPANION trial 2. Atrioventricular nodal ablation
suggesting incremental mortality benefit of adding a defibrillator to 3. Pulmonary vein isolation to cure AF
the CRT device. The sudden cardiac death in heart failure (SCD-HF) 4. Use of device based algorithms to achieve stable ventricular rate.
was the only trial to demonstrate benefit of ICD in mild to moderate Destruction of AV node by catheter ablation is increasingly being
heart failure patients, however the benefit was limited to those with considered in patients with CRT devices having AF. This “Ablate and
less severe heart failure (NYHA class II).16 It is known that as sever- Pace” strategy renders the heart completely pacemaker dependent
ity of heart failure increases more proportion of patients die of wors- hence ensuring effective and complete CRT delivery. In the absence
ening heart failure rather than sudden death, hence the benefits of of randomized controlled trials data from various studies address-
defibrillator are appreciated more in milder heart failure cohorts. In ing this issue is available for examination. This data encompasses 808
the COMPANION study, there was an increased mortality benefit in patients with sinus rhythm and 356 with AF with over half of these
the CRT-D arm but the comparison of each arm was with the medi- undergoing AV nodal ablation.21-25 These studies show that within
cal therapy arm and not with each other. Meta-analysis of published the AF group, only patients who underwent ablation showed a signif-
trials shows the advantage of CRT-D over CRT is achieved at a longer icant increase of EF, reverse remodeling, and improved exercise tol-
follow-up and at a higher cost-benefit ratio which increases with erance. No improvements were observed in AF patients who did not
age.17 The clinical decision to use a defibrillator lead in CRT patients undergo ablation. In one of these studies,24 AF without AVJ ablation
thus should be weighed with regard to age, QOL, patient preferences was independently associated with five-fold increase in mortality
and economic situation. and six-fold risk of hospitalization for HF during the first 12 months.
Gasparini et al. assessed the long term impact on mortality and hos-
NONCONVENTIONAL INDICATIONS FOR pitalization in 1,285 consecutive patients (1,042 in sinus rhythm, 243
in AF) who underwent CRT therapy. Patients with CRT device and
CARDIAC RESYNCHRONIZATION THERAPY
AF who had less than and equal to 85% biventricular pacing under-
Atrial Fibrillation went AV nodal ablation and it was shown that overall survival and
freedom from heart failure was better in patients who under went
The prevalence of atrial fibrillation (AF) progressively increases ablation.25 The disadvantages of ablation are complete pacemaker
with severity of heart failure and varies from 5% in patients with dependency and possibility of occasional spontaneous conversion to
sinus rhythm. There are observational studies where pharmacologi-

PATIENTS WITHOUT OVERT HEART FAILURE
cal rate control measures alone without AV nodal ablation achieved
adequate biventricular pacing and clinical improvement similar to Traditionally, major CRT trials included NYHA Class III or ambu-
those in sinus rhythm. With increasing experience of catheter based latory class IV patients. The benefits of biventricular pacing in less
pulmonary vein isolation in the treatment of AF, there is growing symptomatic heart failure subsets were described only in small
interest in the application of this therapy to heart failure patients. short-term studies. The effectiveness of CRT in mildly symptomatic
Para-aminobenzoic acid (PABA)-CHF is a small trial involving 81 and asymptomatic population with LV dysfunction was studied in
patients with heart failure and AF randomized to AV nodal ablation two large trials-REVERSE trial involving 610 patients and multicenter
with CRT device implantation and pulmonary vein isolation. This automatic defibrillator implanting trial-cardiac resynchronization
study showed the superiority in the pulmonary vein isolation arm in therapy (MADIT-CRT) with 1,820 patients.32,33 In both the trials pa-
improving 6 minutes walk test, QOL and LV function.26 Modern CRT tients had LV dysfunction, wide QRS with minimal or no symptoms.
devices are endowed with algorithms which attempt to maximize As MADIT-CRT included patients with LVEF less than and equal to
ventricular pacing during atrial arrhythmias. These include Ventric- 30%, all of them merited and received an ICD by standard guidelines.
ular Sense Response™ and Conducted AF Response™ of Medtronic In both these studies the additional advantage of biventricular pac-
and Ventricular Rate Regularization™ of Boston Scientific.27 The CRT ing was evaluated. There was no change in exercise capacity or QOL,
counters may however over estimate the efficacy of pacing making it but there were decreased hospitalizations (MADIT-CRT) or increase
difficult to assess the effectiveness of these algorithms. in time to first hospitalization (REVERSE). There was no effect on
mortality as these trials included relatively less symptomatic heart
Narrow QRS failure patients but there was improvement in structure and function
of LV shown by decrease in LV end-systolic & end-diastolic volumes
The effectiveness of CRT is attributed to the presence of underlying and improvement in ejection fraction. These trials suggest implan-
dyssynchrony in the failing hearts and its correction by biventricu- tation of CRT device in milder heart failure population achieves a
lar pacing. With the advent of tissue Doppler imaging, it has been reduction in progression of heart failure predominantly in patients
demonstrated that a significant proportion of heart failure patients with QRS greater than and equal to 150 msec.
with narrow QRS have dyssynchrony. A number of single center stud-
ies have demonstrated the effectiveness of CRT in narrow QRS heart DYSSYNCHRONY AND CARDIAC
failure population.28,29 However, the randomized double blinded
RESYNCHRONIZATION THERAPY
resynchronization therapy in narrow QRS (RETHINQ) study involv-
ing 172 heart failure patients with QRS width less than and equal to The underlying pathophysiological substrate in heart failure is elec-
130 msec and a tissue Doppler determined mechanical asynchrony trical and mechanical dyssynchrony. Identification, assessment
showed no benefit of CRT in improving peak oxygen consumption, and correction of dyssynchrony are important components of CRT.
effort tolerance or LV volumes & LVEF at 6 months.30 However, the Emergence of tissue Doppler imaging (TDI) has created an opportu-
subgroup with QRS duration 120–130 m/sec showed benefit with nity for direct assessment of dyssynchrony.
CRT. At present data does not justify implantation of CRT with a QRS Dyssynchrony is defined as differences in the timing of contrac-
width of less than 120 msec. tion of different myocardial segments. In heart failure patients, dys-
synchrony can occur at three levels—AV, interventricular and intra-
Right Bundle Branch Block ventricular or LV.
Atrioventricular dyssynchrony occurs due to delayed AV con-
Though the CRT guidelines recommend a wide QRS and make no duction or interatrial delay resulting in diastolic mitral regurgitation,
distinction between left bundle branch block (LBBB) and right bun- interference of passive ventricular filling by atrial contraction and
dle branch block (RBBB), the proportion of patients with RBBB in ventricular contraction truncating the “A” wave. A-V synchrony can
major CRT trials have been only 10–13%. A retrospective analysis of be achieved by the pacing functions of the pacemaker and to certain
61 patients with RBBB in the MIRACLE and CONTAK CD trials dem- extent by AV optimization. Interventricular dyssynchrony is defined
onstrated a significant improvement in only NYHA functional class as the time delay between activation of right and left ventricles. This
compared with no CRT, but there was no benefit with respect to exer- can be estimated by pulsed wave Doppler echocardiography by the
cise time or LV function.31 The positive effect on NYHA class was not difference in aortic and pulmonary pre-ejection intervals or by the
corroborated by the much larger COMPANION study, in which CRT time difference in the basal, septal and lateral walls of the LV and the
had a neutral effect among patients with RBBB. In heart failure pa- basal free wall of the RV using TDI. Assessment of interventricular
tients the presence of RBBB does not seem to confer the same benefit dyssynchrony has not shown to be useful for patient selection for
as LBBB unless additional markers of dyssynchrony are used. CRT. Intraventricular or LV dyssynchrony refers to abnormal timing
of motion of different LV regions during systole. TDI has proven to be ences in responder rates. Definitions using clinical response assess a
a reliable tool for assessment of LV dyssynchrony and has unveiled change in NYHA functional class, QOL scores or the distance walked
the limitations of QRS width as a reliable surrogate for underlying in 6 minutes. Echocardiographic parameters used to assess response
dyssynchrony. The lack of consistent concordance between electrical are by quantifying LVEF or LV end-diastolic measurements. Some of
and mechanical dyssynchrony demonstrated by TDI has increased the studies have used a combination of clinical or a combination of
the potential of this modality to be used for patient selection for CRT. clinical and echocardiographic parameters. Though most studies
Different methods involving TDI have been used to assess dyssyn- assess response at 3 or 6 months there is significant inconsisten-
chrony, including pulsed wave TDI, color-coded TDI, tissue track- cy in the length of follow-up at which a patient is deemed to be a
ing, displacement mapping, strain and strain rate imaging and, most responder. Further, if mortality should be classified as nonresponse
recently, tissue synchronization imaging (TSI). There is a significant or to be excluded from analysis is unclear.
inter observer and intra observer variability in interpretation of these
parameters which restricts their universal application in patient REASONS FOR NON RESPONSE TO
selection for CRT. This issue of the limitation of routine clinical appli-
CARDIAC RESYNCHRONIZATION THERAPY
cation of dyssynchrony indices was highlighted by the multi-center
PROSPECT study which evaluated the effectiveness of 12 echocar- There could be several reasons for non effectiveness of CRT.
diographic parameters of dyssynchrony to predict response to CRT.34
The parameters used had wide ranging sensitivity and specificity that Improper Left Ventricular Lead Position
they were unable to distinguish responders from nonresponders. The
two most commonly adopted approaches to assess dyssynchrony Conceptually, LV lead is recommended to be placed in the lateral
are the opposite wall delay (measured by comparing time to peak wall of the LV which corresponds to the location of the posterior or
systolic contraction between opposite walls by color tissue Doppler posterior-lateral tributary of the coronary sinus. This is to ensure
imaging), and the standard deviation of the time to peak systolic pre-excitation of the most delayed segments. Placement of the lead
velocity in a 12-segment model, or the Yu index. The utility of the in this position is important for achieving maximum benefit with
newer techniques of two-dimensional strain imaging by speckle CRT. At the time of the lead placement it is prudent to ensure that the
tracking and TDI-derived strain imaging in detecting and defining local LV electrogram falls in the later part of the QRS complex of the
LV dyssynchrony is being increasingly realized.35,36 electrocardiogram (ECG). In some of the patients there may be
The frequency of dyssynchrony depends on the methodology absence of a good sized vein in this area or the ideal vein may be
used and the cut off values but generally a cut off of 60–65 m/sec is technically inaccessible. In such situations it may be necessary to
used to indicate presence of dyssynchrony. Regional distribution place the lead surgically in the epicardium.
patterns of dyssynchrony may additionally aid in assigning clinical
relevance to the echocardiographic assessment. We found dyssyn- Dependence on QRS Alone for
chrony in a small percentage of normal individuals having LBBB
Patient Selection
without heart failure. In these people lateral wall delay was not seen
and dyssynchrony was confined to septal delay. In the heart failure QRS duration has been traditionally used as a marker of dyssyn-
population though dyssynchrony may be seen in about 70%, only chrony and a wide QRS particularly presence of LBBB is an accept-
a half of these showed delay in lateral wall.37 It remains to be seen ed selection criteria for CRT. There are no definite data of benefit
if CRT outcomes improve if the site of LV lead placement correlates of CRT with patients with RBBB and it is recognized that the extent
with the site of delay. of benefit in this subgroup would be less. Tissue Doppler data has
demonstrated that all patients with LBBB do not necessarily have
THE ISSUE OF RESPONSE dyssynchrony. The study by Yu et al. examined the prevalence of
mechanical dyssynchrony in heart failure patients with wide and
AND NONRESPONSE
narrow QRS complexes.41 This study examined 67 patients with QRS
It is generally accepted that a third of patients who receive CRT are duration greater than 120 msec (in the form of LBBB or IVCD) and
nonresponders. Though a large number of publications in the last 45 patients with QRS duration less than or equal to 120 m/sec. The
few years have addressed this issue, there has been neither uniform- time to peak systolic velocity during ejection phase in the 6-basal,
ity nor consensus on the definition of a nonresponder. Due to the 6-mid-segmental model of the LV was measured, which represents
differential impact of CRT on the symptomatology and outcomes the time at which there is maximal endocardial contraction/excur-
of heart failure patients definitions used in different studies have sion. From this, the standard deviation of the time in the 12 LV seg-
considered varied clinical, echocardiographic, and hemodyna ments was calculated, as “dyssynchrony index”. The cutoff value of
mic or a combination of these parameters to assess response.38-40 the dyssynchrony index was mathematically derived from 88 nor-
Applying different criteria to the same study can result in wide differ- mal controls, which was 32.6 m/sec. It was shown that systolic dys-
synchrony was present in 43% of heart failure patients with narrow

QRS and in 64% with wide QRS complexes. In other words, in about
one-third of heart failure patients LBBB or ICVD ECG patterns are
not associated with significant mechanical dyssynchrony. Electro
anatomical mapping studies also show wide QRS can exist with
homogeneous electrical conduction in LV. Further there is a het-
erogeneous distribution of dyssynchrony patterns in heart failure
patients (Figs 72.1A to C). Delays may exist in inferior or posterior
wall without the presence of lateral wall delay and it is possible that
in these patients placement of LV lead in the lateral wall may not
confer the same benefit as in those with a classical lateral wall de-
lay. However at present it is uncertain if site of dyssynchrony should
guide the LV lead placement. In our own experience dyssynchrony
was present in 68% of patients with heart failure but only about half
of them had lateral wall delay.42
These data point to the fact that QRS duration by ECG is not a A
gold standard to assess dyssynchrony in all patients and patient
selection by this parameter alone is likely to contribute to non
responders.
ETIOLOGY OF HEART FAILURE

In general patients with nonischemic cardiomyopathy respond
better to CRT than those with ischemic cardiomyopathy. This was
demonstrated in the MIRACLE and CARE-HF trials. This difference is
possibly due to increased scarring and hence less opportunity for the
LV to undergo remodeling in the ischemic group. These differences
were not seen in the COMPANION study hence systematic subgroup
analysis is needed to ascertain the contribution of the etiology of
heart failure to benefit from CRT.
B
OPTIMAL PROGRAMMING OF CARDIAC
RESYNCHRONIZATION THERAPY
PARAMETERS
Appropriate programming of the CRT device is an important aspect
in achieving a good responder rate by ensuring optimal mechanical
functioning of the LV and hence cardiac output. The principal objec-
tive in programming is to ensure a constant and consistent biven-
tricular pacing. This would involve careful assessment to look for the
presence of ventricular double counting, inappropriate atrial sens-
ing or atrial arrhythmias which would interfere with proper pacing.
Optimization of AV interval achieves optimal time for diastolic fill-
ing, abolishment of presystolic mitral regurgitation, avoiding trunca-
tion of atrial filling. There are various methods described to program
optimal AV delay. Principles of Doppler echocardiography are used
in the Ishikawa’s or the Ritter’s method. CARE-HF and MIRACLE
trials used the Doppler transmitral flows to achieve AV optimization. C
Optimal AV interval can be calculated by invasive hemodynamic
Figures 72.1A to C: Tissue Doppler images showing dyssynchrony
assessment or by intracardiac conduction signals. This was used by in different regions. Tissue velocity curves correspond to the sample
the COMPANION investigators where an algorithm based on the volumes placed in septal, lateral, inferior or anterior walls. (A) Septal
intrinsic AV interval and baseline QRS width was used to determine delay; (B) Inferior wall delay; (C) Lateral wall delay
a predicted optimum sensed AV delay. Though acute studies have programmable LV stimulation configurations, exposing an avenue to
shown the benefit of AV optimization, there is only limited evidence explore in nonresponders.44
supporting the long term efficacy. It is time consuming and expen-
sive to use echocardiography routinely program the AV delay by FUTURE
optimization methods hence in clinical practice many physicians
leave the device with a fixed AV delay and use optimization methods Cardiac resynchronization therapy has been shown to be effective in
only in nonresponders. A modified version of the algorithm is avail- symptomatic heart failure patients in sinus rhythm with systolic LV
able as smart delay (SD; Boston Scientific, Natick, MA, USA) which dysfunction having wide QRS. More refined and sensitive markers
provides both paced and sensed recommendations by accounting of LV dyssynchrony need to be investigated to extend therapy to pa-
for three inputs: (1) intrinsic AV intervals; (2) interventricular timing; tients with minimal or no QRS prolongation, and to those with RBBB
and (3) LV lead location. SMART AV is an ongoing study to assess and nonspecific intraventricular conduction defects. Larger trials are
if systematic AV optimization impacts the LV remodeling by achiev- needed to assess the impact of multi site LV pacing. Innovations in
ing a reduction of LV dimensions and if the automated Smart AV integrative technologies are likely to make electronic programming
algorithm is as good as echocardiographically determined para and optimization of pacing parameters less time consuming and
meters.43 In the newer generation biventricular devices, the timing of easier.
LV and RV stimulation are independently programmable creating the
possibility of optimizing interventricular delay (V-V optimization). ACKNOWLEDGMENT
As there is a variability of interventricular dyssynchrony, some
patients may benefit from pre-excitation of RV instead of LV. A sin- The author thanks Dr Raghu Krishnaswami MD, DM for the tissue
gle report described the variations in cardiac output with different Doppler images.
REFERENCES
1. Hetzel MR, Ginks WR, Pickersgill AJ, et al. Value of pacing in cardiac failure associated with chronic atrioventricular block. Br Heart J. 1978;40:864-
9.
2. Hochleitner M, Hörtnagl H, Hortnagl H, et al. Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic
dilated cardiomyopathy. Am J Cardiol. 1992;70:1320-5.
3. Gold MR, Feliciano Z, Gottlieb SS, et al. Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: a randomized study.
J Am Coll Cardiol. 1995;26(4):967-73.
4. Cazeau S, Ritter P, Bakdach S, et al. Four chamber pacing in dilated cardiomyopathy. Pacing Clin Electrophysiol. 1994;17:1974-9.
5. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ven-
tricular conduction delay. Circulation. 1999;99:1567-73.
6. Gras D, Leclercq C, Tang AS, et al. Cardiac resynchronization therapy in advanced heart failure: the multicenter InSync clinical study. Eur J Heart
Fail. 2002;4:311-20.
7. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with
heart failure and ventricular conduction delay, for the pacing therapies in congestive heart failure (PATH-CHF) study group. J Am Coll Cardiol.
2002;39:2026 -33.
8. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular con-
duction delay on behalf of the pacing therapies in congestive heart failure (PATH-CHF) II study group. andrew kramer etienne huvelle, on behalf
of the guidant heart failure research group. J Am Coll Cardiol. 2003;42:2109-16.
9. Boriani G, Kranig W, Donal E, et al. A randomized double-blind comparison of biventricular versus left ventricular stimulation for cardiac
resynchronization therapy: the Biventricular versus Left Univentricular Pacing with ICD Back-up in Heart Failure Patients (B-LEFT HF) trial. Am
Heart J. 2010;159:1052-8. e1.
10. Cazeau S, Leclercq C, Lavergne T, Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators, et al. Effects of multisite biventricular
pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344:873-80.
11. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845-53.
12. Cleland JG, Daubert JC, Erdmann E, Cardiac resynchronization-heart failure (CARE-HF) study investigators, et al. The effect of cardiac resynchro-
nization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-49.
13. Saxon LA, Boehmer JP, Hummel J, et al. Biventricular pacing in patients with congestive heart failure: two prospective randomized trials. The
VIGOR CHF and VENTAK CHF Investigators. Am J Cardiol. 1999;83:120D-3D.
14. Young JB, Abraham WT, Smith AL, et al. Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined
cardiac resynchronization therapy and implantable cardioversion defibrillation in patients with advanced chronic heart failure. The Multicenter
InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) trial. JAMA. 2003;289:2685-94.
15. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic
heart failure. N Engl J Med. 2004;350:2140-50.
16. Bardy GH, Lee KL, Mark DB, Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators et al. Amiodarone or an implantable cardio-
verter–defibrillator for congestive heart failure.. N Engl J Med. 2005;352:225-37.
17. Huang Y, Wu W, Cao Y, et al. All cause mortality of cardiac resynchronization therapy with implantable cardioverter defibrillator: a meta-analysis
of randomized controlled trials. Int J Cardiol. 2010;145:413-7.
18. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality. The
Framingham Heart Study. Circulation. 2003;107:2920-5.
19. Hoppe UC, Casares JM, Eiskjaer H, et al. Effect of cardiac resynchronization therapy on the incidence of atrial fibrillation in patients with severe
heart failure. Circulation. 2006;114:18-25.
20. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with
chronic atrial fibrillation. Eur Heart J. 2002;23:1780-7.
21. Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular pacing for refractory heart failure in patients with stable sinus
rhythm or chronic atrial fibrillation. Am J Cardiol. 2000;85:1154-6.
22. Molhoek SG, Bax JJ, Bleeker GB, et al. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic
atrial fibrillation. Am J Cardiol. 2004;94:1506-9.
23. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation
and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol. 2007;99:1252-7.
24. Ferreira AM, Adragão P, Cavaco DM, et al. Benefit of cardiac resynchronization therapy in atrial fibrillation patients vs. patients in sinus rhythm:
the role of atrioventricular junction ablation. Europace. 2008;10:809-15.
25. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression:
the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol. 2006;48:734-43.
26. Khan MN, Jaïs P, Cummings J, PABA-CHF investigators, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J
Med. 2008;359:1778-85.
27. Swerdlow CD, Friedman PA. Advanced ICD troubleshooting: Part II. Pacing Clin Electrophysiol. 2006;29:70-96.
28. Bleeker GB, Holman ER, Steendijk P, et al. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol.
2006;48:2243-50.
29. Yu CM, Chan YS, Zhang Q, et al. Benefits of cardiac resynchronization therapy for heart failure patients with narrow QRS complexes and coexisting
systolic asynchrony by echocardiography. J Am Coll Cardiol. 2006;48:2251-7.
30. Beshai JF, Grimm RA, Nagueh SF, RethinQ Study Investigators, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS com-
plexes. N Engl J Med. 2007;357:2461-71.
31. Egoavil CA, Ho RT, Greenspon AJ, et al. Cardiac resynchronization therapy in patients with right bundle branch block: analysis of pooled data from
the MIRACLE and Contak CD trials. Heart Rhythm. 2005;2:611-5.
32. Linde C, Abraham WT, Gold MR, REVERSE (Resynchronization reverses Remodeling in Systolic left ventricular dysfunction) Study Group, et al.
Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular
dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008;52:1834-43.
33. Moss AJ, Hall WJ, Cannom DS, MADIT-CRT Trial Investigators, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events.
N Engl J Med. 2009;361(14):1329-38.
34. Chung ES, Leon AR, Tavazzi L, et al. Results of the predictors of response to CRT (PROSPECT) trial. Circulation. 2008;117:2608-16.
35. Knebel F, Schattke S, Bondke H, et al. Evaluation of longitudinal and radial two-dimensional strain imaging versus Doppler tissue echocardiogra-
phy in predicting long-term response to cardiac resynchronization therapy. J Am Soc Echocardiogr. 2007;20:335-41.
36. Gorcsan J 3rd, Tanabe M, Bleeker GB, et al. Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization
therapy. J Am Coll Cardiol. 2007;50:1476-83.
37. Rao HB, Krishnaswami R, Kalavakolanu S, et al. Ventricular dyssynchrony patterns in left bundle branch block, with and without heart failure.
2010;10(3):115-21.
38. Lecoq G, Leclercq C, Leray E, et al. Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in
advanced heart failure. Eur Heart. J 2005;26:1094-100.
39. Pitzalis MV, Iacoviello M, Romito R, et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony.
J Am Coll Cardiol. 2002;40:1615-22.
40. Yu CM, Fung JW, Zhang Q, et al. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse
remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 2004;110:66-73.
41. Bax JJ, Abraham T, Barold SS, et al. Cardiac resynchronization therapy: Part 1--issues before device implantation. J Am Coll Cardiol. 2005;46(12):
2153-67.
42. Hygriv Rao B, Raghu K, Sharada K, et al. Patterns of ventricular Dyssynchrony in congestive heart failure- comparison with controls and implica-
tions for patient selection for cardiac resynchronization therapy. Indian Heart Journal. 2010;62(4):308-12.
43. Stein KM, Ellenbogen KA, Gold MR, et al. SmartDelay determined AV optimization: a comparison of AV delay methods used in cardiac resynchro-
nization therapy (SMART-AV): rationale and design. Pacing Clin Electrophysiol. 2010;33(1):54-63.
44. Balasundaram R, Rao HB, Sridevi C, et al. Hemodynamic benefit of multiple programmable pacing configurations in patients with biventricular
pacemakers. Pacing Clin Electrophysiol. 2009;32 Suppl1:S211-3.
45. Epstein AE, DiMarco JP, Ellenbogen KA, et al. acc/aha/hrs 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of
the american college of cardiology/american heart association task force on practice guidelines (writing committee to revise the acc/aha/naspe
2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices): developed in collaboration with the american as-
sociation for thoracic surgery and society of thoracic surgeons. american college of cardiology/american heart association task force on practice
guidelines (writing committee to revise the acc/aha/naspe 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia de-
vices); american association for thoracic surgery; society of thoracic surgeons. Circulation. 2008;117(21):e350-408. epub 2008 may 15. no abstract
available. erratum in: Circulation. 2009;120(5):e34-5.
73 History of Intravascular Ultrasound
Garg N, Bhandari S
INTRODUCTION time-based synchronously, it provides 360° cross-sectional imaging

with less error. In 1966 Wells4 proposed the first design of a practi-
Contrast angiography delineates vascular lumen and has been the cal intravenous probe with mechanical rotation and real-time cross-
principle modality for diagnosing peripheral and coronary artery dis- sectional imaging but limitation was size of the probe.
ease (CAD). Extent and severity of disease are accessed by compar- Eggleton et al. 19695 had recorded cardiac chambers images by
ing luminal dimension of normal appearing adjacent vessels. It does rotating four element catheter. Diagnostic value of these attempt were
not provide vessel wall information and normal appearing luminal limited because of stiffness of catheter, size of transducer, poor image
area may have diffuse disease and underestimate disease burden. quality and slow acquiescing time, but they provide base for future
Noninvasive ultrasound imaging provides cross-sectional images of development. First attempt for developing real-time intracardiac im-
accessible but limited portion of the peripheral arterial system. Fiber aging catheter was done by Bom et al.6 They developed a 9 F catheter
optic angioscopy allows visualization of endothelial surface of arte- with 32 elements arranged in a circular phased array at the circumfer-
rial wall and has provided understanding regarding mechanism of ence of the catheter tip and recorded dog ventricle real-time images.
acute ischemic syndromes (like thrombus), but it has practical limi- In early to middle 1980s several groups began manufactur-
tation as it require complete replacement of blood by translucent liq- ing dedicated IVUS imaging systems and in last 20 years various
uid and as with angiography it does not give arterial wall information modifications in IVUS imaging technique were attempted to make
under the endothelial surface. Intravascular ultrasound (IVUS) offers device more useful with less complication. At present there are two
potential and fundamental advantage. It provides luminal and trans- approaches of IVUS imaging.
mural information of vessel. Intravascular ultrasound demonstrates
atherosclerotic lesion volume, distribution and tissue characteristics Mechanical Scanning
which help in assessing natural history of atherosclerotic disease, its
consequences and deciding management plan. A single transducer element is rotated inside the tip of catheter which
is spun by external motor drive unit attached to proximal end of cath-
DEVELOPMENT OF INTRAVASCULAR eter. Image from each angular position of transducer are collected
by computerized image array processor and constructed into cross-
ULTRASOUND
sectional images. Mechanical IVUS system manufactured by Boston
First approach toward use of IVUS was for diameter measurement. Scientific Corp and coronary catheter frequency is 40 MHz which is
In 1956 Cieszynski1 constructed single element ultrasonic catheter 2.5 F at tip and 3.2 F at the largest dimension and compatible with 6
and obtained good echoes from endocardial surface of right and left F guiding catheter. Larger size with lower frequency catheters is also
ventricle in dogs and also measured chamber dimensions and sug- available for peripheral and intracardiac imaging.
gested this will be useful method for cardiac diagnosis in human.
Kossoff 19662 described transducer which was having 2 mm diam- Non-Mechanical Multi Element (Solid State
eter at the tip of the catheter and operating frequency was 8 MHz for
Dynamic Aperture) Transducer
measuring intracardiac septal and ventricular wall thickness with
adequate accuracy. Stegall et al. 19693 introduced two transducers Non-mechanical multi element (solid state dynamic aperture) trans-
mounted at the end of a catheter carried “feeler gage” to determine ducer with 64 elements arranged around the catheter tip is activated
intra-aortic and intracarotid diameters. The principle of a transducer at different time delays to create an ultrasound beam that sweep
mounted at the tip of catheter from which the beam scan structures the circumference of the vessel. Target vessel length is scanned by
which aligned perpendicularly to it offers the simplest approach motorized or manual withdrawal of entire catheter over 0.014 guide
of cross-sectional imaging via ultrasound. If the transducer rotates wire. Coronary catheters are 2.9 F and compatible with 5 F guiding
Chapter 73  History of Intravascular Ultrasound 623
catheter with frequency of 20 MHz. Both approaches provide 360° cou et al. 199015 used IVUS in ten pulmonary hypertension patients
cross-sectional image of the vessel with high resolution (150 µmm) secondary to possible pulmonary thromboembolic disease and con-
and less penetration (4–8 mm from catheter tip). cluded IVUS safely helped in assessing location and extent of pulmo-
nary thromboembolism and identify patients who will likely to get
PRELIMINARY STUDIES benefit from surgery (thromboendarterectomy).
Visualization of coronary artery via transvenous coronary
First study on catheter imaging for plaque assessment was present- sinus IVUS imaging may offer less invasive technique and Sudhir et
ed at 1988, American College of Cardiology meeting where Mallery al. 199116 have used this technique in canines and humans to assess
et al. 19887 reported the use of a single element catheter to meas- coronary vessel by introduction of 5 F (30 MHz) catheter in cardiac
ure plaque thickness in vitro. Gussenhoven et al. 19898 provided venous system. They were able to obtain real-time dynamic images
initial correlative study between ultrasound images and histology. of circumflex and left anterior descending artery and noted that ul-
Correlation between ultrasound images and microscopic anatomy trasound may be helpful especially in follow-up of orthotopic cardiac
of muscular artery is possible. Internal and external elastic laminae transplant recipients where right heart catheterization for endocar-
and adventitia considered to be backscatter substrates for inner and dial biopsy is repeatedly required.
outer echodense zone. Adventitia measurement may be difficult Recent study of spectral analysis of radiofrequency data ob-
unless vessel is surrounded by different echogenic tissue like fat. In tained at IVUS allowed to carry out more detailed analysis and mor-
muscular artery media layer appears echolucent between echodense phological assessment of plaque components on the basis of color
intima and adventitia layer. These three layers are not readily seen coding which was assigned to various components (fibrotic, fibroli-
in larger vessel such as aorta because of increased elastic content in pid, necrotic core and calcinosis). Jim MH et al. 201017 studied IVUS
media and become echodense layer. Gussenhoven et al.8 described in degenerative aortocoronary saphenous venous graft (SVG) and
four basic plaque components by using 40 MHz IVUS in vitro: observed severity of SVG atherosclerosis parallel to proportionally
• Echolucent—lipid deposit increased fibrofatty tissue. Unstable plaques in SVG were associated
• Soft echo fibromuscular tissue, intimal proliferation with varying with positive remodeling, lipid rich atheroma and less calcium depo-
amount of dispersed lipid sition similar to IVUS imaging in native coronary artery. Uchida Y
• Bright Echo—collagen rich fibrous tissue 201018 has compared angioscopy, IVUS, computed tomography (CT)
• Bright Echo with acoustic shadow—calcified tissue. angiography and angiography for detection of pulmonary throm-
First three-dimensional clinical images were reported by Yock boembolism and found angioscopy (81.6%), IVUS (34.8 %), angiog-
et al.9 in 1988 in peripheral vessel. Graham et al. 198910 conducted raphy (24.4%) and CT angiography (22.5%) sensitivity respectively.
initial clinical trials with non-mechanical multi element catheter and
along with Marco reported the first human coronary image. Pandian THERAPEUTIC STUDIES OF
et al. 199011 published initial descriptions of pulmonary artery and
INTRAVASCULAR ULTRASOUND
intracardiac catheter-based imaging. Numerous studies have com-
pared angiography and IVUS for determining luminal and trans- Ramee et al. 199119 studied angiography, angioscopy and IVUS com-
mural dimension of normal and moderately atherosclerotic human parison for determining the presence of thrombus, residual stenosis
arteries. Most studies revealed IVUS and angiography correlate well or vessel dissection following percutaneous coronary angioplasty
when used to image normal or mildly elliptical lumens, but when and concluded, angioscopy was the most sensitive for diagnosing
used to derive dimensions from severely diseased vessel with ellipti- thrombus and IVUS was the most accurate in determining residual
cal residual lumen, then angiography underestimate disease sever- stenosis.
ity. Percutaneous transluminal coronary angioplasty balloon size
Intravascular ultrasound is being studied as a method to evalu- is often underestimated when selection is made according to an-
ate accelerated CAD as a major cause of morbidity and mortality giogram and observed IVUS provides more accurately balloon size
in cardiac transplant patients (Pinto et al. 1991).12 It has been also (Cacchione et al. 1991).20 It provides information about atheroscle-
found IVUS is useful for localization of site of dissection, extent of rotic plaque (location, extent and eccentricity), vessel wall consist-
dissection and guide endovascular management of aorta (Covaye et ency and quantitative assessment of residual stenosis and dissection
al. 1991).13 Sanzobrino et al. 199114 had utilized IVUS for localizing and it suited to act as a screening and guiding method to improve
and treatment of coarctation of aorta both experimentally and clini- result from balloon angioplasty. Balloon ultrasound imaging cath-
cally. They studied four patients and concluded IVUS is useful in di- eter has been used clinically with promising result. It has been con-
agnostic assessment and management of patients with coarctation firmed that single plane images could be obtained through mid-sec-
of aorta and precluding need for excessive contrast angiography. Ri- tion of angioplasty balloon all the time during angioplasty and can
assess preinflation, inflation and postinflation luminal feature (such Ya DQ 200924 had used IVUS for guiding interventional therapy
as plaque fracture, instant elastic recoil) with real-time IVUS (Crow- for borderline lesion (40–70%) in patients with acute coronary syn-
ley et al. 1991).21 drome and found to be more useful than coronary angiography in
Intravascular ultrasound provides valuable information of decision making.
correct stent size in a particular vessel and also provides expedi- Me Cann 201025 has reported two cases of late occurring drug-
ent method to assess adequacy of stent deployment (Cavaye et al. eluting stent thrombosis where coronary angiography failed to iden-
1991).22 Aretz et al.23 described prototype combined laser/ultrasound tify the cause but IVUS revealed mechanical problem with initial
imaging catheter for target plaque ablation. Intravascular ultrasound stent deployment, which was responsible for stent thrombosis. Kill-
guided laser angioplasty may also offer technique for recanalization ingsworth CD 201026 concluded in his study that IVUS imaging is a
of occluded vessels and reduce complications like perforation and safe and effective option for bedside IVC filter placement in critically
dissection of vessel. ill, immobilized patients.
REFERENCES
1. Cieszynski T. Intracardiac method for the investigation of structure of the heart with the aid of ultrasonics. Arch Immunol Ther Exp. 1960;8:551-7.
2. Kossoff G. Diagnostic applications of ultrasound in cardiology. Australas Radiol. 1966;10(2):101-6.
3. Stegall HF, Pratt JR, Moser PP. Carotid mechanics in Situ. Fed Proc. 1969;28:585.
4. Wells PNT. Developments in medical ultrasonics. World Medical Electronics. 1966;66(4):272-7.
5. Eggleton RC, Townsend C, Kossoff G, et al. Computerised Ultrasonic visualization of dynamic ventricular configurations. Proceedings of the eight
ICBME. Chicago: Palmer House; 1969:87, Session 10-3.
6. Bom N, Lancee CT, Van Egmond FC. An ultrasonic intracardiac scanner. Ultrasonics. 1972;10(2):72-6.
7. Mallery JA, Griffith J, Gessert J, et al. Intravascular Ultrasound imaging catheter assessment of normal and atherosclerotic arterial wall thickness.
J AM Coll Cardiol. 1988;11:22A.
8. Gussenhoven WJ, Essed CE, Frietman P, et al. Intravascular echographic assessment of vessel wall characteristics: a correlation with histology. Int
J Card Imaging. 1989;4(2-4):105-16.
9. Yock P, Linker D, Saether O, et al. Intravascular two-dimensional catheter ultrasound: initial clinical studies Abstracts. Circulation. 1988;78(Suppl
II):II-21.
10. Graham SP, Brands, Sheehan H, et al. Assessment of arterial wall morphology using intravascular ultrasound in vitro and in patients abstracted.
Circulation. 1989;80(Suppl II):II-56.
11. Pandian NG, Weintraub A, Kreis A, et al. Intracardiac, intravascular two-dimensional, high-frequency ultrasound imaging of pulmonary artery
and its branches in humans and animals. Circulation. 1990;81(6):2007-12.
12. Pinto FJ, St Goar FG, Chiang M, et al. Intracoronary ultrasound evaluation of intimal thickening in cardiac transplant recipients: correlation with
clinical characteristics (abstr.). J Am Coll Cardiol. 1991;17:103A.
13. Cavaye DM, White RA, Lerman RD, et al. Usefulness of intravascular ultrasound imaging for detecting experimental induced aortic dissection in
dogs and for determining the effectiveness of endoluminal stenting. AM J Cardiol. 1992;69(6):705-7.
14. Sanzobrino B, Gillam L, Mckay R, et al. Direct clinical role for intravascular ultrasound: utility in the assessment of coarctation of the aorta (abstr).
J Am Coll Cardiol. 1991;17:68A.
15. Ricou FJ, Pinto PH, Moser KM. Intravascular ultrasound imaging of chronic pulmonary thromboembolic disease: correlation with surgical results
(abstr.). Circulation. 1990;83(Suppl III):441.
16. Sudhir K, Fitzgerald PJ, MacGregor JS, et al. Transvenous coronary ultrasound imaging. A novel approach to visualization of coronary arteries.
Circulation. 1991;84(5):1957-61
17. Jim MH, Hau WK, Ko RL, et al. Virtual histology by intravascular ultrasound study on degenerative aortocoronary saphanous vein grafts. Heart
Vessels. 2010;25(3):175-81.
18. Uchida Y, Shirai S, Oshima T, et al. Angioscopic detection of pulmonary thromboemboli: with special reference to comparison with angiography,
intravascular ultrasonography and, computed tomography angiography. J Interv Cardiol. 2010;23(5):470-8.
19. Ramee SR, White CJ, Jain S, et al. Percutaneous coronary angioscopy versus intravascular ultrasound in patients undergoing coronary angioplasty
(abstr.). J Am Coll Cardiol. 1991;17:125A.
20. Cacchione J, Nair R, Hodson J. Intracoronary ultrasound is better than conventional methods for determining optimal PTCA balloon size (abstr.).
J Am Coll Cardiol. 1991;17:112A.
21. Crowley RJ, Hamm MA, Joshi SH, et al. Ultrasound guided therapeutic catheters: recent developments and clinical results. Int J Card Imaging.
1991;6(3-4):145-56.
22. Cavaye DM, Tabbara MR, Kopchok GE, et al. Intraluminal ultrasound assessment of vascular stent deployment. Ann Vasc Surg. 1991;5(3):241-6.
23. Aretz HT, Martinelli MA, LeDet EG. Intraluminal ultrasound guidance of transverse laser coronary atherectomy. Int J Card Imaging. 1989;4(2-
4):153-7.
24. Ya DQ, Lin SG, Chen JY, et al. Intravascular ultrasound-guided interventional therapy for borderline lesions in patients with acute coronary syn-
drome. Nan Fang Yi Ke Da Xue Xue Bao. 2009;29(12);2453-5.
25. McCann A, Maclsaac A, Whitbourn RJ. Late drug-eluting stent thrombosis: importance of intravascular ultrasound. Cardiovasc Revasc Med.
2010;11(1):52-6.
26. Killingsworth CD, Taylor SM, Patterson MA, et al. Prospective implementation of an algorithm for bedside intravascular ultrasound-guided filter
placement in critically ill patients. J Vasc Surg. 2010;51(5):1215-21.
74 History of Interventions for
Congenital Heart Disease
Kohli V
Key Words: Balloon atrial septostomy, device closure, patent in (66 cm) up a vein and into his heart. An X-ray verified that the tube
ductus arteriosus, atrial septal defect, coil stent. was actually inside his heart. In 1956, Forssmann was awarded the
Nobel Prize for his work, shared with two other doctors, Andre
HISTORY OF ANGIOGRAPHY Frederic Coumand and Dickinson W Richards, who had extended
his ideas (Fig. 74.1).
From the beginning of the era of X-ray, cardiac radiology has be- In 1953, a final major milestone was reached when Seldinger
come a target of this new technique. Early pioneers, Ciegem, Rieder, developed his percutaneous technique for cardiac catheterization.
Rosenthal and Williams rapidly accumulated extensive experience Using this technique, the catheter is introduced into the body at a re-
with fluoroscopy and radiography and publications on cardiac dis- mote site, usually the femoral artery and the wire is threaded up the
eases as soon as 1899–1902. Its name comes from the Greek words arterial system to the heart where the dye is introduced. This proce-
angeion, “vessel”, and graphien, “to write or record”. The X-ray film dure is still used today and makes getting an angiogram much safer
or image of the blood vessels is called an angiograph, or more comas neither sharp object needs to be introduced near the heart, nor
monly, an angiogram. does it need to remain inside any vessel.
The Portuguese physician and neurologist Egas Moniz (Nobel When Forssmann published his historical article in November
Prize winner in 1949) developed in 1927 the technique of contrasted 1929, it showed a picture of the catheter in his right atrium. At that
X-ray cerebral angiography to diagnose several kinds of nervous time he was a surgical assistant to Ferdinand Sauerbruch, the direc-
diseases, such as tumors and arteriovenous malformations. Cerebral tor of the surgical clinic at the University of Berlin. Instead of getting
angiography was not quickly accepted because the procedure praise from Sauerbruch, he was fired. When Forssmann delivered
involved an open cut down of the carotid arteries and partly because a short lecture on the future of cardiac catheterization, Sauerbruch
use of the earliest contrast agents, such as sodium iodide often disdainly remarked: “That work has no place in surgery. These are
resulted in seizures and hemiplegia. He is usually recognized as one
of the pioneers in this field.
A German physician, Werner Forssmann, was the first known
doctor to enter the heart with a catheter. He performed this opera-
tion on himself in 1929, when he was 25 years old. This procedure
continued to develop throughout the next 10 years through the work
of Reboul and Rousthoi. A major development came in 1941, when
Dr Cournand performed the procedure on a healthy human male.
Forssmann worked at a small clinic in the town of Eberswald. He
was interested in researching a catheter for the heart, but his superior
at the clinic forbade him to investigate anything so dangerous.
Undeterred, he decided to experiment without his superior’s
consent. But he did not have access to sterile instruments without the
permission of a nurse. Forssmann persuaded a nurse to get him the
instruments, convincing her he would use the catheter on her. The
pliant woman agreed to let him operate on her. But when she was lying
on the operating table waiting to be operated on, Forssmann strapped Figure 74.1: Werner Forssmann (second from left), Dickinson W
her down so she could not interfere and then instead performed the Richards (second from right) and Andre F Coumand (far right) who
operation on him. He anesthetized his arm and then slid a catheter 26 shared the Nobel Prize in 1956
Figure 74.2: William Rashkind 1922–1986
purely questions for the internist and physiologist. As Cournand said

in his Nobel lecture, “the cardiac catheter was the key in the lock”.
HISTORY OF BALLOON ATRIAL Figure 74.3: Title page of the article by Rashkind and Miller on the
SEPTOSTOMY first balloon septostomy
Atrial septostomy is a surgical procedure in which a small hole is

created between the upper two chambers of the heart, the atria. was described by Blalock and Hanlon in 1950. The new technique
This procedure is primarily used to treat dextro-transposition of the introduced by Rashkind in 1966 to create an ASD using a balloon
great arteries or d-TGA, a life-threatening cyanotic congenital heart catheter allowed a lot more children to reach the final repair without
defect seen in infants. Atrial septostomy has also seen limited use undergoing a prior surgery. Park et al. developed the blade septo-
as a surgical treatment for pulmonary hypertension. This technique stomy catheter to overcome this shortcoming. The septum was first
was developed in 1966 by American surgeons William Rashkind (Fig. cut with a tiny retractable blade which created an actual incision in
74.2) and William Miller at the Children’s Hospital of Philadelphia1 the septum. This incision could be extended with the balloon septo-
(Fig. 74.3). stomy procedure to extend the original cut.
In 1961, William J Rashkind wrote: “A technique for producing Since then it has remained an integral part of cardiac catheteri-
an atrial septal defect (ASD) without thoracotomy or anesthesia is zation in neonates, even after the introduction of the arterial switch
presented. It can be performed rapidly in any cardiac catheteriza- procedure by Jatene and associates in 1976. Balloon atrial septo-
tion laboratory.” This was commented upon by Charles Mullins: “The stomy could be of potential benefit in patients with other severe
initial response to this report varied between admiration and horror congenital heart defects, such as tricuspid or mitral atresia, or total
but, in either case, the procedure stirred the imagination of the “inva- anomalous pulmonary venous drainage, with a restrictive foramen
sive” cardiologists throughout the entire cardiology world and set the ovale. The use of two-dimensional transthoracic echocardiography
stage for all future intracardiac interventional procedures—the true to monitor the procedure and the possibility of using the umbilical
beginning of pediatric and adult interventional cardiology.” vein as an access site have simplified this procedure dramatically,
Complete correction has been possible since 1959 with the atrial so that it can be performed at the bedside in the neonatal intensive
switch procedure, first described by Senning. Mustard simplified this care unit. Used primarily in newborn children under 6 weeks of age,
method, reducing mortality rates to a reasonable level. Best results balloon atrial septostomy has limitations in older infants, due to the
with both operations were achieved in children beyond 6 months of increased thickness of the atrial septum. In these cases blade septo-
age. Therefore an early palliation by creation of an intra-atrial com- stomy and static balloon dilation of the atrial septum are preferred to
munication was imperative. A surgical technique widely practiced enlarge the interatrial communication.
Chapter 74  History of Interventions for Congenital Heart Disease 627
acquire some valid data on the use of these balloons and to establish
HISTORY OF VALVULOPLASTY
some order and control in that widespread use, a voluntary registry
of users from 27 separate centers was created. Kan and associates re-
Pulmonary Valvuloplasty
ported the first use of percutaneous balloon valvuloplasty in treating
The birth of therapeutic balloon dilation in the management of car- congenital pulmonic stenosis.8
diovascular disease can be traced to the late William Rashkind who
in 1966 developed balloon atrial septostomy for palliation of patients Mitral Valvuloplasty
with complete transposition of the great vessels. In the field of thera-
peutic dilation by means of a catheter, Dotter and Judkins actually Reports dating from as early as 1923 by Cutler and Levine on the
anteceded Rashkind by 2 years.2 In 1964, they reported the use of various techniques of surgical mitral commissurotomy using finger
progressively larger vessel dilators and passing them coaxially and fractures, transventricular dilators and valvulotomes suggested that
sequentially across an area of stenosis to open atherosclerotic ob- fused commissures in mitral stenosis could be separated with sim-
structions in the iliofemoral circulation. ple mechanical dilation. Sir Thomas Lewis wrote in 1943: “Although
At about the same time that King and Mills developed their um- many symptoms may be complained of by the patients suffering
brella occlude.4 from mitral stenosis, there are none that can be ascribed properly
Gruntzig and Hopff, with the use of small static, fixed diameter and usefully to this deformity of the valve. Equally important in the
balloons on catheters for the dilation of peripheral vessels started a development of the technology for balloon mitral valvuloplasty was
revolution in catheter interventions.5 It was not until the develop- the introduction of Brockenbrough’s transseptal left heart catheteri-
ment by Gruntzig in 1978 of a flexible balloon catheter, which was zation and Rashkind’s balloon atrial septostomy.9 These two tech-
miniaturized to such an extent as to be applicable. The first valve niques are essential to the execution of percutaneous balloon mitral
to be dilated by a balloon was the pulmonic valve. Recognition of valvuloplasty. Inoue in 1984 reported the first clinical application of
the potential use of balloon dilation in the treatment of congenital a balloon catheter in the nonoperative management of mitral ste-
pulmonic stenosis was a natural consequence of the early surgical nosis. Inoue actually began to design and develop a double-lumen
success with mechanical dilation of the stenotic pulmonic valve by co-axial balloon catheter in 1980 to create an ASD in children with
the Brock procedure. In this operation introduced in 1961, a cutting transposition of the great arteries, tricuspid atresia and other types
valvotome was introduced through a small right ventriculotomy and of cyanotic congenital heart disease. The capability of the balloon to
advanced to the pulmonary valve where the congenitally fused com- separate fused commissures of the mitral valve was then evaluated
missures were incised. Still intrigued with the idea of opening the by its use under direct vision as an auxiliary means of open mitral
pulmonary valve in the cardiac catheterization laboratory, Semb et commissurotomy. The first clinical application by Inoue of his bal-
al. utilized a combination of the techniques with the balloon. They loon catheter took place on June 3, 1982, for a 33-year-old male with
actually avulsed the valve by rapidly withdrawing a septostomy cath- severe rheumatic mitral stenosis.
eter backward through the stenosed valve. Although the technique A subsequent innovation designed by Cribier et al. of a metallic
was successful, the balloon ideas from the adult cardiology field and valvulotome for percutaneous mechanical mitral commissurotomy
new technology made this technique obsolete before it was accepted has the advantage of being reusable, which is a major advantage
by others. Consequently, in 1979 Semb et al. reported the success- in countries with limited financial resources and high incidence of
ful use of a Berman angiographic balloon catheter in a critically ill rheumatic mitral stenosis.
2-day-old boy with pulmonic stenosis and tricuspid regurgitation,
reducing the systolic pressure gradient across the pulmonic valve Aortic Valvuloplasty
from 20 mm Hg to 6 mm Hg.6 The real milestone in the treatment of
congenital lesions came with the simultaneous development of larg- Unlike experiences with the treatment of pulmonic stenosis and mi-
er static balloons and their report in 1982 by Singer et al. reporting tral stenosis, early reports on the surgical therapy of acquired aortic
balloon angioplasty of coarctation of aorta. Simultaneously Driscoll stenosis did not predict a favorable response to mechanical valvular
reported unsuccessful dilatation of pulmonary vein while Rochinni dilatation. In 1983, Lababidi et al. reported the first pediatric aortic
reported treatment of SVC obstruction. In 1983, Lock et al. reported valve balloon dilatation and in the subsequent year reported a se-
use of a series of patients for pulmonary artery stenosis, coarctation ries of 23 cases where balloon aortic valve dilatation was done.10
and venous stenosis including baffle obstruction.7 The immediate Since then aortic valve balloon dilatation has become an accepted
success of these procedures stimulated a widespread, generally suc- modality for neonatal and pediatric severe aortic stenosis. The route
cessful, but somewhat uncontrolled use of these balloons in many of balloon dilatation has varied from arterial (retrograde), prograde
centers for obstructive lesions, including native coarctation, branch transvenous transseptal, transcarotid artery bedside and transaxil-
pulmonary arteries, aortic valve and systemic veins. In an attempt to lary artery.
of the legs of these large PDA devices against the atrial septum, they
HISTORY OF DEVICE CLOSURE
suggested a further modification of these larger devices by adding a
joint on each leg to produce the “Clamshell” ASD Double Umbrella
The Early Devices
Occluder. This setback, plus the ongoing problems with approval for
Ever since the pioneering transcatheter device closure of a secun- the PDA device, eventually led Bard-USCI, then the major developer
dum ASD by King in 1974 and the subsequent work of Rashkind, car- and manufacturer of medical devices for congenital lesions to with-
diologists have been trying for this to be the preferred mode of treat- draw production and support for the devices.
ment.4,11 The major technological problem has been delivery of a Sideris et al. began developing their “Buttoned Device” for ASD
device up to several centimeters in diameter via a catheter only a few (and PDA) occlusion in the late 1980. The Sideris “Buttoned Device”
millimeters in diameter. In 1971, Porstmann was the first to develop (Pediatric Cardiology Custom Medical Devices, Athens, Greece and
a technique in which a polyvinyl alcohol plug was implanted into Amarillo, TX, USA) are single polyurethane umbrellas on a frame of
the PDA.12 In 1974, King and Mills reported on the closure of an ASD crossed spring guide-wires. They are fixed on the septum by a “coun-
with a catheter delivered double umbrella. Since then more than 300 ter occluder,” which is attached to the umbrella with unique latex
patients were treated by this technique. This was an arterial-venous “button”.13
sheath and required a large bore sheath in the artery. Rashkind and Nitinol Medical Technologies acquired the original “Clamshell”
Cuaso also were concurrently developing devices to close congenital technology. With new engineering and new materials and working
defects. They first presented the data on a hooked, single umbrella with the original “Clamshell” investigators, Nitinol developed the
for the closure of an ASD in 1977. Shortly thereafter, they reported the “Cardio-SEAL” ASD occluder. The Cardio-SEAL device used the same
successful closure of a PDA in a 3-kg infant with a smaller version of concept and delivery system as the “Clamshell”, but utilized a new
a single hooked umbrella.12 In 1979, Rashkind et al. inserted a foam metal and added an additional “joint” on the legs of the umbrellas
covered device from femoral artery into PDA in infants as small as to minimize the possibility of fractures. The Microvena in the United
3.5 kg. Later the Rashkind device was placed from the venous side States (Microvena Cop., Whitebear Lake, MN, USA) and Oscor Medi-
by Bash and Mullins. Its limitation was it could not be used for ducts cal in Germany developed three separate devices for occlusion of
larger than 9 mm. Successful implant could be done in 90% of the ASD. The Microvena “Angel Wings” device (Fig. 74.4) (Microvena
patients. Corporation, White Bear Lake, MN, USA) and the Oscor ASDOS
In 1981, two separate Rashkind Umbrella occlusion devices be- (Atrial Septum Defect Occluder System) device (Oscor Medical Cor-
gan FDA IDE clinical trials for closure of ASD and PDA. The originally poration. Palm Harbor, FL. USA) utilize the “double disks” concept,
described Rashkind hooked single umbrella was used in the ASD but both in an entirely different fashion than the “Cardio-SEAL”.
trial. In the early stages of this ASD trial, there were problems with
the ASD device hooking on unwanted structures within the heart. As The Sideris Device
a consequence, it was used very sparingly, and after only a few cases,
it was abandoned by the investigators and withdrawn from use by In the early 1990s, Sideris et al. described a buttoned device (Fig.
the manufacturer. Although the device had been used without major 74.4) to close a PDA. After study in the animal model and initial
complications in over 700 patients in the United States and used over favorable clinical trials were undertaken with the buttoned device
10,000 times throughout the rest of the world with resultant approval (Custom Medical Devices, Athens, Greece; Amarillo, TX, USA) and its
in virtually every country outside of the United States, the Rash- modifications during the 1990s. The Sideris buttoned device consists
kind PDA device never achieved FDA approval in the United States of three components: an occluder, a counter-occluder, and a delivery
and eventually was abandoned by the manufacturer for any further system. The device is generally similar to atrial septal occluding but-
modifications to improve it. Babic et al. developed a “combination” toned devices. The occluder consists of a 1/16” thick, square-shaped
of the Porstmann Plug and the Rashkind PDA occluder, with the plug polyurethane foam mounted on an X-shaped, teflon-coated, stain-
supported by a metal double umbrella frame. This device required less steel wire skeleton. The folded occluder can be introduced into a
a complex “through and through rail” technique with the separate 7Fr sheath and when delivered to the implantation site, it will resume
delivery of the two sides of the umbrella and then the locking of these its original square-shaped configuration.
two over the plug. The device never had significant clinical use. Sideris, while working on a single polyurethane umbrella device
for ASD occlusion, modified it for the PDA. The Sideris PDA Button
The Transitional Devices Device had several modifications in US FDA pilot trials and extensive
use overseas, but is not yet approved for use in the United States.14
The few successful uses of the original Rashkind ASD device plus
the continuing success of the “double umbrella” concept in the The Amplatzer ASD Device
PDA-stimulated continued interest and developments in ASD occlu-
sion devices. Lock et al. first had the largest Rashkind PDA occluder The AGA “Amplatzer” device (Fig. 74.4) represents an entirely new
enlarged further to use in the ASD. Because of the poor apposition concept in ASD occluder design. This is a complex “basket” of many
Chapter 74  History of Interventions for Congenital Heart Disease 629
Figure 74.4: Types of ASD device used
strands of fine Nitinol metal specifically shaped into a sort of double decreases the learning curve for new operators. Retrieval of the de-
mushroom joined by a thick neck. Both of the disks and the neck are vice prior to release is much simpler as also is repositioning.
filled with polyester patches to promote thrombosis.
Though there were several devices in use like the Starflex (Fig. HISTORY OF COIL CLOSURE
74.4), Cardio-SEAL, Sideris and the Helex when Amplatzer de-
vice became available, it is the Amplatzer devices for ASD closure, During this same decade of the 80s, Gianturco et al. developed and
which has gained the maximum clinical use. There are several rea- published their first papers on the use of metal “wire coils” for the
sons for this: it is best described as a self-centering, self-expanding, occlusion of abnormal vascular communications. Reports on the
repositionable device. The design of the device constructed with use of the Gianturco coil for occlusion of abnormal vascular com-
0.004–0.005 inch Nitinol is superior to the Sideris button device. The munications first appeared more than 2 decades earlier. Although
two disks are connected to each other via a waist. The waist equals designed for “adult” vascular use, these coils did have significant
the stretched diameter of the ASD. For devices in the range of 11–26 use in the occlusion of “abnormal vessels” in congenital heart pa-
mm, the left atrial disk measures 14 mm more than the waist and the tients, particularly for the occlusion of abnormal or persistent sys-
right atrial disk 10 mm more than the waist. This is the only device temic-aortopulmonary artery collateral vessels. Additional “control”
dependent on endothelial covering over the device for closure of the techniques for the coils were developed independently. The use of
ASD. The profile of this device is probably the highest amongst the a snare to grasp the coil at the initial stage of deployment allows the
available devices, though newer designs of the device with lower pro- coil to be held and withdrawn if not deployed in a proper position.
file are available especially for ventricular septal defects. Gianturco conceived the idea of a wire-filled bag as an occlusion
The other advantages include the ability to reposition the device device. With Grifka, the Gianturco-Grifka Vascular Occlusion Device
without damaging it and its ease of implantation, which significantly (GGVOD) was developed.15,16
1971 Porstmann3 First polyvinyl alcohol plug implanted in

HISTORY OF STENT USE
PDA
The concept of intravascular stents for these lesions was suggested 1974 King and Miller First umbrella occluder developed for ASD
in 1985; however, it was not until Palmaz et al. developed their in- 1975 Gianturco First report of coil closure of aorto-
travascular stent for adult use. The same stent could be used in con- pulmonary collaterals
genital lesions looked possible. Animal work in pulmonary arteries
1979 Semb First static balloon pulmonary valve
and systemic veins was begun in 1986 and demonstrated the feasi- dilatation
bility of delivering the Palmaz stents to these areas. The sustained
1979 Rashkind First PDA device closure in a 3.5 kg infant
results when implanted in these areas led to an FDA clinical IDE
1981 Rashkind FDA trial for device ASD and PDA closure
trial for their use in congenital heart disease. The preliminary, but
spectacular, results from that trial in a variety of very complex and 1982 Kan First pulmonary valve balloon dilatation
difficult pulmonary artery and systemic vein stenosis were pub- 1982 Singer Balloon dilatation of coarctation
lished in 1991. 1982 Inoue First clinical balloon catheter management
of mitral stenosis
TIMELINE OF INTERVENTIONS OF 1983 Locke Balloon dilatation of pulmonary artery,
CONGENITAL HEART DISEASE coarctation, venous baffle
1983 Lababidi First Pediatric aortic valvuloplasty
Year Name Achievement 1986 Palmaz Intravascular stent implantation in an adult
1927 Egas Moniz First contrast angiography (cerebral) 1988 Mullins First use of intravascular stent for
1929 Forssmann First catheter in heart congenital heart ds
1941 Cournand First angiography performed in human 1990 Sideris First description and use of buttoned
device
1953 Seldinger First percutaneous cardiac catheterization
1997 CARDIO-SEAL device enters FDA clinical
1964 Dotter and Judkins Peripheral balloon dilatation angioplasty
trial
1966 Rashkind First balloon atrial septostomy
2001 Amplatzer Amplatzer devices receive FDA approval for
Park First blade septostomy clinical use
REFERENCES
1. Rashkind WJ, Miller WW. Creation of an atrial septal defect without thoracotomy: A palliative approach thoracotomy: Palliative approach to com-
plete transposition of the great arteries. JAMA. 1966;196:991-2.
2. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction: Description of a new technique and a preliminary report of its ap-
plication. 1964. Radiology. 1989;172:904-20.
3. Porstmann W, Wierny L, Warnke H, et al. Ohne horakotomie. Thoraxchir Vask Chir. 1967;15:199-203.
4. King TD, Mills NL. Nonoperative closure of atrial septal defects. Surgery. 1974;75:383-8.
5. Gruntzig AR. Transluminal dilation of coronary artery stenosis. Lancet. 1978;1:263.
6. Semb BKH, Tjonneland S, Strake G, et al. Balloon valvotomy of congenital pulmonary valve stenosis with tricuspid valve insufficiency. Cardiovasc
Radio. I979;1:739-14.
7. Lock JE, Bass JL, Amplatz K, et al. Balloon dilatation angioplasty of aortic coarctation in infants and children. Circulation. 1983;68:109-16.
8. Kan JS, White KIJ, Mitchell SE, et al. Percutaneous balloon valvuloplasty: A new method for treating congenital pulmonary valve stenosis. N Engl
J Med. 1982;307:540-2.
9. Park SC, Zuberbuhler JR, Neches WH, et al. A new atrial septostomy technique. Cathet Cardiovasc Diagn. 1975;l:5-201.
10. Lababidi Z. Neonatal transluminal balloon coarctation angioplasty. Am Heart J. 1983;105:752-3.
11. Rashkind WJ, Cuaso CC. Transcatheter closure of atrial septal defects in children. Proc Assoc Europ Pediatr Cardiol. 1977;13:49.
12. Rashkind WJ, Cuaso CC. Transcatheter closure of patent ductus arteriosus: Successful use in a 3.5 kilogram infant. Pediatr Cardiol. 1979;1:3-7.
13. Sideris EH, Sideris SE, Thanopoulos BD, et al. Transvenous atrial septal defect occlusion by the buttoned device. Am J Cardiol. 1990;66:1524-6.
14. Rao PS, Wilson AD, Sideris EB, et al. Transcatheter closure of patent ductus arteriosus with buttoned device: First successful clinical application
in a child. Am Heart J. 1991;121:1799-1802.
15. Gianturco C, Anderson JH, Wallace S. Mechanical devices for arterial occlusion. AJR. 1975;124:42843-5.
16. Grifka RG, Mullins CE, Gianturco C, et al. Initial studies using the Gianturco-Grifka vascular occlusion device in a canine model. Circulation.
1995;91:1840-6.
75 Wide QRS Tachycardias Diagnosis
and Management
Singhal R, Jaswal A
VA conduction over the AV node or a second accessory AV pathway).6

INTRODUCTION It is also seen in Mahaim tachycardia where AV conduction goes by
When confronted with a tachycardia having a broad QRS complex, it way of a slowly conducting right-sided accessory AV pathway or a no-
is important to differentiate between a supraventricular tachycardia doventricular fiber inserting into the right ventricle.
(SVT) and a ventricular tachycardia (VT). Medication given for the
treatment of a SVT may be harmful to a patient with a VT. A reason- Ventricular Tachycardia
able hemodynamic condition during a tachycardia may erroneously
lead to the wrong diagnosis of SVT.1-3 Familiarity with the electro- Ventricular tachycardia is discussed in following heading:
cardiogram (ECG) signs allowing the diagnosis of a VT is therefore
essential. Electrocardiogram should not only tell how to distinguish ELECTROPHYSIOLOGY OF
VT from other tachycardias with a broad QRS complex, but also to
VENTRICULAR TACHYCARDIA
suspect its etiology and its site of origin in the ventricle. Both aspects
are important in decision-making about the prognostic significance The Electrocardiogram Diagnosis
of VT and correct treatment.
Importance of Atrioventricular Dissociation
CLASSIFICATION OF TACHYCARDIAS
Although dissociation between atrial and ventricular activity during
WITH A BROAD QRS COMPLEX
tachycardia is a hallmark of VT, some form of VA conduction can be
Broad QRS tachycardia can be divided into three groups:4 present during VT, especially at slow rate. Complete AV dissocia-
tion is seen in 20–50% of all VTs. P-wave can be difficult to recog-
Supraventricular Tachycardia nize during a broad QRS tachycardia and it is always useful to look
for non ECG signs, such as variations in jugular pulsations, the loud-
with Bundle Branch Block
ness of the first heart sound and changes in systolic blood pressure.
Bundle branch block (BBB) may be pre-existing or can occur when In patients with slow VT rates occasional conduction from atrium
the refractory period of one of the bundle branches is reached, be- to ventricle over the AV node—bundle branch system may happen
cause of the heart rate of the SVT (so called tachycardia related or resulting in “capture” or “fusion” beats. Sudden narrowing of a QRS
phase 3 block). Bundle branch block can also occur, because of ret- complex during VT may also be the result of a premature ventricu-
rograde invasion in one of the bundle branches. These causes of BBB lar depolarization arising in the ventricle in which the tachycardia
can be found in patients with atrial tachycardia,5 atrial flutter, atrial originates or it may occur when retrograde conduction during VT
fibrillation, atrioventricular (AV) nodal tachycardia and also during produces a ventricular echo beat leading to fusion with the VT QRS
orthodromic circus movement tachycardia. complex. Very rarely, AV dissociation is present in tachycardias other
than VT. It may occur in AV junctional tachycardia with BBB after car-
Supraventricular Tachycardia with diac surgery or during digitalis intoxication.
Atrioventricular Conduction over an

Accessory Atrioventricular Pathway Width of the QRS Complex
This may occur during atrial tachycardia, atrial flutter, atrial fibrilla- The site of origin of the VT plays a role in the width of the QRS com-
tion, AV nodal tachycardia and during antidromic circus movement plex. When the arrhythmia arises in the lateral free wall of the ven-
tachycardia (with AV conduction over an accessory AV pathway and tricle, sequential activation of the ventricles occurs resulting in a
very wide QRS. The QRS complex will be smaller when the VT has its Interval onset QRS to Nadir of S-wave in precordial leads: Bru-
origin in or close to the interventricular septum (IVS). Other factors gada et al. and colleagues suggested that an RS interval greater than
also play a role in the QRS width during VT, such as scar tissue [after 100 ms in one or more precordial leads is highly suggestive for VT.8
myocardial infarction (MI)], ventricular hypertrophy and muscular However, such a duration may occur in SVT with AV conduction over
disarray (as in hypertrophic cardiomyopathy). It is of interest that a an accessory pathway, SVT during administration of drugs that slow
QRS width of more than 0.14 seconds in right bundle branch block intraventricular conduction (in particular, flecainide) and in SVT
(RBBB) tachycardias and 0.16 seconds during left bundle branch with pre-existent BBB, especially LBBB.
block (LBBB)7 argues for a VT, but a QRS width below such values Concordant pattern: When all precordial leads show either nega-
may occur in VTs having their origin in or close to the IVS. QRS width tive or positive QRS complexes, this is called negative or positive
is not helpful in differentiating VT from a tachycardia with AV con- concordance. Negative concordance is diagnostic for a VT arising in
duction over an accessory AV pathway, because such a pathway in- the apical area of the heart. Positive concordance means that in the
serts into the ventricle leading to eccentric ventricular activation and horizontal plane, ventricular activation starts left posteriorly. This
a wide QRS complex. An SVT can have a QRS width of more than 0.14 can be found either in VT originating in the left posterior wall or dur-
(RBBB) or 0.16 (LBBB) seconds under three circumstances: ing tachycardias, using a left posterior accessory AV pathway for AV
1. In the presence of pre-existent BBB in the elderly with fibrosis in conduction.
the bundle branch system and ventricular myocardium Tachycardia QRS narrow than sinus QRS: When during tachycar-
2. When during SVT, AV conduction occurs over an accessory AV dia the QRS is narrower than during sinus rhythm a VT should be di-
pathway agnosed. A very wide QRS is present during sinus rhythm because of
3. When patient on class IC drugs (especially, flecainide) are sequential activation of first the right and then the left ventricle. Dur-
present during SVT. ing tachycardia, the QRS is narrower. This can only be explained by
a ventricular origin close to the IVS, resulting in more simultaneous
QRS Axis in the Frontal Plane activation of the right and left ventricle than during sinus rhythm.
Presence of QR complexes: Coumel and colleagues called atten-
The QRS axis is not only important for the differentiation of the broad tion to the significance of a QR (but not a QS) complex during a broad
QRS tachycardia, but also to identify its site of origin and etiology. A QRS tachycardia, showing that their presence indicates a scar in the
VT origin in the apical part of the ventricle has a superior axis (to the myocardium usually caused by MI.9 QR complexes during VT are
left of −30), inferior axis when VT has an origin in the basal area of present in approximately 40% of VTs after MI.10
the ventricle. The presence of a superior axis in patients with RBBB
shaped QRS very strongly suggests VT. This does not hold for an CRITERIAS TO DIFFERENTIATE
LBBB shaped tachycardia. On the contrary, presence of an inferior
WIDE QRS TACHYCARDIA
axis in LBBB shaped QRS tachycardia argues for a VT arising in the
outflow tract of the right ventricle. Brugada’s Criteria
Configurational Characteristics Brugada diagnostic algorithm for wide QRS tachycardia is given in
Figure 75.1.
of the QRS Complex
Leads V1 and V6: Marriott described that in RBBB shaped tachycar- Newer Algorithm
dia, presence of a QR or R complex in lead V1 strongly suggests VT,
while a three phasic (RSR) pattern suggested a SVT.6 Apart from lead Wide QRS tachycardia can be represented as a newer algorithm,
V1, lead V6 can also be helpful in differentiating RBBB shaped tachy- which is shown in Figure 75.2 in four steps.
cardia. When in V6 the R:S ratio is less than 1, a VT is very likely. An
R:S ratio is greater than 1 in V6 is typically found when there is left ETIOLOGY OF VENTRICULAR TACHYCARDIA
axis deviation in the frontal plane. If the axis is inferiorly directed,
lead V6 often shows an R:S ratio greater than 1. In LBBB shaped VT, Most VTs have a previous MI as their etiology and a QR complex
lead V1 (and also V2) shows an initially positive QRS with positiv- during VT can be very helpful to make that diagnosis. However,
ity measuring more than 0:03 seconds; slurring or notching of the characteristic of ECG patterns can also be found in idiopathic VT11
down stroke of the S-wave; an interval between the beginning of the and VT in patients with arrhythmogenic right ventricular dysplasia
QRS and the nadir of the S-wave of 0.07 seconds or more. When lead (ARVD).12
V6 shows a QR pattern during LBBB shaped tachycardia, VT is very Figure 75.3 shows three patterns of idiopathic VT arising in
likely. In SVT with LBBB, lead V1 shows no or minimal initial posi- or close to the outflow tract of the right ventricle. All the three pat-
tivity, a very rapid down stroke of the S-wave and a short interval terns have an LBBB-like QRS complex indicating a right ventricular
between the beginning of the QRS and the nadir of the S-wave. origin. In Figure 75.3A, the frontal QRS axis is +70 and lead 1 shows
Chapter 75  Wide QRS Tachycardias Diagnosis and Management 633
Figure 75.1: Brugada diagnostic algorithm for wide-QRS tachycardia
A B C
Figure 75.2: Newer algorithm Figures 75.3A to C: Shows three types of idiopathic ventricular
Source: European Heart Journal 2006 tachycardia
a positive QRS complex, indicating an origin of the tachycardia in Figures 75.4A and B give an example of an LBBB shaped VT in
the lateral part of the outflow tract of the right ventricle. In Figure a patient with ARVD. When the broad QRS is identical during tachy-
75.3B, the frontal QRS axis is inferior and the QRS is negative in lead cardia and sinus rhythm, one has to differentiate SVT with pre-exist-
1, pointing to an origin on the septal side in right ventricular outflow ent BBB from bundle branch re-entrant tachycardia.13
tract (RVOT). In Figure 75.3C, an inferior frontal QRS axis and QRS In diseased hearts, especially when the bundle branches and
negativity in lead 1 are also present, but leads V1 and V2 show initial the IVS are involved, a tachycardia may occur based upon a circuit
positivity of the QRS complex. This is a tachycardia not arising on the with anterograde conduction down one bundle branch or one of
endocardial surface of the RVOT, but epicardially in between the root the left-sided fascicles and after septal activation retrograde con-
of the aorta and the posterior part of the outflow tract of the right duction over another branch of the bundle branch system known
ventricle. It is important to recognize this pattern, because this site of as bundle branch re-entrant tachycardia. Figure 75.5 shows an
origin of the VT cannot be treated with catheter ablation in contrast example of this tachycardia. This type of re-entry may occur in
to the tachycardias depicted in panel A and B. patients with anteroseptal MI, idiopathic dilated cardiomyopathy,
The QRS configuration in idiopathic left VT has an RBBB shape, myotonic dystrophy, after aortic valve surgery and after severe
because of an origin in the left ventricle. frontal chest trauma.
In ARVD, there are three predilection sites in the right ventri-
cle: the inflow tracts, outflow tracts and the apex, while the first two VALUE OF THE ELECTROCARDIOGRAM
sites have a QRS configuration during tachycardia which is difficult
DURING SINUS RHYTHM
to differentiate from right ventricular idiopathic VT, left axis devia-
tion in a young person with an LBBB shaped VT should immediately The ECG during sinus rhythm may show changes such as pre-
lead to the suspicion of ARVD. In fact, there is an important role in existent BBB, ventricular pre-excitation or an old MI, which are very
LBBB shaped VT with left axis deviation that cardiac disease should helpful in correctly interpreting the ECG during broad QRS tachycar-
be suspected and that idiopathic right ventricular VT is extremely dia.10 Also, the presence of AV conduction disturbances during sinus
unlikely. rhythm make it very unlikely that a broad QRS tachycardia in that
A B
Figures 75.4A and B: A left bundle branch block shaped ventricular Figure 75.5: Bundle branch re-entrant tachycardia
tachycardia in a patient with arrhythmogenic right ventricular dysplasia.
(A) Tachycardia; (B) Normal sinus rhythm
Figure 75.6: Treatment of wide-QRS tachycardia with regular rhythm
patient has a supraventricular origin and a QRS width during tachy-

cardia more narrow that during sinus rhythm points to a VT.
VALUE AND LIMITATIONS OF THE

ELECTROCARDIOGRAM IN BROAD QRS
TACHYCARDIA
• Atrioventricular dissociation suggests VT, but VA conduction
may be present during VT
• QRS width of more than 160 ms suggests VT, but need to rule out
the following:
– Pre-existent BBB (especially LBBB)
– SVT with AV conduction over an AP
– Use of drugs that slow intraventricular conduction (flecain-
Figure 75.7: Treatment of wide-QRS tachycardia
ide).
with irregular rhythm
• Left axis deviation (to the left of −30) suggests VT, but is not
helpful in the following:
– LBBB shaped QRS7
– SVT with conduction over a right-sided or posteroseptal AP
– SVT during use of class IC drugs. Hemodynamically Stable
• Right axis deviation (to the right of +90) suggests VT in LBBB
shaped QRS • Wide QRS tachycardia with regular rhythm (Fig. 75.6)
• Concordant pattern in precordial leads suggests VT, but positive • Wide QRS tachycardia with irregular rhythm (Fig. 75.7)
concordancy may occur during SVT with AV conduction over a In VT, a lidocaine bolus may be tried, as it has high success rate
left posterior AP in the setting of MI or acute myocardial ischemia (AMI), whereas it is
• R nadir S more than 100 ms in one or more precordial leads sug- rarely effective in VTs arising from an arrhythmogenic chronic sub-
gests VT, but may be found in the following: strate (previous MI, cardiomyopathy, etc.). A synchronized DC shock
– SVT on drugs slowing intraventricular conduction is the treatment of choice in case of lidocaine failure.
– SVT with AV conduction over an AP Magnesium sulfate is the treatment of choice in torsade de pointes.
– Pre-existent BBB (especially LBBB) This arrhythmia is typically due to an excessive lengthening of repo-
• QR complexes during VT suggest previous MI as an etiology. larization and is facilitated by bradycardia. Ventricular pacing (100–
110 bpm) by shortening repolarization is very effective in preventing
MANAGEMENT OF WIDE QRS TACHYCARDIA recurrences of the arrhythmia.
In patients where a definite diagnosis of SVT with aberrant con-
Hemodynamically Unstable duction has been made, the treatment is the same as for narrow-QRS
tachycardias avoiding drugs, which adversely affect intraventricular
Direct current (DC) shock must be performed without delay, defer- conduction (namely, IC class agents). Conversely, these drugs are
ring a precise diagnosis, which will be based on a subsequent retro- of first choice in antidromic AV re-entrant tachycardias13 or in pre-
spective analysis of the ECG.9 excited atrial fibrillation.
rhythmia by placing catheters at different sites in the heart.21,22

CONCLUSION
Soon after, on both sides of the Atlantic, this technique was used
Wide QRS tachycardias certainly poses challenge however, one to unravel the place of origin of different types of supraventricular
should not get confused when confronted with these tachycardias. tachycardias.23-27 The first book on the use of programmed stimu-
One should look for clinical signs of AV dissociation and evalu- lation of the heart in the analysis of supraventricular tachycardias
ate the 12 lead ECG systematically applying different criteria, also was published in 1971.28
important to look at the 12 lead ECG during sinus rhythm. This In the late 1960s, Scherlag et al.29 made another important
approach usually gives the correct diagnosis of VT versus SVT. breakthrough in the analysis of cardiac arrhythmias with the re-
One should keep in mind that statistically VT is much more com- producible registration of the His bundle electrogram. Not only
mon than SVT in the broad QRS tachycardia and should never did this advance allow accurate localization and risk stratification
make the mistake of rejecting VT because the broad QRS tachy- of atrioventricular conduction disturbances, but, as shown by
cardia is hemodynamically well tolerated. When in doubt, do groups led by Ken Rosen, Onkar Narula, and Paul Puech, much
not give verapamil or adenosine; procainamide should be used better identification of the path for impulse propagation during a
instead. tachycardia was now possible.30
Before 1967, cardiac arrhythmias were documented electro- A very exciting aspect of the use of programmed electric stim-
cardiographically, and their possible mechanisms were analyzed ulation of the heart, when combined with recording the His bun-
ingeniously and explained beautifully by giants, such as Katz and dle electrogram, was the progress made in the interpretation of
Pick,14 Scherf and Schott15 and Bellet.16 In the 1940s and 1950s, the 12-lead ECG during cardiac arrhythmias. Careful reexamina-
Hecht,17 Latour and Puech18 and Giraud et al.19 used catheters to tion of the ECG after an intracardiac study brought new insights,
measure intracardiac electric activity and to record the sequence ultimately leading to a clinically useful classification of tachycar-
of cardiac activation. In 1958, Furman and Robinson20 showed dias and allowing correct recognition of different types of arrhyth-
that in patients with atrioventricular block, the heart could be mias from the 12-lead ECG.31
stimulated by connecting an intraventricular catheter to a stimu- A very important advance in rescuing patients with life-
lator. threatening arrhythmias was the implantable automatic defibril-
In 1967, the analysis of the site of origin and mechanism of lator pioneered by Mirowski et al.32 Major advances in technology
cardiac arrhythmias became possible in the intact human heart resulting in increasing effectiveness have led to widespread ac-
through the use of programmed electric stimulation combined ceptance of the device.33
with intracardiac activation mapping. Independently, Durrer Another important development has been the use of pacing in
et al.20 in Amsterdam (in patients with the Wolff-Parkinson-White heart failure patients with intraventricular and/or interventricu-
syndrome) and Coumel and coworkers21 in Paris (in a patient with lar conduction disturbances. Resynchronization of ventricular
an atrioventricular junctional tachycardia) showed that by con- activation by permanent pacing with transvenous leads inserted
necting intracardiac catheters to a versatile stimulator, it was pos- into the coronary veins34 resulted in improvements in exercise tol-
sible to reproducibly initiate and terminate clinically occurring erance, well-being, and ventricular performance and decreases in
tachycardias and to identify the site of origin of the tachycardia hospitalizations, neurohumoral activity, and death35,36 for 70% of
and, in the case of a reentrant mechanism, the pathway of the ar- selected patients.
REFERENCES
1. Stewart RB, Bardy GH, Greene HL. Wide complex tachycardia: misdiagnosis and outcome after emergent therapy. Ann Intern Med. 1986;104(6):766-
71.
2. Buxton AE, Marchlinski FE, Doherty JU, et al. Hazards of intravenous verapamil for sustained ventricular tachycardia. Am J Cardiol.
1987;59(12):1107-10.
3. Dancy M, Camm AJ, Ward D. Misdiagnosis of chronic recurrent ventricular tachycardia. Lancet. 1985;2(8450):320-3.
4. Wellens HJ, Bar FW, Lie KI. The value of the electrocardiogram in the differential diagnosis of a tachycardia with a widened QRS complex. Am J
Med. 1978;64(1):27-33.
5. Harvey WP, Ronan JA Jr. Bedside diagnosis of arrhythmias. Prog Cardiovasc Dis. 1966;8(5):419-45.
6. Marriott HJ. Differential diagnosis of supraventricular and ventricular tachycardia. Geriatrics. 1970;25(11):91-101.
7. Kindwall E, Brown J, Josephson ME. Electrocardiographic criteria for ventricular tachycardia in wide complex left bundle branch block morphol-
ogy tachycardias. Am J Cardiol. 1988;61(15):1279-83.
8. Brugada P, Brugada J, Mont L, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation.
1991;83(5):1649-59.
9. Coumel P, Leclerq JF, Attuel P, et al. The QRS morphology in postmyocardial infarction ventricular tachycardia. A study of 100 tracings compared
with 70 cases of idiopathic ventricular tachycardia. Eur Heart J. 1984;5(10):792-805.
10. Wellens HJJ. The electrocardiographic diagnosis of arrhythmias. In: Topol E (Ed). Textbook of Cardiovascular Medicine. Philadelphia: Lippincott,
Raven; 1998. pp. 1591-609.
11. Wellens HJJ, Rodriguez LM, Smeets JL. Ventricular tachycardia in structurally normal hearts. In: Zipes DP, Jalife J (Eds). Cardiac Electrophysiol-
ogy—from Cell to Bedside. 2nd edition. Philadelphia: WB Saunders; 1995. pp. 780–8.
12. Leclercq JF, Coumel P. Characteristics, prognosis and treatment of the ventricular arrhythmias of right ventricular dysplasia. Eur Heart J. 1989;10
(suppl D):61-7.
13. Touboul P, Kirkorian G, Atallah G, et al. Bundle branch re-entrant tachycardia treated by electrical ablation of the right bundle branch. J Am Coll
Cardiol. 1986;7(6):1404-9.
14. Katz LN, Pick A. Electrocardiography. Philadelphia, Pa: Lea and Febiger.1941.
15. Scherf D, Schott A. Extrasystoles and Allied Arrhythmias. London, UK: Heinemann. 1953.
16. Bellet S. Clinical Disorders of the Heart Beat. Philadelphia, Pa: Lea and Febiger. 1953.
17. Hecht HH. Potential variations of the auricular and right ventricular cavities in man. Am Heart J. 1946;32:39-52.
18. Latour H, Puech P. Electrocardiographie Endocavitaire. Paris, France: Masson. 1957.
19. Giraud G, Puech P, Latour H, et al. Variations de potentiel liees a l’activite du systeme de conduction auriculo-ventriculaire chez l’homme. Arch
Mal Cour. 1960; 53: 575-84.
20. Furman S, Robinson G. Use of intracardiac pacemaker in correction of total heart block. Surg Forum. 1958;9:245-52.
21. Durrer D, Schoo L, Schuilenburg RM, et al. The role of premature beats in the initiation and the termination of supraventricular tachycardias in
the Wolff-Parkinson-White syndrome. Circulation. 1967;36:644-62.
22. Coumel Ph, Cabrol C, Fabiato A, et al. Tachycardie permanente par rhythme reciproque. Arch Mal Coeur. 1967;60:1830-45.
23. Haft JL, Kosowsky BD, Lau SH, et al. Termination of atrial flutter by rapid electrical pacing of the atrium. Am J Cardiol. 1967;20:239-46.
24. Lister JW, Cohen LS, Bernstein WH, et al.. Treatment of supraventricular tachycardias by rapid atrial stimulation. Circulation. 1968;38:1044-59.
25. Goldreyer BN, Bigger J. Spontaneous and induced re-entrant tachycardia. Ann Intern Med. 1969;70:87-98.
26. Rosen KM, Mehta A, Miller RA. Demonstration of dual atrioventricular nodal pathways in men. Am J Cardiol. 1974;33:291-4.
27. Zipes DP, Joseph RL, Rothbaum DA. Unusual properties of accessory pathways. Circulation. 1974;49:1200-06.
28. Wellens HJJ. Electrical Stimulation of the Heart in the Study and Treatment of Tachycardias. Baltimore, Md: University Park Press; 1971.
29. Scherlag BJ, Lau SH, Helfant RH, et al. Catheter technique for recording His bundle activity in men. Circulation.1969;39:13-8.
30. Wellens HJJ, Lie KI, Janse MJ, (Eds). The Conduction System of the Heart. Philadelphia, Pa: Lea and Febiger; 1976.
31. Wellens, HJJ, Kulbertus HE, (Eds). What Is New in Electrocardiography? The Hague, Netherlands: M. Nijhoff; 1981.
32. Mirowski M, Reid PR, Mower MM, et al. Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator. N Engl J
Med. 1980;303:322-5.
33. Lee DS, Green LD, Liu PP, et al. Effectiveness of implantable defibrillators for preventing arrhythmic events and death: a meta-analysis. J Am Coll
Cardiol. 2003;41:1573-82.
34. Daubert JC, Ritter P, Le Breton, et al. Permanent left ventricular pacing with transvenous leads inserted into the coronary veins. Pacing Clin Elec-
trophysiol. 1998;21 (pt 2):239-45.
35. Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized
controlled trials. JAMA. 2003;289:730-40.
36. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, for the Cardiac Resynchronization-Heart Failure (CARE-
HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-49.
76 History of Peripheral Vascular
Interventions
Rao SS, Khanna NN
In 1956, Forssmann received the Nobel Prize for medicine.

INTRODUCTION
Percutaneous transluminal angioplasty (PTA) for treating
Over the past few decades, the technique of peripheral vascular peripheral vascular atherosclerosis was initially described by the
interventions to treat patients with peripheral arterial disease, aneu- US interventional radiologist Charles Theodore Dotter in 1964.1 On
rysmal and venous disorders has grown dramatically. Improvements January 16, 1964, Dotter percutaneously dilated a tight, localized
in catheter, sheath, wire, balloon and stent design, as well as the stenosis of the superficial femoral artery (SFA) in an 82-year-old
advent of emboli protection devices and other novel technolo- woman, Laura Shaw, with painful leg ischemia and gangrene who
gies, have collectively enabled the safe and durable treatment of refused leg amputation. After successful dilation of the stenosis with
obstructive and aneurysmal disease and an array of venous disorders. a guide wire and coaxial teflon catheters, the circulation returned to
Although endovascular therapy is a relatively recent concept, it has her leg.2 The dilated artery stayed open until her death from pneu-
a rich history. monia two and a half years later. Charles Dotter is commonly known
The technique of angiography was first developed in 1927 by as the “Father of Interventional Radiology” and was nominated for
the Portuguese physician Egas Moniz at the University of Lisbon for the Nobel Prize in medicine in 1978.
viewing the brain vasculature (cerebral angiography). German cardiologist, Andreas Gruntzig revolutionized the tech-
Coronary catheterization was first performed when Werner For- nique in 1974 when he developed a soft, flexible, double-lumen bal-
ssmann, in 1929, created an incision in one of his left antecubital loon catheter for peripheral and coronary dilatations, as well as renal
veins and inserted a catheter into his venous system. He then guided occlusive disease. He performed the first coronary angioplasty in
the catheter by fluoroscopy into his right atrium. Subsequently, he September 1977.3
documented the procedure by having a chest roentgenogram per- Since the introduction of percutaneous transluminal coronary
formed. It was a pity that he was initially suspended for his so called angioplasty (PTCA) by Gruntzig in 1977 (Figs 76.1A to C), major ad-
misconduct which later on became a game changer in the practice of vancements have been made in the clinical practice of percutaneous
vascular medicine. vascular intervention. Puel and Sigwart, in 1986, deployed the first
A B C
Figures 76.1A to C: In September 14, 1977 Andreas Gruentzig performed the first percutaneous coronary angioplasty at the University Hospital
of Zurich. (A) Coronary angiography performed showing a stenosis of the proximal LAD; (B) Results after balloon angioplasty of the coronary artery;
(C) Angiographic result after 1 month
Chapter 76  History of Peripheral Vascular Interventions 639
intravascular stent to act as a scaffold (Figs 76.2A to C), thus prevent- angioplasty, with a significantly lower incidence of abrupt closure
ing vessel closure during angioplasty, and reducing the incidence of and periprocedure complications. At approximately the same time,
angiographic restenosis, which had an occurrence rate of 30–40%.4 Cordis (a division of Johnson & Johnson) was developing the Cypher
Stent technology improved rapidly, and in 1989, the Palmaz- stent, a stent that would release sirolimus over time. The first study of
Schatz balloon-expandable stent was developed by Dr Julio Palmaz these individuals revealed an incredible lack of restenosis (zero per-
(Figs 76.3A and B). It focused on preventing late adverse events cent restenosis) at 6 months.6 This led to the approval for the stent to
(such as stent restenosis and late thrombosis).5 Initial results with be used in Europe in April 2002. About a year after approval in Eu-
the Palmaz-Schatz stents were excellent when compared to balloon rope, the United States FDA approved the use of the Cypher stent as
the first drug-eluting stent for use in the general population in the
United States.
CAROTID ANGIOPLASTY
Carotid artery stenting has emerged as an endovascular treatment
alternative to carotid endarterectomy for the management of athero-
sclerotic obstructive extracranial carotid artery disease. Percutane-
A
ous transluminal balloon angioplasty for carotid artery stenosis was
reported by Kerber et al. in 1980.7
In 1987, Theron et al. published findings on internal carotid an-
gioplasty in 48 patients with de novo atherosclerosis or postsurgical
restenosis.8 Technical success was achieved in 94% of cases, with a
4.1% rate of serious morbidity. In Kachel’s review of the literature
through 1995, 523 carotid angioplasty procedures had subsequently
B
been reported.9 The overall technical success rate was 96.2%, with a
2.1% rate of morbidity, 6.3% rate of transient minor complications,
and no deaths. Despite apparently favorable results, simple balloon
angioplasty has a number of potential drawbacks, including vessel
C wall recoil, angiographically evident intimal dissection and plaque
dislodgment with particulate embolization. Endovascular revascu-
Figures 76.2A to C: March 28, 1986, Dr Jacques Puel (Toulouse)
larization of carotid occlusive disease may result in cerebral hypop-
implanted for the first time, a stent in a coronary artery. (A) Restenosis
at 6 months of a balloon dilation; (B) The first self-expanding stent erfusion from luminal compromise because of catheters and guide
implanted in the world; (C) 18 years after implantation wires that cross the stenotic lesion and/or during balloon inflation.
A B
Figures 76.3A and B: (A) Julio Palmaz; (B) Richard Schatz

This is of even greater relevance in the presence of contralateral The acculink for revascularization of carotids in high-risk pa-
carotid artery occlusion or stenosis. tients (ARCHeR) was a prospective trial with CAS and EPD using the
RX AccuLink carotid stent system and the RX accunet embolic pro-
ADVANCEMENT—THE AGE OF tection system in high-risk surgical patients.12 This study enrolled, in
three single-arm trials, 581 patients who met the following criteria:
CEREBRAL PROTECTION
50% symptomatic stenosis or 80% asymptomatic stenosis with one of
In general, the primary complication from coronary artery stenting the following:
(CAS) was periprocedural stroke from the liberation of débris during Two or more coronary lesions; severe pulmonary disease; end-
balloon inflation. Therefore, in theory, if distal embolization could stage renal disease; history of neck radiation; contralateral carotid
be mitigated, CAS could be performed with lower risk. The first distal occlusion; myocardial infarction in the previous 30 days; uncon-
protection device was actually developed by Theron in 1990;10 how- trolled diabetes mellitus.
ever, recent technical refinements have enabled the widespread use The primary endpoint of death, myocardial infarction, and stroke
of a variety of distal embolic protection devices (EPDs) in conjunc- at up to 2 years in ARCHeR 1 and 2 were 8.3% and 10.2%, respectively.
tion with CAS. ARCHeR 1 used the acculink nitinol stent without cerebral protec-
In 2001, the SAPPHIRE trial11 (stenting and angioplasty with tion, whereas archer 2 used a cerebral protection device. ARCHeR 3
protection in patients at high-risk for endarterectomy) was started by was similar in the usage of the stent and EPD; however, the monorail
the US Food and Drug Administration (FDA) involving CAS with the delivery system was used exclusively during this phase of the trial.
simultaneous use of EPDs. Not enough patients in this trial have reached 1 year; therefore, the
The aim of this trial was not to show that stenting is superior to ARCHeR 3 results are unavailable.
surgery, but that it is not inferior by a difference of 3%. A total of 747 Currently, a new large study, carotid revascularization: endarter-
patients were enrolled in this trial. The study protocol randomized ectomy versus stenting trial (CREST), has shown that CAS is better
high-risk patients defined as: than CEA.
Age over 80 years; severe pulmonary disease; severe congestive Carotid endarterectomy has been a mainstay in the treatment of
heart failure or concomitant severe coronary artery disease; contral- carotid occlusive disease. Many critics have viewed CAS as a niche
ateral cervical carotid artery occlusion; unstable angina; carotid ste- procedure, which they feel will not withstand the pressures of multi-
nosis inaccessible to vascular surgeons; previous radiation therapy discipline physician and government involvement. Unfortunately, in
in the carotid stenosis site. the CEA trials, investigators have looked only at low-risk patients and
Symptomatic patients with 50% luminal stenosis or asympto- have extrapolated the results to high-risk patients in clinical practice.
matic patients with 80% luminal stenosis were accepted into this ran- Others complain that there are no long-term data. Then, on the
domized trial. Cardiologists, radiologists, surgeons and neurologists basis of recent trial data, it is fair to state that in high-risk patients,
all participated in the decisions on which patients would be allowed CAS is the procedure of choice. In the future, as endovascular ther-
into the trial. Actually, the nonrandomized stent arm (NRSA) of this apy becomes further refined, with better EPDs, better stents (drug-
trial was defined by the surgeons themselves. The EPD used in SAP- eluting), and more experienced operators, mortality and morbidity
PHIRE was the Angioguard, by Cordis. The study had three arms: rates associated with the procedure will continue to decline.
1. Randomized carotid endarterectomy (CEA) versus CAS with History is fickle. When surgeons pioneered carotid endarterec-
EPD (334 patients) tomy, they outpaced medical therapy. Surgical therapy was a mov-
2. Nonrandomized stent arm for patients who were refused surgery ing target and medical therapy could not keep up. Times are again
(406 patients) changing. Endovascular therapy—with its innovations—is now the
3. Nonrandomized surgical arm for patients who were refused CAS moving target, while surgical therapy has had minor changes. Just as
(7 patients). medical therapy has a role in mild-to-moderate lesions, endovascu-
At 2 years, patients receiving CAS with EPD fared signifi- lar therapy has a role in this huge population, but its exact nature
cantly better than those undergoing CEA in the composite end- remains to be seen.
point of death, stroke and myocardial infarction (12.0% vs 20.1%,
P < 0.05). However, this result was driven primarily by myocardial RENAL ANGIOPLASTY
infarction, because there was no significant difference in death or
stroke (the trend still favored CAS). In symptomatic patients, no Percutaneous transluminal angioplasty was first used in patients
statistically significant difference existed between the CAS and the with renal artery stenosis in 1978 by Gruntzig, et al.13 Since then,
CEA groups (16.8% vs 16.5%). Again in asymptomatic patients, no percutaneous transluminal renal angioplasty (PTRA) has become
difference existed between the CAS and the CEA groups (5.4 vs widely used for renal artery stenosis treatment and has tended
10.2, P = 0.20). to replace surgical revascularization as the first-line treatment in
Chapter 76  History of Peripheral Vascular Interventions 641
hypertensive patients with renal artery stenosis. The use of revascu- minimally invasive alternative to surgical bypass, requiring shorter
larization techniques for the management of renal artery stenosis hospital stays and permitting faster recovery. Although dilatation of
in patients with hypertension, renal insufficiency, pulmonary ede- the common femoral and profunda femoral arteries is sometimes
ma and unstable angina has become increasingly prevalent. Renal indicated, the most commonly treated femoropopliteal vessels are
artery stent placement has gained increasing acceptance on the basis the SFA and popliteal artery.
of historical results of renal angioplasty.14-15 Endovascular treatment is now an alternative to surgery for the
treatment of iliac artery aneurysms (IAAs). A variety of minimally
ANGIOPLASTY FOR AORTOILIAC invasive therapeutic options are available (e.g. coil embolization,
stent-graft placement) and choosing an appropriate option is essen-
OCCLUSIVE DISEASES
tial for achieving excellent long-term results and reducing potential
In 1964, Dotter first performed percutaneous iliac angioplasty using complications.
a coaxial system of metal dilators. This procedure proved to have lim-
ited application due to the cumbersome nature of the device. How- ENDOVASCULAR REPAIR OF
ever, Dotter’s early work paved the way for Grüntzig, who, in 1974,
AORTIC ANEURYSM
developed a catheter with an inflatable polyvinyl chloride balloon
that could be passed over a guide wire. This device became the cor- The world’s first EVAR was performed in 1987 by Nicholas Volodos in
nerstone for the percutaneous treatment of arterial occlusive lesions Kharkov, Soviet Union and introduced in an article written in 1988.16
today. In 1985, Julio Palmaz introduced the first stent that helped to In Argentina it was first introduced in 1991 by Juan Parodi and the
improve the results of angioplasty for arterial occlusive disease. Since very same year in the USA by Michael Dake.17
the advent of angioplasty and stenting, the technology has evolved On September 7, 1990, Dr Juan C Parodi and his team at the
at an astronomical rate. The design and quality of endovascular Instituto Cardiovascular de Buenos Aires (ICBA, Buenos Aires,
devices, as well as the ease and accuracy of performing the proce- Argentina) treated the first endovascular AAA patient. The aneurysm
dures, have improved. These improvements have led to improved was excluded endoluminally with a Dacron graft that was anchored
patient outcomes following endovascular interventions for aortoiliac at the proximal infrarenal neck with a stainless steel balloon-expand-
occlusive disease (AIOD). able stent. The system was assembled by affixing (with sutures) the
The iliac arteries are technically among the easiest vessels to ap- fabric tube to an undeployed stent mounted on a large-diameter
proach percutaneously and are the largest peripheral lower extrem- angioplasty balloon. The contraption was then sheathed inside a
ity vessels with the highest flow rates. These factors optimize the out- large-bore catheter that served as the delivery system. Access to
come of percutaneous transluminal angioplasty (PTA) and stenting. the aorta for delivery and deployment was achieved in a retrograde
Aortic bifurcation reconstruction, once the sole realm of surgi- transluminal fashion through the surgically exposed common femo-
cal bypass, is now performed successfully using percutaneous tech- ral artery. It worked, resulting in exclusion and depressurization of
niques. the large aneurysm in a patient who had been deemed an unsuit-
able candidate for standard surgical repair. Much work, experimen-
ANGIOPLASTY FOR INFRAINGUINAL tation and design preceded the launch of the clinical program. And
while the initial few patients in the series were treated using a similar
PERIPHERAL VASCULAR DISEASE
approach, subsequent technical iterations and modifications
On January 16, 1964, Dotter percutaneously dilated a tight, local- became necessary as lessons were learned with rapidly mounting
ized stenosis of the SFA in an 82-year-old woman, Laura Shaw, with clinical experience.
painful leg ischemia and gangrene who refused leg amputation. After Unknown to anyone in the Western world at the time, the Ukrain-
successful dilation of the stenosis with a guide wire and coaxial teflon ian surgeon Nicholas Volodos had performed endovascular repair of
catheters, the circulation returned to her leg. a traumatic-origin thoracic aortic aneurysm as early as 1986. Many
The role of infrainguinal angioplasty and stenting in the treat- years passed before knowledge of such a feat reached this side of the
ment of lower-extremity ischemia is more controversial than PTA then-prevailing East-West divide. But this and other developments
and stenting for aortoiliac occlusive disease. Because of the small in the US and elsewhere notwithstanding, it was Parodi’s initial clini-
size of the infrainguinal vessels above and below the knee, dissec- cal experience with endovascular treatment of AAA that became the
tions are more likely to be flow-limiting, spasm is more common, driving force and stimulus for the truly explosive growth in interest,
and relatively mild intimal hyperplasia or recoil of treated lesions creativity and investment that followed throughout the 1990s and
may lead to recurrence of clinical symptoms. Although percutane- beyond. Resisted by many surgeons initially, it was to become the
ous revascularization plays a less prominent role in the infrainguinal most potent agent of change for a specialty that was about to trans-
vasculature than in the aortoiliac system, it remains attractive as a form itself—dramatically and irreversibly.
easily migrate and not perforate the IVC or adjacent tissues. By 2011,
HISTORY OF IVC FILTERS
at least 16 different types of permanent/retrievable filters became
The first surgical interruption of the IVC was performed by Bottini in available.
1893. In 1959, external clipping of the IVC was first done by Moretz. Peripheral vascular intervention has grown from the basic con-
The first transvenous caval filter was developed in 1967. After intro- cept of serial dilatations with oversized catheters and plain balloon
duction of the first IVC filter (stainless steel Greenfield filter) in 1973, angioplasty to a stage where practically all the vascular diseases
several types of permanent and temporary filters have been devel- (obstructive, nonobstructive or hemorrhagic) are being treated by
oped. Historically, subsequent filter designs were made to improve various endovascular techniques. The interventional strategies have
upon their predecessors. Structurally, the filter should be durable, taken over the work of vascular surgeons in a major way and have
made of a biocompatible material that is noncorrosive and non- led to significant decrease in mortality and morbidity associated with
thrombogenic. Also, it should be easily deployable, but it should not treatment and a major reductions in amputation rate.
REFERENCES
1. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction. Circulation. 1964;30:654-70.
2. Rösch J, Keller FS, Kaufman JA. The birth, early years, and future of interventional radiology. J Vasc Interv Radiol. 2003;14(7):841-53.
3. Biographic sketch of Andreas Gruentzig. [online] Available from website http://www.ptca.org/archive/bios/gruentzig.html. [Accessed July 2012]
4. Serruys PW, Kutryk MJB, Ong ATL. Coronary-artery stents. N Engl J Med. 2006;354:483-95.
5. Palmaz JC, Sibbitt RR, Reuter SR, et al. “Expandable intraluminal graft: a preliminary study. Work in progress”. Radiology. 1985;156 (1):73-7.
6. Morice MC, Serruys PW, RAVEL study group, et al. Randomized study with the sirolimus-coated Bx velocity balloon-expandable stent in the
treatment of patients with de novo native coronary artery lesions. “A randomized comparison of a sirolimus-eluting stent with a standard stent for
coronary revascularization”. N Engl J Med. 2002;346(23):1773-80.
7. Kerber CW, Hornwell LD, Loeden OL. Catheter dilatation of proximal carotid stenosis during distal bifurcation endarterectomy. AJNR Am J Neu-
roradiol. 1980;1:348-9.
8. Theron J, Raymond J, Casasco A, et al. Percutaneous angioplasty of atherosclerotic and postsurgical stenosis of carotid arteries. AJNR Am J Neuro-
radiol. 1987; 8:495-500.
9. Kachel R. Results of balloon angioplasty in the carotid arteries. J Endovasc Surg. 1996;3:22-30.
10. Theron J, Courtheoux P, Alachkar F, et al. New triple coaxial catheter system for carotid angioplasty with cerebral protection. AJNR Am J Neurora-
diol. 1990;11:869-77.
11. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med. 2004;351(15):
1493-501.
12. Gray WA, Hopkins LN, ARCHeR Trial Collaborators, et al. Protected carotid stenting in high–surgical-risk patients: the ARCHeR results. J Vasc
Surg. 2006;44:258-69.
13. Gruntzig A, Kuhlmann U, Vetter W, et al. Treatment of renovascular hypertension with percutaneous transluminal dilatation of a renal artery
stenosis. Lancet.1978;1:801-2.
14. Baert AL, Wilms G, Amery A, et al. Percutaneous transluminal renal angioplasty: initial results and long-term follow-up in 202 patients. Cardiovasc
Intervent Radiol. 1990;13:22-8.
15. Beebe HG, Chesebro K, Merchant F, et al. Results of renal artery balloon angioplasty limit its indications. J Vasc Surg. 1988;8:300-6.
16. Volodos’ NL, Karpovich IP, Shekhanin VE, et al. A case of distant transfemoral endoprosthesis of the thoracic artery using a self-fixing synthetic
prosthesis in traumatic aneurysm. (Article in Russian) Grudn Khir. 1988;(6):84-6.
17. Dake MD, Miller DC, Semba CP, et al. Transluminal placement of endovascular stent-grafts for the treatment of descending thoracic aortic aneu-
rysms. N Engl J Med. 1994;331(26):1729-34.
Intracardiac Echocardiography:
77 Historical Perspective, Current
Applications and Future Directions
Katikireddy CK, Kort S
INTRODUCTION TYPES OF ICE CATHETERS AND

TRANSDUCERS2
Intracardiac echocardiography (ICE) is the invasive, noncoronary
intracardiac, echocardiographic imaging modality used predomi- 1. Boston Scientific Ultra ICE catheter is a 9 F, 110 cm catheter, with
nantly during percutaneous interventional and electrophysiologic a 9 MHz rotating, mechanical transducer. This catheter system
(EP) procedures to better delineate the complex, intracardiac structures provides 360°, radial, 2D imaging on a transverse plane with a
such as the interatrial septum (IAS), fossa ovalis (FO), pulmonary penetration depth of approximately 5 cm (Figs 77.1A and B).
veins (PVs), valves and atrial appendage. In addition to providing This limited field of view restricts the imaging to only the right
accurate, real time, spatial visualization of intracardiac structures, side of the heart, and hence is used predominantly during right-
ICE allows the assessment of the procedural outcomes such as the sided EP procedures. High frequency transducers used with
positioning of closure devices across patent foramen ovale (PFO) as this catheter system permit excellent, cross sectional, near-field
well as monitoring of procedural complications such as pericardial intravascular imaging which allow accurate diagnosis of coro-
effusion. Historically, fluoroscopy has been used to guide these pro- nary stenosis and stent deployment. The disadvantages of this
cedures; however, it is limited by the shortcoming of poor anatomi- catheter system include lack of Doppler capabilities, limited
cal visualization and radiation exposure risk. Limitations of transtho- depth, nonsteerability and usage for only a single time. Additional
racic echocardiography (TTE) for procedural guidance include the limitation is the requirement of a guide wire for the advancement
need for an additional operator, interference with the sterile field and placement of this catheter in the desired position within the
and variable image quality depending on acoustic windows. Simi- right heart.
larly, the disadvantages of transesophageal echocardiography (TEE) 2. A second catheter system developed is an advanced phased-
are the need for sedation, esophageal intubation and requirement array catheter.3 This catheter (AcuNav, Siemens, Mountain
of an additional echocardiographer to perform the procedure. ICE View, CA) is a steerable, 8 F (110 cm)–10 F (90 cm) catheter
overcomes these limitations with the advantages of improving pro- connected to a 64-element vector phased-array transducer
cedural efficacy, reducing procedural time, and monitoring for and (5.0–10.0 MHz) with penetration depth up to 16 cm. These
potentially preventing procedural complications. transducers have full Doppler capabilities (color, spectral
and tissue) and produce a 90° sector analogous to TTE and
HISTORY TEE (Figs 77.2 and 77.3). Achieving the deeper penetration
by using lower frequency transducers allows the visualization
Early on in the 1920s, a device consisting of a tube fitted with a glass of left-sided heart structures from the right heart. Four-way
or plastic window and illuminated by transmitted or incident light steerability of the catheter tip facilitates optimal imaging.
was used to assist performing surgical procedures such as mitral In addition, a locking control at the handle allows fixing the
commissurotomy.1 Later on, firberoptics were introduced to exam- catheter tip in a desired position. This system can be inter-
ine the heart from inside during cardiopulmonary bypass when the faced with a standard ultrasound platform during imaging.
chambers were empty. Catheter-based two-dimensional (2D), intra- A 11 F sheath is recommended for the introduction of 10 F
vascular, high frequency, ultrasound systems were first used in the (90 cm long) catheter either by femoral or internal jugular
1980s primarily for coronary imaging. Mechanical and rotational im- venous approach. The 8 F catheter (110 cm long) can be intro-
aging of a catheter tipped single piezoelectric crystal allowed imag- duced through a smaller 8 F sheath. The catheter is advanced
ing of only limited field of depth, due to the usage of higher frequency to the right side of the heart under fluoroscopy without a need
transducers (20–40 MHz). Introduction of low frequency catheter- for a guide wire.
based intracardiac ultrasound systems in the 1990s allowed better Comparison between the two types of ICE catheters is provided
penetration and visualization of intracardiac structures.2 in Table 77.1.
A B
Figures 77.1A and B: (A) Rotating, mechanic transducer catheter (arrow) with a radial sector image (star) of a shallow depth of penetration; (B)
360°, radial sector image with an excellent near field view. Abbreviations: RA, right atrium; RV, right ventricle; LA, left atrium; TA, tricuspid annulus;
AO, ascending aorta; PA, pulmonary artery. Source: Biosense Webster, Inc.
Figure 77.2: Phased-array transducer catheter (arrow), displaying 90° Figure 77.3: Home view of interatrial septum (arrow) as imaged
sector image with a deeper penetration. Abbreviations: RA, right atrium; using intracardiac echocardiography. Source: Biosense Webster, Inc.
RV, right ventricle; AO, ascending aorta. Source: Biosense Webster, Inc.
Chapter 77  Intracardiac Echocardiography: Historical Perspective, Current Applications... 645
TABLE 77.1 Comparison of ICE catheters

Features Phased-Array Catheter Radial/Mechanical
Size 8 F, 10 F 9F
Length 90 cm, 110 cm 110 cm
US frequencies 5.0–10.0 MHz 9 MHz
US modes 2D, spectral and color 2D
Doppler
Penetration 15 cm 8 cm
depth
Insertion 8 F or 11 F vascular Guide wire and 10 F long,
technique access guiding sheath extending to
right atrium
Advantages Full echo and Doppler Less expensive, excellent
capabilities, 4-way near-field visualization
steerability, adjustable
frequency and depth Figure 77.4: Tenting of IAS by needle (arrow) approaching from RA;
LA; IAS. Abbreviations: RA, right atrium; LA, left atrium; IAS, interatrial
Disadvantages Expensive, larger sheath 2D only, limited frequency septum. Source: Biosense Webster, inc.
size, one time use only range and depth, not
steerable, one time use only
Abbreviations: ICE, intracardiac echocardiography; US, ultrasound; 2D,
two-dimensional aging can be utilized for further guiding the remaining interventional
procedure.
ICE APPLICATIONS Electrophysiological Procedures

In the EP lab, ICE is used to guide TSP as described above, in order to
Transseptal Puncture
access the left side of the heart. In addition, ICE is useful to guide the
Transseptal puncture (TSP) is performed to access the left atrium ablation of cardiac arrhythmias that are anatomically based which
(LA) from the right atrium (RA). TSP is an integral part of ablation include crista terminalis and cavotricuspid isthmus based right atrial
of left-sided arrhythmias including pulmonary vein isolation for reentry arrhythmias, outflow tract based ventricular tachyarrhyth-
atrial fibrillation (AF) ablation, PFO/atrial septal defect (ASD) clo- mias and atrial fibrillation.6 ICE is the most commonly used non-
sure, percutaneous valvular procedures such as mitral valvuloplasty, fluoroscopic imaging modality which is used during the ablation of
and left atrial appendage (LAA) ligation. TSP performed exclusively AF targeting the PVs and the LA posterior wall.
under fluoroscopic guidance is known to be associated with a higher
incidence of complications. Numerous studies indicate that optimal Atrial Fibrillation Ablation
visualization of the IAS and the FO with the guidance of ICE, allow for
safer TSP.4,5 This is particularly true when the anatomy is distorted or Real-time imaging by ICE has been shown to define the anatomical
double TSP is required. location and size of the ostia of the PVs better than traditional meth-
For visualization of the IAS, initially the ICE probe is positioned ods of fluoroscopy or preprocedural CT/MRI. Following TSP, by ro-
in the mid RA facing the tricuspid valve (TV). Subsequently, by tating the ICE probe clockwise, one can visualize the PVs. In addition
advancing the probe cranially and rotating clockwise with a poste- to defining the anatomy, ICE is helpful in assessing the catheter’s po-
rior tilt, the IAS is visualized (Fig. 77.3). The ultrasound beam of ICE sition, stability, catheter tip-tissue contact and ablation lesions.7 ICE
should be perpendicular to the IAS for achieving the optimal echo is useful for monitoring for development of complications related to
signal. The size, location, thickness of FO and presence or absence of AF ablation, such as perforation of the aorta or LA posterior wall re-
PFO is assessed. Thickness of FO determines if a powered transseptal sulting in pericardial effusion/tamponade, thrombus formation and
needle should be used. The site of TSP is localized by ICE by visual- pulmonary vein stenosis.8 Incidence of stroke from thromboembo-
izing the tenting of the IAS, while applying pressure by the needle lism during AF ablation is about 1%. ICE has been shown to assist
(Fig. 77.4). Direct imaging of the IAS and surrounding anatomy by in preventing this complication by close monitoring for thrombus/
ICE reduces the risk of perforation of adjacent vital structures such as coagulum formation on catheters, sheaths and endocardial lesion
the aorta anteriorly and LA wall posteriorly. Following TSP, ICE im- surface, the presence of which should result in titration of the radi-
Figure 77.5: Color Doppler by intracardiac echocardiography shows Figure 77.6: Patent foramen ovale (PFO) visualization (arrow) by
laminar flow of the left upper pulmonary vein (arrow). Source: Biosense a bubble study. Abbreviations: RA, right atrium; LA, left atrium; IAS,
Webster, Inc. interatrial septum. Source: Biosense Webster, Inc.
ofrequency (RF) energy.9 In addition, the delivery of RF energy could

be titrated by monitoring for dense microbubble formation which
may be indicative of excessive tissue heating. Continuous monitor-
ing of pulmonary venous flow by ICE Doppler allows early detec-
tion of flow limitation and, therefore, prevention of pulmonary vein
stenosis (Fig. 77.5).10 In addition, imaging of the esophagus by ICE
may allow for prompt diagnosis of LA-esophageal fistula, another
rare but serious complication of AF ablation.
Percutaneous PFO/ASD Closure

During the last several years, ICE has been used routinely during per-
cutaneous PFO and ASD closure procedures.
From mid RA position, facing the TV, ICE catheter is advanced
cranially and with clockwise rotation, the ‘septal’ view is obtained. A
PFO or ASD can be precisely visualized using ICE by a bubble study
(Fig. 77.6) or color Doppler, but most importantly ICE is used to Figure 77.7: Direct measurement of the ASD size (arrow) by
define the anatomy of the septum. In the presence of an ASD, it is used intracardiac echocardiography, along the interatrial septum.
Abbreviation: ASD, atrial septal defect. Source: Biosense Webster, Inc.
to define the location of the defect, measure the size of it, and assess
the presence and size of the surrounding rim in order to determine
the suitability, type and size of the closure device. Using ICE, ASD
size is determined either by direct measurement of the defect similar During the closure procedure of PFO/ASD, ICE guidance is used
to TEE (Figs 77.7 and 77.8A) or by measuring the ‘stretched’ or ‘stop- in placing the guide wire across the septum from RA to LA and sub-
flow’ diameter using the sizing balloon (Fig. 77.9).11 In the presence sequently advancing the sheath over the guide wire (Fig. 77.8B).
of a PFO, ICE is used to define the location of the PFO and to meas- Spatial relationship of the guide wire, sheath and closure device
ure the height and length of the tunnel. ICE imaging is also useful for with surrounding structures can be examined in detail. Prior to the
excluding the presence of anatomical variants such as hypertrophic deployment of the closure device, ICE imaging with color Doppler
superior limbus, fenestrated IAS, sinus venousus ASD and anoma- can be used to confirm that the septum is well-seated between left
lous pulmonary venous return, which will assist the operator in plan- and right arms of the device (Fig. 77.8C). Following the deployment
ning of complex closure procedure or surgery. of the device, the presence of any residual shunt can be assessed by
bubble study and color flow imaging by ICE (Fig. 77.8D)12 allowing The ICE transducer should be positioned near the TV annulus to
for prompt attention and correction. obtain a short-axis view that displays the aortic valve and IAS similar
to the ‘short-axis’ view obtained by TEE, but with the RA seen in the
Percutaneous Valvular Procedures near field and the LA in the far field view. The pulmonic valve and the
pulmonary artery can be visualized with the ICE catheter in the right
Valvuloplasty ventricular outflow tract (RVOT) with the transducer facing up. The
mitral valve can be visualized by positioning the ICE catheter in the
Percutaneous valvuloplasty is a validated treatment option for RA or right ventricle (RV). Additional views of the mitral valve can be
patients with valvular stenosis. Rheumatic mitral stenosis, congeni- obtained by passing the catheter into the LA by TSP.
tal pulmonic stenosis and severe aortic stenosis in patients who are The ICE is useful to facilitate crossing the IAS and positioning
nonsurgical candidates are some of the valve pathologies that could the balloon apparatus in the proper place (Fig. 77.10A).13 Color and
potentially be treated by percutaneous valvuloplasty. In both animal spectral Doppler ICE are used to estimate the valvular gradients and
and human studies, ICE has been shown to be useful during these degree of insufficiency (Fig. 77.10B) before, during, and following
procedures. balloon inflations in order to assist in monitoring the progression
A B
C D
Figures 77.8A to D: Atrial septal defect (ASD) closure: (A) ASD by color Doppler; (B) Sheath (arrow) in the LA; (C) Confirmation of the interatrial
septum (IAS) positioning in between the two arms of closure device during the deployment; (D) Color Doppler to assess the residual shunt (arrow)
across the septum, following ASD closure; RA; LA; AV. Abbreviations: RA, right atrium; LA, left atrium; AV, aortic valve. Source: Biosense Webster, Inc.
Figure 77.9: Estimating ASD size (arrow) indirectly by measuring a

balloon-stretched diameter. Abbreviation: ASD, atrial septal defect.
Source: Biosense Webster, Inc.
and outcome of the procedure. In addition, procedure-related com-

plications such as pericardial effusion can be identified by ICE.
Transcatheter Valve Implantation

This implantation has been increasingly performed in pediatric pa-
tients with congenital heart defects.14 ICE imaging is an integral part
of the percutaneous pulmonic valve implantation to guide the place-
ment, as well as to assess the valve function (Fig. 77.11), the degree
of valvular insufficiency and transvalvular gradients (Figs 77.12A
and B) prior to and immediately following procedure. Similarly, B
percutaneous aortic valve implantation under ICE guidance is Figures 77.10A and B: (A) Inflation of the balloon (arrow) during
becoming an increasing option for nonsurgical candidates. balloon valvuloplasty. Mitral valve leaflets are indicated by the asterisks;
(B) Mild degree of mitral regurgitation (arrow) after balloon inflation
Percutaneous Mitral Valve Repair
Percutaneous mitral valve repair has been gaining popularity for obtained from the RA through the septum, from the coronary sinus
managing the functional mitral regurgitation in patients with heart (CS) and directly from the LA. Three-dimensional (3D) echo (3D TEE
failure. In addition, the percutaneous, nonsurgical approach for currently, 3D ICE in the future) may be a better imaging modality to
valve repair may be an attractive option for certain patients with or- guide this intervention by providing the ability to visualize the whole
ganic mitral regurgitation. Studies have shown that ICE imaging has circumference of the device in relationship to the appendage.
a great potential to provide a comprehensive guidance during the
procedure.15 Exclusion of an Intracardiac Thrombus
Percutaneous Left Atrial Appendage Occlusion The presence of LA/LAA intracardiac thrombus is a contraindication
for performing procedures such as ablation of AF and mitral valvu-
Percutaneous occlusion of the LAA has been shown to be beneficial loplasty. ICE imaging is commonly used for excluding the presence
in prevention of thromboembolism in a few trials.16 ICE is helpful of intracardiac thrombus during interventional, especially electro-
in positioning of the device to occlude the LAA and ensuring that physiological ablation procedures. ICE is useful for screening for
there is no residual flow around the device. ICE imaging views are intracardiac thrombus at the beginning of the procedure; and for
Figure 77.11: Two-dimensional (2D) and color Doppler images of

pulmonic valve (PV) (arrow), following PV deployment. Source: Dr
Ruchira Garg Miami Children’s Hospital
monitoring for the development of thrombus or coagulum during

ablation of arrhythmias, in particular during lengthy left-sided pro-
cedures, in order to prevent stroke.17 In a study that examined the
LA “mechanical stunning” by ICE during atrial flutter ablation, both
TEE and ICE have been shown to provide similar information regard-
ing the presence of thrombus/spontaneous echo contrast within the
LA and LAA, LAA emptying velocity, pulmonary venous and mitral
inflow velocities.
B
Coronary Sinus Cannulation
for Biventricular Pacing Figures 77.12A and B: Transpulmonic pressure gradient as assessed
by intracardiac echocardiography: (A) Prior to transcatheter pulmonic
Biventricular pacing for cardiac resynchronization therapy in heart valve implantation; (B) Following pulmonic valve implantation. Source:
failure patients requires CS cannulation by an LV pacing wire. At Dr Ruchira Garg Miami Children’s Hospital
times, this can be challenging, because of altered CS anatomy from
a dilated heart. Direct imaging of the CS and pacing catheter by ICE
may facilitate CS cannulation quicker and thus reduce the procedural
and fluoroscopy time as well as procedural-related complications.18 A list of potential applications for the use of ICE is provided in
Table 77.2.
Miscellaneous Applications
ICE IN THE PEDIATRIC POPULATION
The ICE has been reported to be used in other interventional pro-
cedures such as pacemaker laser lead extraction, percutaneous ven- The ICE imaging during device closure for PFO/ASD is superior to
tricular septal defect (VSD) closure19 and septal ablation for hyper- TEE in the pediatric population as the near field imaging by TEE is
trophic cardiomyopathy (HCM).20 ICE may have a role guiding a limited because of the proximity of the LA to the esophagus. Tran-
site specific diagnostic myocardial biopsy for diagnosing infiltrative scatheter pulmonic valve implantation for congenital heart defects
cardiomyopathies or cardiac tumors.21 In addition, ICE can provide can be performed effectively under ICE imaging guidance. Smaller
prompt identification of potential complications of such procedures, catheters utilizing smaller sheaths are available now, allowing usage
such as cardiac perforation and pericardial effusion. of ICE catheters in smaller pediatric patients.22,23
TABLE 77.2 Major applications of intracardiac echocardiography TABLE 77.3 Potential complications of intracardiac echocardiography
• Transseptal puncture and catheterization • Vascular bleeding and hematoma
• Balloon or blade atrial septostomy • Arteriovenous (AV) fistula or pseudoaneurysm formation
• Valvular: Percutaneous balloon valvuloplasty, percutaneous mitral • Retroperitoneal bleeding
valve repair, percutaneous pulmonic, aortic valve replacement • Cardiac perforation, pericardial effusion/tamponade
(stented valve prosthesis)
• Cardiac arrhythmias: Atrial, ventricular tachyarrhythmias
• Percutaneous PFO and ASD closure
• Heart block
• Electrophysiological procedures: Pulmonary vein isolation for
• Thromboembolism
atrial fibrillation ablation, ablation of RVOT/LVOT VT, left ventricle
epicardial/endocardial VT
• Deployment of percutaneous LAA occlusive device
• Biopsy of endomyocardium and cardiac tumors
• Alcohol septal ablation in HCM development; therefore, usage of ICE may be limited in small chil-
• Percutaneous VSD closure dren. Finally, current imaging using ICE provides only monoplane
imaging requiring considerable manipulation and movement of the
• As an alternative to TEE
catheter in order to obtain detailed views.
• Diagnostic imaging for the evaluation of aorta, prosthetic valves and
congenital heart disease
Abbreviations: PFO, patent foramen ovale; ASD, atrial septal defect; FUTURE DIRECTIONS
RVOT, right ventricular outflow tract; LVOT, left ventricular outflow
Rapidly growing, innovative and superior technology would allow
tract; VT, ventricular tachycardia; LAA, left atrial appendage; HCM,
further refinement of ICE catheters’ configuration, maneuverability
hypertrophic cardiomyopathy; VSD, ventricular septal defect; TEE,
transesophageal echocardiography with added capabilities such as biplane and 3D imaging. Integrating
ICE technology with tissue Doppler imaging and velocity vector im-
aging has been under investigation. Acoustic radiation force imaging
in combination with ICE, for quantifying lesion progression during
ACCURACY OF ICE RF ablation is an ongoing research work. Merging the ICE catheter
with the EP mapping catheter and RF ablation catheter is another
In a study evaluating the accuracy of ICE imaging,24 by comparing endeavor taking place. Multiplane, 3D imaging and reconstruction to
them with cardiac MRI images and postmortem sections, good cor- achieve better spatial orientation and visualization have been under
relation was demonstrated. development. Integrating the cardiac images, obtained from various
technologies (CT, MRI, ICE), may provide complementary informa-
COMPLICATIONS OF ICE tion. Preliminary studies have shown that integrating real-time 3D
ICE imaging with preprocedural 3D CT or MRI imaging of the heart
In early trials addressing safety and feasibility of ICE,3 no major, but is feasible.25
only minor vascular complications were reported. Serious compli-
cations are rare but could potentially include pulmonary embolism, CONCLUSION
pericardial tamponade, and vascular complications from puncture
site such as bleeding. Intracardiac echocardiography with a phased-array catheter has
A list of potential complications is provided in Table 77.3. been increasingly used to guide numerous procedures including
TSP, EP ablation procedures, PFO/ASD closure and valvuloplasty.
LIMITATIONS OF ICE Monitoring for the development of cardiac complications such as
thrombus formation or tamponade during the arrhythmia abla-
The ICE catheter is approved in the United States for single use only, tion procedures is another great use of ICE. ICE provides real-time
adding additional cost to the procedure. However, usage of ICE may anatomical and physiological information during these procedures.
curb the expenses from not requiring an additional operator and It has been shown to reduce procedural and fluoroscopy time, and
avoiding likely general anesthesia as may be used in TEE, as well as improve patient outcomes. Advancement in ICE technology and in-
reducing procedural time and procedural complications. Because of corporating it with other imaging and interventional modalities has
these reasons, expenses were shown to be similar for both ICE and been under investigation and will further broaden the potential use
TEE.22 At present, catheters and sheaths of smaller size are still under of this technology.
REFERENCES
1. Cutler EC, Levine SA, Beck CS. The surgical treatment of mitral stenosis: experimental and clinical studies. Arch Surg. 1924;9:689-821.
2. Kort S. Intracardiac echocardiography: evolution, recent advances, and current applications. J Am Soc Echocardiogr. 2006;19(9):1192-201.
3. Packer DL, Stevens CL, Curley MG, et al. Intracardiac phased-array imaging: methods and initial clinical experience with high resolution, under
blood visualization: initial experience with intracardiac phased-array ultrasound. J Am Coll Cardiol. 2002;39:509-16.
4. Hung JS, Fu M, Yeh KH, et al. Usefulness of intracardiac echocardiography in transseptal puncture during percutaneous transvenous mitral com-
missurotomy. Am J Cardiol. 1993;72:853-4.
5. Epstein LM, Smith T, TenHoff H. Nonfluoroscopic transseptal catheterization: safety and efficacy of intracardiac echocardiographic guidance. J
Cardiovasc Electrophysiol. 1998;9:625-30.
6. Chu E, Kalman JM, Kwasman MA, et al. Intracardiac echocardiography during radiofrequency catheter ablation of cardiac arrhythmias in hu-
mans. J Am Coll Cardiol. 1994;24:1351-7.
7. Martin RE, Ellenbogen KA, Lau YR, et al. Phased-array intracardiac echocardiography during pulmonary vein isolation and linear ablation for
atrial fibrillation. J Cardiovasc Electrophysiol. 2002;3:873-9.
8. Marrouche NF, Martin DO, Wazni O, et al. Phased-array intracardiac echocardiography monitoring during pulmonary vein isolation in patients
with atrial fibrillation: impact on outcome and complications. Circulation. 2003;107:2710-6.
9. Kalman JM, Fitzpatrick AP, Olgin JE, et al. Biophysical characteristics of radiofrequency lesion formation in vivo: dynamics of catheter tip-tissue
contact evaluated by intracardiac echocardiography. Am Heart J. 1997;333:8-18.
10. Ren JF, Marchlinski FE, Callans DJ, et al. Intracardiac Doppler echocardiographic quantification of pulmonary vein flow velocity: an effective
technique for monitoring pulmonary vein ostia narrowing during focal atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2002;13:1076-81.
11. Jan SL, Hwang B, Lee PC, et al. Intracardiac ultrasound assessment of atrial septal defect; comparison with transthoracic echocardiographic,
angiocardiographic, and balloon-sizing measurements. Cardiovasc Intervent Radiol. 2001;24:84-9.
12. Hijazi Z, Wang Z, Cao Q, et al. Transcatheter closure of atrial septal defects and patent foramen ovale under intracardiac echocardiographic guid-
ance: feasibility and comparison with transesophageal echocardiography. Catheter Cardiovasc Interv. 2001;52:194-9.
13. Salem MI, Makaryus AN, Kort S, et al. Intracardiac echocardiography using the AcuNav ultrasound catheter during percutaneous balloon mitral
valvuloplasty. J Am Soc Echocardiogr. 2002;15:1533-7.
14. Zahn EM, Hellenbrand WE, Lock JE, et al. Implantation of the melody transcatheter pulmonary valve in patients with a dysfunctional right ven-
tricular outflow tract conduit early results from the US Clinical trial. J Am Coll Cardiol. 2009;54:1722-9.
15. Naqvi TZ, Zarbatany D, Molloy MD, et al. Intracardiac echocardiography for percutaneous mitral valve repair in a swine model. J Am Soc Echocar-
diogr. 2006;19:147-53.
16. Sick PB, Schuler G, Hauptmann KE, et al. Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in
atrial fibrillation. J Am Coll Cardiol. 2007;49:1490-5.
17. Keane D, Mansour M, Singh J. Detection by intracardiac echocardiography of early formation of left atrial thrombus during pulmonary vein isola-
tion. Europace. 2004;6:109-10.
18. Shalaby AA. Utilization of intracardiac echocardiography to access the coronary sinus for left ventricular lead placement. Pacing Clin Electro-
physiol. 2005;28:493-7.
19. Cao QL, Zabal C, Koenig P, et al. Initial clinical experience with intracardiac echocardiography in guiding transcatheter closure of perimembra-
nous ventricular septal defects: feasibility and comparison with transesophageal echocardiography. Catheter Cardiovasc Interv. 2005;66:258-67.
20. Pedone C, Vijayakumar M, Ligthart JM, et al. Intracardiac echocardiography guidance during percutaneous transluminal septal myocardial abla-
tion in patients with obstructive hypertrophic cardiomyopathy. Int J Cardiovasc Intervent. 2005;7:134-7.
21. Oishi Y, Okamonto M, Sueda T, et al. Cardiac tumor biopsy under the guidance of intracardiac echocardiography. Jpn Circ J. 2000;64:638-40.
22. Alboliras ET, Hijazi ZM. Comparison of costs of intracardiac echocardiography and transesophageal echocardiography in monitoring percutane-
ous device closure of atrial septal defect in children and adults. Am J Cardiol. 2004;94:690-2.
23. Luxenberg DM, Silvestry FE, Herrmann HC, et al. Use of a new 8 French intracardiac echocardiographic catheter to guide device closure of atrial
septal defects and patent foramen ovale in small children and adults: initial clinical experience. J Invasive Cardiol. 2005;17:540-5.
24. Zanchetta M, Rigatelli G, Pedon L, et al. Intracardiac echocardiography: gross anatomy and magnetic resonance correlations and validations. Int
J Cardiovasc Imaging. 2005;21:391-401.
25. Daccarett M, Segerson NM, Günther J, et al. Blinded correlation study of three-dimensional electro-anatomical image integration and phased
array intra-cardiac echocardiography for left atrial mapping. Europace. 2007;9:923-6.
SECTION
Cardiac Surgery
4
78. History and Advances in Cardiac Surgery
79. History of Valvular Heart Surgery
80. History of Surgery for Ischemic Heart Disease
81. History of Robotically Assisted Cardiac Surgery
82. History of Aortic Surgery
83. History of Heart Transplantation and its Future
84. The History of Congenital Heart Surgery
78 History and Advances
in Cardiac Surgery
Trehan N, Malhotra R, Dhir U
INTRODUCTION et al.16-18 was real technological advancement, which improved tis-

sue perfusion, reduced hemolysis and inadvertent donor blood ex-
Christian Billroth spoke “any surgeon who wishes to preserve the posure. Advances in pump design from roller pumps to centrifugal
respect of his colleagues would never attempt to suture the heart” pumps have caused them to be used in wide range of flows with less
at a meeting in Vienna medical society in 1880. “Surgery of heart spallation and low hemolysis and with no major difference in neuro-
has probably reached the limits set by nature to all surgery: no new logic or inflammatory outcome. Diagonal pumps have the capability
method and no new discovery can overcome the natural difficulties of generating pulsatile flow with a small size and simple design.19,20
that attend a wound of heart” the following statement was published From this cardiac surgery has progressed in respect to operating
in 1897 edition of Paget’s Surgery of the Chest.1 for complex coronary artery disease to complex congenital and valvu-
With this atmosphere and preoccupations with “off limits” set, lar cardiac surgery. Initially started with sternotomy and progressed
Ludwig Rehn of Franfurt2 operated on 22-year-old man with 1.5 cm from port access to robotic surgery now. With the advancement of
wound of right ventricle and repaired with three interrupted sutures, technology, surgeons have progressed to use transmyocardial laser
leading to initial step in cardiac surgery. Since then there was no revascularization with stem cell therapy for diffuse and nonrevascu-
looking back, no doubt the path to present status was not smooth, larizable coronary artery disease to produce angiogenesis and myo-
and it cannot be summarized in words. From discovery of heparin by genesis. Tissue engineering is progressing to make valves from native
McLean3 in laboratory of Howell to the concept of hypothermia by tissue with longer durability and less tissue reaction. Surgeons are
Bigelow4 which paved the way for open heart surgery. venturing the concept of percutaneously insertion of valves through
However, failure of the concept was uniform when applied to transfemoral and transapical routes. Fetal cardiac surgery is in in-
complex operations hence the need for better methods. Le Gallois fancy stage but showing promising results for near future.
concept in Experiments on the Principle of Life and the fact that all
mammals sustain their offspring through placenta, were the initial CORONARY ARTERY DISEASE
seeds for birth of cardiopulmonary bypass (CPB) circuit. Initial dis-
heartening results were faced by John Gibbon due to massive flow Historical Perspective
and air embolism5 perpetuated “azygos flow principle” of Lillehei
and Andreasen, which was not a low flow, but the physiologic flow.6,7 William Heberden21 published his description of angina pectoris in
World viewed the tale of two cities, Minneapolis and St. Paul, 1772 in literary magazine. The range of symptoms and cardiac events
they were the birth place of extracorporeal circulation and open attributable to coronary artery disease were defined by James Her-
heart surgery. Lillehei8 with armamentarium of “controlled cross cir- rick of Chicago22 in 1912. After establishing the relationship of cor-
culation” and bubble oxygenator of De Wall, mastered cardiac sur- onary artery disease and angina, next step was treatment. Thomas
gery at Minnesota while Kirklin9 at Mayo clinic with Mayo-Gibbon Louder Brunton23 was the first physician to achieve effective relief of
apparatus, which was expensive and impressive state of handicraft, angina by amyl nitrate.
were severing the Gordian knot and making cardiac surgery feasible. Initial surgical attempts for relief of angina were thoracocervi-
Bubble oxygenators were cheap, efficient and simple, but with cal sympathectomy proposed by Charles Emile Francois-Frank24
the problem of debubbling and defoaming. Rotating disk oxygena- and performed by Charles Mayo in 1913. Levine et al.25 performed
tor by Earl Kay and Frederick Cross10,11 and membrane o xygenators total thyroidectomy with objective to relieve from angina. Earlier
described by Kolff et al.12 were considered alternatives to bubble attempts to increase myocardial blood flow by Claude Beck,
oxygenators. Membrane oxygenators were considered more hema- professor of neurosurgery at the Western Reserve School of Medi-
tologically tolerant as compared to bubble oxygenators.13-15 The in- cine, Cleveland by performing, Beck I26 procedure which included
tegrated hard shell technique has been the basis for further refine- abrasion of pericardium and grafting pericardium or mediastinal fat
ment of both the oxygenators. The concept of hemodilution by Zuhdi around heart or Beck II procedure which included brachial artery
656 Section 4  Cardiac Surgery
interposition between aorta and coronary sinus to retroperfuse the has been introduced which consists of three small independent
heart and increase collateral circulation. From cardio-omentopex- suctions cups with vacuum tubes and elastic strings and no articu-
ies of O’Shaughnessy,27 to institution of talc within pericardium to lating arm, thus minimizing possibility of myocardial disruption and
ligation of internal mammary artery (IMA) to increase collateral accidental detachment.
blood flow, all met with limited success.
Arthur Vineberg28 at McGill University, cut the IMA and im-
planted its bleeding end into myocardium close to left anterior de- Intracoronary Shunts and Coronary Occlusion
scending (LAD) coronary artery. He reported 140 operations, of 109 We need a bloodless field for adequate coronary anastomosis.
surviving 91 had either no angina or slight pain. Progressing with this Shunts are used in off-pump CABG with major advantages of myo-
concept came the “snake-heart operation” based on reptilian heart cardial protection and its hemostatic effect. A safe occlusion would
by Sen et al.,29 which was a concept of transmyocardial acupuncture be a spring-equipped force adjustable tourniquet that would be less
to perfuse the ischemic heart. Major advance came with direct coro- invasive to endothelium and providing the benefit of dry field.
nary angiography developed by Sones.30
Longmire31 at University of California in Los Angeles reported Total Arterial Revascularization
direct-vision coronary endarterectomy in patients. Kolessov anasto-
mozed IMA to LAD artery in Leningrad in 1964.32 Favaloro and Ef- The evidence of LIMA to LAD coronary artery graft patency up to 21
fler33 at Cleveland clinic began performing reversed saphenous vein years and long-term survival benefit has made it a Gold standard.42,43
bypass grafting and performed 741 such operations between May However, the recurrence of angina, due to progression of disease in
1967 and January 1971. In Milwaukee in 1971, Flemma, Johnson and native coronary artery and venous graft, led to find alternative con-
Lepley34 described the technique and advantages of sequential graft- duits. Surgeons ventured to extrapolate the results with other arte-
ing. Thus laid the foundation and rapid spread of coronary artery by- rial conduits, as right internal mammary artery (RIMA), radial artery,
pass grafting (CABG). right gastroepiploic and inferior gastric artery.
Several authors have shown superior patency of right IMA and
Evolution from On-Pump to Off-Pump and radial artery bypass grafts44,45 over venous grafts. Trehan et al.46 have
shown radial artery patency of 92.4% at mean interval of 18 months
Minimally Invasive Coronary Surgery
as compared to venous graft patency of 76.2%, proven angiographi-
There is seldom logic in sequence of surgical development. The only cally. Lytle and coworkers47 and Rankin et al.48 have in their large ret-
requirement for coronary bypass is bloodless field. Ankeney (1972)35 rospective series shown survival benefit of using two IMA grafts over
described 143 patients in whom CPB was not used. Buffolo36 from single graft. Guru et al.49 have shown that multiple arterial grafts is
Sao Paulo, Brazil reported bypass by simple interruption of coro- associated with better survival and less morbidity. Zacharias et al.50
nary flow (1985), same year Benetti37 from Buenos Aires described have shown all arterial revascularization is associated with better 12-
700 off-pump coronary surgeries. Benetti, Calafiore, Subramanian38 year survival compared to the standard single IMA with saphenous
achieved direct anastomosis between LAD and left internal mam- vein bypass operation.
mary artery (LIMA) through 10 cm incision in 4th left intercostals Today we use other arterial conduits in many strategic opera-
space. Fonger39 demonstrated feasibility of subxiphoid approach for tions, but we should be aware that they should be handled and dealt
anastomosis of gastroepiploic artery to posterior descending artery differently from venous grafts. There are certain basic principles of
(PDA). use of arterial conduits. The first is to give patient as many blood
source as possible. In cases of mild coronary stenosis, arterial graft
Stabilizers and Positioners in Off-Pump CABG adapt immediately to native coronary flow, this causes reduction
in size of arterial conduit (string sign) to total occlusion, avoid us-
Invention of stabilizers in late 1990 significantly improved anas- ing arterial conduits in such circumstances. The media of the arteries
tomotic quality on beating heart. Borst et al.40 introduced the con- makes them prone to spasm and thus proper handling of conduits is
cept of suction stabilizer. Recent suction stabilizer such as Octopus of utmost importance.
(Medtronic Inc., Minneapolis, MN) and Acrobat (Guidant Corp.,
Santa Clara, CA, USA) are in vogue. Most challenging step in bypass Minimal Invasive and Robotic CABG
surgery is positioning of the heart for easy access to all vessels. The
heart can be elevated and rotated by pulling on Lima sutures placed Calafiore’s left anterior small thoracotomy (LAST) operation51 was
on posterior pericardium named after Ricardo Lima from Brazil.41 a step in both off-pump and minimal invasive coronary surgery.
Apical suction devices such as StarfishTM (Medtronic Inc.) and For long minimally invasive direct coronary artery bypass (MID-
XposeTM (Guidant Corp.) cause less hemodynamic changes due to CAB) remained in spotlight, undue retraction is needed in harvest-
vertical displacement of heart. More recently multisuction heart po- ing IMA. This led to the development of closed chest thoracoscopic
sitioner TENTACLESTM (Sumitomo Bakelite Co., Ltd., Tokyo, Japan), IMA harvesting, but still the distal anastomosis was done through
Chapter 78  History and Advances in Cardiac Surgery 657
minithoracotomy. Angelini52 suggested a hybrid approach with IMA constructing a vascular anastomosis in early 1900s. Despite advance
grafting surgically and the remaining vessels to be revascularized ment in technology and engineering the ideal anastomotic device
percutaneously. which provides: minimal graft manipulation, no material in vessel
Computer-assisted or robotic cardiac surgery helped surgeon lumen, optimal anastomotic angle and compliance and above all
with limited hand motion in small spaces. Six degree of freedom are easy to handle with evidence of long-term effectiveness is still to
required to allow any free space orientation, standard endoscopes come. But few devices nearing the ideal sutureless anastomotic
have only four degree of freedom. There are two types of computer- device in clinical use are enumerated in Table 78.1.
enhanced surgical system in use: the automated endoscopic system Heartstring Proximal Seal System (Guidant Corp., Santa Clara,
for optimal positioning (AESOP) guides endoscopes through voice CA) and Enclose II (Novare Surgical Systems, Inc., Cupertino, CA);
activated control, the second is surgical telemanipulators, to fa- these devices allow surgeon to perform a clampless proximal anasto-
cilitate remote fine movements through “micro-wrist” instruments mosis with either vein or arterial graft. With the Enclose II one is able
mounted on robotic arm, which allows full seven degree of freedom to perform more than one proximal anastomosis through a single in-
with tremor filtering and enhanced dexterity. The da Vinci system sertion port.
(Intuitive Surgical, Inc., Mountain view, CA), comprising of surgeon
console, instrument cart and a vision platform, is most commonly Valve Surgery
used telemanipulation system.
Terms used in minimally invasive coronary operations: Preliminary note on the “possibility of treating mitral stenosis by sur-
• MIDCAB—IMA harvesting and LAD anastomosis performed gical methods”, “by sense of touch”—Sir Lauder Brunton in the Lan-
through small anterior thoracotomy incision under direct vision. cet,55 drew attention to the hopelessness of medical treatment for
• Endoscopic-assisted coronary artery bypass (Endo-ACAB)— mitral stenosis. This idea leads Cutler56 to dilate mitral valve through
IMA harvesting through an endoscope and distal anastomosis valvulotome from left ventricular apex and Souttar57 to finger dilation
through a minithoracotomy. of mitral valve through left atrial appendage. This appears to be birth
• Multivessel small thoracotomy (MVST) CABG: Single or Bilateral of mitral valve surgery. It was the particularly difficult problem of
IMA through robot and distal anastomosis through small mi- aortic regurgitation which led to the development of artificial valve.
nithoracotomy using composite IMA radial Y-grafts. Harken et al. in Bostan and Starr and Edward in Oregon used ball and
• Totally endoscopic coronary artery bypass (TECAB): IMA har- cage mechanical prosthesis in the aortic and mitral position. Hark-
vesting and distal anastomosis performed using robotic system en’s58 “ten commandments” could not be fulfilled by any valve led
with the help of endoscopic heart positioner (Medtronic Corp., to the evolution of the valve from ball cage to tilting disk to bileaflet
Minneopolis, MN), which is a suction device stabilizing the heart valve and bioprosthetic valve, homografts and autografts. Duran and
with limited hemodynamic compromise. Trehan et al.53 have Carpentier, proposed the basic principles of repair in classic paper
shown feasibility of robotic technology for complete endoscopic “The French Correction” presented in front of American Association
anastomosis with good results. for Thoracic Surgery in 198359 to combat the need for replacement.
Bioprosthetic valves are either stented or stentless devices. The
Sutureless Proximal and Distal material of cusps ranges from xenograft valve, pericardium, fascia
lata and dura mater. Second generation stent mounted bioprosthesis
Anastomotic Devices in CABG
(Hancock II, Carpentiar Edwards pericardium valve) have improved
Any vascular reconstruction without the use of hand sewing or hand effective orifice area (EOA) compared to first generation and third
tying knots is considered mechanical or sutureless anastomosis. generation stentless (Medtronic Freestyle, St. Jude Toronto SPV)
Payr54 first expressed the concept of wall eversion and pins for have even better EOA. There is difference in their decalcification
TABLE 78.1 Major characteristic of sutureless anastomotic devices for coronary artery bypass now available for clinical use
Connector and Type Material Anastomotic Device Graft Device Native Graft Manipulation Foreign Arteriotomy
of Anastomosis Site Connection Vessel Connection Material in
Lumen
Q-CAB side to end Nitinol Proximal Seven pins Squeezing Transfer sheath Yes Cutter
Core link Nitinol Proximal Five pins and Five pins Eversion device No Cutter
(side to end) wall eversion
Graft connector Nitinol and PTFE Distal Wall eversion Radial force of IMA’s eversion Yes Standard
(side to end) covered stent scissors
SJM distal connector Stainless steel Distal Pins Pins Cul-de-sac Yes Cutter
(side to side)
TABLE 78.2 Factors in consideration for choice of prosthetic heart assisted mitral valve repair through right minithoractomy. Chit-
valve (PHV) wood73 in 1997 described first mitral valve replacement using video-
• Age of patient scopic vision. Mohr74 from Leipzig described his series of 51 patients
• Comorbid conditions: cardiac and noncardiac of mitral valve using port access technology and videoscopy. “Solo
mitral surgery” term proposed by Mohr to the endoscopic mitral
• Expected life span of patient
surgery using AESOP technology and thus bringing robotic era for
• Probability of adherence and compliance of anticoagulation therapy mitral surgery. Trehan et al.75 have shown robotically controlled mitral
• Patient’s wishes and expectations valve surgery as safe and advantageous over conventional surgery.
• Other circumstances
Aortic Valve Replacement through

Smaller Incisions
treatment and preservation and more durability has been achieved
with newer generation valves. A variety of incisions smaller than standard median sternotomy have
The choice of the valve is largely dependent on the age of patient, been introduced, but limited partial sternotomy has evolved as the
choice of patient pertaining to his choice of avoiding risk of antico- most popular incision. Parasternal and transverse incision were
agulation with bioprosthetic valve and abetting risk of reoperation tried, but abandoned for the reason of limited exposure, injury to
due to absence of structural valve deterioration with mechanical IMA and lung herniation.76,77 It is always desirable to make incision
prosthesis (Table 78.2). over the location of cardiac valves and the length and habitus of the
With more and more valve replacement, came the “annuloven- patient guides the decision for dividing the sternum in second or
tricular” concept by Wiggers and Katz60 later proposed by Rushmer third intercostals space.
et al.61,62 Chordal disruption impairs torsional deformation thereby Several reports show lesser surgical morbidity with smaller
causing abnormal diastolic function and disruption of normal LV incision. There is an added cosmetic benefit with difference in
stress—strain pattern postvalvular replacement. Transaction of intensity of postoperative pain, length of stay and cost as compared
chordate to anterior mitral leaflet (AML) reduces function to a great- to conventional sternotomy incision.78 Byrne79 reported the use of
er degree as compared to posterior mitral leaflet (PML). This aware- partial upper hemisternotomy for redo cases and found it effective
ness has made chordal preservation during mitral valve replacement in terms of reduced bleeding and reduced operating time. With this
as a standard procedure now. Though the credit for conceptualiz- wisdom, the approach to the diverse population of patients should
ing it goes to Lillehei,63 further propogated by David64 and various be tailored on the basis of age of patient and other comorbid factors,
techniques from Miki65 to Khonsari66 and Rose and Oz67 procedures, which will ultimately affect the outcome.
surgeons have various options to preserve the subvalvular apparatus.
Study by Chowdhary et al.68 and Hetzer69 clearly shows reduction in Aortic Valve Repair (Table 78.3)
operative mortality, improvement in early and late ventricular func-
tion, improvement in long-term survival and elimination of risk of Aortic valve which opens and closes over 3 billion times during a
ventricular rupture. Not only does chordal preservation has impact normal life span. With the consensus regarding the terminology of
on LV function it shows significant improvement in right ventricular different parts of aortic root and valve, a strategy to classify aortic
(RV) function also.70 valve repair was needed. In aortic valve stenosis, valve replacement
is the surgical strategy of choice in most cases. Aortic valve recon-
Minimally Invasive Mitral Valve Surgery struction needs to be considered in cases of valve regurgitation and
its indications have been reviewed in American Heart Association
Traditionally, cardiac surgery is performed through median ster- (AHA) guidelines.
notomy. However, during the past decade with the culture of mini- Aortic valve preserving technique of remodeling and reimplan-
mal invasiveness in several surgical subspeciality, cardiac science tation can be distinguished, remodeling technique by Yacoub et al.80
was not left untouched. Endovascular port access technology first and reimplantation technique by David et al.81 Many surgeons prefer
allowed less invasive surgical approach for mitral valve. Advance reimplantation technique in patients of acute type A dissection with
in closed chest CPB and myocardial protection, with improved in- involvement of whole aortic root, Marfan syndrome or other tissue
strumentation and intracardiac visualization, robotic technology is disorders. The remodeling technique preserves annular distensibil-
being increasingly used for mitral surgery. ity and preserves aortic root physiology, but the dynamics and stabi-
Right thoracotomy was employed by Lillehei and colleagues in lization of annulus are achieved by reimplantation technique hence
their first open operation for mitral valve disease. Minimal access modification to these procedures were inevitable to combine ben-
incisions provided adequate direct vision mitral valve exposure and efits of both procedures.
surgeons showed comparable results to conventional surgery.71 These modification ranged from creation of “pseudosinuses”
With gaining experience, Carpentier72 in 1996 performed first video- by using oversized graft to a pre-shaped vascular graft with a
TABLE 78.3 Classification of aortic valve regurgitation with surgical than 21 mm/m2, there is dilatation of right chambers and inferior
repair technique vena cava and there is right ventricular overload.
Classification Presentation Surgical Technique The choice of repair exceeds replacement at this valve. Replace-
I Cusps ment should be done only if competence of valve cannot be achieved
macroscopically and in case of drug users and with endocarditis where the valve is
normal, no restriction completely destroyed. A meta-analysis and UK Heart Valve Registry
in cusps movement, Study showed no difference for biological or mechanical prosthesis,
central regurgitation rather bioprosthetic valve replacement has favorable durability in
Ia Dilation of Supracommissural replacement tricuspid position.
sinotubular function of ascending aorta
Ib Aortic root dilation Remodeling and reimplantation Ischemic Mitral Regurgitation
technique
Ic Dilation of surgical Annuloplasty, subcommissural Ischemic mitral regurgitation (IMR) is becoming a focus of increas-
annulus stitch; reimplantation technique ing amount of cardiovascular research, as patients with IMR have
higher cardiovascular mortality and heart failure. There are no such
II Isolated perforation/ Repair using pericardial patch
fenestration of cusp set guidelines for surgical intervention but a consensus is to tackle
moderate to severe mitral regurgitation at the time of coronary artery
III Prolapse of one or Plication of the free margin
bypass, STS database suggests concomitant mitral valve surgery in-
more cusps, eccentric of cusp in zone of nodules of
regurgitation jet Arantius, partial excision of creases preoperative risk twofold.89
cusps tissue in central zone with Whether mitral valve be replaced or repaired is of concern to
closure of defect, resuspension the treating surgeon with no fixed guidelines, but still replacement
of free margin of prolapsing cusp should be considered with acute IMR, patients with chronic IMR
IV Cusp extension or Cusp retraction with restricted and multiple comorbidities, complex regurgitation jets or severe
replacement of a cusp movement and potential tethering of both mitral valve leaflets.90-92 Calafiore et al.91 recom-
whole cusp using stenotic component pericardial mends replacement when the distance between coaptation point
tissue of leaflet and plane of mitral annulus exceeds 10 millimeters.
Trehan et al.93 considers coaptation depth as deciding parameter
for repair. Initial suboptimal results of replacement, and results
pseudosinus created by De Paulis et al.82 Another valved conduit of Gillinov et al.92and Grossi et al.94 showing lower perioperative
with three sinuses to compensate for single sinus of previous conduit mortality with mitral valve repair led the fraternity to opt for repair
was introduced by Thubrikar et al.83 Further improvement in surgical as primary goal.
technique and graft design may lead to better long-term outcome. Bolling and colleagues95 popularized the concept of under-
sized mitral annuloplasty. The type of ring, whether rigid or flex-
Tricuspid Valve Disease ible, complete verses incomplete still remains unsettled. A new
remodeling annuloplasty ring, the Carpentier-McCarthy-Adams
Tricuspid valve disease, the most common entity is tricuspid regurgi- IMR ETlogix ring by Edwards Lifesciences, which combines the
tation which affects 8–35% of patient with acquired rheumatic mitral principle of undersizing with specific asymmetric deformation
valve disease. In 70–86% of these it is labeled as “functional” and rest observed in IMR has come out to be a good future prospective in
as “organic” due to direct involvement with rheumatic process84,85 repair of mitral valve.
and its hallmark is commissural fusion. The initial results of downsized mitral annuloplasty were en-
Deloche et al.86 conceptualized dilation of tricuspid annulus couraging, but Cleveland Clinic experience of 585 patients spanning
is affected in irregular manner with least dilatation at anteroseptal 17 years showed moderate or more mitral regurgitation in 28% of
commissure and septal leaflet. Based on these finding, De Vega87 de- patient within 6 months postoperatively.96 This relatively high recur-
veloped the procedure of plicating the annulus with double continu- rence led investigators to look for alternative surgical therapies. The
ous suture. The suture may pull out of tissues and “guitar string” syn- alternative surgical procedures were IInd order chordal cutting by
drome occurs, to overcome this came the Anutunes and Girdwood Messas and coworkers,97 infarct plication, papillary muscle imbrica-
modification with interposition of Teflon pledgets in each bite.88 tions, papillary muscle sling, surgical relocation of posterior papil-
The routine use of annuloplasty ring, whether rigid or semi-rigid, as lary muscle and posterior mitral valve restoration. Alfieri edge-to-
Carpentier ring or flexible as Duran ring is considered superior and edge repair creating a double orifice mitral valve was a new idea. But
recommended by many groups. Authors recommend surgeons to be Bhudia98 in his study of 143 patients with ischemic cardiomyopathy
more liberal in indication for annuloplasty, it should be performed showed 30% of patients having moderate to severe MR, 1 year post-
if TR is more than mild, valve is rheumatic, size of annulus is greater operatively after Alfieri repair. There is no definite solution and every
patient of IMR needs customized approach. This lacuna also leads us • Edwards Viking device:104 This consists of proximal and distal
to investigate and search for newer therapies. self expanding stent connected by strut. The strut consists of
spring in partially open position with a absorbable suture. Over
period of weeks the suture dissolves causing compression of
Newer Therapies spring and ultimately leading to reduction of mitral regurgita-
• Percutaneous, Alfieri repair—a double armed clip device diploid tion. This approach achieves a 25% reduction in mitral septal to
through femoral vessels. lateral dimensions.
• Percutaneous annuloplasty—through coronary sinus. • The Coapsys device105 (Myocor Inc., Maple Grove, MN): This de-
• Septolateral annular cinching—a single anchoring suture vice consisting of anterior and posterior pads on epicardial sur-
through midseptal annulus exteriorizing through posterolater- face. Trehan et al.106 have shown Coapsys system to be effective
al annulus. Tightening of the suture under echocardiographic in reduction of functional mitral regurgitation and improvement
guidance to correct regurgitation. in NYHA class.
• Myocar Coapsys—the device consisting of two epicardial pads In the edge-to-edge technique of repair most clinical experience
and expanded polytetrafluoroethylene (PTFE)-coated subvalvular is with Evalve clip. Preliminary results of Everest trial (Endovascu-
chord designed to restore septolateral annular geometry. lar Valve Edge-to-Edge Repair Study) were encouraging and analysis
• Dacron patch-inflatable balloon device—this balloon device is gave shown the success is likely when flail segment prolapses less
secured externally on infarcted myocardium to reverse left ven- than 10 mm beyond mitral annular plane and greater than 2 mm of
tricular remodeling and reduce IMR. mitral leaflet is available for grabbing. Another is Edward Milano II
device, which uses suction port to capture mitral valve leaflet and
PERCUTANEOUS VALVE REPAIR place a stitch through it.
Several issues pertaining to repair which require solution for uti-
AND REPLACEMENT
lization of these technique to full potential are:
Mitral Stenosis • Echo imaging difficult—need for real time four dimensional
echo.
Percutaneous commissurotomy for native valve mitral stenosis has till • Common terminology between interventionist and echo cardi-
now the longest track experience of all percutaneous valve repair. In ographer.
properly selected patients who have commissural fusion, the balloon • The onus on physicians to conduct clinical trials for assurance of
(single or double) or rigid mechanical device are advanced through a safety and efficacy with high clinical standards of care.
trans-septal puncture across mitral valve. The entire procedure is per- Although surgical repair of mitral valve is mature, percutaneous
formed under transesophageal echocardiography (TEE) and fluoro- devices are still far to match its efficacy in near future. Transcatheter
scopic guidance in cardiac catheterization laboratory. The balloon is insertion of valved stent within a degenerated bioprosthetic mitral
inflated repeatedly until mild to moderate mitral regurgitation is pro- valve has been accomplished,107 but still implantation into native
duced or maximum balloon diameter is achieved. Multiple randomized mitral valve is far from accomplishment.
controlled trials have shown results equivalent to surgery.99,100 This
technique is applicable only to patients who have commissural fusion Aortic Stenosis
not to patients with annular calcification.
Growing number of patients with severe aortic stenosis and advanced
Mitral Regurgitation age, with comorbid factors and previous cardiac surgery; with results
of percutaneous balloon aortic valvuloplasty disappointing, paved
Most percutaneous technique to repair mitral regurgitation fall way for percutaneous aortic valve replacement. The balloon expand-
into one of the two groups: (1) sinoplasty: mitral annular reshaping able Cribier-Edwards valve, composed of equine pericardial valve
through coronary sinus and (2) edge-to-edge repair on concept of leaflet sutured on a stent can be delivered either via antegrade route
Alfieri et al.101 through trans-septal approach or retrograde through femoral arte-
Multiple devices for mitral annulus remodeling are: rial route.108 Some of these patients have severe peripheral vascular
• The Mitralign:102 Performs modified suture annuloplasty by us- disease and transfemoral route is out of option, this necessitated the
ing magnets in coronary sinus and left ventricle to place special- transapical approach.
ized guidewires in the P1, P2 and P3 zones of annulus; specialized
anchors are placed at these location and plicated together to Transapical Aortic Valve Implantation
produce a 2–3 cm reduction in posterior annular circumference.
• The Viacor device:103 Placing a multilumen delivery catheter It is a truly minimally invasive, off-pump technique without the
into coronary sinus and introducing nitinol treatment devices to need for CPB and cardioplegia. With this antegrade approach with
reshape the annulus. minimal manipulation of ascending aorta and arch as compared to
transfemoral approach.The patient requires a minithoracotomy, can wall either between or including the papillary muscles. Dowling and
be done in patients with severe peripheral vascular disease even. colleagues112 reported 12-month freedom from death or transplant
The valve is stent based transcatheter xenograft and its positioning listing of 56% which is not promising and few centers if any under-
is performed in hybrid cardiac OT under fluoroscopic and echocar- take this surgery now.
diographic guidance during rapid ventricular pacing. Its feasibility
has been proven by clinical studies.109,110 For future, one of the most
exciting prospects is an implantable, nano-synthesized, nitinol valve Left Ventricular Aneurysmectomy
with durability of mechanical valve but without necessity of antico- In the attempt to exclude the infarcted septum and free wall and to
agulation. reshape globular ventricular cavity to elliptical without reducing cav-
ity volume, Jatene recommended encircling stitch about the aneu-
SURGERY FOR HEART FAILURE rysm neck, Cooley and Dor independently recommended a patch to
the remaining defect.
“A complex clinical syndrome that can result from any structural and In Dor procedure, or the Buckberg modification, the left ventri-
functional cardiac disorder that impairs the ability of ventricle to fill cles is opened through scar, and subtotal endocardectomy is per-
or eject blood”: AHA defines heart failure. formed over the septum and posterior wall.113 In the event of recur-
Clinical improvement in cardiac output is the primary target rent ventricular arrhythmias, cryotherapy is applied at the limits of
which can be approached surgically by either removing the resection. Survival of patients with exclusion of scar was worse than
primary ventricular insult or ameliorating the damaged ventricle heart transplantation at five years. Marchenlso et al. describes a
so-called “reverse remodeling” or “ventricular restoration surgery” trend of redilatation of the left ventricle with time (Table 78.4). The
(Fig. 78.1). level of recommendation by AHA/ACC is IIb.
Intra-Aortic Balloon Pumping The Acorn CorCap Device

Percutaneous device, introduced by Kantrowitz, which works on The CorCap, a polypropylene mesh, designed to be placed about the
principle of diastolic augmentation of coronary perfusion. Intra-aor- ventricle. The basis was the Kass114 group conclusion that dynamic
tic balloon pumping (IABP) is used in initial management of acute myoplasty was just a physical constraint preventing dilatation of
coronary syndrome and those with heart failure the level of recom- damaged heart. With this device there is significant reduction in left
mendation by AHA/American College of Cardiology (ACC) is I. ventricular volumes and improvement in quality of life, but no differ-
ence in mortality or readmission for heart failure has been noted.115
Partial Left Ventricular Resection The recommendation level by AHA/ACC is IIb.
The aim of surgery is to normalize cardiac volume/mass ratio, reduc- Surgical Strategies to Repower Failing Heart
ing left ventricular volume and improving systolic function. With
(Table 78.5 and Fig. 78.2)
the intention to treat surgically patients of dilated cardiomyopathy
especially from Chagas disease, Batista developed this procedure in Cardiac Resynchronization Therapy
Brazil.111 It involves wedge resection of posterolateral left ventricular
Biventricular pacing has shown to reduce interventricular mechani-
cal delay, when there is evidence of lack of interventricular synchro-
nous contraction. With cardiac resynchronization therapy (CRT)
improvement in left ventricular ejection fraction (LVEF) and reduc-
tion in mortality is documented and there is improvement in NYHA
class of the patient. This therapy is directed toward patients who
TABLE 78.4 End diastolic ventricular (EDV) volumes before, early after
and late (12 months) after left ventricular aneurysmectomy with linear
closure, septal remodeling or endoventricular patch plasty (endo VP)
Technique EDV (me) pre Early Post Late Post
Linear 189 (25) 143 (291) 165 (24)
Septal 199 (36) 150 (27) 170 (26)
Figure 78.1: Algorithm for surgical approach Endo VP 251 (64) 174 (32) 187 (27)
to patients of heart failure Values are presented as mean (SD)
TABLE 78.5 Surgical strategy to repower the failing heart without resecting it, while total artificial heart (TAH) anatomically
• Cardiac resynchronization therapy (CRT) and functionally replaces the failing heart; they can also be grouped
as pulsatile or nonpulsatile (Table 78.6).
• Ventricular assist devices (right, left, biventricular and total artificial
heart) The second and third generation pumps (Table 78.7), to circum-
vent the shortcoming of first generation pumps, are downsized and
• Biological
utilize features of nonpulsatile pumps. As valves are not required
• Dynamic cardiac myoplasty they are cheap and small. Except for its non-physiological question-
• Heart transplantation able issue, they are intended as a bridge to transplant not destination
• Cell transplantation device.
• Gene therapy
• Up regulation of natural pathways Dynamic Cardiac Myoplasty
Autologous skeletal muscle (latissimus dorsi muscle) on its neuro
are in NYHA Class III and IV for at least 6 weeks despite standard vascular pedicle brought into chest through a small thoracotomy
pharmacological treatment, reduced LVEF (< 35) and QRS duration is wrapped around heart to repanel it. This muscle is continuously
greater than 120 ms, the recommendation level by AHA/ACC is I. Im- paced to transform fast twitch muscle to slow twitch and to
provement of symptoms and quality life has been reported also.116 synchronize with cardiac contraction despite premising animal work,
improvement in patients has been inconsistent. This procedure is
Ventricular Assist Device rarely undertaken now as level of recommendation is IIb AHA/ACC.
Ideal treatment for chronic refractory heart failure should be reliable, Stem Cell Therapy
cost-effective, easy to implement, and capable of providing a physi-
ological level of circulatory support. Implantable pacemaker and Stem cells, be the pleuripotent cells of bone marrow, adipose tissue,
defibrillator are already widely used. Ventricular assist device (VAD) skeletal muscle or embryo, are injected into the myocardium where
offloads the heart by delivering blood into arterial tree. VAD may the new cells are expected to be retained, engaged and put of car-
be continuous flow or pulsatile, pulsatile pumps are larger. Pumps diac syncytium, differentiate into myoblasts, leading to improvement
may be placed within body or lie outside, being connected to heart of contraction and improving symptomatology of the recipient. The
by pipes that cross the skin. VAD may be used as bridge to recov- cells can be injected in coronary arterial system or directly into the
ery or as a “destination therapy”. REMATCH trial has explored its myocardium. There are suggestions that it may improve ventricular
efficacy for same. VAD assists the functioning of failing heart function, but at present level of recommendation is IIb by AHA/ACC.
Figure 78.2: Suggested treatment algorithm for management of end stage heart failure
TABLE 78.6 Features of pulsatile and nonpulsatile pumps TABLE 78.8 Guidelines for coronary bypass versus transplantation in end
Pulsatile Nonpulsatile stage coronary artery disease
Blood pumps CABG Transplant
Size Large Smaller Prevailing hibernation Prevailing scar
Mechanism Complex Simpler Short duration of heart failure Prolonged heart failure
Control Complex Simpler Low dose diuretic High dose diuretic
Valves Two None No right ventricular failure Chronic right ventricular failure
Compliance One None Stable cardiac output Progressively lower output
Implantability Complex Simpler Cardiac index > 2 l/min/m2 Cardiac index < 2 l/min/m2
Overall system Same Same LVEDP < 24 mm Hg LVEDP > 24 mm Hg
Cost Higher Lower Good target vessels Poor vessels
Physiological acceptance Ok ?? First operation Previous revascularization
TABLE 78.7 Three generation of ventricular assist devices

Ist Generation IInd Generation IIIrd Generation heart failure patients have 28% at 1 year survival falling to 8% at 2
Jarvik 7 TAH Micro/Med De Bakey VAD HeartMate III years as against patients who have had their cardiac transplant and
HeartMate I Jarvik 2000 VAD have 1 year survival of over 80% and 70% survival at 3–5 years post-
transplantation.
Novacor VAD HeartMate II VAD
Absolute indication for heart transplantation: For hemodynamic
Abicor TAH Downsized centrifugal and Magnetic levitation
compromise due to heart failure:
axial flow devices with aiming for over 10
• Refractory cardiogenic shock
contact bearing years durability
• Documented evidence on IV inotropic support to maintain ad-
equate organ perfusion. Peak VO2 less than 10 ml/kg/min with
Gene Therapy and Upregulation
achievement of anaerobic metabolism. Severe less than 10 ml/
of Natural Pathways kg/min with achievement of anaerobic metabolism.
The aim appears to be upregulation of biochemical pathways by gene Severe symptoms of ischemia that constantly limit routine activ-
delivery, though this arena is in embryonic stage of development. ity and are not amenable to coronary artery bypass surgery or percu-
Initial animal work is showing promising results. taneous coronary intervention.
Promotion of intrinsic pathways would result in improvement Relative indications for heart transplantation: Peak VO2 11–14 ml/
power production by the heart. Recent trials have demonstrated kg/min (or 55% of predicted) and major limitation of patient’s daily
both cellular hypertrophy and new myocyte production within myo- activity:
cardium stressed by aortic stenosis, similarly clenbuterol, anabolic • Recurrent unstable ischemia not amenable to other intervention
steroid with b-agonist properties have shown likelihood of recovery • Recurrent instability of fluid balance/renal function not due to
in patients being bridged to transplantation by VAD. patient noncompliance with medical regimen
• Recurrent symptomatic ventricular arrhythmias refractory to all
Heart Transplantation therapeutic modalities.
Decision for transplantation versus coronary artery bypass in pa-
“A new heart also will I give you, and a new spirit will I put within you; tients of end stage coronary artery disease is a dilemma. But certain
and I will take away the stony heart out of your flesh, and I will give guidelines can make us wiser (Table 78.8).
you heart of flesh.” Prediction in surgery is like tying a knot without a thread. The
Metaphorically throws insight into fibrotic nature of failing heart future of cardiac surgery rests on a solid background of struggle in
and option of transplantation. The technique developed by Norman initial years. With the advanced technology the future would be a
Shumway and Richard Lower at Stanford University set the stage cardiac patient being investigated through satellite transmission in
for transplantation. Though the credit for first transplant goes to his office or house a day prior to surgery. Computerized analysis and
Barnard in South Africa in 1969 with the advent and development of plan would be formulated and he walks into operating room on day
immunosuppressive drugs it has become the procedure of choice for of surgery. With few holes in chest, surgery will be performed; he will
patients with severe refractory heart failure. be extubated on operating table, absolutely pain free scarless experi-
The donor and recipient need careful selection, to avoid significant ence. The patient walks out that evening and starts his routine next
secondary complication secondary to immunosuppression. Severe day with very few medications if at all.
REFERENCES
1. Paget S. The Surgery of the Chest. Bristol: John Wright and Co; 1896.
2. Rehn L. On penetrating cardiac injuries and cardiac suturing. Ach Klin Chir. 1897;55:315.
3. McLean J. The discovery of heparin. Circulation. 1959;19:75-8.
4. Bigelow WG, Callaghan JC, Hopps JA. General hypothermia for experimental intracardiac surgery. Ann Surg. 1950;132:531-9.
5. Dennis C. Perspective in review. One group’s struggle with development of a pump-oxygenator. Trans Am Soc Artif Intern Organs. 1985;31:1-11.
6. Andreasen AT, Watson F. Experimental cardiovascular surgery. Br J Surg. 1952;39:548-51.
7. Cohen M, Lillehei CW. A quantitative study of the “ azygous factor” during vena caval occlusion in the dog. Surg Gynecol Obstet. 1954;98:225-32.
8. Lillehei CW, Varco RL, Ferlic RM, et al. Results in the first 2,500 patients undergoing open heart surgery at the University of Minnesota Medical
Center. Surgery. 1967;62:819-32.
9. Kirklin JW, DuShane JW, Patrick RT, et al. Intracardiac surgery with the aid of mechanical pump-oxygenator system (gibbon type): report of eight
cases. Proc Staff Meet Mayo Clin. 1955;30:201-6.
10. Kay EB, Zimmerman HA, Berne RM, et al. Certain clinical aspects of the use of a pump oxygenator. J Am Med Assoc. 1956;162:639-41.
11. Cross FS, Berne RM, Hirose Y, et al. Description and evaluation of a rotating disc type reservoir-oxygenator. Surg Forum. 1957;7:274-8.
12. Kolff WJ, Effler DB, Groves LK, et al. Disposable membrane oxygenator (heart-lung machine) and its use in experimental surgery. Clev Clin Q.
1956;23:69-97.
13. van den Dungen JJ, Karliczek GF, Brenken U, et al. Clinical study of blood trauma during perfusion with membrane and bubble oxygenators.
J Thorac Cardiovasc Surg. 1982;83:108-16.
14. van Oeveren W, Kazatchkine MD, Descamps-Latscha B, et al. Deleterious effects of cardiopulmonary bypass. A prospective study of bubble versus
membrane oxygenation. J Thorac Cardiovasc Surg. 1985;89:888-99.
15. Boers M, van den Dungen JJ, Karliczek GF, et al. Two membrane oxygenators and a bubbler: a clinical comparison. Ann Thorac Surg. 1983;35:
455-62.
16. Zuhdi N, McCollough B, Carey J, et al. Hypothermic perfusion for open-heart surgical procedures. Report of the use of a heart-lung machine
primed with 5% dextrose in water inducing hemodilution. J Int Coll Surg. 1961;35:319-26.
17. Zuhdi N, McCollough B, Carey J, et al. Double-helical reservoir heart-lung machine designed for hypothermic perfusion; primed with 5% glucose
in water; inducing hemodilution. Arch Surg. 1961;82:320-5.
18. Yeh TJ, Ellison LT, Ellison RG. Hemodynamic and metabolic responses of the whole body and individual organs to cardiopulmonary bypass with
profound hypothermia. J Thorac Cardiovasc Surg. 1961;42:782-92.
19. Dembinski R, Kopp R, Henzler D, et al. Extracorporeal gas exchange with the DeltaStream rotary blood pump in experimental lung injury. Artif
Organs. 2003;27:530-6.
20. Agati S, Mignosa C, Ciccarello G, et al. Pulsatile ECMO in neonates and infants: first European clinical experience with a new device. ASAIO J.
2005;51:508-12.
21. Heberden W. Commentaries on the History and Cure of Disease. Boston: Wells & Lilly; 1818. p. 292.
22. Herrick JB. Landmark article (JAMA 1912). Clinical features of sudden obstruction of the coronary arteries. J Am Med Assoc. 1983;250:1757-65.
23. Brunton TL. On the use of nitrite of amyl in angina pectoris. Lancet. 1867;2:97.
24. Francois-Frank CA. Signification physiologique de la resection du sympathiqe dans la maladie du basedow, 1’epilepsie, l’idiotic et le glaucoma.
Bull Acad Med Paris. 1899;41:565-94.
25. Levine SA, Cutler EC, Eppinger EC. Thyroidectomy in treatment of advanced congestive heart failure and angina pectoris. New Engl J Med.
1933;209:667.
26. Beck CS, Leighninger DS. Operations for coronary artery disease. JAMA. 1954;156:1226-33.
27. O’ Shaughnessy L. Experimental method of providing collateral circulation to heart. Br J Surg. 1936;23:6635-70.
28. Vineberg A, Miller G. Internal mammary coronary anastomosis in the surgical treatment of coronary artery insufficiency. Can Med Assoc J.
1951;64:204-10.
29. Sen PK, Udwadia TE, Kinare SG, et al. Transmyocardial acupuncture: a new approach to myocardial revascularization. J Thorac Cardiovasc Surg.
1965;50:181-9.
31. Longmire WP, Cannon JA, Kattus AA. Direct-vision coronary endarterectomy for angina pectoris. N Engl J Med. 1958;259:993-9.
32. Kolessov VI. Mammary artery-coronary artery anastomosis as method of treatment for angina pectoris. J Thorac Cardiovasc Surg. 1967;54:535-44.
33. Favaloro RG. Saphenous vein graft in the surgical treatment of coronary artery disease: operative technique. J Thorac Cardiovasc Surg. 1969;58:178.
34. Flemma RJ, Johnson WD, Lepley D. Triple aorto-coronary vein bypass as treatment of coronary insufficiency. Arch Surg. 1971;103:82.
35. Ankeney JL. To use or not to the pump oxygenator in coronary bypass operations. Ann Thorac Surg. 1975;19:108-9.
36. Buffolo E, de Andrade JC, Branco JN, et al. Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg. 1996;61:63-6.
37. Benetti FJ, Naselli G, Wood M, et al. Direct myocardial revascularization without extracorporeal circulation. Experience in 700 patients. Chest.
1991;100:312-6.
38. Subramanian VA, Sani G, Benetti FJ, et al. Minimally invasive coronary bypass surgery: a multicenter report of preliminary experience (abstract).
Circulation. 1995;92:645.
39. Fonger JD, Doty JR. The expanded role of minimally invasive coronary grafting. Eur J Cardiothorac Surg. 1998;14:S3-6.
40. Borst C, Jansen EW, Tulleken CA, et al. Coronary artery bypass grafting without cardiopulmonary bypass and without interruption of native coro-
nary flow using a novel anastomosis site restraining device (“Octopus”). J Am Coll Cardiol. 1996;27:1356-64.
41. Lima R. Surgical techniques of coronary artery exposure. In: Salerno TA, Ricci M, Karamanoukian HL (Eds). Beating Heart Coronary Artery Sur-
gery. Armonk: Futura Publishing company; 2001. pp. 21-34.
42. Loop F, Lytte B, Cosgrove D, et al. Influence of internal mammary-artery graft on 10 year survival and cardiac events. N Engl Med. 1986;314:1-6.
43. Zeff RH, Kongtahworn C, Lannone LA, et al. Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery:
prospective randomized study with 10-year follow-up. Ann Thorac Surg. 1988;45:533-6.
44. Grondin CM, Campeau L, Lesperance J, et al. Comparison of late changes in the internal mammary artery and saphenous vein grafts in two con-
secutive series of patients 10 years after operation. Circulation. 1984;70:I208-12.
45. Zacharias A, Habib RH, Schwann TA, et al. Improved survival with radial artery versus vein conduits in coronary artery bypass surgery with left
internal thoracic artery to left anterior descending artery grafting. Circulation. 2004;109:1489-96.
46. Meharwal ZS, Trehan N. Routine use of the radial artery for coronary artery revascularization. Asian Cardiovasc Thorac Ann. 2002;10:20-4.
47. Lytle BW, Blackstone EH, Sabik JF, et al. The effects of bilateral internal thoracic artery grafting on survival during 20 postoperative years. Ann
Thorac Surg. 2004;78:2005-12.
48. Rankin JS, Tuttle RH, Wechsler AS, et al. Techniques and benefits of multiple internal mammary artery bypass at 20 years of follow-up. Ann Thorac
Surg. 2007;83:1008-14.
49. Guru V, Fremes SE, Tu JV, et al. How many arterial grafts are enough? A population-based study of midterm outcomes. J Thorac Cardiovasc Surg.
2006;131:1021-8.
50. Zacharias A, Schwann TA, Riordan CJ, et al. Late results of conventional versus all-arterial revascularization based on internal thoracic and radial
artery grafting. Ann Thorac Surg. 2009;87:19-26.
51. Calafiore AM, Giammarco GD, Teodori G, et al. Left anterior descending coronary artery grafting via left anterior small thoracotomy without car-
diopulmonary bypass. Ann Thorac Surg. 1996;61:1658-63.
52. Angelini GD, Lloyd CT, Calafiore AM, et al. Integrated left anterior small thoracotomy and angioplasty for coronary artery revascularization. Ann
Thorac Surg. 1999;68:908-11.
53. Mishra YK, Wasir H, Sharma KK. Totally endoscopic coronary artery bypass surgery. Asian Cardiovasc Thorac Ann. 2006;14:447-51.
54. Payr E. Beitrage zur Technique der Blutgefass-und Nervennaht nebst Mittheilungen uber die Verwendung eines resorbirbaren Metalles in de
Chirurgie. Arch Klein Chir. 1900;62:67-93.
55. Brunton L, Edin MD. Preliminary note on the possibility of treating mitral stenosis by surgical methods. Lancet. 1902;1:352.
56. Cutler EC, Levine SA. Cardiotomy and valvulotomy for mitral stenosis: experimental observations and clinical notes concerning an operated case
with recovery. Boston Med Surg J. 1923;188:1023-7.
57. Souttar HS. The surgical treatment of mitral stenosis. Br Med J. 1925;2:603-6.
58. Harken DE. Heart valves: ten commandments and still counting. Ann Thorac Surg. 1989;48:S18-9.
59. Carpentier A. Cardiac valve surgery–the “French correction”. J Thorac Cardiovasc Surg. 1983;86(3):323-37.
60. Wiggers CS, Katz LM. Contour of the ventricular volume curves under different conditions. Am J Physiol. 1922;58:439-75.
61. Rushmer RF. Initial phase of the ventricular systole; asynchronous contraction. Am J Physiol. 1956;184:188-94.
62. Rushmer RF, Finlayson BL, Nash AA. Movement of mitral valve. Circ Res. 1956;4:337-42.
63. Lillehei CW, Lovy MJ, Bonnabeau RC. Mitral valve replacement with preservation of papillary muscles and chordae tendinae. J thorac Cardiovasc
Surg. 1964;47:5322-43.
64. David TE. Mitral valve replacement with preservation of chordae tendinae: rationale and technical considerations. Ann Thorac Surg. 1986;41:
680-2.
65. Miki S, Kusuhara K, Ueda Y. Mitral valve replacement with preservation of chordae tendinae and papillary muscles. Ann Thorac Surg. 1988;45:
28-34.
66. Sintek CF, Pfeffer TA, Kochamba GS, et al. Mitral valve replacement: technique to preserve subvalvular apparatus. Ann Thorac Surg. 1995;59:
1027-9.
67. Rose EA, Oz MC. Preservation of anterior leaflet chordae tendinae during mitral valve replacement. Ann Thorac Surg. 1994;57:768-9.
68. Chowdhury UK, Kumar AS, Airan B, et al. Mitral valve replacement with or without chordal preservation in a rheumatic population: serial echo-
cardiographic assessment of left ventricular size and function. Ann Thorac Surg. 2005;79(6):1926-33.
69. Hetzer R, Drews T, Siniawaski H, et al. Preservation of papillary muscles and chordae during mitral valve replacement; possibilities and limita-
tions. J Heart valve Dis. 1995;4:S115-23.
70. Dubier TW, Borowiec JW, Manntig F, et al. Mitral valve prosthetic implantation with preservation of mitral valve apparatus. Scand J Thorac Car-
diovasc Surg. 1994;28:115-21.
71. Mishra YK, Malhotra R, Trehan N, et al. Minimally invasive mitral valve surgery through right anterolateral minithoracotomy. Ann Thorac Surg.
1999;68:1520-4.
72. Carpentier A, Loulmet D, Aupècle B, et al. Computer assisted open heart surgery. First case operated on with success. C R Acad Sci III. 1998;321:
437-42.
73. Chitwood WR, Wixon CL, Elbeary JR, et al. Video assisted minimally invasive mitral valve surgery. J Thorac Cardiovasc Surg. 1997;114:773.
74. Mohr FW, Falk V, Diegeler A, et al. Computer enhanced “robotic” cardiac surgery: experience in 148 patients. J Thorac Cardiovasc Surg.
2001;121:842.
75. Trehan N, Mishra YK, Sharma M, et al. Robotically controlled video-assisted port-access mitral valve surgery. Asian Cardiovasc Thorac Ann.
2002;10:133-6.
76. Cosgrove DM, Sabik JF. Minimally invasive approach for aortic valve operations. Ann Thorac Surg. 1996;62:596.
77. Coher LH, Adams DH, Couper GS, et al. Minimally invasive cardiac valve surgery improves patient satisfaction while reducing costs of cardiac
valve replacement and repair. Ann Surg. 1997;226:421.
78. Cosgrove DM, Sabik JF, Navia JL. Minimally invasive valve operations. Ann Thorac Surg. 1998;65:1535.
79. Byrne JG, Karavas AN, Aklog L, et al. Aortic valve reoperation after homograft or autograft replacement. J Heart Valve Dis. 2001;10:451.
80. Yacoub MH, Genle P, Chandrasekaran V, et al. Late results of a valve sparing operation in patients with aneurysms of the ascending aorta and root.
J Thorac Cardiovasc Surg. 1998;115:1080-90.
81. David TE, Feindel CM. An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta. J Thorac
82. De Paulis R, De Matteis GM, Nardi P, et al. One-year appraisal of a new aortic root conduit with sinuses of Valsalva. J Thorac Cardiovasc Surg.
2002;123:33-9.
83. Thubrikar MJ, Robicsek F, Gong GG, et al. A new aortic root prosthesis with compliant sinuses for valve sparing operations. Ann Thorac Surg.
2001;71:S318-22.
84. Simon R, Oelert H, Borst HG, et al. Influence of mitral valve surgery on tricuspid incompetence concomitant with mitral valve disease. Circula-
tion. 1980;62;I152-7.
85. King RM, Schaff HV, Danielson GK, et al. Surgery for TR late after mitral valve replacement. Circulation. 1984;70:S193-7.
86. Deloche A, Guerinon J, Fabiani JN, et al. Anatomical study of rheumatic tricuspid valve disease: application of the study of various valvuloplasties.
Ann Chir Thorac Cardiovasc. 1973;12:343-9.
87. De Vega NG. La anuloplastia selective, reguable y permanente. Rev Esp Cardiol. 1972;25:6-9.
88. Antunes MJ, Girdwood RW. Segmental annuloplasty: a modified technique. Ann Thorac Surg. 1983;35:676-8.
89. Mallidi MR, Pelletier MP, Lamb J, et al. Late outcome in patients with uncorrected mild to moderate mitral regurgitation at the time of isolated
coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2004;127:636-44.
90. Miller DC. Ischemic mitral regurgitation redux to repair or to replace? J Thorac Cardiovasc Surg. 2001;122:1059-62.
91. Calafiore AM, Di Mauro M, Gallina S, et al. Mitral valve surgery for chronic ischemic mitral regurgitation. Ann Thorac Surg. 2004;77:1989-97.
92. Gillinov AM, Wierup PN, Blackstone EM, et al. Is repair preferable for ischemic mitral regurgitation? J Thorac Cardiovasc Surg. 2001;122:1125-41.
93. Kohli V, Mehta Y, Trehan N, et al. Mitral valve repair for ischemic mitral regurgitation in dilated cardiomyopathy. Asian Cardiovasc Thorac Ann.
2005;13:267-70.
94. Grossi EA, Goldberg JD, La Pietra A, et al. Ischemic mitral valve reconstruction and replacement: comparison of long-term survival and complica-
tions. J Thorac Cardiovasc Surg. 2001;122:1107-24.
95. Bolling SF, Pagani FD, Deeb GM, et al. Intermediate term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg.
1998;115:381-6.
96. Tahta SA, Oury JM, Maxwell JM, et al. Outcome after mitral valve repair for functional ischemic mitral regurgitation. J Heart Valve Dis. 2002;11:
11-8.
97. Messas E, Pouzet B, Touchet B, et al. Efficacy of chordal cutting to relieve chronic persistent ischemic mitral regurgitation. Circulation.
2003;108:111-5.
98. Bhudia SK, McCarthy PM, Smedira NG, et al. Edge-to-edge (Alfieri) mitral repair. Ann Thorac Surg. 2004;77:1598-606.
99. Glower DD, Landolfo KP, Davis RD, et al. Comparison of open mitral commissurotomy with mitral valve replacement with or without chordal
preservation in patients with mitral stenosis. Circulation. 1998;98:II120-3.
100. Ben FM, Ayari M, Maatouk F, et al. Percutaneous balloon versus surgical closed and open mitral commissurotomy: seven year follow up of a ran-
domized trial. Circulation. 1998;97:245-50.
101. Alfieri D, Maisano F. An effective technique to correct anterior mitral leaflet prolapsed. J Card Surg. 1999;14:468-70.
102. Baim D. Mitralign retrograde transventricular mitral annuloplasty. In: Valvular Heart Disease 2005 AATS Postgraduate Course. Chicago: American
Association for Thoracic Surgery; 2005. p. 91.
103. Hayase M. Indirect coronary sinus annuloplasty III. Viacor: animal experimental results. In: Valvular Heart Disease 2005 AATS Postgraduate
Course. Chicago: American Association for Thoracic Surgery; 2005. pp. 97-8.
104. Kaye D, Byrne M, Alferness C, et al. Feasibility and short term efficacy of percutaneous mitral annular reduction for therapy of heart failure in-
duced mitral regurgitation. Circulation. 2003;108:1795-7.
105. Fukamachi K, Inoue M, Popovic Z, et al. Optimal mitral annular and subvalvular shape change created by the Coapsys device to treat functional
mitral regurgitation. ASAIO J. 2005;51:17-21.
106. Mishra YK, Mittal S, Trehan N, et al. Coapsys mitral annuloplasty for chronic functional ischemic mitral regurgitation: 1-year results. Ann Thorac
Surg. 2006;81:42-6.
107. Webb JG. Transcatheter valve in valve implants for failed prosthetic valves. Catheter Cardiovasc Interv. 2007;70:765-6.
108. Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific aortic stenosis with percutaneous heart valve: mid-term follow-up from initial feasi-
bility studies: the French experience. J Am Coll Cardiol. 2006;47:1214-23.
109. Welther T, Simon P, Dewey T, et al. Transapical minimally invasive aortic valve implantation: multicentre experience. Circulation. 2007;116:
I240-5.
110. Lichtenstein SV, Cheung A, Ye J, et al. Transapical transcatheter aortic valve implantation in humans: initial clinical experience. Circulation.
2006;114:591-6.
111. Batista RJ, Nery P, Bocchino L, et al. Partial left ventriculectomy to treat end-stage heart disease. Ann Thorac Surg. 1997;64:634-8.
112. Dowling RD, Koenig S, Laureano MA, et al. Results of partial left ventriculectomy in patients with end-stage idiopathic cardiomyopathy. J Heart
Lung Transplant. 1998;17:1208-12.
113. Dor V, Sabatier M, Di Donato M, et al. Efficacy of endoventricular patch plasty in large postinfarction akinetic scar and severe left ventricular func-
tion: comparison with a series of large dyskinetic scars. J Thorac Cardiovasc Surg. 1998;116:50-9.
114. Kass DA, Baughman KL, Pak PH, et al. Reverse remodeling from cardiomyoplasty in human heart failure. External constraint versus active assist.
Circulation. 1995;91:2314-8.
115. Mann DA, Acker ML, Jessup M, et al. Rationale, design, and methods for a pivotal randomized clinical trial for assessment of a cardiac support
device in patients with New York Heart Association class III-IV heart failure. J Card Fail. 2004;10:185-92.
116. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization therapy on morbidity and mortality in heart failure. N Engl J
Med. 2005;352:1539-49.
79 History of Valvular Heart Surgery
Yadava OP
“Science grows step by step and every man depends on the work of his predecessors. Inevitably, the monuments of success have been built on
the rubble of failure, rubble which nevertheless plays its part in the foundations of the success.”
—Sir Earnest Rutherford
INTRODUCTION SURGERY FOR MITRAL STENOSIS

Though we start our story of development of surgery for valvular heart Ambitious and daring attempts at opening the cardiac valves were
disease from around the turn of the 19th century, lot of ancillary de- made by pioneers like Theodore Tuffier on July 13, 1912 and few
velopments contributed to make heart surgery feasible. George Cal- months later by Doyen using a finger and a tenotomy, respectively.
lendar’s operation on an injured heart in October 1872 at St. Bartho- As these attempts failed, Evarts Graham and Duff Allan in USA de-
lomew’s Hospital, Bloch’s demonstration of the feasibility of stitching vised a cardioscope with a lens at the tip with the aim of doing val-
wounds on beating heart in rabbits and thereafter in 1896, the suc- votomy under direct vision.2 However, Sir Lauder Brunton’s wishful
cessful suturing of a cardiac wound by Rehn laid the foundations for prophecy, hypothesizing closed MV valvotomy, “if one could divide
more daring attempts at the valves directly. Just about then, other the constriction as easily during life, as one can after death”, in a 1902
landmark developments took place, like the description of sternum article was actually brought to fruition by Cutler and Henry Souttar
splitting incision by Herbert Milton and his prophecy, “Heart surgery in the late 1920s. The first successful mitral valvotomy was performed
is still quite in its infancy, but it requires not a great stretch of fancy to by Cutler along with his associate Levine on May 20, 1923 at the Peter
imagine the possibility of plastic operations of its valvular lesions.”1 Bent Brigham Hospital in United Kingdom (UK).3 With the sobering
He found great support in Daniel Samways and Sir Lauder Brunton.2 results of the Cutler and the Levine valvotomy procedure, Sir Henry
However, whenever pathbreaking ideas are proposed, there is always Souttar, on May 6, 1925 achieved a major advance, when he intro-
some resistance, even bordering on hostility, before there is sub- duced a finger in the left atrial (LA) appendage and successfully split
dued acceptance. Sometimes even great people may falter in their the fused commissures of a rheumatic MV.4 However, such was the
judgment, for Christian Billroth in 1897 wrote, “Surgery of the heart unshakeable faith of the cardiologists then that the myocardium is
has probably reached the limits set by nature to all surgery: no new the main culprit rather than the valve in rheumatic heart disease that
method and no new discovery can overcome the natural difficulties despite these daring and successful attempts at opening the MV, mi-
that attend a wound of the heart.” Similarly, Sir Brunton drew char- tral valvotomy was not attempted in the UK for more than two dec-
acteristically vitriolic attack and his suggestion of passing a suitable ades1,2—an eclipse phase in MV surgery.
instrument blindly through the mitral valve (MV) orifice to open it Claude Beck very succinctly surmised this moratorium, “I have
was viewed with disapprobation. Parallel developments in the form been asked the question, why did Cutler stop the operation for mitral
of introduction of ether anesthesia by William Morton and the use of stenosis? There were several reasons. The valves we examined were
chloroform in 1847 by James Young Simpson were in giant steps to- calcified and rigid, and it looked as though a piece of valve should be
wards the development of targeted valvular heart surgery. Needless cut away in order to relieve the stenosis. It is probable that the pathol-
to say, development of antibiotics, instrumentation, introduction of ogy of mitral stenosis has been changed by the use of sulphonamides
the pump oxygenator, cardioplegia and imaging too have contrib- and antibiotics, for we did not then see the soft, pliable valves that
uted immensely. could be opened by finger dilatation. Furthermore, I cannot recall
any words of encouragement for Cutler after he operated on his sev- finally successful one, I was sure that I was, at the very least, in dan-
enth and last patient with mitral stenosis.”1 ger of losing all of my hospital operating privileges.” With tenacity,
The virtue of patience and perseverance with a focused mind was Bailey posted on the same day, one case at the Philadelphia General
demonstrated by Charles Bailey. Devastated by his father’s death at Hospital in the morning and another at the Episcopal Hospital in the
a young age, when Bailey was just 12-year-old, he was forced to work afternoon, having lost the operating rights in three other hospitals.
and sell ladies girdles door-to-door after school and during summer This was with the premise that if the morning attempt failed, he would
holidays. This actually turned out to be a boon as it increased his un- be underway with the second operation, before he could be stopped.
derstanding of the structure of the MV, which he likened to a skirt However, as the luck would be, Bailey developed measles and had
with numerous garters arising from the lower margin and attaching to postpone both the operations. On June 10, 1948, he operated his
front and back to the top of the two stockings as akin to the chor- fourth case at the Philadelphia General Hospital in the morning, but
dae tendineae attaching to the mitral papillary muscles (Figs 79.1A the patient died before his valve could be reached. As preplanned,
and B). He devised a commissurotomy knife fixed to the palmar sur- he drove directly to the Episcopal Hospital to start the fifth surgery
face of the index finger (Fig. 79.2) and used the LA approach for split- preempting any action on the part of the administrators after they
ting the MV.5 His first four clinical attempts were failure and three of heard the death of fourth patient. Lo and behold, this was a success
the five hospitals in Philadelphia cancelled his operating privileges. and the patient lived 38 years to die of an unrelated complication!1
With a charged state of mind, as captured in his own words, “Finally After great heroics at the World War II arena, Dwight Harken6
however, you have to face the “moment of truth”, and the poignancy diverted his attention to mitral valvotomy, but he had mixed luck,
is so great that I cannot really express it. You know that almost all the and after losing 6 out of his 10 patients, he was so devastated that
world is against it, and yet you feel that it has to be done and that it he vowed never to operate again. It was then that his cardiologist
has to be right. At the time, I did the last of those five operations, the Laurence Ellis, giving an example of highest degree of camaraderie
and comradeship said, “You have never killed anybody. I have never
sent you a patient who was not dying.” Harken, rejuvenated by this
encouragement, resumed operating and had success in 14 out of his
next 15 patients.
The operations by Smithy on January 30, 1948; Bailey on June 10,
1948; Harken on June 16, 1948 and Lord Brock on September 16, 1948
made 1948 the annus mirabilis of MV repair.1 Unfortunately, Cutler
who envisioned this did not live to see the success of his pioneering
efforts and died in 1947.
Other ingenious modalities like creation of an atrial septal de-
fect to protect the lungs in mitral stenosis (Jarotzky, 1926; O’Farrell
and Harken, 1948); anastomosing the inferior pulmonary vein to the
azygos (Bland and Sweat, 1948; d’Allaines; Lenegre; Dubost, Mathi-
vat and Seebat, 1948) and denervation of the heart to slow the rate
for improvement of the diastolic filling, with or without ligation of
A B the inferior vena cava (Harken, 1948; Pedro Cossio, 1949)2 were tried,
Figures 79.1A and B: Cartoon shows papillary but with the introduction of finger directed mitral valvotomies and
muscles drawn by Walt Disney1 sophisticated valvulotomes (Logan’s, Dubost’s, Tubb’s and Brock’s)
in 1953–54,2 closed mitral valvotomy became an established norm,
edging the other procedures into oblivion.
SURGERY FOR AORTIC STENOSIS

After the initial exploits of Tuffier in 1912 with mitral valvotomy and
in 1914 with aortic valvotomy, the first realistic attempt at address-
ing the problem of aortic stenosis was made by Brock who used a
cardioscope, introduced retrogradely through the subclavian artery
and also tried finger fracture, as suggested earlier by Souttar in 1925,
unfortunately with disastrous results. Driven by his own severe aortic
stenosis, Horace Smithy worked with a sense of urgency on devel-
Figure 79.2: Bailey’s commissurotomy knife fixed to the palmar oping a valvulectomy procedure for both aortic and mitral stenosis,
surface of the index finger3 and achieved fair degree of success with a thin, barbed valvulotome.
Chapter 79  History of Valvular Heart Surgery 669
However, aortic stenosis in general proved to be a tough nut to crack. Other workers too tried indigenous designs and techniques to im-
Bailey tried excising a piece of the aortic valve (AV) and slinging a plant artificial valves.
length of dog’s external jugular vein across the native valve to act as In 1952, Bailey introduced a ball and plastic flap valve, which
an artificial valve to take care of the aortic regurgitation. Imaginative was suspended in aorta by nylon tails and designed to fall back into
approaches like bypassing the AV by creating an apico-aortic conduit the regurgitant orifice during diastole. Near about the same time,
of homograft material too were tried, and though sound in princi- Murray suggested bypassing the regurgitant valve with an aortic xe-
ple, it led to more failures than successes. Bailey thus diverted his nograft and was also the first person in October 1955 to try an aortic
attention to valvotomy techniques and devised an instrument with homograft taken from a cadaver and preserved in saline solution at
an umbrella like tip, albeit with mixed results. Guided by the mitral 4°C for 36 hours with excellent clinical results even up to 6 years.11
experience, he tried using a pericardial sleeve in the aorta to insert As pump oxygenator was not in universal use, these operations were
a finger to palpate-guide the dilator into the AV and did a guided performed at the level of descending aorta. WG Bigelow’s hypother-
valvotomy.1 However, all these techniques were soon to become ob- mia and John Lewis’s inflow occlusion methods were important in-
solete with the introduction of more sophisticated and precise tech- novations, but did not permit extensive procedures.
niques, like CPB, cardioplegia, hypothermia and inflow occlusion. In Introduction of CPB in 1953 opened new vistas. In 1959, Huf-
fact first successful aortic valvotomy using a heart lung machine was nagel implanted a single valve cusp made of Dacron cloth impreg-
performed on November 17, 1955 by Swan.7 This was soon followed nated with silicone rubber in aortic position using CPB. However,
by another surgery by Brock on January 26, 1956 using hypothermia the results were at best sobering. The first complete excision and
and by Lillehei on January 31, 1956 using pump oxygenator and ret- replacement of the MV took place on March 10, 1960 by Braunwald
rograde coronary perfusion, thereby putting valvular heart surgery and Morrow, using a mitral prosthesis made of polyurethane rein-
on a trajectory of exponential blast off. forced with Dacron fabric and tails to mimic chordae. Soon there-
after in May 1960, Harken implanted the first ball and cage valve in
MITRAL REGURGITATION the aortic position using interrupted silk sutures under CPB. Most
of the efforts till then led to short-term survivors and it was left to
Having conquered stenotic lesions, it was but natural for the sur- Albert Starr from Portland, Oregon and his engineering colleague
geons to divert their attention to regurgitant lesions. Bailey in 1950 Miles Lowell Edwards, to design a ball and cage valve, an idea con-
was probably the first person to report on a valve repair procedure ceived from 1858 wine bottle stopper patent. The cage was cast in one
using vascularized pericardial pedicle based on the experimental piece of stainless steel with a Teflon sewing ring and a silastic ball.
work by John Templeton and John Gibbon earlier.1 After an unsuccessful attempt in August 1960, success was achieved
The genius in Dwight Harken, egged on by the acrimonious re- on September 21, 1960 and first successful MV replacement was
lationship that he had with Charles Bailey, developed his own tech- performed in human beings.12 The valve design subsequently un-
nique of closed annuloplasty using nylon sutures to plicate the valve derwent a lot of compositional and structural changes like the cage
annulus. Harken also tried creating an artificial valve leaflet using sequentially changed from a lucite to stainless steel cage and finally
a plastic baffle.8 The bottom line, however, to all these procedures a satellite 21 cast. The struts of the cage were covered in cloth with a
was that they were blind in nature and therefore imprecise. Finger view to encouraging epithelialization and reducing the potential for
guided mitral annuloplasty techniques were also tried, but they all thromboembolism. Aortic models 1200 and 1260, MV model 6120
remained essentially ineffective. Introduction of cardiopulmonary were used for a number of years with satisfactory results. However,
bypass (CPB) on May 6, 1953 by John Gibbon9 was a major landmark these models were discontinued in 1980 to be replaced with valves
in the development of open repairs of valvular heart disease and it with uncovered struts and a silicone ball instead of silastic, as the
was Sir Walton Lillehei who performed the first MV repair for insuf- latter had a tendency to imbibe water. The concept of chordal pres-
ficiency on May 23, 1956 thus starting the era of pump supported MV ervation to prevent postoperative low cardiac output was forwarded
surgical interventions. by Lillehei in 1964. These developments opened the floodgates for
artificial valves. Such was the rush to develop valves that most emi-
ARTIFICIAL HEART VALVE nent cardiac surgeons teamed up with engineering colleagues, spe-
cially Edwards, Cutter or Surgitool to launch their own valves, e.g.
The pioneering efforts of Hufnagel in the 1940s led to the first clinical Magovern-Cromie (1962), Kay-Shiley (1965), Smeloff-Cutter (1966),
implantation of a caged ball valve in the descending aorta on Sep- Beall-Surgitool (1967), DeBakey-Surgitool (1967), Braunwald-Cutter
tember 11, 1952 and heralded the era of rapid development of treat- (1968), Cooley-Cutter (1971), etc. (Fig. 79.3).13
ment options for valvular heart disease in the 1960s.10 Applauding The first surgical treatment of multiple valvular disease was done
Charles Hufnagel’s historic and monumental accomplishment, Ed- by Trace et al14 who sequentially dilated mitral and tricuspid valves
ward A Lefrak and Albert Starr, in the book “Cardiac Valve Prosthesis” at a gap of 2 weeks. Combined mitral and tricuspid commissurotomy
wrote, “Hufnagel ignited the fire of prosthetic valve implantation...” at one sitting was accomplished by Brofman in 1953.15 Robert Cart-
Figure 79.3: Landmark mechanical valves13
wright of Pittsburg is credited with carrying out the first combined used this technique in anecdotal patients.17 In 1961, Heimbecker,
aortic and MV replacement on November 1, 1961. A quadruple valve Murray’s colleague in Toronto, implanted the first orthotopic aortic
commissurotomy was performed by Borman in October, 1973.16 homograft valve, obtained aseptically from a cadaver and preserved
in a saline-penicillin mixture at 4°C. However, the patient died within
AORTIC HOMOGRAFT 24 hours from coronary thrombosis. Meanwhile, Carlos Duran and
Alfred Gunning carried on with their experimental work on AV har-
Encouraged by the excellent 6-year results and uneventful survival vest and preparation, but it was Sir Donald Ross who performed the
of the aortic homograft placed by Murray11 in the descending tho- first subcoronary homograft implantation on June 24, 196218 more
racic aorta in October 1955, others like Beall, Cooley and DeBakey by default than by design,—“Such was our state of unpreparedness
that in June 1962, an AV that I was decalcifying disappeared down the of the day. Because of logistics of availability of human tissue as also
sucker tubing at a time when Starr valves were only a distant rumor. the disappointment with available bioprosthetic materials, alterna-
We had no alternative, but to reconstitute one of our freeze dried tive materials were tried including autogenous pericardium, fascia
aortic homograft valves and sew it in with a single suture layer—a lata from thigh (Senning) and heterologous pericardium (Ionescu).
technique which fortunately had already been suggested to us by Dr Eurcylites J Zerbiny and Dr Luiz B Puig from Brazil reported the
our colleagues Gunning and Duran of Oxford. You can imagine our use of homologous dura mater and even kits for instant valve assem-
delight when the first valve was not rejected and continued to func- bly and fabrication using autologous pericardium were introduced
tion in that patient for 4 years. We forgot about the newly available by Dr Jack W Love of California.
mechanical valves—a state of amnesia, which I must confess per-
sists to this day. The homograft valve became an established surgical Second Generation Prosthetic Valves
technique although eventually with only a few persistent and coura-
geous exponents of the method, largely in the Antipodes.” Others like With experience gained with the first generation caged ball valves,
Sir Barratt-Boyes at Green Lane Hospital,19 Paneth and Mark O’Brien newer valve designs were introduced and low profile caged disk
at the Brompton Hospital and Kirklin, Angell and Shumway adopted valves came into vogue in the mid-1960s, albeit only for a short pe-
and further pioneered homograft valve replacement techniques. riod. Pivoting disk occluders were a landmark introduction in valve
However, the technique was difficult and available to only a gifted technology by Juro Wada of the Sapporo Medical College in Japan.
few. Therefore to simplify matters, Weldon from the Johns Hopkins In fact the first total artificial heart used by Liotta and Cooley in 1969
Hospital started mounting aortic homograft’s on a frame with a view employed four Wada-Cutter valves. Learning from the experience of
to providing easy implantation and decreasing the incidence of early Wada of lower gradient across a tilting disk valve, Bjork suggested to
postoperative aortic regurgitation. However, soon it was realized that Don Shiley, the Chief Engineer at the Edwards Laboratories to design
the stent mounted homograft had limited durability, and if mastered, a tilting disk valve with no hinges, but the pivoting mechanism, as
free hand sewn homograft’s functioned better in the long-run. he strongly felt that was the way forward, and first such Bjork-Shiley
Even native autogenous pulmonary valves were used experi- valve was implanted on January 16, 1969 in Stockholm. The disk of
mentally in the descending thoracic aorta by Lower, Shumway and the first model was made of delrin, which gave satisfactory long-term
Stofer, but it was in 1967 that Sir Donald Ross first performed the pul- results with some of these valves functioning over 20 years.23 The
monary autograft replacement of the AV in human beings.20 Initially disk was later changed to pyrolytic carbon. Sequential changes were
the autogenous pulmonary valve was used as a subcoronary implant, brought in the valve in terms of change of disk to pyrolytic carbon,
but later as a full aortic root substitute with coronary reimplantation. change of the opening and closing angles, change of conical disk to a
spherical disk, introduction of the radiopaque marker and the provi-
DEVELOPMENT OF TISSUE VALVES sion of the rotational capability of the valve housing in the sewing
ring. The convexo-concavo model with an opening angle of 60–70°
Realizing the paucity of availability of human cadaveric tissue and was introduced in 1976 with the aim of improving flow through the
problems faced with mechanical valves, efforts were directed ini- lesser orifice and for eliminating the low flow area caused by the disk
tially by Duran and Gunning, to use other biological tissues. They edge touching the valve ring. Subsequently in 1980s, this valve was
implanted for the first time on September 23, 1964 a stent mounted withdrawn due to inordinately high incidence, initially of inflow and
porcine valve into the human being. Subsequently, Binet et al.21 and subsequently outflow strut fractures at the site of welding. In fact this
Mark O’Brien used varying techniques of preserving the valve and led to disintegration of the Shiley company and the introduction of
implanting it in the human beings. However, the long-term results the much tighter regulatory rules in the USA that prohibits, even to-
were suboptimal with all of them. In 1966, Ionescu and Wooler de- day, the use of a lot of drugs and devices till much later date, even
veloped a stent for mounting aortic homografts, which subsequently when the European Union has warranted their usefulness and safety.
became popular as the Ionescu-Shiley pericardial valve. Similarly, The first generation valves established the feasibility and safety
Carpentier developed and pioneered his own stent marketed in of implanting artificial material in human circulation, but also glar-
1967 as Carpentier-Edwards valve for human use. Within no time, ingly pointed to the fact that the design was suboptimal and needed
Shumway and Angell bioprosthetic valve and Hancock valves too hit significant improvement. A major advance in the valve technology
the market and various kind of preservatives, like Mercurochrome, was the introduction of the bileaflet valve by the St. Jude Company.
Formaline, b-propiolactone, etc. were tried, culminating in the use In March 1976, Manuel Villafana, an Ex-Medtronic employee, found-
by Carpentier of glutaraldehyde fixation techniques in 1968. This ed a new company called St. Jude Medical Incorporated (St. Jude is
led to the first generation of the contemporary bioprosthetic valves the patron saint of lost causes and Villafana had named his son Jude
through mainly the efforts of Carpentier,22 Hancock and Angell and after surviving serious medical problems in infancy). Building on the
glutaraldehyde treated stented porcine valves, which required much crude design submitted by Nicoloff and Posis, a bileaflet valve was
less clinical judgment and skills to implant, which became the norm introduced with pyrolytic carbon as a thromboresistant surface. The
later material was developed by Jack Bokros at General Atomic (sub- degeneration in stented technology and this included elimination of
sequently, CarboMedics incorporated), but it was extremely costly. the porcine muscle bar in the Hancock valve, flexible valve stents,
Therefore, initially they used semicircular leaflets made of tungsten antimineralization treatments and zero pressure leaflet fixation as
and coated with pyrolytic carbon and first such valve was clinically advocated by Grant Christie and Sir Brian Barratt-Boyes.
implanted in October 1977 and demonstrated excellent hemody-
namics with low thromboembolic potential. Valiathan et al.24 at the Mitral Valve Repair
Sree Chitra Tirunal Institute of Medical Sciences, Trivandrum, too
developed an indigenous tilting disk valve in the late 1970s, which Though the repair techniques antedated valve replacement by
was put into clinical use in 1990. almost half a century, the true era of modern and contemporary MV
Thus in late 1970s and 80s, there were two designs competing repair began in Leeds in early 1960s, where Geoffrey Wooler first
for honors. The dual disk St. Jude and single tilting disk design of looked at surgical methods to correct mitral incompetence. Reed
Medtronic-Hall. Subsequently, bileaflet designs were marketed by built on these techniques, but it was not till the development of
Duromedics and CarboMedics with minor modifications like carbon the annuloplasty ring by Carpentier in 196826 and later, in 1975, by
coating to discourage pannus formation of the sewing ring in Carbo- Duran27 that universal adoption of the repair techniques occurred.
Medics and variations in the design of the struts and pivot guards. Stimulated by Lev’s comment, “MV diseases are like women, the
Later Villafana left St. Jude Medical to establish his own company, more you study them, the less you understand them”, Carpentier and
Advancing the Standard (ATS) Heart Valve Company, with a design Chauvoud described 10 acquired and 14 congenital valve lesions.
akin to that of St. Jude but with a number of improvements like self- Carpentier, the father of modern MV repair, systematically looked at
washing pivots, absence of pivot guards and rotatability. Despite repair techniques at the leaflet, annulus and subchordal levels and
these innovations, an ideal valve is far from sight. Toward this quest, gave his famous classification.28
polymeric valves too are being developed especially at the Penn-
sylvania State University and later Dr Richard T Schoephoerster of PULMONARY AND TRICUSPID VALVES—
Florida in collaboration with Dr Kasyanov from Latvia are working
POOR COUSINS
on a heart valve design that incorporate polypropylene threads em-
bedded in polyurethane with the thread configuration mimicking in Right-sided valves deemed attention a little later than the left-sided
vivo collagen architecture. Newer materials like Peak—Optima are valves. The first successful pulmonary valvotomy was performed by
undergoing rigorous biocompatibility and biostability assays to as- Thomas Holmes Sellers on December 4, 194729 using a tenotomy
sess the suitability for implantation and even fiber optic valves are knife passed through the right ventricle in a case of Tetralogy of Fal-
being developed by Bokros and Stupka on the basis of the conceptual lot. This was followed by a series of cases by Brock using various
ideas by Dr James D Byrne. techniques.30 It was Bailey who performed the first closed tricuspid
commissurotomy for rheumatic heart disease in the 1950s. Kay intro-
Stentless Valves duced his simple technique of bicuspidization of the tricuspid valve
for tricuspid regurgitation with satisfactory results. But probably the
Despite all these modifications and designs, problems of the anti- most popular operation, which has stood the test of time and is prac-
coagulation and those of thromboembolic potential remained with ticed even today in 2010 was introduced by DeVega in 197231 who
mechanical valves and therefore there was a kind of resurrection of described a semicircular annuloplasty to reduce the circumference
the use of stentless valves in late 1980s, pioneered by Tirone David of the tricuspid annulus. Later, for increasing durability of repair,
from Canada.25 He developed a low pressure fixed, stentless, cloth Carpentier and Duran introduced the annuloplasty rings for the tri-
covered valve known as the Toronto Stentless Porcine Valve (SPV) cuspid position.
with excellent mid-term results. Following suit Medtronic intro-
duced the stentless “Freestyle” valve in the form of porcine aortic Aortic Valve Repair
root with Dacron covering of the inflow portion in 1992. This gluter-
aldehyde treated root was fixed with a zero transvalvular pressure Repair techniques of the AV essentially started in the 1960s with Ca-
drop to preserve the natural collagen crimps and integrity of cusp brol describing a technique for aortic annuloplasty in 1966.32 He
structure. Advanced anticalcification treatment with alpha immuno was pre-empted by Harken et al. and Starzl et al. in the pre-CPB era,
oleic acid was provided to prevent late degeneration. These stent- who described techniques like circumclusion and bicuspidization
less porcine xenografts thereby provided an alternative to aortic and in the post-CPB era by Lillehei (single cusp extension), Mulder
homograft, which remained in limited supply despite the introduc- et al. (valvuloplasty) and Garamella (cusp resuspension). Fagih and
tion of cyropreservation. They also provided better hemodynamics Duran forwarded certain principles for cusp repair or extension us-
compared to the stented bioprostheses and led to better resolution ing pericardium in young patients with aortic regurgitation. Frater,
of left ventricular hypertrophy. Pari Passu with the resurgence of the Trusler, Carpentier, Cosgrove and lately Tirone David too have con-
stentless technology, efforts continued to look for means to avoid tributed immensely in this arena.
Tissue Engineered Heart Valves hoeffer in the year 2000.38 This valve was subsequently acquired by
Medtronic and renamed the Melody valve. Thereafter on April 16,
This is a relatively recent, but rapidly expanding field. The term “tis- 2002, Alain Cribier introduced the first human percutaneous AV re-
sue engineering” was coined by Fung in 1987 at a National Science placement, using a valve with three equine pericardial leaflets and
Foundation workshop in Washington, DC. Perhaps the first example inserted within a stainless steel balloon expandable stent antegrade-
of heart valve tissue engineering came out of the University of Vienna ly through the trans-septal route39 (Figs 79.4A to C). This being com-
in 1991, when Grimm et al. presented their success in inducing en- plex and potentially hazardous, was soon replaced by the retrograde
dothelium to grow on gluteraldehyde-fixed bovine pericardium.33 transfemoral and antegrade transapical techniques.
The basic idea is to transplant autologous cells on to a biocompat- Regurgitant valvular lesions have become another major
ible and biodegradable scaffold that is shaped like a heart valve. The target for transcatheter therapies. Novel percutaneous devices are
cells form their own extra cellular matrix and they get attached and currently being evaluated in animal models, while a few others are
take the shape of the scaffold. By the time the valve gets fabricated by being explored in humans. John Webb40 from Vancouver, Canada
replication, the polymer scaffold starts degrading thereby leaving a and Ted Feldman from Evanston Northwestern Hospital in Chicago,
viable, living, autologous heart valve quite akin to the natural valve. Illinois, deserve historical recognition for their important contribu-
First successful implant of a decellularized allograft seeded with au- tions to these MV therapies.
tologous vascular endothelial cells was done by Dohmen and col-
leagues with satisfactory results.34 ROBOTIC VALVE SURGERY
PERCUTANEOUS APPROACHES TO The term “robot” was coined in 1921 by the Czech play writer Karel
Capek based on the Czech language word “Robota” meaning forced
VALVULAR HEART DISEASES
labor, and he used this notion in his play “Rossom’s Universal Ro-
First human percutaneous valvuloplasty was performed in 1985 by bots.”
Alain Cribier for critical aortic stenosis.35 It was Andersen, who in The potential advantages of telerobotics and telepresence were
1988, conceptualized combining a prosthetic valve and a stent to cre- recognized by Scot Fisher, a National Aeronautics and Space Ad-
ate a device that he deployed into an animal heart using a catheter ministration (NASA) scientist and Joe Rosen, a Stanford plastic sur-
and guidewire percutaneously in 1992.36 geon, and they collaborated with Phil Green of Stanford Research
Philipp Bonhoeffer, in 1999, offered an absolutely new and ex- Institute to develop a robotic arm, which subsequently drew the at-
citing vista of percutaneous valves. He used the bovine jugular vein tention of Pentagon’s Defence Advanced Research Projects Agency
with a valve inside and he sutured it inside a cardiopulmonary (CP) (DARPA) with the goal of “bringing the surgeon to the wounded
stent and delivered, using a balloon catheter through a 22 Fr deliv- soldier– through telepresence.” This later on became available to the
ery system.37 The first human implantation was performed by Bon- civilian population and the involvement of Computer Motion Inc
A C
Figures 79.4A to C: (A) Top view of the percutaneous heart valve in the closed position showing the three pericardial leaflets sutured to the
stainless-steel stent; (B) Side view of the percutaneous heart valve crimped over a 3 cm by 22 mm balloon catheter; (C) Side view of the percutaneous
heart valve after being expanded by the delivery balloon35
Figure 79.5: Da Vinci system set-up Figure 79.6: ZEUS system set-up
of Santa Barbara, CA led to the development of the first Automated smoother and more precise video control, which further facilitates these
Endoscopic System for Optimal Positioning (AESOP), a robotic arm, operations. Mitral repairs using the da Vinci Surgical System were first
controlled by the surgeon’s voice commands to manipulate an endo- performed in May 1997 by Carpentier in Paris48 and by Mohr in Leip-
scopic camera. Shortly thereafter, Integrated Surgical Systems (now, zig.49 Chitwood and colleagues50 too have contributed immensely and
Intuitive Surgical) after extensive designing and redesigning intro- have pioneered their own technique of micro-MV operations using di-
duced the da Vinci surgical system (Fig. 79.5) and to counter that rect transthoracic aortic clamping and antegrade cardioplegia through
within a year Computer Motion put the ZEUS system into production ascending aorta.
(Fig. 79.6).
Interestingly, the use of videoscopy in cardiac surgery is not new; CONCLUSION
Cutler41 and Sakakibara42 used cardioscopy clinically earlier in the
20th century, but technical limitations at the time precluded widespread Ever since Harken enumerated his 10 commandments for the ideal
adoption. Developments in minimally invasive mitral surgery began prosthetic heart valve, incredible strides like robotics, port access
only in the mid-1990s with the pioneering work of Cohn,43 Cosgrove44 system, genetic engineering notwithstanding, a heart valve prosthe-
and others. In 1994, surgeons at Stanford University first used a periph- sis, which is safer than the condition it corrects, remains a mirage.
eral perfusion system with intra-aortic occlusion balloon (popularized However, tissue engineering is likely to give an unlimited supply of
later as Port-Access) for MV surgery.45 In 1996, Kaneko first used video heart valves “off the shelf” with no need for any anticoagulation with
assistance during a sternotomy-based MV replacement.46 Carpentier long-term durability—a leap towards the quest for an ideal valve. For
performed the first true video-assisted MV repair in early 1996, through the moment, the exciting journey of development of valvular heart
a minithoracotomy using cold fibrillatory arrest.47 The addition of a disease remains an unfulfilled agenda, but future certainly looks
voice-activated robot (AESOP 3000) for camera control now enables promising and bright.
REFERENCES
1. Westaby S, Bosher C. Landmarks in Cardiac Surgery. Oxford, UK: Isis Medical Media Ltd; 1997.
2. Yacoub AA. Rheumatism and the history of mitral valvotomy. Ann R Coll Surg Engl. 1974;54(6):309-12.
3. Cutler EC, Levine SA. Cardiotomy and valvulotomy for mitral stenosis: Experimental observations and clinical notes concerning an operated case
with recovery. Boston M & S J. 1923;188:1023-7.
4. Souttar HS. The surgical treatment of mitral stenosis. Br Med J. 1925;2(3379):603-6.
5. Bailey CP. The surgical treatment of mitral stenosis (mitral commissurotomy). Dis Chest. 1949;15(4):377-97.
6. Harken DE, Ellis LB, Ware PF, et al. The surgical treatment of mitral stenosis; valvuloplasty. N Engl J Med. 1948;239(22):801-9.
7. Kortz AB, Swan H. Direct vision trans-aortic approach to the aortic valve during hypothermia: experimental observations and report of successful
clinical case. Ann Surg. 1956;144(2):205-14.
8. Harken DE, Taylor WJ, Lefemine AA, et al. Aortic valve replacement with a caged ball valve. Am J Cardiol. 1962;9:292-9.
9. Gibbon JH. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med. 1954;37(3):171-85.
10. Hufnagel CA, Harvey WP, Rabil PJ, et al. Surgical correction of aortic insufficiency. Surgery. 1954;35(5):673-83.
11. Murray G. Homologous aortic-valve-segment transplants as surgical treatment for aortic and mitral insufficiency. Angiology. 1956;7(5):466-71.
12. Starr A, Edwards ML. Mitral replacement: clinical experience with a ball-valve prosthesis. Ann Surg. 1961;154:726-40.
13. Gott VL, Alejo DE, Cameron DE. Mechanical heart valves: 50 years of evolution. Ann Thorac Surg. 2003;76(6):S2230-9.
14. Trace HD, Bailey CP, Wendkos MH. Tricuspid valve commissurotomy with a one-year follow-up. Am Heart J. 1954;47(4):613-8.
15. Brofman BL. Right auriculoventricular pressure gradients with special reference to tricuspid stenosis. J Lab Clin Med. 1953;42:789.
16. Borman JB, Applebaum A, Hirsch M, et al. Quadruple valve commissurotomy. J Thorac Cardiovasc Surg. 1975;70(4):712-6.
17. Beall AC Jr, Morris GC Jr, Cooley DA, et al. Homotransplantation of the aortic valve. J Thorac Cardiovasc Surg. 1961;42:497-506.
18. Ross DN. Homograft replacement of the aortic valve. Lancet. 1962;2(7254):487.
19. Barratt-Boyes BG. Homograft aortic valve replacement in aortic incompetence and stenosis. Thorax. 1964;19:131-50.
20. Ross DN. Replacement of aortic and mitral valves with a pulmonary autograft. Lancet. 1967;2(7523):956-8.
21. Binet JP, Duran CG, Carpentier A, et al. Heterologous aortic valve transplantation. Lancet. 1965;2(7425):1275.
22. Carpentier A. The concept of bioprosthesis. Thoraxchir Vask Chir. 1971;19(5):379-83.
23. Wieting DW. The Bjork-Shiley Delrin tilting disc heart valve: historical perspective, design and need for scientific analyses after 25 years. J Heart
Valve Dis. 1996;5(Suppl 2):S157-68.
24. Bhuvaneshwar GS, Muraleedharan CV, Vijayan GA, et al. Development of Chitra tilting disc heart valve prosthesis. J Heart Valve Dis. 1996;5(4):448-
58.
25. David TE, Pollick C, Bos J. Aortic valve replacement with stentless porcine aortic bioprosthesis. J Thorac Cardiovasc Surg. 1990;99(1):113-8.
26. Carpentier A, Deloche A, Dauptain J, et al. A new reconstructive operation for correction of mitral and tricuspid insufficiency. J Thorac Cardiovasc
Surg. 1971;61(1):1-13.
27. Duran CG, Ubago JL. Clinical and hemodynamic performance of a totally flexible prosthetic ring for atrioventricular valve reconstruction. Ann
Thorac Surg. 1976;22(5):458-63.
28. Carpentier A. Cardiac valve surgery–the “French Correction”. J Thorac Cardiovasc Surg. 1983;86(3):323-37.
29. Sellors TH. The surgery of pulmonary stenosis; a case in which the pulmonary valve was successfully divided. Lancet. 1948;1(6513):988.
30. Shumaker HB Jr. The evolution of cardiac surgery. Bloomington: Indiana University Press; 1992. p. 98.
31. De Vega NG. [Selective, adjustable and permanent annuloplasty. An original technic for the treatment of tricuspid insufficiency]. Rev Esp Cardiol.
1972;25(6):555-6.
32. Cabrol C, Cabrol A, Guiraudon G, et al. [Treatment of aortic insufficiency by means of aortic annuloplasty]. Arch Mal Coeur Vaiss. 1966;59(9):1305-
12.
33. Grimm M, Eybl E, Grabenwoger M, et al. Biocompatibility of aldehyde-fixed bovine pericardium. An in vitro and in vivo approach toward im-
provement of bioprosthetic heart valves. J Thorac Cardiovasc Surg. 1991;102(2):195-201.
34. Dohmen PM, Lembcke A, Hotz H, et al. Ross operation with a tissue-engineered heart valve. Ann Thorac Surg. 2002;74(5):1438-42.
35. Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific aortic stenosis with percutaneous heart valve: Mid-term follow-up from the initial
feasibility studies: the French experience. J Am Coll Cardiol. 2006;47(6):1214-23. Epub 2006.
36. Andersen HR, Knudsen LL, Hasenkam JM. Transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and
initial results with implantation by catheter technique in closed chest pigs. Eur Heart J. 1992;13(5):704-8.
37. Bonhoeffer P, Boudjemline Y, Saliba Z, et al. Transcatheter implantation of a bovine valve in pulmonary position: a lamb study. Circulation.
2000;102(7):813-6.
38. Bonhoeffer P, Boudjemline Y, Saliba Z, et al. Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic
conduit with valve dysfunction. Lancet. 2000;356(9239):1403-5.
39. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first hu-
man case description. Circulation. 2002;106(24):3006-8.
40. Webb JG, Harnek J, Munt BI, et al. Percutaneous transvenous mitral annuloplasty: initial human experience with device implantation in the coro-
nary sinus. Circulation. 2006;113(6):851-5. Epub 2006.
41. Cutler E, Beck C. Surgery of the heart and pericardium. In: Nelson (Ed). Loose Leaf Surgery. New York: Thos. Nelson & Sons; 1927. pp. 233-6.
42. Sakakibara S. Direct visual operation of aortic stenosis with a cardioscope: studies on cardioscope no. 2. Bull Heart Inst Jap. 1958;2:1-21.
43. Cohn LH, Adams DH, Couper GS, et al. Minimally invasive cardiac valve surgery improves patient satisfaction while reducing costs of cardiac
valve replacement and repair. Ann Surg. 1997;226(4):421-6; discussion 427-8.
44. Cosgrove DM 3rd, Sabik JF, Navia JL. Minimally invasive valve operations. Ann Thorac Surg. 1998;65(6):1535-8; discussion 1538-9.
45. Pompili MF, Stevens JH, Burdon TA, et al. Port-access mitral valve replacement in dogs. J Thorac Cardiovasc Surg. 1996;112(5):1268-74.
46. Kaneko Y, Kohno T, Ohtsuka T, et al. Video-assisted observation in mitral valve surgery. J Thorac Cardiovasc Surg. 1996;111(1):279-80.
47. Carpentier A, Loulmet D, Carpentier A, et al. [Open heart operation under videosurgery and minithoracotomy. First case (mitral valvuloplasty)
operated with success]. C R Acad Sci III. 1996;319(3):219-23.
48. Carpentier A, Loulmet D, Aupecle B, et al. [Computer assisted open heart surgery. First case operated on with success]. C R Acad Sci III.
1998;321(5):437-42.
49. Falk V, Walther T, Autschbach R, et al. Robot-assisted minimally invasive solo mitral valve operation. J Thorac Cardiovasc Surg. 1998;115(2):470-1.
50. Chitwood WR Jr, Wixon CL, Elbeery JR, et al. Video-assisted minimally invasive mitral valve surgery. J Thorac Cardiovasc Surg. 1997;114(5):773-80;
discussion 780-2.
80 History of Surgery for Ischemic
Heart Disease
Katariya K
INTRODUCTION not perform another such surgery till 20 years thereafter, stating in a
letter to Dr Dwight Harken in 1961 that it was useless to be 20 years
Surgery for ischemic heart disease is a relatively recent phenomenon ahead of the times.4
which began, in a physiological sense, only a little more than 50 years To perform true open heart surgery, a machine was needed to be
ago. By the same token, surgery for any heart disease does not have able to bypass the pump function of the heart and the gas exchange
a much longer history either. It was in the late 19th century when the function of the lungs simultaneously.
great Austrian surgeon, Christian Billroth pronounced surgery on the The first person to correlate angina with coronary arteriosclero-
heart to be “a foolish endeavor”, “certain to cause a mortality” and sis was none other than Edward Jenner, famous for many other rea-
“one to be attempted not by surgeons, but by butchers and murder- sons. He did so in 1799, about 3 decades after William Heberdeen
ers”. had presented the first classical description of angina pectoris at the
Prior to addressing the pathology at question, surgery for is- Royal College of Physicians.5 By the 1920s, it was well established
chemic heart disease was aimed at symptomatic relief. The com- and agreed that the major cause of angina pectoris was some sort
monest or may be the only symptom focused on at that time was of a blockage to blood flow in the coronary arteries, although there
angina and multiple types of surgical procedures were performed to were multiple articles in journals, newspapers and other media that
alleviate the misery of this pain, some of which, actually, were quite rubbished this explanation.6 The blockage was envisaged to be in the
effective. Nonetheless, none of these early procedures, as described first part of the ascending aorta, the coronary arteries or their small-
below, tried to change the natural course of the disease by attacking est branches (Fig. 80.2).7
the reason for the ischemia in the first place.
By all accounts, Dr Daniel Hale Williams, an African American
surgeon, one evening in March 1893, was the first person to operate
successfully on a patient with a stab wound to the heart.1 On opening
the pericardium, it seemed that the right ventricle was not bleeding
anymore, and so, no suture was placed on the heart and the patient
survived, what may otherwise have been a situation of tamponade.
A few years later, in September 1896, Dr Ludwig Rehn successfully,
for the first time, sutured a stab wound on the heart and the patient
survived.2 Over the next 10 years, he had the opportunity to operate
on 124 such patients with a 60% survival, quite remarkably.
Surgery around the heart, on the pericardium and the pulmo-
nary vessels was carried out in the years to follow, mostly unsuccess-
fully, by several pioneers such as Weill, Delorme and Sauerbruch.
Theodore Tuffier was the first to attempt opening up of a stenotic
(aortic) valve in 1912, in the presence of the Nobel Laureate, Alexis
Carrel (Fig. 80.1).3 Although the procedure did not involve opening
of any of the cardiac chambers or great vessels, amazingly, the patient
did well and returned home. Mr Henry Souttar, a British surgeon, in
1925, was the first to perform a successful mitral commissurotomy
using his finger. He was ridiculed by his fellow physicians and did Figure 80.1: Alexis Carrel
Chapter 80  History of Surgery for Ischemic Heart Disease 677
innervation of the heart and the benefit of sympathetic denervation

leading to alleviation of the pain.
Kerr was not the first to suggest denervation surgery for relief of
angina. Francois Franck had suggested this in 1899 and this was first
adopted by Jonessco sixteen years later in Bucharest.10 Wenkleback,
White and Senque had all suggested denervation leading to a radical
or selective cervicothoracic sympathectomy during the same period,
with differing success rates.7 White summarized the approximately
300 reported cases until then in his review in 1933, suggesting a 50%
success rate and mortality varying between 7% and 20% in the vari-
ous series.10 Needless to say, although the symptoms were relieved in
many patients, by their accounts, the pathology was still untreated.
By 1935, cervicothoracic sympathectomy for treatment of angina had
fallen into disfavor.10
Paravertebral Injection of Alcohol

in Dorsal Nerve Roots
Figure 80.2: Operative treatment of angina pectoris; exposure of
the superior sympathetic ganglion by an oblique incision in front of the In the mid-1920s, Mandl in Europe and Swetlow in New York started
sternocleidomastoid muscle. The superior cardiac nerve is seen passing injections of alcohol into the dorsal nerve roots on the left side to
forward and downward under the carotid sheath which has been abolish angina pain on the anatomical basis that these nerve roots
retracted forwards. Source: The Annals of Surgery, 1925 were the critical pathway carrying pain of cardiac and aortic origin.
Between 1926 and 1930 anatomical and physiological validation of
this concept was carried out and published by a number of investi-
gators including Cannon, Braeucker and Kuntz.11,12 In early reports
SURGICAL TREATMENT OF ISCHEMIC of the procedure, there was no standardization as to the number of
HEART DISEASE: THE FIRST ERA (PRE 1935) roots to be injected. However, by the late 1920s, Swetlow reported in-
jecting between 2 and 9 nerve roots with excellent results. His second
In 1880 Langer8 first described the existence of extensive, minute series with this standardization technique relieved 18 of 26 patients
vascular communications between the normal coronary circulation so injected of their angina pain completely. It became important to
and the vascular supply of surrounding extracardiac structures such show that these nerve roots carried the pain signals which was why
as the diaphragm, bronchi, and the pericardium, what came to be even total cervical sympathectomy was failing in some patients.
known later as extracardiac collaterals. This finding laid the foun- James White from Boston, along with his colleagues developed
dation for surgery for ischemic heart disease utilizing extracardiac a canine model where a ligature around the left anterior descending
blood vessels to carry blood to coronary arteries beyond the dis- (LAD) artery was brought out through the skin of the animal. Pull-
eased areas. Another future avenue of surgical revascularization was ing on this ligature obstructed the LAD that caused acute systemic
opened in 1898 when Pratt9 suggested that coronary sinus blood flow changes in the dog which were thought to be due to the severe angi-
could be reversed by the insertion of an artery, thereby enhancing na pain induced by the occlusion. Various neurosurgical procedures
myocardial blood flow. Although this suggests that the pathology were then attempted to alleviate the pain to demonstrate a cause and
causing ischemic heart disease was understood, early surgical thera- effect mechanism of ablating the neural pathway through the dorsal
py did not directly attempt to affect it. Rather, other approaches were root ganglia. These experiments between 1926 and 1930, which were
utilized to try and achieve symptomatic relief. eventually reported in 1933 by White13 led to the definition of the su-
perior, middle and inferior cardiac nerves. This hypothesis was fur-
Cervicothoracic Denervation Surgery ther tested among 40 patients at the Massachusetts General Hospital
suffering from severe angina pain.10
By 1925, 63 cases had been recorded in the literature that had Thirty other patients were treated using this method at Presbyte-
undergone one or another surgical procedure for the treatment of rian hospital, New York, by Robert Levy and reported in 1931.14 Both
angina pectoris, most of which were denervation of the sympathetic series of White and Levy showed significant relief of pain in over two-
or parasympathetic innervation of the heart and aorta.7 Eight more thirds of patients with, what they termed as failure, in less than 20%
cases were reported by Harry Hyland Kerr at his presentation to the patients. Failure was ascribed to poor, improper or misplaced injec-
American College of Surgeons in 1925.7 He spoke in detail about the tion technique.
Despite the blind injection technique, reported complications due to cardiac events. Only a few patients received thyroid extract in
were few and there were no mortalities reported due to the proce- some dosage after surgery.16
dure. Marvin, in his review paper in 1935, asked a pertinent ques- This operation still did not address the pathology causing the
tion of whether it was safe to actually abolish pain in these patients angina or the ischemic heart disease, but rather than just target
with the underlying condition that they had not being physiologically the pain, there was some physiological basis to the treatment. How-
corrected. He concluded to say there was no apparent hastening of ever, it was quite a wonder that 29 patients with severe angina could
death or morbidity by this technique and no one, at that time, could undergo surgery of this magnitude, and that too under local anesthe-
prove otherwise. sia, since the surgeons wanted to keep the patients awake during
the procedure, to hear them talking for fear of injuring the recurrent
Complete Thyroidectomy laryngeal nerve during surgery. The summary of the report from
Boston in 1932 stated that the operation provided patients with
Removal of the normal thyroid gland for the treatment of heart dis- severe angina hope, heretofore wanting. Further, it summarized that
ease was first proposed by Blumgart, Levine and Berlin,15,16 although total thyroidectomy produced a reduction in pain disproportionate
this was based on the observation by Kocher in 1902, of a patient to the depression of the basal metabolic rate. This fact, coupled with
who had her angina pain vanish following a subtotal thyroidectomy. the immediate and dramatic relief, the skin temperature changes, the
Subtotal thyroidectomy for angina was first performed by Boas in effect of adrenalin before and after operation, the effect of adrena-
1926 and was then tried by many others but without much success. lin in the production of experimental angina pectoris, the known
The first total removal of the thyroid gland for heart disease was per- relationship between the thyroid, the adrenal and the sympathetic
formed on December 14, 1932 at the Peter Bent Brigham Hospital in system suggested that adrenal secretion is an important factor in the
Boston. The rationale behind this operation was to lower the meta- attacks of angina pectoris.
bolic rate and thus the total work of the heart. Total thyroidectomy
was also thought to lower the effects of adrenaline on the heart and Alexis Carrel
thus make it less susceptible to abrupt changes in heart rate and in-
crease in cardiac work. The initial report from Boston included 53 While others around the United States and Europe were utilizing the
patients in two groups who underwent total thyroidectomy for heart above approaches in trying to alleviate angina, the legendary French
disease.17 One group of patients had congestive heart failure and the born surgeon, Alexis Carrel, was the first to take speculation into the
other had severe angina pectoris (angina decubitus). The group of operating room, and thereby laid the basis for the future approach of
patients with angina exhibited striking improvement after this sur- aortocoronary bypass grafting using arterial and venous grafts.
gery. This improvement and alleviation of pain was much more than In 1910, he reported on an amazing series of experiments that
in patients who had undergone cervicothoracic sympathectomy for constitute the earliest forms of direct coronary artery bypass. He re-
the same symptom. That the benefit appeared almost immediately ported the anastomoses of the innominate artery of one dog into the
after surgery could not be explained by the gradual lowering of the distal coronary artery of another. In other animals, he performed di-
basal metabolic rate, which took up to 4 weeks to develop, as evi- rect coronary artery bypass by suturing a homologous, free carotid
denced by the appearance of surgical myxedema.16 Tests using sub- artery graft between the descending thoracic aorta and the left coro-
cutaneous adrenaline injections in patients before and after thyroid- nary artery.18 Although the animals died quickly, these procedures
ectomy were used to check response to the operation. More than 90% were the predecessors and foundations of today’s mammary artery
of patients did not experience chest pain after subcutaneous adrena- bypass procedures. In other animals, Carrel performed the first vein
line injection after surgery compared to the crushing chest pain that bypass grafting of the arterial tree by interposing a vein segment into
almost all patients felt prior to removal of their thyroid. a dog’s transected aorta.19 This work was the obvious foundation of
Various theories propounded in articles published about this the current used saphenous vein coronary bypass procedure. The
technique included a psychological cause of angina that was not Nobel Prize in Medicine or Physiology awarded to Carrel in 1912 for
adequately treated by thyroidectomy or some sort of neurogenic his work on transplantation and vascular grafting was the first to be
disturbance that led to pain relief in these patients. The power of awarded for medical research performed in the United States.
suggestion and the introspective nature of these patients due to the
suffering from sever pain were also alluded to as causes that were left Coronary Venous Ligation
untreated by and sometimes worsened due to myxedema caused by
the surgery. In January 1928, Joseph Wearn20 presented evidence to show a di-
In the series reported from Boston there were only two immedi- rect connection other than through the capillaries between the coro-
ate postoperative deaths out of 29 patients in the angina group who nary arteries and the chambers of the heart through the Thebesian
underwent surgery and four late postoperative deaths. All these were veins. This connection was shown by perfusion, injections and serial
sections of the myocardium. Communications between the larger observations that would lead him to change his focus towards car-
coronary veins and the Thebesian veins were also demonstrated by diac surgery and lead pioneering efforts towards clearing the future
the same methods. Under certain conditions it was shown that as of surgery for ischemic heart disease.22 He was studying the effects of
much as 90% of the arterial flow may escape via Thebesian vessels. pericardial adhesions and scars on cardiac compression and noted
Wearn also reported that in the event of gradual closure of the orific- that these experimentally created adhesions were quite vascular.
es of the coronary arteries, Thebesian vessels could supply the heart Meanwhile, Moritz and his colleagues23 also noted enhanced anas-
muscle with sufficient blood to enable it to maintain an efficient tomoses between the coronary arteries and extracardiac structures
circulation. Others would subsequently exploit this concept by in humans dying of pericarditis, as well as vascular anastomoses
partially ligating the venous drainage of the heart to redirect flow between pericardial fat pads and branches of the aorta. In 1934, Beck
back into the myocardium. noted brisk bleeding from both ends of a transected pericardial scar
and this sparked in him an interest in devising methods of coronary
Cardiac Irradiation revascularization. He developed several procedures for increasing
the vascular anastomoses between the coronary arteries and sur-
In 1930 Sussman21 was the first to report the use of cardiac irradia- rounding tissues, beginning in 1932 with animals and in 1935 in
tion to denervate the heart in an attempt to produce coronary vaso- humans. In the first of these procedures, he induced sterile pericar-
dilation. The relief of angina was marginal in the best cases and the ditis by mechanically abrading the epicardium and visceral pericar-
procedure did not gain much popularity. dium. This caused vascular adhesions to form, leading him to hope
that this neovascularization would communicate with myocardial
THE SECOND (PRE HEART-LUNG MACHINE) vessels. This procedure, termed cardiopericardiopexy or pericardial
poudrage, was described in the literature in 1935.24
ERA (1932-1954)
In 1935, Beck pioneered the use of cardiomyopexy,25 in which,
In this second era the surgical treatment of ischemic heart disease first powdered bone was instilled into the pericardial space and me-
moved from observations and indirect operations to operations tar- chanical abrasion of the visceral and parietal pericardium was per-
geting the physiology and pathology more directly, assaulting the formed using a burr. Then a pectoralis major muscle was brought
heart in countless ways in an effort to induce neovascularization into the pericardium and sutured onto the epicardial surface. In
and improve collateral circulation to the myocardium. The heart was experimental animals, Beck reported, that with the muscle flap in
abraded, irritated, scarred, wrapped, implanted, denervated and place, both the coronary arteries could be safely occluded simulta-
perforated with acupuncture needles; the cardiac venous drainage neously without significant change. Heinbecker and Barton, in 1939,
was ligated and arterialized. suture retrosternal tissues to the epicardial surface after chemical
poudrage, to induce neovascularization.
Cardiopericardiopexy/Pericardial Poudrage Over the next few years, Beck and others further experimented
by bringing a variety of other tissues into the pericardium, including
and Cardiomyopexy
omentum. Other agents such as sodium morrhuate and sand, talc,
Claude Beck (Fig. 80.3), initially a neurosurgeon at the Cleveland phenol, silver nitrate, polyvinyl ether foam (Ivalon), and even asbes-
clinic and the Western Reserve University, reported, in 1930, several tos were used to induce pericarditis and eventual vascular adhesions
over the next 20 years.26-28 Harken used phenol as an agent to effect
“de-pericardialization” to eliminate the barrier to collateral blood
flow.
Beck’s cardiomyopexy was modified by O’Shaughnessy and oth-
ers who brought a variety of vascular organs into contact with me-
chanically or chemically abraded pericardium.29,30 Everything from
the omentum (cardio-omentopexy) to the lung (cardiopneumopexy),
jejunum (cardio-jejunopexy), pedicled skin grafts, the stomach (car-
diogastropexy) and the spleen (cardiolienopexy) were used to bring
new blood flow to the heart. These techniques achieved good success
in alleviating symptoms, allowing for increasing exercise tolerance
and were used by some investigators up until the mid-1950s due to
their popularity with the surgical fraternity.
Other methods of improving collateral flow to the myocardium
were utilized by many investigators using a variety of techniques. In
Figure 80.3: Claude Beck 1956, Kline and associates28 occluded the left pulmonary artery in
dogs in order to increase bronchial artery collateral flow (intended to Beck I and II Operation/Coronary
then improve myocardial flow by anastomoses), then sutured parts Sinus Procedures
of the lung to epicardium denuded by silver nitrate. Similarly, in 1957
Kownacki increased pulmonary collateral flow to the heart by ligat- In 1941, Fateux and Palmer reported the use of great cardiac vein
ing the lingular vein, then suturing the lingula to the epicardium. ligation (earlier described by Gross in 1939).34 Beck, who had initially
reported that coronary sinus ligation was unjustified, was routinely
Myocardial Retroperfusion using it by 1954 and, along with poudrage and mediastinal fat graft-
ing, came to be known as the Beck I operation.
Robertson in 1934 and Gross in 1936, took a new approach to revas- Roberts, in 1943, reported experimental arterialization of the
cularization by adapting the thoughts earlier expressed by Pratt in coronary sinus to increase coronary blood flow by utilizing brachio-
18989,30 about redirecting the venous drainage of the heart through cephalic, subclavian or innominate artery grafts placed through glass
the Thebesian veins. They caused venous congestion to occur in tubes and sutured onto the coronary sinus.35 Further, the coronary
the myocardium by partially ligating the great cardiac vein and the sinus procedure, not sufficient by itself, was used and reported in
coronary sinus. This raised venous pressure intramyocardially and conjunction with pericoronary plexus neurectomy, using sharp dis-
caused a reversal of flow in the Thebesian veins thus forcing the section and chemical sclerosis, by Fateux in 1946, somewhat similar
blood from the ventricular chambers directly through the Thebesian to his experimental report from a decade before.30
system into the myocardium. This retroperfusion technique was uti- In 1946, Beck also turned to arterialization of the coronary sinus,
lized for many years and formed the basis of the currently employed first performing it in dogs using either common carotid or intercostal
synchronized coronary sinus catheter retroperfusion, a technique arterial as well as free autografts of the jugular vein, before being the
used during high-risk angioplasty. Wang and his colleagues from first to apply the method in humans in 1948, using either free vein or
Columbia re-visited this technique and reported use of a conduit to brachial artery autografts. He began to perform coronary sinus arte-
establish ventricular to great cardiac vein retroperfusion in dogs as rialization followed by partial sinus ligation as a staged procedure,
an alternative revascularization technique in patients with end stage which became known as the Beck II operation.30
coronary artery disease.31
Vineberg Operation
Direct Implantation of Vessels
Arthur Vineberg (Fig. 80.5), a surgeon at McGill University, reported
into Myocardium
another very important advance. He implanted the internal mammary
Griffith and Bates first reported direct implantation of vessels into arteries directly into the myocardium in dogs, to increase myocar-
the myocardium in 1938.32 This was accidental, when in trying to dial blood flow. He believed that the large venous sinusoids present
repair a perforation of the left ventricle they had caused during the in the myocardium would absorb the increased blood flow, while at
course of surgery for coronary artery disease; they sutured part of the
pectoral muscle, along with its branches of the internal mammary
artery into the hole. This predated the deliberate Vineberg procedure
by a decade (Fig. 80.4). Fieschi, in 1939, suggested and then reported
in 1942,33 bilateral ligation of the internal mammary artery that was
thought to shunt blood flow through the pericardiophrenic branches
back to the heart through anastomoses with the epicardium. Lillehei,
also in 1939, created a surgical communication between the pulmo-
nary artery and the left atrium in patients in an effort to increase left
heart and thus anterograde coronary artery blood flow.
By the early 1940s, Gordon Murray from Toronto, began to use
a variety of different techniques for coronary artery surgery includ-
ing the first experimental coronary divisions followed by direct arte-
rial repair and venous interposition homografts (paper read at the
Graduate Fortnight of The New York Academy of Medicine, Octo-
ber 17, 1951).30 Murray’s report, like Carrel’s operations on the dog Figure 80.4: Angiogram 2 months after insertion of a Vineberg
aorta previously, would become the predecessor of saphenous vein to internal mammary artery into the left ventricle of a dog. Note the open
coronary anastomosis. communications with branches of the coronary artery.
while Thal performed experimental mammary artery grafting onto

coronary arteries, carried out on a beating heart using a suture tech-
nique. Finally, Goldman and associates40 described a new approach
to myocardial revascularization, which involved channeling left ven-
tricular blood through a carotid homograft into the myocardium.
In 1957, Massimo and Boffi reported a novel experimental tech-
nique using T-tubes to channel blood from the ventricle to a lacuna
created within the myocardium.41 About the same time Smith and
his colleagues reported cases using saphenous vein, homologous
carotid artery or prosthetic arterial grafts from the thoracic aorta to
the myocardium.42 In 1957, Sabiston, Fateux and Blalock published
a report describing angiographic findings of anastomoses between
implanted mammary arteries and myocardial vessels (the Vineberg
principle) and their modification of the Vineberg technique utiliz-
ing free carotid arteries in dogs.43 In 1958, Senning reported his
experimental split graft patch technique where he used a split seg-
ment of the autologous mammary artery to patch a defect created
Figure 80.5: Arthur Vineberg by performing coronary endarterotomy.44 Carter and Roth reported
a nonsuture, metal ring technique for grafting the mammary artery
to coronary arteries in the beating dog heart and Longmire and col-
the same time preventing intramyocardial hemorrhage or rupture. leagues reported an antegrade, open coronary endarterectomy pro-
Vineberg performed the first human mammary artery implanta- cedure, performed on humans without cardiopulmonary bypass.30
tions in 1950 and reported those a year later.36 This procedure often
relieved angina and physiologically increase myocardial blood flow, POST HEART-LUNG MACHINE ERA
and was used until the early 1970s. In 1962, Mason Sones proved the
(AFTER 1954)
merit of the Vineberg operation when he angiographically demon-
strated the connections between the mammary artery implant and Many innovators were working on various iterations of the heart-
the myocardial vessels in humans.37 lung machine to allow its successful use in humans and not all of
Sones later reported38 on angiographic assessment of 1,100 in- them were surgeons. The first perfusion device was created by Alex-
ternal mammary implants performed at the Cleveland clinic up to is Carrel working side by side with Charles Lindbergh, the famous
1968 in which the implant was patent in 92% of patients and IMA— aviator. John Gibbon (who worked alongside IBM) probably con-
coronary artery communications were observed in 54%. It is of inter- tributed more to the development of the heart-lung machine than
est that in 1968-69, when the Cleveland clinic was starting to perform anyone else over the course of 20 years from the mid-1930s on-
direct coronary artery bypass grafting with saphenous vein con- wards at various laboratories at the Massachusetts General Hospital,
duits, they were still doing Vineberg procedures, especially double University of Pennsylvania and Thomas Jefferson University in
implants. Philadelphia. Others, including Forest Dodril (who worked with
GM), John Kirklin, C Walton Lillehei, Hank Edmunds, Clarence Den-
Other Operations on the Beating Heart nis, Clarence Crafoord, Ake Senning and Mario Digliotti were among
those whose contributions were invaluable towards the develop-
In 1954, Gordon Murray reported his experiments with direct bypass ment of what would become the holy grail of cardiac surgery, the
grafting of the coronary arteries using systemic arteries including the heart-lung machine.
carotid, axillary and internal mammary arteries.30 In 1955, May from Further contributions towards the development of better
San Francisco, performed the first experimental closed, retrograde oxygenators, improvement in cardioplegia, filters and circuit led to
on dogs and cadavers using a special corkscrew catheter to extract significant decrease in morbidity associated with using the heart-
the atheroma.39 Soon thereafter, Charles Bailey performed the first lung machine.
closed endarterectomy on a human in October 1956 using a retro- Many stories of innovative excellence, personal achievements,
grade technique, but with poor results. In 1956, Absolon performed envy and sheer luck are part of the folklore, spoken about with much
endarterectomies, as well as end-to-end or end-to-side arterial— reverence, today, that the heart-lung machine is taken for granted,
coronary artery grafting (using carotid, subclavian, or mammary and in fact, in many parts of the world, is no longer used for many
arteries, with or without Ivalon prostheses) in dogs and cadavers, surgeries on the heart.
Surgery for ischemic heart disease was still being performed on the left internal mammary artery to the LAD coronary artery in a
the beating heart as described above, in the mid-1950s and the heart- 44-year-old man.48,49 He did this on the beating heart without use of
lung machine was not used since it was not needed. cardiopulmonary bypass.
Kolesov’s team was also the first to use mechanical coronary
Coronary Artery Bypass Grafting anastomosis using stapling devices clinically. The first coronary sta-
pling device, called the “vascular circular stapling apparatus (VCA)”,
Dubost and colleagues were the first to perform an operation on the underwent several modifications.49 Its earliest prototype, the VCA-4,
coronary arteries using cardiopulmonary bypass when they per- was first applied to clinical surgery on March 22, 1967, when Kolesov
formed coronary ostial reconstruction on a patient with syphilitic constructed an end-to-end anastomosis between the left ITA and the
aortitis.45 Robert Goetz and his colleagues published, as an adden- LAD coronary artery in a 52-year-old man. A modification of the sta-
dum, in 1961, that they had performed right mammary artery to right pler with elongated bushing and vacuum suction to hold the ITA wall
coronary artery bypass in a 38-year-old patient in the Bronx, NY. while the stapling was performed was also used in several patients.49
Their main paper’s subject was the description of mammary artery Further, Kolesov was the first to perform mammary artery graft-
to coronary artery bypass grafting using a non-suture tantalum ring ing for management of acute myocardial infarction in 196830,49 and
technique on beating dog hearts.46 The addendum to this paper actu- the use of bilateral mammary grafts for the left and right coronary
ally documented the first mammary—right coronary artery bypass arteries. Kolesov initially presented his data at a cardiology meet-
in a human. ing in Leningrad where the society decided that surgical treatment
The first saphenous vein, coronary artery bypass graft procedure of coronary artery disease was impossible and had no future and
on a human was performed by David Sabiston Jr at Johns Hopkins should thus be abandoned.
Hospital on a patient he had operated upon a year prior at which Garrett, DeBakey and Dennis performed what was probably
time he had performed a right coronary endarterectomy. The artery the second saphenous vein to coronary artery bypass grafting in
had re-occluded and Sabiston then performed a saphenous vein by- November 1964 on a 42-year-old patient. Due to the unsuitability of the
pass using an end-end distal anastomotic technique after tying off native vessel up to the left main bifurcation, the scheduled endarter-
the proximal end of the native right coronary artery. He did this with- ectomy could not be performed and so a saphenous vein graft was
out the use of cardiopulmonary bypass. Unfortunately the patient used to bypass the lesion employing an end to side anastomosis with
died 3 days later of a stroke and autopsy revealed a thrombus at the the LAD coronary artery. This was not reported until 1973. However,
proximal end of the bypass graft. Sabiston presumed this thrombus angiographic evaluation of the patient in 1971 revealed a patent graft
to be the cause of the stroke and was disheartened enough to not try and an occluded native LAD proximal to the anastomotic site.30
vein bypass again for 6 years. In addition, he did not report his first While these reports of coronary bypass grafting continued to
case until 1974.47 come in from around the United States and Europe, the older tech-
The first sutured mammary artery to coronary artery bypass niques of direct myocardial implantation of the mammary artery
graft in a human was performed by a Russian surgeon, Vasilii Kolesov (Vineberg operation) and others such as the gastroepiploic artery,
(Fig. 80.6), at the First Leningrad Medial Institute, by anastomosing omentum, intercostal artery, etc. were still being used and reported
by a variety of surgeons such as Bailey, Sewell, Pearce and Dietrich.30
Sen and colleagues reported the application of myocardial
acupuncture, or the use of needles to create channels between ven-
tricular blood into the myocardium, to humans in 1965. This tech-
nique laid the foundation for what was to become the transmyocar-
dial revascularization procedure, using laser in the 1990s.50
A young Argentinian thoracic surgeon, Rene Favolaro, was just
completing his thoracic surgery fellowship at the Cleveland clinic
in the late 1960s. Much of what led to the mainstream adoption of
coronary artery bypass grafting over the next decade or two is cred-
ited to him. He had moved from being a rural physician in La Plata,
Argentina to the Cleveland clinic where he worked during his fellow-
ship alongside Mason Sones, Willem Kolff and Donald Effler who, all,
influenced him greatly. Favolaro was able to study large numbers of
angiographic studies performed by Sones and concluded that one of
the best methods of treating occlusive coronary disease would be to
connect the portion of the coronary proximal to the occlusion with a
Figure 80.6: Vasilii Kolesov portion distal to the occlusion using saphenous vein.51
Others were not willing to give up on the much practiced

Vineberg operation just yet, though. Charles Bailey commented on
one of Favaloro’s series by reflecting upon the 24-year follow-up with
the human myocardial implantation technique and called for con-
tinuation of that procedure. Favaloro was quick to concede that the
Vineberg operation had a definite role in myocardial revasculariza-
tion.52 The landmark ventriculoatrial (VA) cooperative study in 1970
which compared surgical to medical therapy for coronary artery dis-
ease still included the Vineberg operation as part of the protocol.53
Dudley Johnson and his group from Milwaukee presented in
1969, what was the first large series (301 patients) operated over a
19-month period. Only after that did surgeons and cardiologists
begin to believe that any more than 5–7% of patients with occlu-
sive coronary artery disease would be amenable for bypass grafting
surgery. This was remarked by Frank Spencer, is his discussion of
Figure 80.7: Rene Favaloro
Johnson’s paper.54
By 1969 and the early 1970s, several groups reported using the
mammary artery for routine coronary bypass grafting. Bailey first
It was for such lesions that they proposed vein interposition reported the use this in 1968 and subsequently Reed, Spencer and
and modified it into the bypass technique; the native vessel was Green from the New York University (NYU) group utilized cardiopul-
still transected and the distal anastomosis was still made end-to- monary bypass in operations using the mammary artery as a graft.
end with the distal right coronary. However, instead of making the By 1973, Carpentier reported the use of a free radial artery autograft
proximal anastomosis with the other cut end of the native vessel, and then by 1975 Bulkley had reported using arterial xenografts in
they moved more proximally by creating an anastomosis with the humans. Unfortunately, the early results using radials and xenografts
ascending aorta; the cut end of the proximal coronary was then li- were poor and only in the last two decades have radial autografts
gated. On May 9, 1967, Favaloro (Fig. 80.7) performed the first docu- become more popular for routine use in coronary surgery.
mented saphenous aortocoronary bypass, in a 51-year-old woman As techniques of cardiopulmonary bypass and myocardial pro-
with total occlusion of the proximal third of the right coronary artery. tection improved through the 1970s and standardization occurred,
Eight days later, Sones would confirm by angiography that the bypass more and more surgeons opted to operate on the arrested heart with
was patent. At first these surgeons often grafted the right coronary dry conditions. Multivessel coronary bypass became commonplace
artery with the heart beating, but they and others later routinely used and accepted worldwide, being performed with low morbidity and
cardiopulmonary bypass, especially when they then ventured into mortality for a variety of presentations of ischemic heart disease
bypassing the left coronary artery system. Favaloro then settled on including acute myocardial infarction, unstable angina, complicated
performing vein bypass grafting with an end-to-side distal anasto- myocardial infarctions, as a combination with other heart surgeries
mosis, which quickly became the standard operation throughout such as valve surgery, etc. Once again, surgical innovators contin-
the world. Favoloro and his colleagues were not the earliest to use ued to stretch the limit of risk they were willing to accept for surgical
vein bypasses in humans, but it was the broad clinical application treatment of ischemic heart disease and improvements in anesthesi-
of the technique in 1967 and 1968 that revolutionized the treatment ology and critical care as well as supportive mechanisms, such as the
of ischemic heart disease. Initially, Favaloro and colleagues often intra aortic balloon pump and, much later, ventricular assist devices
combined saphenous vein grafting of the right coronary artery with allowed for such surgeries to be performed successfully on many
single or double internal mammary artery myocardial implantation. patients heretofore thought to be inoperable.
It was because of their tendency to combine the Vineberg procedure
with theirs that Favaloro’s team initially avoided performing internal Transmyocardial Laser Revascularization
mammary artery, coronary artery anastomoses.30,51,52
Many other groups in the United States and Europe were using Other techniques too, started to emerge in the 1990s for patients who
the techniques popularized by Favaloro and Effler from the Cleve- were not seen to be candidates for coronary bypass surgery. These
land clinic by the early 1970s with good results. Modifications of this were patients in whom the coronary disease was too diffuse, those
technique led to the use of multiple vein grafts in the same patients that had very significant small vessel disease or a group of those
and in treatment of acute myocardial infarction as well as for unsta- patients in whom coronary artery bypass surgery was deemed to be
ble angina. prohibitively risky. The common denominator across these subsets
of patients was the presence of severe intractable angina despite endothelium growth factor and beta fibroblast growth factor or genes
maximal medical therapy. encoding these and other growth factors.
Transmyocardial laser revascularization (TMR) had its origins in
the late 1960s when Sen and Udwadia reported a series of patients50 Re-Emergence of Beating Heart Surgery
in whom acupuncture needles were used to make transmyocardial
channels that were thought to bring blood from the left ventricular As discussed earlier, the coronary artery bypass grafting procedures
cavity to the oxygen starved myocardium. The presence of myocar- being performed in the 1960s and many till the 1970s were being
dial sinusoids had been shown by Wearn and colleagues in 193355 performed on the beating heart. Most notably, Ankeney reported his
although two centuries prior to that, Vieussens in 170656 had series of operations on the left and right coronary arteries in 197561
described fleshy vessels connecting the left ventricle to the myocar- and then reviewed once again, his series of 733 patients, in 1985.62
dium. These were different than the ones described by Thebesius in While the comfort of using cardiopulmonary bypass afforded the
1708,57 which we know well as the Thebesian veins. modern cardiac surgeon with a still and bloodless field, the continu-
Mirhoseini and coworkers provided the pioneering efforts in ing effort to reduce the already very low morbidity and mortality of
TMR when they reported the use of CO2 lasers for TMR in 198158 the CABG operation brought to the fore, problems associated directly
and then a consolidated series in 1988.59 From that point on, mul- or indirectly with the heart-lung machine. Neurological complica-
tiple investigators demonstrated many different types of lasers, such tions, such as stroke, associated with cannulation or clamping of the
as the yttrium aluminum garnet (YAG) laser, the thulium, holmium aorta and the actual nonpulsatile flow from the heart-lung machine
and chromium (THC) laser, the pulsed laser coating (PLC) laser, the and its associated systemic inflammatory response causing changes
excimer laser, the holmium:YAG laser and the neodymium (Nd):YAG in cerebral blood flow leading to a “pump-head” were issues leading
laser for creating the channels between the left ventricular cavity and to surgeons re-examining the abandoned technique of beating heart
the surface of the myocardium. Some of these lasers were used in coronary artery bypass grafting. The systemic inflammatory response
other applications in medicine and others (the PLC laser, PLC sys- generated by cardiopulmonary bypass was also being implicated in
tems, Franklin, MA) were made specifically for this operation.60 the causation or worsening of significant hemodynamic changes,
Multiple clinical studies published over a decade and a half uti- renal failure, hypercoagulability or hypocoagulability, platelet dis-
lizing a variety of different lasers, varying numbers of channels cre- orders, gastrointestinal complications, endocrine problems, respira-
ated and whether in combination with coronary artery bypass graft tory or pulmonary complications, etc.63,64
(CABG) or by itself have shown significant relief of angina symp- From the early 1990s, the initial reports that were published by
toms. Although initially thought to relieve angina by the mechanical Benetti65 and Buffolo66 started to pique the interest of surgeons in
creation of channels bringing fresh blood into the sinusoids of the the United States and Europe and by 1995, off-pump coronary artery
myocardium, it has now believed that there are two mechanisms bypass surgery (OPCAB), had caught the imagination of many. Nu-
that lead to the symptomatic relief in these patients.60 These include merous discussions and debates between leading surgeons around
laser-induced angiogenesis with improvement in regional myo- the world ensued about the benefits of using or avoiding cardio-
cardial blood flow and laser-induced denervation of the myocar- pulmonary bypass for coronary artery surgery. Hundreds of reports
dium resulting in an improvement in angina symptoms without the describing the benefit of OPCAB have been published in the last
requirement for any improvement in oxygen delivery.60 The Soci- decade.67-69 Some of these show the ability of a group of surgeons
ety of Thoracic Surgeons evidenced based workforce presented a to perform this surgery safely in certain high risk sub-groups of
thorough review in 2004 of the various aspects of TMR available up patients undergoing coronary artery bypass surgery such as those
until then.60 The report looked at the design and completion of five with severe renal failure, severely reduced ejection fraction, severe
published randomized trials comparing TMR with medical therapy. peripheral vascular disease, etc. while others demonstrate the abil-
In each randomized trial, TMR patients demonstrated a statistically ity to safely perform OPCAB in patients who would ordinarily need
significant improvement in angina compared with patients treated cardiopulmonary bypass support such as those with left main coro-
with medical therapy alone, although none of the trials demon- nary artery disease, severe heart failure and reduced ejection frac-
strated a significant survival benefit. That report concluded that TMR tions, acute myocardial infarctions, diffuse coronary artery disease,
may be an acceptable form of therapy for selected patients—as sole etc. Yet others propounded the benefits of OPCAB showing a lower
therapy for a subset of patients with refractory angina and as an postoperative inflammatory response or a reduction in myocardial
adjunct to coronary artery bypass graft surgery for a subset of patients damage with reduction in ICU and total hospital lengths of stay.70-76
with angina who cannot be completely revascularized surgically.60 Completeness of grafting, long and short-term graft patency, periop-
Due to the angiogenesis induced by TMR, there is the poten- erative major adverse cardiac events and long-term outcomes were
tial to improve these results further by combining this technique some of the issues that were not clear with OPCAB even though
with the co-administration of growth factors such as vascular large number of centers around the world had adopted this as their
preferred technique. Till 2010, only about 20–25% of all coronary by- introduction of robotic surgery. Multiple different groups around the
pass grafting procedures in the United States were being performed world have reported successful multivessel coronary artery bypass
without use of the heart-lung machine. grafting or totally endoscopic coronary artery bypass (TECAB) sur-
The randomized on/off bypass (ROOBY) trial77 conducted as a gery although there have been recent reports looking at longer term
prospective randomized multicenter VA trial was reported in 2009, results that show a higher morbidity and mortality when compared
comparing 2,203 patients assigned to off-pump or on-pump coro- to conventional open off-pump coronary artery bypass.78 In addi-
nary artery bypass surgery in a blinded randomized fashion. Ma- tion, the availability of hybrid operating rooms has led to combined
jority of the patients had multivessel disease. Although, complete procedures where minimally invasive techniques can be utilized for
revascularization was the goal for both groups, the on-pump group bypass grafting of the anterior vessels while others can be percutane-
received more grafts (3 per patient) than the off-pump group (2.9 per ously managed by balloon angioplasty and stenting.79
patient). Similarly, one year graft patency (angiographically demon- Ischemic heart disease and its complications remain one of the
strated) and composite one year outcomes were worse for the off- leading causes of death, disability and morbidity of the entire human
pump group. Particularly, the rate of internal mammary artery graft race and the quest to adequately and appropriately treat this pathol-
patency was similar for both groups. Despite the statistical power of ogy continues to progress. The innovation and pioneering efforts over
this study, no demonstrable difference in neuropsychological out- the last century of surgeons involved in pushing the envelope has
comes was seen at the end of one year between the two groups. resulted in significant improvements in longevity and lifestyle of
Many centers to date continue to use OPCAB as the primary patients suffering from this malady. The chapter is not a closed one
mode of coronary artery bypass grafting. and certainly, the horizon is filled with exciting prospects of attack-
Different approaches to coronary artery bypass grafting with or ing the root cause of ischemic heart disease, not just the symptoma-
without the use of cardiopulmonary support have emerged after the tology.
REFERENCES
1. Olivier AF. Classics in thoracic surgery. In proper perspective: Daniel Hale Williams MD. Ann Thorac Surg. 1984;37:96-7.
2. Blatchford JW 3rd. Ludwig Rehn: The first successful cardiorrhaphy. Ann Thorac Surg. 1985;39:492-5.
3. Gibson CL. Theodore Tuffier 1857-1929. Ann Surg. 1930;91(4):636-7.
4. Gonzalez-Lavin L. Charles P. Bailey and Dwight E. Harken: The dawn of the modern era of mitral valve surgery. Ann Thorac Surg. 1992;53:916-9.
5. Fuster V, O’Rourke R, Walsh R. Hurst’s The Heart. McGraw-Hill Professional Publishing; 2008.
6. Logan Clenending. The Doctor Says, Calgary Herald. 1941.
7. Kerr HH. Operative treatment of angina pectoris. Ann Surg. 1925;82(3):354-63.
8. Langer L. Die Foramina thebesu in Herzen des Menschen. Sitzungsberichte Akad Wiss Wien. 1880;82:25-9.
9. Pratt FH. The nutrition of the heart through the vessels of thebesius and the coronary veins. Am J Physiol. 1898;1:86-9.
10. Marvin HM. An evaluation of the surgical treatment of angina pectoris. Bull N Y Acad Med. 1935;11(7):453-66.
11. Cannon WB, Lewis JT, Britton BW. Am J Physiol. 1926;77:326.
12. Kuntz A, Morehouse A. Thoracic sympathetic cardiac nerves in man: their relation to cervical sympathetic ganglionectomy. Arch Surg. 1930;20:607-
13.
13. White JC, Garrey WE, Atkins JA. Cardiac innervation: experimental and clinical studies. Arch of Surgery. 1933;26:765-86.
14. Levy RL, Moore RL. Paravertebral injections of alcohol for the relief of cardiac pain: a review of experience to date and a report of nine cases. Arch
Int Med. 1931;48:146.
15. Blumgart Herrman L, Levine, Samuel A, and Berlin, David D. Congestive Heart Failure and Angina Pectoris. The therapeutic effect of thyroidec-
tomy on patients without clinical or pathologic evidence of thyroid toxicity. Arch Int Med. 1933;51:866-77.
16. Cutler EC, Schnitker MT. Total thyroidectomy for angina pectoris. Ann Surg. 1934;100(4):578-605.
17. Levine, Samuel A, Cutler, Elliott C., and Eppinger, Eugene C.: Thyroidectomy in the Treatment of Advanced Congestive Heart Failure and Angina
Pectoris. New Eng J Med. 1933;209:667-79.
18. Carrel A. On the experimental surgery of the thoracic aorta and heart. Am J Surg. 1910;52:83-95.
19. Carrel A. Ultimate result of aortic transplantation. J Exp Med. 1912;15:389-92.
20. Wearn JT. The extent of the capillary bed of the heart. J Exp Med. 1928;47:273-90.
21. Sussman ML. The treatment of angina pectoris by paravertebral short wave radiation. Am J Roentgenol. 1930;24:163-8.
22. Beck CS, Griswold RA. Pericardiectomy in the treatment of the Pick syndrome; experimental and clinical observations. Arch Surg. 1930;21:1064-
71.
23. Moritz AR, Hudson CL, Orgain ES. Augmentation of the extracardiac anastomoses of the coronary arteries through pericardial adhesions. J Exp
Med. 1932;56:927-31.
24. Beck CS, Tichy VL, Moritz AR. Production of a collateral circulation to the heart. Proc Soc Exp Biol Med. 1935;32:759-61.
25. Beck CS. The development of new blood supply to heart by operation. Ann Surg. 1935;102:801-13.
26. Thompson SA. Development of cardio-pericardial adhesions following the use of talc. Proc Soc Exp Biol Med. 1939;40:260-1.
27. Harken DE, Balck H, Dickson JF, et al. De-epicardialization: a simple effective surgical treatment for angina pectoris. Circulation. 1955;12:955-62.
28. Kline JL, Stern H, Bloomer WE, et al. Application of a bronchial collateral circulation to the coronary arteries by cardiopneumopexy. Am J Pathol.
1956;32:663-93.
29. O’Shaughnessy L. Experimental method of providing collateral circulation to the heart. Br J Surg. 1936;23:665-70.
30. Mueller RL, Rosengart TK, Isom OW. The history of surgery for ischemic heart disease. Ann Thorac Surg. 1997;63:869-78.
31. Yi GH, He KL, Dang NC, et al. Direct left ventricle to great cardiac vein retroperfusion: a novel alternative to myocardial revascularization. Heart
Surg Forum. 2006;9(2):E579-86.
32. Griffith GC, Bates W. Heart surgery. A ventricular perforation in transplanting a new blood supply. New Int Clin. 1938;2:17-28.
33. Fieschi D. Criteri anatomo-fisiologici per intervento chirurgico lieve in malati di infarto and cuore e di angina. Arch Ital Chir. 1942;63:305-10.
34. Fauteux M, Palmer JH. Treatment of angina pectoris of atheromatous origin by ligation of great cardiac veins. Can Med Assoc J. 1941;45:295-9.
35. Roberts JT, Browne RS, Roberts G. Nourishment of myocardium by way of the coronary veins. Fed Proc. 1943;2:90.
36. Vineberg AM. Development of an anastomosis between the coronary vessels and transplanted internal mammary artery. Can Med Assoc J.
1946;55:117-9.
38. Fergusson DJ, Shirey EK, Sheldon WC, et al. Left internal mammary artery implant—postoperative assessment. Circulation. 1968;38 (4 Suppl):
1124-6.
39. May AM. Coronary endarterectomy; curettement of coronary arteries in dogs. Am J Surg. 1957;93:969-73.
40. Goldman A, Greenstone SM, Preuss FS, et al. Experimental methods for producing a collateral circulation to the heart directly from the left ventri-
cle. J Thorac Surg. 1956;31:364-74.
41. Massimo C, Boffi L. Myocardial revascularization by a new method of carrying blood directly from the left ventricular cavity into the coronary
circulation. J Thorac Surg. 1957;34:257-64.
42. Smith S, Beasley M, Hodes R, et al. Auxiliary myocardial vascularization by prosthetic graft implantation. Surg Gynecol Obstet. 1957;104:263-8.
43. Sabiston DC, Fauteux JP, Blalock A. An experimental study of the fate of arterial implants in the left ventricular myocardium: with a comparison of
similar implants in other organs. Ann Surg. 1957;145:927-38.
44. Senning A. Strip-graft technique. Acta Chir Scand. 1959;118:81-5.
45. Dubost C, Blondeau P, Piwnica A, et al. Syphilitic coronary obstruction: correction under artificial heart-lung and profound hypothermia. Surgery.
1960;48:540-7.
46. Goetz RH, Rohman M, Haller JD, et al. Internal mammary–coronary artery anastomosis. A nonsuture method employing tantalum rings. J Thorac
47. Sabiston DC Jr. The William F. Rienhoff, Jr. Lecture. The coronary circulation. John Hopkins Med J. 1974;134:314-29.
48. Kolesov VI, Potashov LV. Operations on the coronary arteries. Exp Chir Anaesth. 1965;10:3-8.
49. Konstantinov IE. Vasilli I Kolesov: a surgeon to remember. Tex Heart Inst J. 2004;349-58.
50. Sen PK, Udwadia TE, Kinare SG, et al. Transmyocardial acupuncture: A new approach to myocardial revascularization. J Thorac Cardiovasc Surg.
1965;50:181-9.
51. Cooley DA. In Memoriam. Tribute to René Favaloro, Pioneer of coronary bypass. Tex Heart Inst J. 2000;27(3):231-2.
52. Effler DB, Favaloro RG, Groves LK. Coronary artery surgery utilizing saphenous vein graft techniques: clinical experience with 224 operations. J
Thorac Cardiovasc Surg. 1970;59:147-54.
53. Veterans administration coronary artery bypass surgery cooperative study group. Eleven-year survival in the Veterans Administration Coronary
Artery Bypass Surgery Cooperative Study Group. N Engl J Med. 1984;311:1333-9.
54. Johnson WD, Flemma RJ, Lepley D Jr, et al. Extended treatment of severe coronary artery disease: a total surgical approach. Ann Surg. 1969;171:460-
70
55. Wearn JT, Mettier SR, Klump TG, et al. The nature of the vascular communications between the coronary arteries, and the chambers of the heart.
Am Heart J. 1933;9:143-70.
56. Vieussens R. Nouvelles dé couvertes sur le coeur expliqué es dans une lettre é crite á Boudin (in French). Paris: 1706.
57. Thebesius AC. Disputatio medica inauguralis de circulo sanguinis in corde (in Latin). Lugduni Batavorum; 1708. p. 3.
58. Mirhoseini M, Cayton MM. Revascularization of the heart by laser. J Microsurg. 1981;2:253-60.
59. Mirhoseini M, Shelgikar S, Cayton MM. New concepts in revascularization of the myocardium. Ann Thorac Surg. 1988;45:415-20.
60. Bridges CR, Horvath KA, Nugent WC, et al. The Society of Thoracic Surgeons practice guideline series: Transmyocardial Laser Revascularization.
Ann Thorac Surg. 2004;77:1494-502.
61. Ankeny JL. Editorial: To use or not to use pump oxygenator in coronary bypass operations. Ann Thorac Surg. 1975;19:108-9.
62. Ankeney JL. Off-pump bypass surgery: The early experience, 1969-1985. Tex Heart Inst J. 2004;31:210-3.
63. Kirklin JK, Westaby S, Blackstone EH, et al. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg.
1983;86:845-57.
64. Edmunds LH. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 1998;66:S12-6.
65. Benetti FJ, Naselli G, Wood M, et al. Direct myocardial revascularization without extracorporeal circulation. Experience in 700 patients. Chest.
1991;100:312-6.
66. Buffolo E, de Andrade CS, Branco JN, et al. Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg. 1996;61:63-6.
67. Calafiore AM, Di Mauro M, Contini M, et al. Myocardial revascularisation with and without cardiopulmonary bypass in multivessel disease: im-
pact of the strategy on early outcome. Ann Thorac Surg. 2001;72:456-62.
68. Angelini GD, Taylor FC, Reeves BC, et al. Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic
Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomised controlled trials. Lancet. 2002;359:1194-9.
69. Diegeler A, Hirsch R, Schneider F. Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation.
Ann Thorac Surg. 2000;69:1162-6.
70. Hart JC, Puskas JD, Sabik JF 3rd. Off-pump coronary revascularization: current state of the art. Semin Thorac Cardiovasc Surg. 2002;14(1):70-81.
71. Selke FW, DiMaio JM, Caplan LR, et al. Comparing on-pump and off-pump coronary artery bypass grafting. Numerous studies but few conclu-
sions. A scientific statement from the american heart association council on cardiovascular surgery and anesthesia in collaboration with the
interdisciplinary working group on quality of care and outcomes research. Circulation. 2005;111:2858-64.
72. Cleveland JC Jr, Shroyer AL, Chen AY, et al. Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. Ann Thorac
Surg. 2001;72:1282-8.
73. Savageau JA, Stanton BA, Jenkins CD, et al. Neuropsychological dysfunction following elective cardiac operation. II. A six-month reassessment. J
74. Vassiliades TA Jr, Nielsen JL, Lonquist JL. Hemodynamic collapse during off-pump coronary artery bypass grafting. Ann Thorac Surg. 2002;73:
1874-9.
75. Caputo M, Reeves BC, Rajkaruna C, et al. Incomplete revascularization during OPCAB surgery is associated with reduced mid-term event-free
survival. Ann Thorac Surg. 2005;80:2141-7.
76. Virani SS, Lombardi P, Tehrani H, et al. Off-pump coronary artery grafting in patients with left main coronary artery disease. J Card Surg.
2005;20(6):537-41.
77. Shroyer AL, Grover FL, Hattler B, Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group, et al. On-pump versus off-pump coronary
artery bypass surgery. N Engl J Med. 2009;361:1827-37.
78. Dhawan R, Roberts JD, Wroblewski K, et al. Multivessel beating heart robotic myocardial revascularization increases morbidity and mortality. J
79. Gao C, Yang M, Wu Y, et al. Hybrid coronary revascularization by endoscopic robotic coronary artery bypass grafting on beating heart and stent
placement. Ann Thorac Surg. 2009;87(3):737-41.
81 History of Robotically
Assisted Cardiac Surgery
Mishra YK, Collison SP
“I think it is the same emotion that the first people to walk on the Moon must have felt.”
—Alain Carpentier, after the first robotic heart surgery in 1998
India, too, there was interest in this concept and in 1050 AD Parama-
INTRODUCTION
ra King Bhoja of Dhar wrote the Samarangana Sutradhara, an ency-
The Meriam-Webster dictionary defines a robot as “a device that au- clopedic work on classical Indian architecture.2 In verses 101–107, he
tomatically performs complicated, repetitive tasks”, while the Oxford mentions a sort of robot acting as a guard. There are other references
dictionary uses a definition more pertinent to this discussion, “a main this text to the construction of yantras (Sanskrit for instrument or
chine that looks like a human being and performs various complex machine) capable of acting alone. The next important contribution
tasks, like human beings”. Although the use of robotic systems in car- to robotics was provided by Leonardo Da Vinci (1452–1519 AD). In
diac surgery has evolved only in the past few decades and is still in 1495, he designed the first humanoid robot in the western world—a
evolution, the story of the evolution of robots as a concept is perti- gentleman in armor, able to sit up, wave its arm, move its head and
nent to the development of robotic cardiac surgery. Although a tech- open and close its jaw, now-a-days referred to as Leonardo’s robot
nologically advanced procedure, the idea of using robots and robotic (Fig. 81.1). This was a result of Leonardo’s anatomical research en-
technology to assist humans has been present since ancient times. shrined in the Canon of Proportions describing the Vitruvian Man.
This contribution resulted in naming of the currently available surgi-
HISTORICAL ASPECTS OF THE cal robot as the da Vinci system. The name of the company Intuitive
Surgical Corporation derives from one of the primary goals of robotic
DEVELOPMENT OF CURRENT ROBOTIC
surgery: the creation of a surgeon-robot interface so transparent that
TECHNOLOGY the surgeons’s full set of skills can be used in a natural and instinctive
The idea of creating “artificial human or animal” substitutes de- manner.3
signed to perform tasks was present even before the industrial revo- In the modern era, Devol is credited as being the father of the
lution. The image of a robot as a machine to resemble humans has robot4 and in 1954 he patented the world’s first robotic telemanipula-
prevailed in many cultures through the centuries, even though these tor.
machines were not called “robots” during this time. In Chinese his- The term “robot” was actually introduced only in the year 1921.
tory, an engineer during the reign of King Tse-su (500 BC) had cre- Karel Capek (Fig. 81.2A), a Czech playwright, introduced this term
ated a wooden horse that could jump. Archytas is believed to be the in his play “Rossum’s Universal Robot” which was written that year.5
founder of mathematical mechanics.1 In 400 BC, he built the first ar- Capek derived the term robot from the Czech word, robota, meaning
tificial self-propelled flying device, a bird-shaped model said to have serf or slave labor. The play described the development of robots for
flown some 200 meters, which he named “automaton”. In 322 BC, the the purpose of doing work so that people would have more leisure
great philosopher Aristotle imagined “If every tool, when ordered, or time (Fig. 81.2B). As the fictional robotic technology improved, the
even of its own accord, could do the work that befits it then there robots evolved and acquired intelligence. Ultimately the robots be-
would be no need either of apprentices for the master workers or of came stronger and smarter than their masters and believing that hu-
slaves for the lords”.1 mankind was a nuisance, began to exterminate the population. The
After that, from 200 BC to 600 AD, there are numerous reports of play caused uproar; people became afraid that robots may replace
the creation of similar automatons in many diverse civilizations. In them on the assembly line. From this concept the idea of robots has
Chapter 81  History of Robotically Assisted Cardiac Surgery 689
progressed rapidly in the last century, especially in popular culture, technology has been slower.6 Over the last century, robots have made
to the ultra-intelligent anthropomorphic robots of Isaac Asimov’s their way into factories to perform dangerous, repetitive, accurate
science fiction (books like I, Robot, 1950) of the 1950s, to the R2D2 tasks (automobile assembly), handling of hazardous wastes in the
and C3PO of the Star Wars series of the 1970s to the cyborgs of the nuclear industry and in the computer chip industry where there is a
Terminator series. In reality, of course, the actual progress of robotic requirement of great dexterity and precision.
DEVELOPMENT OF ROBOTIC
CARDIAC SURGERY
Although robotic technology has been evolving over the past few
decades, for long there has been a lack of crossover between indus-
trial robots and the field of medicine especially surgical practice.
However, during the past 3 decades, two disparate forces emerged
that drove the innovations required to allow the application of
robotic technology to cardiac surgery. The first was the introduction
of minimally invasive surgery with the first laparoscopic cholecys-
tectomy and the second was the US army initiative in establishing
telepresence surgery.7
LAPAROSCOPIC SURGERY
Although gynecologists had embraced laparoscopy and incorpo-
rated the technique into their practice by 1970, it was not until 1987
that Phillipe Mouret performed the first laparoscopic cholecystec-
tomy in Lyons, France using video technique.8 Following this, the
laparoscopic technique was soon applied to a variety of surgical pro-
cedures. The advantages of this technique were soon appreciated—
Figure 81.1: Leonardo’s robot was the first smaller incisions, less risk of infection; shorter hospital stays and
attempt at animating a human form better postoperative immune function. Guided by this experience,
A B
Figures 81.2A and B: (A) Czech playwright Karel Capek, who introduced the word “robot”;
(B) A scene from Capek’s play “Rossums Universal Robot”
cardiac surgeons in the mid-1995, too, attempted to apply port ac- when the National Aeronautics and Space Administration (NASA)
cess technology to cardiac procedures like coronary artery bypass proposed to develop a method of providing surgical care to orbit-
and mitral valve procedures. However, the problems of applying ing astronauts.5 At that time, since technology, computers and data
port access techniques to cardiac surgery were quickly appreciated9 transfer speeds had not yet been created the idea could not be devel-
and were attributable to limitations of early technology: loss of both oped further.
tactile and force haptic feedback, counterintuitive instrument move- In the early part of the 1990s, research supported by the US De-
ments, amplification of physiologic tremors by the long instruments, fense Department’s Star Wars program was undertaken at the Stan-
loss of hand-eye coordination since the surgeon has to look at two- ford Research Institute to develop a “master-slave telemanipulator”,
dimensional images on the monitor instead of his hands, and limited wherein a computer and robotic manipulators intervened between
degree of motion in view of the fixed entry point leading to a fulcrum the patient and the operator.6 To this end Dr Scott Fisher, PhD (Fig.
effect. These difficulties were difficult to surmount in the context of 81.3A) and Dr Joseph Rosen, MD (Fig. 81.3B), a plastic surgeon,
operating in the thorax. joined with Dr Phil Green (Fig. 81.4A) of Stanford Research Institute
When suitable robotic technology (see below) became avail- to develop this system. It was a synergistic combination; Dr Green
able it was rapidly applied to the procedures which were routinely had expertise in human interface technology; Dr Fisher was at the
performed by laparoscopy (robotically assisted laparoscopic chole- NASA Ames Research Centre, Palo Alto; Dr Rosen was motivated by
cystectomy in 1997) and this early experience generated the concept the desire to improve the techniques of microvascular dissection
that in surgery, the best use of the robot lay in the following scenari- and anastomosis required in hand surgery, and NASA had expertise
os:10 in virtual reality. Together they created the first robotic system, the
• A small, deep, fixed operating field Green Telepresence Surgery System and demonstrated the efficacy
• Requirement of fine dissection and accurate endoscopic sutur- of the system by performing vascular anastomosis in rats.7
ing During this time the US army through the Pentagon’s Advanced
• Micro-anastomosis Research Projects Agency was also interested in telesurgery (Fig.
These observations prompted the use of robotic technology in 81.5A). The US army had found that during the Vietnam War ap-
cardiac surgery. proximately one third of casualties occurred in the time between
injury and transfer to army surgical facilities.7 The US army wanted
THE DEVELOPMENT OF TELEPRESENCE to explore telesurgery with the view of providing remote care and
damage-control surgery at the frontline to soldiers who would oth-
SURGERY
erwise exsanguinate. Dr Richard Satava, MD (Fig. 81.4B), was a gen-
Telepresence surgery is the ability for a doctor to perform surgery eral surgery endoscopist working for the US army and was aware of
on a patient even though they are not physically in the same loca- the Green Telepresence System and introduced it to the US army.
tion with control and feedback done by telemetry over wires, optical The system subsequently developed was the Defense Advanced Re-
fibers, wireless links or the internet. This concept emerged in 1972 search Biomedical Technologies Program.6 It was envisioned that the
A B
Figures 81.3A and B: Early pioneers in the development of robotic surgical systems
(A) Scott Fisher of NASA; (B) Joseph Rosen, a Plastic Surgeon
A B
Figures 81.4A and B: Early pioneers in the development of robotic surgical systems
(A) Dr Phil Green of Stanford research institute; (B) Dr Richard satava, MD
A B
Figures 81.5A and B: (A) In 1984, artistic rendering of the US army concept of telepresence surgery; (B) Depiction of the MEDFAST system in
which a robot on a mobile vehicle (white bracket) would provide damage control prior to evacuation by helicopter
robotic manipulator arms would be mounted in a vehicle for medi-

MILESTONES IN THE DEVELOPMENT OF
cal forward advanced surgical treatment (MEDFAST) (Fig. 81.5B).
The work station would be located at a Mobile Advanced Surgical
ROBOTIC CARDIAC SURGERY
Hospital (MASH). This system would perform just enough surgery to Video assistance was first used for closed chest internal mammary
stop the bleeding prior to shifting to the MASH. This system even un- artery harvests and congenital heart operations in 1996. Although
derwent a military field test in 1996. However, the battlefields of the Kaneko12 was the first to describe the use of video assistance for
1990s were shifting to the close quarters of urban terrain, which was mitral valve surgery, it was the team of Alain Carpentier13 who per-
ill-suited for the MEDFAST and the program was terminated in 1995. formed the first video assisted mitral valve repair via a minithoraco
However, this was only the beginning of another story. Dr tomy using ventricular fibrillation on February 26, 1996. On May 28,
Frederic Moll, MD (Fig. 81.6A), a physician, saw the commercial 1996, Chitwood’s group14 performed a “micro-mitral” valve replace-
value of the emerging robotics technology and the business oppor- ment for a rheumatic mitral valve using a video-assisted minimally
tunity it presented. In 1995, he obtained the licenses of the telepres- invasive approach. However, these experiences were without robotic
ence robotic surgical systems from the US army and the Stanford telemanipulation and cannot be called true robotic operations.
Research Institute and started the company Intuitive Surgical Inc.7 Cardiac surgery truly entered the robotic age in June 1997 when
He also collaborated with other institution like Massachusetts Insti- Falk et al. from Leipzig used the AESOP 3000 to perform endo-
tute of Technology and International Business Machines (IBM) to scopic, port access mitral operations with endo-aortic clamping in
further evolve the telepresence system into the master-slave robotic eight patients.15 A year later, the first North American experience was
system he has named da Vinci. reported by Chitwood’s group16 who performed a video-directed
In 1989, Yulun Wang, PhD (Fig. 81.6B), a graduate engineer mitral operation using the AESOP 3000 robotic arm and a Vista
founded a medical robotics company with funding from the US gov- (Vista Cardiothoracic Systems, Westborough, Massachusetts) three-
ernment and private capital. His company, Computer Motion Inc. dimensional camera.
created the automated endoscopic system for optimal positioning On May 7, 1998 the first totally robotic and endoscopic cardiac
(AESOP), a robotic telescope manipulator and the robotic surgical procedure was performed by the team of Carpentier at the Brous-
system ZEUS in 1999. AESOP received the US Food and Drug Admin- sais Hospital in Paris.17 The first case was carried out on a 52-year-
istration (FDA) approval in 1994 and ZEUS in 2001.7 old woman presenting a large defect of the atrial septum. The patient
In June 2003, Computer Motion Inc. merged with Intuitive Surgi- was extubated 8 hours after the operation, returned to her room
cal Inc. and currently Intuitive Surgical Inc. owns the rights to both 16 hours later and was discharged from the hospital 8 days postoper-
ZEUS and AESOP; and the ZEUS is not being marketed anymore. atively with normal heart function and no residual shunt. By the end
However, the ZEUS will always be remembered as the system used of May of 1998, they had performed six robotic operations including
in the Lindburgh operation in 2001, which was a transatlantic lapar- some mitral valve operations and robot-assisted coronary bypass.
oscopic cholecystectomy on a patient in Strasbourg, France per- The news of these operations was carried in all the major newspapers
formed by a surgeon seated at a console in New York.11 (Daily Mail, London, May 23, 1998).
A B
Figures 81.6A and B: Founding heads and business leaders in creating commercial availability of surgical robotic systems
(A) Dr Frederic Moll, MD, founder of intuitive surgical corp; (B) Yulun Wang, creator of AESOP and ZEUS robots
the results of Multicenter Investigational Device Exemption Trial22

ROBOTIC CORONARY ARTERY BYPASS
and FDA approval for robotically performed coronary artery bypass
Experimental Studies was obtained on the basis of this study.
Reichenspurner was the first to report on endoscopic roboti-
As early as 1996, the group at Penn State University18 began to explore cally assisted coronary anastomosis using the Zeus system in 1999.
the use of robotic systems to perform micro-anastomosis. They con- However, a standard stabilizer inserted through a minithoracotomy
ducted a number of experiments to perform endoscopic anastomosis was used.23 Damiano first expanded coronary surgery with ZEUS to
(n = 25) on cadaveric hearts in an endoscopic trainer. In a calf study, the US; and Boyd, at the London Health Services Center in Cana-
Stephenson et al. demonstrated the feasibility of an endoscopic by- da, reported on the first six successful closed-chest beating-heart
pass graft procedure of the left internal thoracic (IT) artery to the left single-vessel revascularizations (October 1999) using the same
anterior descending (LAD) artery on the arrested heart using the Zeus system.24
system.18 In a cadaver model, the Leipzig group led by Falk was able
to develop a technique for total endoscopic coronary artery bypass MITRAL VALVE SURGERY
grafting through three ports and without assistance. Using a transdia-
phragmatic approach, double vessel grafting of the LAD and the right The first robotic mitral valve repair was performed in May 1998
coronary artery using both IT arteries was shown to be feasible.18 by Carpentier using an early prototype of the da Vinci articulate
On May 25, 1998, Mohr and Falk harvested the left internal mam- intracardiac “wrist” robot.17 A week later, Mohr et al. at Leipzig had
mary artery with the da Vinci system and performed the first hu- repaired five mitral valves with the device.25 Grossi et al. of New York
man coronary anastomosis through a small left anterior thoracotomy University partially repaired a mitral valve using the ZEUS system,
incision.19 By April 2000, a total of 131 patients had been operated but no annuloplasty was done. Four days later, in May 2000, the team
on with the da Vinci system at the Heart Center in Leipzig. The first of R Chitwood performed the first complete da Vinci mitral repair in
totally endoscopic coronary artery bypass (TECAB) was performed North America.25 Subsequently, this group took the lead in organiz-
on an arrested heart at the Broussais Hospital in Paris.20 Between ing the phase I and phase II trials needed for FDA approval of robotic
June 26, 1998 and July 2, 1998, six patients were operated with femo- mitral repairs26 and FDA approval of the da Vinci system for mitral
ral cannulation, endoaortic clamping, robotic left internal mammary surgery was obtained in November 2002.
takedown and endoscopic mammary coronary anastomosis.17 In
2000, the Leipzig group reported the first off pump TECAB using an ATRIAL FIBRILLATION SURGERY
endoscopic stabilizer in two cases.21
The US first robotically-assisted, TECAB surgery was performed By 2004, Bololtin et al.27 had published case reports in which
at Columbia on January 15, 2002. In 2006, Argenziano et al. presented patients undergoing robotic mitral valve surgery at East Carolina
A B C
Figures 81.7A to C: Cardiac surgical pioneers in the application of surgical robotics to cardiac surgery.
(A) Volkmar Folk; (B) Alain Carpentier; (C) Randolph Chitwood
TIME LINE OF SALIENT EVENTS IN THE DEVELOPMENT OF ROBOTIC CARDIAC SURGERY
Abbreviations: AESOP, Automated endoscopic system for optimal positioning; ASD, Atrial septal defect; FDA, Food and drug administration
University received concomitant radiofrequency ablation in an implanted percutaneous through coronary sinus cannulation, failing
attempt to abolish pre-existing atrial fibrillation. In 2005, the same which it may be implanted through a mini-thoracotomy. In 2004,
group was the first to apply microwave energy utilizing the Flex-10 DeRose et al.30 first reported the possibility of robotically-assisted
microwave catheter (Guidant, Indianapolis, IN) to perform ablation lead implantation in 13 patients. This approach is very attractive as
of atrial fibrillation. In 2009, the team of Roberts et al.28 was the first to it allows the introduction of mapped stimulation and thereby opti-
attempt a totally robotic on-pump endocardial approach to ablation mal placement of the lead, which may be better than transvenous
of atrial fibrillation, what they have called the robotic endoscopic implantation.
Cox-Cryomaze. Using a warm beating heart technique, they are able
to perform a complete set of left atrial argon based cryolesions and CONGENITAL HEART DISEASE
left atrial appendage closure.
Robotic surgery for lone atrial fibrillation was first attempted It may be recalled that the first ever totally robotic procedure per-
in animal models in 2002. Subsequently, in 2004, Loulmet et al.29 formed by Carpentier was in fact for a congenital anomaly, an atrial
Gerosa et al. and Jansens et al. reported totally endoscopic pulmo- septal defect (ASD) in an adult patient. However, after this report,
nary vein isolation in humans. there were no other applications of robotics to congenital heart dis-
ease. Torracca et al.31 were the first to report small series of patients
LEFT VENTRICULAR LEAD PLACEMENT undergoing robotic ASD repair in Europe. In the US, Argenziano
et al.32 demonstrated that ASDs in adults can be closed safely and
Numerous recent studies support cardiac resynchronization therapy effectively using totally endoscopic robotic approaches in US FDA
for patients with symptomatic heart failure and delayed intraven- Investigational Device Exemption Trial. Del Nido’s group from the
tricular conduction in spite of optimal medical therapy. The left ven- Boston Children’s Hospital was the first to apply robotics to manage-
tricular lead that needs to be implanted for this therapy is usually ment of patent ductus arteriosus and vascular rings.33
REFERENCES
1. Sánchez-Martín FM, Jiménez Schlegl P, Millán Rodríguez F, et al. History of robotics: from Archytas of Tarentum until da Vinci robot (Part I). Actas
Urol Esp. 2007;31(2):69-76.
2. Roy M. The concept of the Yantra in the Samarangana Sutradhara of Bhoja. IJHS. 1984;19(2):118-24.
3. Satava RM. Emerging technologies for surgery in the 21st century. Arch Surg. 1999;134(11):1197-202.
4. George C Devol [online] Available from website http://www.britannica.com/EBchecked/topic/160299/George-C-Devol. [Accessed July 2012]
5. Satava RM. Emerging medical applications of virtual reality: a surgeon’s perspective. Artif Intell Med. 1994;6(4):281-8.
6. Satava RM. Virtual reality, telesurgery, and the new world order of medicine. J Image Guid Surg. 1995;1(1):12-6.
7. Satava RM. Surgical robotics: the early chronicles: a personal historical perspective. Surg Laparosc Endosc Percutan Tech. 2002;12(1):6-16.
8. Polychronidis A, Laftsidis P, Bounovas A, et al. Twenty years of laparoscopic cholecystectomy: Philippe Mouret–March 17, 1987. JSLS.
2008;12(1):109-11.
9. Wimmer-Greinecker G, Matheis G, Dogan S, et al. Complications of port-access cardiac surgery. J Card Surg. 2007;14(4):240-5.
10. Patel SR, Pareek G. The history of robotics in urology. Med Health R I. 2009;92(10):325-6.
11. Marescaux J, Leroy J, Gagner M, et al. Transatlantic robot-assisted telesurgery. Nature. 2001;413(6854):379-80.
12. Kaneko Y, Kohno T, Ohtsuka T, et al. Video-assisted observation in mitral valve surgery. J Thorac Cardiovasc Surg. 1996;111(1):279-80.
13. Carpentier A, Loulmet D, Le Bret E, et al. Open heart operation under videosurgery and minithoracotomy. First case (mitral valvuloplasty) oper-
ated with success. C R Acad Sci III. 1996;319(3):219-23.
14. Chitwood WR, Elbeery JR, Chapman WH, et al. Video-assisted minimally invasive mitral valve surgery: the “micro-mitral” operation. J Thorac
Cardiovasc Surg. 1997;113(2):413-4.
15. Falk V, Walther T, Autschbach R, et al. Robot-assisted minimally invasive solo mitral valve operation. J Thorac Cardiovasc Surg. 1998;115(2):470-1.
16. Chitwood WR, Wixon CL, Elbeery JR, et al. Video-assisted minimally invasive mitral valve surgery. J Thorac Cardiovasc Surg. 1997;114(5):773-80.
17. Carpentier A, Loulmet D, Aupècle B, et al. Computer assisted open heart surgery. First case operated on with success. C R Acad Sci III.
1998;321(5):437-42.
18. Falk V, Diegler A, Walther T, et al. Developments in robotic cardiac surgery. Curr Opin Cardiol. 2000;15(6):378-87.
19. Mohr FW, Falk V, Diegeler A, et al. Computer-enhanced coronary artery bypass surgery. J Thorac Cardiovasc Surg. 1999;117(6):1212-4.
20. Loulmet D, Carpentier A, d’Attellis N, et al. Endoscopic coronary artery bypass grafting with the aid of robotic assisted instruments. J Thorac Car-
diovasc Surg. 1999;118(1):4-10.
21. Falk V, Diegeler A, Walther T, et al. Total endoscopic computer enhanced coronary artery bypass grafting. Eur J Cardiothorac Surg. 2000;17(1):
38-45.
22. Argenziano M, Katz M, Bonatti J, et al. Results of the prospective multicenter trial of robotically assisted totally endoscopic coronary artery bypass
grafting. Ann Thorac Surg. 2006;81(5):1666-74.
23. Reichenspurner H, Boehm DH, Gulbins H, et al. Robotically assisted endoscopic coronary artery bypass procedures without cardiopulmonary
bypass. J Thorac Cardiovasc Surg. 1999;118(5):960-1.
24. Rodriguez E, Chitwood WR. Robotics in cardiac surgery. Scand J Surg. 2009;98(2):120-4.
25. Nifong LW, Chu VF, Bailey BM, et al. Robotic mitral valve repair: experience with the da Vinci system. Ann Thorac Surg. 2003;75(2):438-42.
26. Nifong LW, Chitwood WR, Pappas PS, et al. Robotic mitral valve surgery: a United States multicenter trial. J Thorac Cardiovasc Surg. 2005;129(6):1395-
404.
27. Bolotin G, Kypson AP, Nifong LW, et al. Robotically-assisted left atrial fibrillation ablation and mitral valve repair through a right mini-thoracoto-
my. Ann Thorac Surg. 2004;78(4):63-4.
28. Cheema FH, Weisberg JS, Khalid I, et al. Warm beating heart, robotic endoscopic Cox-cryomaze: an approach for treating atrial fibrillation. Ann
Thorac Surg. 2009;87(3):966-8.
29. Loulmet DF, Patel NC, Patel NU, et al. First robotic endoscopic epicardial isolation of the pulmonary veins with microwave energy in a patient in
chronic atrial fibrillation. Ann Thorac Surg. 2004;78(2):24-5.
30. Derose JJ, Belsley S, Swistel DG, et al. Robotically assisted left ventricular epicardial lead implantation for biventricular pacing: the posterior ap-
proach. Ann Thorac Surg. 2004;77(4):1472-4.
31. Torracca L, Ismeno G, Alfieri O. Totally endoscopic computer-enhanced atrial septal defect closure in six patients. Ann Thorac Surg. 2001;72(4):
1354-7.
32. Argenziano M, Oz MC, Kohmoto T, et al. Totally endoscopic atrial septal defect repair with robotic assistance. Circulation. 2003;108(Suppl 1):
191-4.
33. Suematsu Y, Mora BN, Mihaljevic T, et al. Totally endoscopic robotic-assisted repair of patent ductus arteriosus and vascular ring in children. Ann
Thorac Surg. 2005;80(6):2309-13.
82 History of Aortic Surgery
Bhan A
“The more extensive a man’s knowledge of what has been done, the In 1817, Astley Cooper one of the great English surgeons was
greater will be his power of knowing what to do.” called to see a man in extremis with a leaking iliac aneurysm. Cooper
—Benjamin Disraeli (1804–1881) decided that the only possible treatment was ligation of the aor-
ta above the aneurysm. He managed to ligate the aorta by a small
ARTERIAL ANEURYSMAL DISEASE transperitoneal incision and passed a single ligature around the
vessel. The ligature was tied. The result was not very pleasant. The
Evolution of cardiac surgery is based on the development of vascu- patient died 40 hours later because of the critical ischemia of the op-
lar surgical technique. In the history of military surgery, hemorrhage posite limb.5 All subsequent attempts to ligate the aorta for the treat-
from major blood vessel was always the greatest surgical challenge. ment of aneurysmal disease were a failure. It was only in 1923, Ma-
The first written account of blood vessel ligation was attributed tas successfully ligated the abdominal aorta in the treatment of the
to great Indian surgeon Sushruta between 800 and 600 BC. He de- aneurysm. The patient died 18 months later because of pulmonary
scribed peripheral aneurysm in his word, Samhita, as localized, tuberculosis.6
pulsatile swellings in blood vessel. Sushruta recommended treating Another major contribution of Rudolph Matas was the proce-
these swellings with compression, cauterization or excision. dure called endoaneurysmorrhaphy. This procedure was performed
Studies based on Egyptian mummies have revealed that athero- in the year 1888.7 The procedure ensured the preservation of the
sclerosis and arterial calcification were relatively common 3500 years collateral blood supply in the patient and markedly reduced the
ago.1 The Ebers Papyrus is among the earliest medical writings and incidence of gangrene and amputation that followed the procedure
thought to have been prepared around 2000 BC. The writer identified in a high percentage of patients who underwent the Hunterian liga-
arterial aneurysms, probably peripheral aneurysms.2 The word aneu- tion for popliteal aneurysm. A number of other methods have been
rysm is derived from the Greek verb meaning to dilate or enlarge. applied over the years to treat aneurysms. These methods included
Antyllus, a Greek surgeon of the 2nd century AD, has left the needling, wiring, proximal banding, ligation and cellophane wrap-
earliest record of attempted therapy of aneurysms. His writings have ping. All these procedures had dismal outcome.
been destroyed but his ideas were recorded in the works of Oribasius, Early days of the aortic surgery were not as routine or predictable
who lived in the 4th century AD. Antyllus had applied ligatures to the as they are today. A lot of courage, perseverance and self-sacrifice
arteries that entered and left the aneurysm and then cut the aneu- were necessary for both the surgeon and the patient to undergo aor-
rysm sac and evacuated the contents and packed the cavity.3 tic surgery in early years. However, in the last 50 years there has been
Few advances happened after that till Ambroise Pare (1510– a tremendous development in the field of vascular surgery. Year 2006
1590) advocated the application of a proximal ligature to aneurysms, marked 50th anniversary of the first thoracoabdominal replacement
but did not believe that sac should be opened because of the dan- and the first ascending aorta operation using the pump oxygenator.
ger of severe and fatal hemorrhage. Pare also described a ruptured Among the foundation of vascular surgery one cannot forget the
aneurysm of the thoracic aorta and wrote, “The aneurysms which contribution of Carrel and Guthrie, earlier in the last century. Carrel
happen in the internal parts are incurable”.1,2 Andreas Vesalius (1514– performed homograft aortic replacement and other vascular proce-
1564) was a friend of Pare and was the first to describe thoracic and dures on experimental animals. For his pioneering role in the vas-
abdominal aortic aneurysms.3 cular surgery and organ transplantation, Alexis Carrel was awarded
On December 12, 1785, John Hunter ligated the superficial femo- Nobel Prize for physiology and medicine in 1912.8-10
ral artery high in the thigh in the area now known as Hunter’s canal to Jose Goyanes of Madrid had performed the first successful
treat popliteal aneurysms. The patient did well and he and the limb replacement of human artery in 1906 using a venous autograft to
survived.4 replace the excised popliteal artery aneurysm.11
In the pre-World War II era, a number of bold attempts were deterioration of the structural integrity of the homograft over time
made to treat patients with enlarging aortic aneurysm or progressive became a serious issue for the continued use of these as conduits for
thrombosis of terminal aorta. Rigid tubes were made with a variety of vascular repair.
materials in an effort to preserve vascular continuity, with uniformly On June 11th, 1951, there was the first encounter between Cooley
poor results. and DeBakey. A 48-year-old patient with syphilitic, saccular, aortic
Arthur Blakemore of Columbia Presbyterian Medical Center in arch aneurysm became the point of discussion. As DeBakey exam-
New York resurrected a previously described method for the intro- ined Mitchell during his staff round at the Old Jefferson Davis City
duction of wire and application of an electrical current to induce Country Hospital, he paused to ask Cooley how he would approach
thrombosis of the aortic aneurysm sac. In 1938, he reported a series this problem. Cooley’s reply was that he would excise the aneurysm
of “patients who had thoracic or abdominal aortic aneurysm—most produced a stunned silence. DeBakey asked Cooley to elaborate.
eventually died of aneurysm rupture but one patient survived for 2 Cooley explained that he would place a clamp across the neck of the
years”.12,13 Around the same time, attempts were made to wrap the aneurysm, remove and oversew it and that this was the patient’s only
expanding aneurysm with a variety of materials. The concept was chance for survival. DeBakey asked if had done this before and to
also to induce fibrosis around the aneurysm, hoping to arrest the everyone’s amusement, Cooley responded that he had done it twice.
growth of the aneurysm. Cellophane was the commonly used mate- Cooley got opportunity to operate two aneurysms at the John’s
rial for this. Other material like fascia later, skin and polyvinyl sponge Hopkins Institute. One of these aneurysms had been created after
were also used but largely without any benefit. In a study at Emory, it the erosion of the sternal implant into the aorta and another one had
was found that the wrapping method was no match for lateral pres- developed after the repair of coarctation of aorta by Alfred Blalock.
sure exerted by an expanding aneurysm.14 This was followed by the experience of operating Mitchell at Houston
Many alternative techniques were tried as a part of direct for a pseudoaneurysm from the aortic arch. This was the first opera-
approaches to the handling of aortic aneurysms namely the ligation tion of its kind in Houston and probably in the world.
or handling of the aorta or tangential excision of suitable saccular DeBakey and Cooley performed the first successful resection
aneurysm. Halsted was an advocate of banding but the outcome and graft replacement of a fusiform aneurysm of the thoracic aorta
was dismal because of erosion of the bands of the aorta. In spite of on January 5th 1953 using an interpositional graft.23 By July 1955,
all their attempts to treat the aortic aneurysm and aortic obstructive Cooley and DeBakey had performed 245 aneurysm repairs, far sur-
disease, the attitude was quite pessimistic—this can be reflected in passing any other series in volume and success.
Bigger’s address to the American surgical association in 1940. “Judg- The first successful operation on an aortic arch aneurysm was
ing from the literature, only a small number of surgeons have felt that performed by Bahnson in 1955. This saccular aneurysm was clamped
direct surgical attack on aneurysm of the abdominal aorta was justi- and the neck oversewn. In 1956, Cooley and DeBakey successfully
fiable and it must be admitted that the results obtained by surgical resected a fusiform aneurysm of the proximal aortic arch using
intervention have been discouraging”.15 the cardiopulmonary bypass. A homograft was used to replace the
The enthusiasm however increased in 1944 when Alexander and excised segment. The routine use of cardiopulmonary bypass greatly
Byron of Ann Arbor reported the first successful proximal and distal simplified surgery of the ascending aorta and arch. In 1975, Grieep
ligation of the thoracic aorta for removal of the fusiform aneurysm.16 described complete resection of the aortic arch with graft replace-
In the same year, Clarence Crawford of Sweden successfully ment using profound hypothermia and total circulatory arrest. In
resected and performed end to end anastomosis for the coarctation this series, there were three survivors out of first four patients oper-
of the thoracic aorta, an important milestone in the edifice of vascular ated.24 The combination of hypothermia, cardiopulmonary bypass
surgery.17 The procedure was repeated successfully in United States and total circulatory arrest provided the basis for a rapid increase in
of America in 1945 at Boston Children Hospital.18 Denton Cooley the scope of thoracic aortic surgery. The open-end technique for the
and Michael DeBakey from Houston successfully performed lateral surgical treatment of the aortic dissection by Cooley and the use of
aortorrhaphy of a saccular aneurysm of the thoracic aorta. Similar biological glues by Bachet and other led to important reduction in
attempt was successfully done by Henry T Bahnson at Baltimore.19,20 the operative mortality.
This brought forth the need for an appropriate conduit. Robert Gross Kouchoukos pioneered the use of circulatory arrest for repair of
was credited with a major innovator because he was the first to use descending thoracic and thoracoabdominal aneurysm.
the harvested, preserved homograft for the treatment of the coarcta- For extensive aneurysm that involved the aortic arch and the
tion of aorta. This started the new era of modern vascular grafting.21 descending thoracic aorta, Borst described the elephant trunk tech-
In 1951, Charles Dubost and associates treated an infrarenal nique to simplify the second stage by leaving a vascular graft within
abdominal aortic aneurysm by insertion of the thoracic aortic hom- the descending thoracic aneurysm.25
ograft.22 The enthusiasm for homografts swelled over the next decade The role of the valve replacement in the aortic root pathologies
but then weaned because of frequent degeneration of the grafts, as was questioned by David and Yacoub and they recommended the
well as harvesting and preservation of the grafts. Serious and rapid valve conservation in preference to the classical Bentall procedure.26
Chapter 82  History of Aortic Surgery 699
Looking over the phenomenal accomplishments of the 1st dec- Aortic surgery has had a fascinating history from Cooper to
ade of modern vascular surgery, Hufnagel observed, “Only to the few Matas. 106 years were needed to obtain a successful outcome of aor-
is given the great gift of perception which permits them to introduce tic ligation of abdominal aortic aneurysm. However, more progress
and demonstrate the feasibility of new ideas.”27 has been made in the last 50 years than in the preceding 2000 years
“The farther backward you can look, the farther forward you are likely since Antyllus ligated, incised and packed his cases of aneurysm.
to see.” Last 5 decades have marked a major progress in diagnosis and
—Sir Winston Churchill treatment of aortic disease. A thorough understanding of the genetic
In 1951, Charles Dubost in Paris performed the first successful basis and natural history of aortic disease has been possible. This has
resection of abdominal aortic aneurysm using aortic homograft. lead to better treatment planning and better outcome. Introduction
Henry T Bahnson is credited with the first successful repair of rup- of the endovascular treatment marked another leap in the treatment
tured abdominal aortic aneurysm in 1953. of aortic disease. Future lies in evidence-based balance between the
Thoracic aortic aneurysms have presented a challenge to cardio- open surgical technique, endovascular treatment and the hybrid
vascular surgeon. These aneurysms can be saccular or fusiform or procedures.
associated with coarctation of aorta. In 1941, John Alexander sim- In 2000, the UK cardiac surgical register reported mortality rates
ply resected the aneurysm with the coarctation and sewed off the of 14.6% for the aortic root, 28% for the aortic arch and 31.5% for
ends without anastomosis or graft in case of lesion associated with descending aorta replacements.29 This created a dilemma for cardi-
coarctation. In 1949, Henry Swan apparently was the first to resect ologists who wished to refer young Marfan patients for surgery. The
an aneurysm associated with a coarctation of aorta and to replace solution lies in concentrating on the physicians who achieve accept-
the resected area with a homograft. In the early 1950s, Bahnson and able morbidity and mortality. The simple step of creating dedicated
Cooley and DeBakey resected saccular aneurysm and repaired the aortic surgery center is now as relevant as the specialist cardiac pedi-
arterial walls by the lateral suture. After the first successful resection atric practice.
of an infrarenal abdominal aortic aneurysm by Dubost in 1951, the Life expectancy in Marfan’s syndrome is transformed by
technique of the aortic surgery developed very fast. In 1954, Ellis first elective aortic root surgery. The gold standard was established by
re-implanted a renal artery during aortic aneurysm resection. Later Gott and colleagues using the Bentall procedure.30 Nevertheless,
in 1954, Etherede resected an atherosclerotic thoraco-abdominal the long-term mortality from a prosthetic valve and anticoagula-
aortic aneurysm at the Veteran’s Administration Hospital at Oakland, tion is significant for the young patients. This prompted David and
California. Feindel and other to develop aortic valve sparing procedure for
In 1965, Crawford described his method for repair of thoraco- aortic root disease.26 However, such procedures need to be under-
abdominal aneurysm. This technique involved proximal and dis- taken by only surgeons who would perform these procedures on
tal clamping and suturing the graft from within the aneurysm and regular basis.
re-implantation of the visceral vessel, either as a patch or individu- One of the major concerns in aortic surgery has been the organ
ally. The aortic wall was not excised but wrapped around the graft to preservation. Special techniques have been evolved for protection of
minimize bleeding. brain, spinal cord and visceral protection. Deep hypothermic circu-
Cooley and DeBakey (1956) and Bahnson and Spencer (1960) latory arrest (DHCA) has played a vital role in organ preservation.
then reported separate series of patients with excision of the entire However, careful studies from the Mount Sinai and John’s Hopkins
ascending aorta. Starr in 1963 described excision of the incompetent groups have defined the safe duration of DHCA to be about 40 min-
aortic valve in the aortic root aneurysm with replacement by the Starr utes at 16°C. Adjuncts have been identified to refine the technique of
Edwards valve and graft replacement of the aneurysmal aorta. protection of vital organs. Retrograde cerebral perfusion through the
In 1964, Wheat reported first successful replacement of the en- superior vena cava has proven to be less reliable. Selective antegrade
tire ascending aorta (from aortic annulus to the innominate artery) cerebral perfusion as promoted by Bachet and colleagues31 and
with implantation of the coronary ostia and separate replacement of Kazui et al. and visceral artery perfusion popularized by Coselli
the aortic valve. Subsequently Bentall and DeBono (1968) described and colleagues in thoracoabdominal surgery are combined with
the technique from complete replacement of the ascending aorta profound or moderate hypothermia.
using a composite-valved conduit and re-implantation of the coro-
nary ostia.28 Cabrol modified this operation by creating a fistula ARTERIAL OCCLUSIVE DISEASE
between the wrap around and the right atrial appendage to take care
of any collection of blood around the valve conduit used to replace In 1923, Rene Leriche from France started “The ideal treatment of
the aortic root and ascending aorta. However, the procedure was arterial thrombosis is the replacement of obstructed segment with
further modified to avoid the wrap-up by mobilizing the coronary vascular graft”. The same Rene Leriche went on to describe the syn-
buttons and re-implanting them onto the graft. This has eliminated drome of occlusive disease of the terminal abdominal aorta 17 years
the formation of pseudoaneurysm from the various suture lines. later which is identified by his name.32
In 1936, Leriche advocated terminal aortectomy and bilateral more favorable physical properties, namely teflon, nylon and dacron.
lumbar sympathectomy for treatment of aortic occlusive disease in Michael DeBakey and associates in Houston rapidly became the
the belief that thrombus in the aorta lumen tended to migrate and leading advocates of dacron. Within less than 4 years, this group
that thrombus incited an inflammatory response with peripheral implanted more than 1,000 synthetic grafts with 90% success rate.36
vasoconstriction. Many other materials were experimented with; however, dacron and
A direct attack on occluded vessels was made by Dos Santos of teflon had the maximum acceptability.
Portugal in 1946.33 He performed the first successful thromboendar- Pioneers like James Tapp, a physical chemist at the Chemstrand
terectomy for peripheral occlusive disease and established this pro- Corporation gave the concept of crimping cylindrical grafts to allow
cedure as feasible. However, over a period of time, the endarterec- greater flexibility and to provide better handling characteristics.37
tomy has gradually given way to bypass grafting, except in the carotid
area and in certain localized obstruction in other large vessels. Aortic Dissections
A major advance in the treatment of aortic occlusive disease was
made on November 14, 1950. Oudot, a French man, who was first According to Scarpa, the disease leading to separation of the aortic
to resect the terminal aorta for the Leriche syndrome34 and replaced layers was first mentioned in the broader context of aortic aneurysm
the aorta with a preserved homologous aortic graft with end-to-end in the medieval writings of Sennertin.38,39 A clearer picture of this
anastomosis. Six months later the same patient developed thrombo- disease emerged in 1761 in the Morgani’s study of dissecting aneu-
sis of the right iliac limb of the graft. Oudot placed a crossover graft rysm.40 In the same year, Nicholls presented the autopsy report of the
from the left distal external iliac to the right external iliac graft, the King George II of Great Britain and Ireland, who had died on Octo-
first extra anatomic bypass graft. ber 26, 1760 of a condition characterized by pericardial temponade,
an intimal tear and separation of the aortic wall layers. An explicit
DEVELOPMENT OF VASCULAR GRAFTS description of the disease process, now called dissection was given
by Maunoir 40 years after Morgagni.41 In 1819, great French surgeon
Based on his experiments on animals, Arthur Voorhees observed Rene Laennec described several cases of aortic dissection.
that silk sutures bridging the ventricular cavity was coated with a The first diagnosis of dissection in a live patient was made by
glistening layer of what appeared to be endocardium. As an exten- Latham (1855). This 51-year-old man presented with severe chest
sion of the observation it was conceived that if the arterial defects pain followed by the loss of power in the legs and unconsciousness.
were bridged by prostheses constructed of a fine mesh cloth, leakage Leg pulses were absent and on autopsy the diagnosis was confirmed.
of blood through the walls of the prosthesis would be terminated by Rindheisch described the breakthrough of blood into the aortic
the formation of fibrin plugs and would thus allow the cloth tube to wall to the wear and tear of the vessel at certain predilected sites. Two
conduct arterial flow. Based on his experiment, he concluded, “The decades after his first publication Peacock had collected 80 cases of
cloth had to be strong, inert, stable, of the right porosity, supple, and dissection and divided the dynamics of the disease into three stages
yet easily traversed by a fine needle.” that still are valid:
One of the principal problems, particularly for the intratho- • Rupture of the internal aortic coats
racic vascular repair was control of bleeding. Attempts were made • Dissection and possible external rupture
to standardize the degree of porosity in order to reduce bleeding • Re-canalization.
through the fabric. In a fully heparinized patient undergoing cardio- He also noted that high death rate of patients with aortic dissec-
pulmonary bypass, it was necessary to use tightly woven, low porosity tion within the first 24 hours.
grafts, but these had less desirable handling and suture characteris- Eppinger in 1885 gave a clear description of what now would be
tics than the knitted velour graft used peripherally. Cooley had intro- termed as intramural hematoma.
duced method of autoclaving a porous graft soaked with autologous Shennan in 1934 published 300 cases of aortic dissection and
plasma, which rendered it completely impervious to blood. Later on the series of Hirst et al. summarized 500 such cases complied up to
better techniques became available including impregnation with 1958.42,43
bovine collagen or albumin. The handling of the grafts and the su- The association of the Marfan’s syndrome with aortic dissection
turing characteristics are inherently superior. By the middle of 1951, and rupture was first noted by Etter and Glover in 1943.
there was sufficient data to prepare an optimistic preliminary report Guria et al. in 1935, fenestrated the dissecting membrane of iliac
that was published in the Annals of Surgery in March 1952, “The use artery for restoring blood flow to the leg.44 Similar procedures were
of tubes constructed from Vinyon “N” cloth in bridging the arte- described later by many surgeons. Shaw coined the term “fenestra-
rial defects,” co-authored by Voorhees, Jaretzki and Blakemore.35 In tion” performed by excision of a window from the internal wall of
1954, Voorhees reviewed the data at a symposium on vascular trans- dissection to allow reperfusion of occluded visceral arteries.45
plants sponsored by the National Research Council. By this time, it Hunter et al. in 1976 and others made significant contribution
was clear that a new era had started in the area of vascular surgery. to the understanding and proper management of malperfusion
Very soon Vinyon-N rapidly gave way to variety of other fibers with phenomenon resulting from compromise of the true lamina of both
aorta and its side branches.46 Paullin and James in 1948 and Abott in have evolved into today’s technique of visualization of all the vessels
1949 attempted the first palliative treatment of the chronic dissection of the body.
by wrapping the descending thoracic aorta with cellophane.47,48 The earliest CT scanner, developed by Sir Godfrey Hounsfield
More definitive treatment of aortic dissection began with suc- and independently developed by Allen Cormack, was first used
cessful replacement of the descending thoracic aorta for fusiform for brain imaging in 1972. Each single tomographic slice required
aneurysm by DeBakey and his group in 195349 and by Shumcker and hours of scan time and days of computation to render what was a
Harris in 1956.50 DeBakey reported their early experience with dis- truly revolutionary image of skull, brain and cerebrospinal fluid. The
section of the descending aorta in 1955. Following the Cooley and early 1990s saw the introduction of the first helical CT scanners into
DeBakey’s first successful replacement of the aneurysmatic ascend- clinical practice, using a slip-ring mechanism that allowed the X-ray
ing aorta with a tube graft had become a standard procedure for tube/detector array gantry to rotate continuously while the patient
dealing with chronic nondissecting aneurysm. Many publications was moved smoothly into the scanner. CT angiography had arrived,
appeared in the literature applying this technique for aortic dissec- but only in very limited applications.
tions and the important principle of sandwiching the friable aortic Toward the mid-1990s, computers had advanced to the point that
layers between strips of teflon feet. large image data sets could be reconstructed into a CTA image using
One of the problems with the Type A aortic dissection is the con- a dedicated workstation. X-ray tube technology had also advanced,
comitant aortic valve regurgitation. This was addressed to by many with the production of tubes that could withstand the amount of heat
surgeons in different ways. Warren et al. and Müller et al achieved the loading that was generated during continuous X-ray production.
same by narrowing the annulus converting the valve into a bicuspid However, scanners were still too slow. This problem was solved in the
valve. Spencer and Blake introduced the valid principle of commis- late 1990s with the advent of multiple rows of detectors so that many
sural resuspension.51-53 images could be acquired during a single helical revolution. Simulta-
In 1955, DeBakey, Cooley and Creech first attempted the fenes- neous acquisition of multiple slices not only led the way to improved
tration of thoracic aorta.54 Müller in 1960 first introduced resection of Z-axis resolution, but also reduced the scan time and finally allowed
the ascending aorta for chronic dissecting aneurysm combined with scanning through long segments of the body using acceptable vol-
bicuspidization of the aortic valve to correct aortic regurgitation. umes of rapidly delivered intravenous contrast. CTA scanning had
Morris and colleagues (1963) were the first to repair acute dis- finally become a reality, although manipulation of the huge image
section of the ascending aorta.55 This patient had residual aortic re- data sets that resulted from these extensive, thin-collimated studies
gurgitation which was managed by elective aortic valve replacement was relatively slow and required purchase of an expensive worksta-
in 1977. tion that was dedicated to the sole task of three-dimensional (3D)
In 1965, Wheat emphasized that role of blood pressure control in image manipulation. With ongoing workstation advances during the
the medical management of acute aortic dissections. Blood pressure past few years (faster computers, increased random access memory
management is the mainstay of treatment prior to Type A dissection and improved 3D software) and high-speed data transfer networks in
and usually the definitive approach to management of Type B dissec- most imaging environments, affordable and clinically useful CTA has
tion in the absence of any complication.56 finally been realized. In fact, today most CT scanners are sold with
The first large report of aortic dissection was made in 1965 by some form of workstation that can be used for 3D image postprocess-
DeBakey, Cooley and others. The operative survival in this series was ing. In the near future, it is likely that 3D software and computational
79% and based on this large report the classification of the aortic dis- power currently located in a dedicated 3D workstation will reside
section was made.57 somewhere within the imaging picture archiving and communica-
From the beginning of modern surgery for aortic dissection to tion system network so that any volumetric angiographic imaging
the present date, the Baylor University group pioneered the surgical study (CT, magnetic resonance imaging, rotational angiography) can
approach for all aspects of aortic dissection. be reconstructed into a 3D angiogram simply by retrieving that study
from the data archive. Today rapid sequence CT scanners are avail-
DEVELOPMENT OF IMAGING able to get excellent quality images.
As anticipated the development of vascular radiology and develop- PIONEERS OF PRESENT DAY
ment of aortic surgery had to go hand-in-hand. It was important to
AORTIC SURGERY
image the vascular system for a precise anatomic definition and also
precise treatment planning. In 1895, Roentgen first introduced the
Michael DeBakey
new rays that would become a cornerstone of our diagnostic arma-
mentarium. In 1923, Barney Brooks initiated clinical angiography for Michael Ellis DeBakey was born in Lake Charles, Louisiana of
imaging of the femoropopliteal system. In 1927, first cerebral arteri- Lebanese parents. He studied in Tulane University. He spent 2 years
ography was performed by Egas Moniz of Portugal. In 1929, Dos San- in Europe to study under Rene Lerriche at Strasbourg University
tos reported translumbar aortography. There tremendous attribute and under Dr Kirschner at University of Heidelberg. At that time,
Dr Leriche was doing Lumbar sympathectomies. After spending “disease of the aorta” with his son Dr John Lloyd Crawford II. He was
2 years in Europe, he came back to Tulane. Dr DeBakey writes when the co-founder of the Baylor Rapid Autologous Transfusion System,
he was in the process of developing vascular grafts I went downtown a machine that recycles a patient’s red blood cells during surgery,
to get nylon shirt material, and when I got these, the clerk said “We which reduces the number of transfusions needed during chest and
are fresh out of nylon, but we have a new material called Dacron.” aneurysm surgery. He was a heavy smoker and died of lung cancer in
In 1934, DeBakey developed a blood transfusion pump, eventu- 1992. He was succeeded in Baylor by his student Dr Coselli who has
ally used in Gibbon’s heart lung machine. carried on the great work done by his mentor.
In 1948, he became the first chairman of the department of sur- Things have improved in last 5 decades of aortic surgery. Newer
gery at the Baylor University College of Medicine. modalities of treatment will keep emerging and future lies in the vas-
In 1956, DeBakey presented a paper at the American Surgical As- cular surgeons and the interventional teams working together in a
sociation meeting describing the excision and replacement of aortic hybrid operating room. Teamwork will play an important role in im-
aneurysm with homograft. proving outcomes and as outcomes will improve the threshold for
DeBakey developed the Dacron and Dacron-Velour artificial intervention will keeping coming down and many more patients will
grafts for the replacement of the diseased aorta. benefit from these treatment modalities. For sure, surgery will play a
In addition, DeBakey did extensive work on the mechanical as- very important role in the patients with aortic diseases.
sist devices. DeBakey had also special interest in the production of “An exact knowledge of the past is an aid in the interpretations of the
surgical instruments. He trained more than 500 surgeons who have future.”
established the “Michael E DeBakey Cardiovascular Surgical Soci- —Thucydides
ety”, a worldwide organization.
LANDMARKS IN AORTIC SURGERY
Denton Arthur Cooley
1817—Astley Cooper ligated an aortic bifurcation in a 38-year-old
Dr Cooley was born in Houston, Texas. He studied at University of man with ruptured external aortic aneurysm.
Texas and Johns Hopkins where he did his internship and residen- 1923—Rudolph Matas ligated the abdominal aortic aneurysm.
cy. He also worked with Lord Brock at Brompton Hospital. In 1951, 1944—Alexander and Byron excised a large thoracic aneurysm
Cooley was invited by DeBakey to establish a comprehensive cardiac associated with coarctation and ligated aorta proximally and distally.
program at Baylor Medical College. In 1969, he resigned from the 1944—Crawford performed resection of coarctation with end-to-end
Baylor Medical College and established the Texas Heart Institute. anastomosis.
Together with DeBakey, he pioneered the removal of aortic an- 1945—Cooley (as an intern) repairs an ascending aortic false aneu-
eurysms by resection with graft replacement. rysm.
In the later part of 1956, Cooley described the first replacement 1948—Gross uses preserved arterial grafts in coarctation resection.
of the ascending aorta using the pump oxygenator in the Journal of 1950—Jacques Oudot repaired a thrombosed aortic bifurcation.
American Medical Association. 1951—Dubost repairs an abdominal aortic aneurysm with an aortic
In addition to his contribution to aortic surgery, Dr Cooley made homograft.
significant contribution in the repair of postinfarction ventricular 1952—First synthetic (Vinyon N) graft replacement of the abdominal
septal defects, repair of left ventricular aneurysms, heart transplan- aorta by Voorhees, Jaretzki and Blakemore.
tation and ventricular assist devices. He contributed immensely to 1953—Cooley and DeBakey perform homograft replacement of the
pediatric cardiac surgery. He also contributed in designing various descending aorta.
prosthetic heart valves. 1955—Bahnson successfully resects a saccular aortic arch aneurysm.
1956—Cooley and DeBakey replace the ascending aorta using the
E Stanley Crawford pump oxygenator.
1956—DeBakey, Creech and Morris describe thoracoabdominal
Dr Crawford was born in Alabama. He studied at Harvard Medical replacement.
School and served at Massachusetts General Hospital as an intern, 1959—Shumacker reported an ascending aorta to abdominal aorta
resident, and chief resident. He joined Baylor College of Medicine bypass for a rupture of descending thoracic aorta.
in 1954 and worked there till he breathed his last. The extraordinary 1956—Cooley and DeBakey use cardiopulmonary bypass to resect
work Dr Crawford did was in the field of thoracoabdominal aortic an arch aneurysm.
aneurysms. 1961—Hufnagel and Conrad presented a series of seven patients in
Dr Crawford became internationally known for his innova- whom they repaired ascending aortic dissections using tube graft
tive surgical technique in treatment of complex aortic disease par- and valve suspension for aortic regurgitation.
ticularly Marfan’s syndrome and aortic dissection. He discussed 1963—Starr replaces the aortic valve and ascending aorta.
1963—Morris, Hanley and DeBakey repaired acute Type A dissec- 1983—Borst uses the elephant trunk technique.
tion. 1990—Kouchoukos uses hypothermic circulatory arrest for extensive
1964—Wheat replaces the aortic valve, sinuses and ascending aorta. thoracoabdominal aneurysm resection.
1967—Gott describes his vascular shunt. 1992—David describes his valve-sparing operation for ascending
1968—Bentall and DeBono perform full aortic root replacement by aortic aneurysm.
mobilizing the coronary arteries. 1994—Dake and Miller describe endovascular stent grafts in de-
1973—Crawford performs repair of descending aortic dissection. scending aortic aneurysms.
1975—Griepp uses hypothermic circulatory arrest for complete arch 1994—Svennson describes one-stage complete aortic replacement
replacement. from valve to bifurcation.
1986—Griepp inaugurates the Mount Sinai aortic surgery sympo- 1999—Inoue describes an endovascular bifurcated aortic stent graft
sium. for aortic arch replacement.
REFERENCES
1. Slaney G. A history of aneurysm surgery. In: Greenhalgh RM, Mannick JA, Powell JT (Eds). The cause and management of aneurysms. London: WB
Saunders; 1990. pp. 1-18.
2. Barker WF. CLIO: the arteries. Austin (TX): RG Landers;1992. pp. 2-502.
3. Garrison FH. An introduction to the history of medicine. Philadelphia: WB Saunders; 1929. pp. 217-21.
4. Perry MO. John Hunter-triumphs and tragedy. J Vasc Surg. 1993;17:7-14.
5. Brock RC. The life and work of Astley Cooper. Edinburgh: E&S Livingstone; 1952. pp. 1-174.
6. Matas R. Ligation of the abdominal aorta. Ann Surg. 1925;81:457-64.
7. Matas R. Traumatic aneurysm of left brachial artery. Incision and partial excision of the sac-recovery. Med News: New York. 1888;53:462-6.
8. Osler W. The principles and practice of medicine. 7th Edition. New York: D. Appleton; 1909. pp. 862-3.
9. Carrel A, Guthrie CC. Uniterminal and biterminal venous transplantations. Surg Gynecol Obstet. 1906;2:266-86.
10. Carrel A. Results of the transplantation of blood vessels, organs and limbs. J Am Med Assoc. 1983;250:944-53.
11. Goyanes J. Nuevos trababjos de cirugia vascular, substitution plastica de las arterias por la vena o arterioplastic venosa aplicada como nuevo
metodo del tratamiento de los aneurismas. El Siglo Medico. 1906;53:546-61.
12. Blakemore AH, Voorhees AB. Aneurysm of the aorta: a review of 365 cases. Angiology. 1954;5:209-31.
13. Blakemore AH, King BG. Electrothermic coagulation of aortic aneurysms. J Am Med Assoc. 1938;111:1821-7.
14. Smith RB, Costantino MJ, Perdue GD. Is there a place for external grafting of arterial aneurysms in selected patients? J Cardiovasc Surg (Torino).
1979;20:13-20.
15. Bigger IA. The surgical treatment of aneurysm of the abdominal aorta. Ann Surg. 1940;112:879-94.
16. Alexander J, Byron FX. Aortectomy for thoracic aneurysm. JAMA. 1944;126:1139-45.
17. Crafoord C, Nylin G. Congenital coarctation of the aorta and its surgical treatment. J Thorac Surg. 1945;14:347-61.
18. Gross RE. Surgical correction for coarctation of the aorta. Surgery. 1945;18:673-8.
19. Cooley DA, DeBakey ME. Surgical considerations of intrathoracic aneurysms of the aorta and great vessels. Ann Surg. 1952;135:660-80.
20. Bahnson HT. Considerations in the excision of aortic aneurysms. Ann Surg. 1953;138:377-86.
21. Gross RE, Hurwitt ES, Bill AH, et al. Preliminary observations on the use of human arterial grafts in the treatment of certain cardiovascular defects.
N Engl J Med. 1948;239:578-9.
22. Dubost C, Allary M, Oeconomos N. Resection of an aneurysm of the abdominal aorta: reestablishment of the continuity by a preserved human
arterial graft, with result after five months. Arch Surg. 1952;64:405-8.
23. Cooley DA, DeBakey ME. Resection of entire ascending aorta in fusiform aneurysm using cardiac bypass. J Am Med Assoc. 1956;162:1158-9.
24. Griepp RB, Stinson EB, Hollingsworth JF, et al. Prosthetic replacement of the aortic. Arch J Thorac Cardiovasc Surg. 1975;70:1051-63.
25. Borst HG, Walterbusch G, Schaps D. Extensive aortic replacement using “elephant trunk” prosthesis. Thorac Cardiovasc Surg. 1983;31:37-40.
26. David TE, Feindel CM. An aortic valve sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta. J Thorac
27. Hufnagel CA. Foreword. In: Wesolowski SA, Dennis C (Eds). Fundamentals of vascular grafting. New York: McGraw-Hill Book Co.; 1963. p. 293.
28. Bentall H, De Bono A. A technique for complete replacement of the ascending aorta thorax. 1968;23:338-9.
29. The Society of Cardiothoracic Surgeons of Great Britain and Ireland. National adult cardiac surgical database report, 2000-1.
30. Gott VL, Greene PS, Alejo DE, et al. Replacement of the aortic root in patients with Marfan’s syndrome. N Engl J Med. 1999;340:1307-13.
31. Bachet J, Guilmet D, Goudot B, et al. Antegrade cerebral perfusion with cold blood: a 13-year experience. Ann Thorac Surg 1999;67:1874-8.
32. Leriche R, Morel A. The syndrome of thrombotic obliteration of the aortic bifurcation. Ann Surg. 1948;127:193-206.
33. Dos Santos JC. Sur la desobstruction des thromboses arterielles anciennes. Memoirs de la Academie Chirurgie. 1947;73:409-11.
34. Oudot J. La greffe vasculaire dans les thromboses du Carrefour aortique. Presse Medicale. 1951;59:234-6.
35. Voorhees AB, Jaretzki A, Blakemore AH. The use of tubes constructed from Vinyon “N” cloth in bridging arterial defects. Ann Surg. 1952;135:332-6.
36. DeBakey ME, Cooley DA, Crawford ES, et al. Clinical application of a new flexible knitted Dacron arterial substitute. Am Surg. 1958;24:862-9.
37. Edwards WS, Tapp JS. Peripheral artery replacement with chemically treated nylon tubes. Surg Gynecol Obstet. 1956;102:443-9.
38. Scarpa A. Treatise on aneurysm 1804. Translated by Wishort JA. A treatise on antomy, physiology and surgical treatment of the aneurysm. Doing
and sterston: Edinburgh; 1808.
39. Sennertus D. Cap 42. Op Omn Lib. 1650;5:306.
40. Morgagni GB. De Sedibus et causis morborum per. Anatomen Indagatis Libri Quinque. Remondiniana, Venetiis. 1761;41-42:16.
41. Mannoir JP. Memoives physiology et pratiques surl’ aneurysme et la ligature des arteres. JJ. Paschoud Geneva; 1802.
42. Hist AE, Johns VJ, Kimse SW. Dissecting aneurysm of aorta: a review of 505 cases. Medicine. 1958;37:217.
43. Shennan T. Dissecting aneurysm. Medical Research Council Special Report Series No. 193). London:HMSO; 1934. p. 138.
44. Gurin D, Bulmar JH, Derby R. Dissecting aneurysm of the aorta, diagnosis and operative relief of the aortic arterial obstruction due to this cause.
New York State J Med. 1935;35:1200.
45. Shaw RS. Acute disecting aortic aneurysms, treatment by fenestration of the internal wall of the aneurysm. N Engl J Med. 1955;253:331.
46. Hunter JA, Dye WS, Javed H, et al. Abdominal aortic aneurysm in thoracic dissection. Arch Surg. 1976;111:1258.
47. Abbott OA. Clinical experience with application of polythene cellophane upon aneurysms of thoracic vessels. J Thorac Surg. 1949;18:435.
48. Paullin JE, James DF. Dissecting aneurysms of the aorta. Postgrad Med. 1948;4:291.
49. DeBakey ME, Cooley DA. Successful resection of aneurysm of thoracic aorta and replacement by graft. J Am Med Assoc. 1953;152:673.
50. Shumacker HG, Harris J. Cure of dissecting aneurysm of the thoracic aorta by total excision. Arch Surg. 1956;73:991.
51. Warren WD, Beckwith J, Müller WH. Problems in the surgical management of acute dissecting aneurysms of aorta. Ann Surg. 1956;144:530.
52. Müller WH, Dammann JF, Warren WD. Surgical correction of cardiovascular deformities in Marfan’s syndrome. Ann Surg. 1960;152:506.
53. Spencer FC, Blake H. A report of the successful surgical treatment of aortic regurgitation from dissecting aortic aneurysm in a patient with the
Marfan’s syndrome. J Thorac Cardiovasc Surg. 1962;44:238.
54. DeBakey ME, Cooley O, Creech O. Surgical considerations of dissecting aneurysms of aorta. Ann Surg. 1955;142:586-92.
55. Morris GC, Henly WS, DeBakeyME. Correction of acute dissecting aneurysm of aorta with valvular insuffiency. J Am Med Assoc. 1963;184:63.
56. Wheat MW, Palmer RF, Bartley TD, et al. Treatment of dissecting aneurysms of the aorta without surgery. J Thorac Cardiovasc Surg. 1965;50:364.
57. DeBakey ME, Henly WS, Cooley DA, et al. Surgical management of dissecting aneurysms of the aorta. J Thorac Cardiovasc Surg. 1965;49:130.
83 History of Heart Transplantation
and Its Future
Kohli V, Krishan K
INTRODUCTION work proved that the cardiac allograft was capable of assuming the
circulatory load of the recipient. At the same time, Marcus and asso-
Cardiac transplantation has an extraordinary history that is rooted in ciates6 were engaged in similar experimentation with different tech-
the evolution of insight into human anatomy, physiology and human nique. They used interim parabiotic perfusion to achieve several dif-
spirit. The idea of transferring an organ from one body to another has ferent versions of heterotopic heart and heart-lung transplantation.
been around for a long time. The first account of an actual transplant In 1954, Dr Joseph Murray performed the first successful trans-
took place in the 2nd century BC. The Indian surgeon Sushruta transplant of a kidney. He transplanted a kidney from one identical twin
planted skin from one man to help rebuild the nose of another man.1 to another. The next major organs to be transplanted were the lungs
In the early 20th century a French surgeon, Alexis Carrel began to in 1963 by James Hardy of Mississippi.7 In 1964 the same team of
experiment with the transplantation of arteries and veins, one of his James Hardy attempted orthotopic human heart transplantation
few successful human procedures.2 This work would earn him the with chimpanzee as donor heart but it remained unsuccessful as
Nobel Prize in 1912. He also attempted to transplant kidneys into recipient died 1 hour after coming off bypass. Corticosteroids were
the neck of dogs. In his subsequent work with Charles Guthrie, “The one of first drugs used in the early phase of organ transplantation as
Transplantation of Veins and Organs,” he described many operations, an immunosuppressive agent. Blumenstock and associates showed
including the first heterotopic heart transplant. Carrel also was the that chemical immunosuppression with methotrexate could delay
first to identify the problem of rejection, a dilemma that would stymie rejection in the orthotopic heart transplantation in canine models.8
many scientists and doctors. Carrel learned the recipient body most The history and development of cardiac transplantation is
often rejects donor organ material. Mann and associates3 from Mayo particularly full of challenges that have been overcome with the
Clinic published a complete report of two techniques for heterotopic research phase alone spanning a century. During that time, essen-
cardiac transplantation. According to him autotransplantations were tial contributions came from all over the world. In the early history
successful, but homotransplantations were rarely successful. They of open heart surgery in 1950s several techniques were established
attributed failure of homotransplantations to some biological factor. using cross circulation, heart lung machine, inflow occlusion, etc.
After Carrel and Mann a Russian researcher Vladimir Demikhov was Simultaneously research kept on going to search an ideal way of pro-
the next surgeon to experiment with heart transplantation. By 1940, tecting the myocardium during the procedure. Norman Shumway,
while working in the department of human physiology at Moscow the master of cold observed that isotonic saline cooled between 0°C
State University he had already developed an artificial heart that and 5°C can protect the myocardium up to an hour. He called this
could substitute for a dog’s heart for as long as 5.5 hours.4 Clearly, revolutionary technique “topical hypothermia’’. A half century earlier
a gifted and visionary surgeon, Demikhov began transplanting aux- in 1958 Shumway along with Richard Lower had started their heart
iliary hearts into the chests of dogs in 1946. He was the first to per- stopping experiment in the research laboratory of Stanford univer-
form this “piggyback” heart operation, with survival up to 32 days. He sity.9 Three years later repetitive success of Shumway and Lower’s
also began the first series of orthotopic canine heart transplants and fantastic experiments with topical hypothermia encouraged them
combined heart-lung transplants when hypothermia had not been to proceed for autotransplantation in dogs. Yet the initial challenge
used and heart-lung bypass had not been invented. This remained of autotransplantation was immense, that the left over tissues were
unknown till his work was published in English in 1962. terribly fragile and little spare tissue to work with. Lower produced
Cardiac transplantation research began to benefit from the the inspirational shift in the strategy. Instead of the impractical
technologies of hypothermia and heart-lung bypass. The first use autotransplantation, he suggested a portion of walls of both atria to
of hypothermia in heart transplantation was reported in 1953 by be left intact with that segment of the original heart in place; it would
Neptune et al. from Philadelphia.5 After many failed attempts, be easier to attach a donor heart from a different dog. Their several
Neptune’s group successfully transplanted the heart-lung unit. This successful and unsuccessful attempts led to the opinion that heart
transplantation is possible in human. During this experimental work, 1968 and continued transplanting hearts at furious rate. He achieved
they knew that rejection was a big hurdle to keep donor heart func- longer survival times than the previous studies. They used blood
tioning. In the same era Adrian Kantrowitz was also going through group compatibility, lymphocyte cross match studies and a matching
the experimental phase of transplantation. He concentrated exclu- grade system in an attempt to predict the success of transplantation.
sively on the transplantation of puppies in the hope that their under- They also administered antilymphocyte globulin as an adjunct to
developed immune systems would not be as affected by rejection. azathioprine and prednisolone. Many centers started doing trans-
In 1965 Richard Lower moved to the University of Virginia as he plant. Even some of the most skilled and renowned surgeons were
was offered to head the department of cardiac surgery. In 1966 Chris- sucked into the vortex. Soon the death toll climbed as rejection and
tiaan Barnard visited University of Virginia for 3 months to study re- infection dogged their efforts. Transplant surgeons were forced to
jection in kidney transplantation as would like to become a precur- confront an unanswerable truth. The inadequate understanding of
sor to start kidney transplantation in Cape Town.10 Dr Barnard was a the rejection process and the inability to diagnose and treat rejec-
cardiac surgeon in his home country and he had gone through most tion did not allow the surgeons to proceed. Almost every center in
of the articles of Lower and Shumway over the past 6 years without the world had shut down the transplant unit. Adrian Kantrowitz, af-
seriously considering the possibility of following them into cardiac ter his first two transplants, moved back into the world of mechanical
transplantation. During his stay at Medical College of Virginia he got assist devices. His seminal work in developing the intra-aortic bal-
the opportunity to watch Dr Lower transplanting dog‘s heart in ex- loon pump saved many lives and till today it is part of the standard
perimental laboratory. The procedure was done using hypothermia practice.
and same surgical technique Lower had developed with Shumway. The first epic of cardiac transplantation ran from 1967 through
Barnard resolved to steal every moment and absorbed every detail of the early 1970s with the tragic record of heart transplants as rudi-
transplantation. Barnard told one of the technicians of Lower that he mentary immunosuppression with azathioprine and prednisolone
would do human heart transplant once he return to home country. did not do the job well. During this period struggle was also going on
Lower ignored his statement as he believed one had to do years of ethical and moral grounds as concept of brain death was not well-
research before trying in human. At the same time there was a race defined. Some surgeons were charged with murder for retrieving
to transplant first human heart in United States. Surgeons were sur- beating hearts from patients with irreversible coma until brain death
rounded by stringent medical legislation and undefined definition of was legally acknowledged. In 1968 Uniform Anatomical Gift Act was
death. Meanwhile, Barnard took the plunge and in the dark hours of passed, creating the “Donor Card” and allowing families to accept
Sunday morning on December 3, 1967 in the Groote Schuur hospital to or refuse donation. It also prohibited doctors attending the donor
of Cape Town, South Africa he performed the revolutionary medical from participating in organ removal or transplantation. (Anatomical
operation, the first clinical human to human heart transplantation.11 means separating organs to rebuild or restructure part of the body).
This was accomplished when Barnard placed a 25-year-old, an auto In 1978 Uniform Brain Death Act was passed, expanding for the first
accident victim Denise Darvall’s heart into the chest of a 55-year-old time the traditional definition of death. “Brain death” is death.
Louis Washkansky who was dying of cardiomyopathy. Barnard had Although Shumway continued to prove validity of the procedure
won the race and grabbed the surgical immortality in the medical in the walls of Stanford University, thirteen long years after he proved
history. He had become the first man to transplant a heart from one that immunology and physiology are cornerstones for transplant. He
human being to another. The recipient though succumbed to death had obtained long-term survival in the laboratory, refining the op-
18 days later due to double pneumonia. erating technique, monitored the denervated, established the pro-
On December 6, 1967 Kantrowitz did the second heart transplant tocols for selection of patients and for measuring and treating rejec-
at Maimonides Medical Center, Brooklyn, New York.12 He transplant- tion. In his study model he developed methods, though not perfect,
ed an anencephalic donor heart into a 3-month-old baby using hypo- to signal the rejection process and treat the rejection effectively. He
thermia and full circulatory arrest. On January 2, 1968 Barnard per- also observed that incidence and severity of rejection were higher in
formed the world’s third heart transplant. Three days later Norman first 2 months and then significantly decreased. He also mentioned
Shumway performed his first and world’s fourth cardiac transplant.13 late acute rejection treated successfully with prednisolone and
In his report Shumway also mentioned the problems encountered chronic rejection manifested as diffuse allograft vasculopathy. Based
in suturing during surgery due to mismatch in size of recipient and on his work cardiac transplantation had resumed in hospitals around
donor hearts. Patients used to receive azathioprine and methyl- the world. Simultaneously, important advances in tissue typing and
prednisolone as antirejection drugs. Although Barnard became the immunosuppressant drugs allowed more transplant operations to
most famous man in this field, Lower and Shumway remained at the take place and increased patients’ survival rates. The most notable
forefront of the transplant battle. First heart transplant in Europe development in this area was discovery of cyclosporine,14 a medicine
was done by Parisian surgeon Claude Cabrol followed by Donald made from a Norwegian fungus with immunosuppressive properties,
Ross who led the first British heart transplant. A day before Ross’s led to a resurgence of heart transplants in the 1980s. Sir Roy Calne, the
first British transplant Denton Cooley made his blistering debut in pioneering British kidney and liver transplant surgeon who had been
Chapter 83  History of Heart Transplantation and Its Future 707
instrumental in developing azathioprine for transplantation. He ran and standardizing the nomenclature system for diagnosis of heart
clinical trials for kidney and liver transplant15 with the discovery of allograft rejection.17
cyclosporine as a nonsteroidal immunosuppression. Cyclosporine Most infants would die until Dr William Norwood reported suc-
worked to keep the body from rejecting a donated organ as well as cessful reconstructive surgery for hypoplastic left heart syndrome.
helped to protect patients from infection. It was a very helpful inven- Dr Leonard Bailey from Loma Linda University Medical Center was
tion. The FDA approved cyclosporine for use to prevent transplant al- convinced that cardiac transplantation would help these infants.
lograft rejection in November 1983. Many heart transplant programs In his laboratory he tried cross species xenotransplantation, ini-
restarted performing heart transplant of the second epic driven sub- tially in pigs and then in baby goats. After his encouraging laboratory
stantially by the availability of this new drug. Cyclosporine prevented results he tried xenotransplantation with a baboon heart into human
the body from rejecting the organ transplants without completely neonate. After best possible matching Dr Bailey implanted a walnut
destroying the immune system. This led to a precipitous drop in the size baboon heart into a 12 days old neonate, Baby Fae.18 Baby Fae suc-
mortality rate as doctors had more control over infection while also cumbed to death on 21st postoperative day. Dr Bailey received a lot of
being able to prevent rejection. The discovery and application of media attention and the case became famous as a “Baby Fae opera-
this new antirejection drug was a paradigm shift. Stahelin and Jean tion”.19 This case ended up with defame to the institution, his laboratory
F Borel (researchers at Sandoz, Basel, Switzerland) played a critical and to Dr Bailey. Despite all the difficulties encountered, he continued
role in the discovery of this miraculous drug. Their seminal contri- his work to transplant babies. At the end, his courage and determina-
bution in identification and understanding the biologic activity of tion to pursue infant heart transplantation have enriched many lives.
cyclosporine should be recognized. Advances in immunosuppres- The other advancement that happened in those times was
sion have most recently involved the development and expanded organ recovery used to take place at local level during early days.
use of polyclonal and monoclonal antibodies to counteract steroid- Each center had a network of physicians and they would contact
resistant rejection. In late 1980s Tacrolimus (FK-506) was incorpo- each other when potential donor was identified. Some transplant
rated into clinical trials of immunosuppression in comparison to cy- programs started transporting the entire donor on life support to
closporine. At the same time experimental work on mycophenolate the center where recipient was located. First to recover a heart from
mofetil and sirolimus was also initiated. OKT3 was being used as an transplantation was recorded on May 8, 1977. It was from University
induction therapy and new approach was introduced for acute rejec- of Virginia where Dr Lower was the chief of the transplant program.
tion that was methotrexate, photopheresis and lymphoid irradiation. After that a lot of refinements were done in terms of procurement
Research continues into the management, reversal and avoidance methods, solutions for cardioplegia and immersion to preserve the
of accelerated atherosclerosis in the transplanted heart, believed to myocardium until heart reaches to the destination. Nowadays it has
be caused or aggravated by the required suppression of the body’s become a standard practice to harvest a heart from distant center
normal immunology. From the development of more powerful and safely if travel time on way back falls within 4 hours. Different kinds
specific immunosuppressants to new treatments for accelerated of pumps are also being tried to provide continuous perfusion to the
graft atherosclerosis, advances in the science of immunology appear heart after harvesting. Some centers have tried theses investigational
to hold the key to expanding the success of heart transplantation in pumps for clinical trials. When heart transplant became a standard
our treatment of end-stage cardiac disease. With the advent of these practice and started being done frequently, to prevent malpractice,
immunosuppressive agents, heart transplantation has become a glo- National Organ Transplant Act was passed in 1984, prohibiting the
bally accepted modality of treatment. Thanks to the persistence of sale of human organs and setting up a national transplant network to
pioneers in immunosuppression research, transplant patients have procure and distribute organs. The United Network for Organ Shar-
dramatically expanded life expectancies. ing received the federal contract to oversee the network starting in
In the first few years of clinical heart transplantation rejection 1986 in United States. Since then organ distribution has become
used to be measured by imprecise and complicated method of com- more uniform and methodical in countries where they have an in-
paring fall in electrocardiogram voltages. In 1971 a young and inno- tegrated network.
vative surgeon named Philip K Caves joined the Stanford transplant In 1981, a formal society was established to exchange the ideas
center as a research fellow.16 He decided to study the diagnosis of and progress of experimental and clinical work related to heart and
rejection. With the help of Werner P Shultz, a machinist and lung transplantation. The first meeting of the society was held in San
instrument maker, a bioptome was designed to take biopsies of Francisco on March 14, 1981. Since then for the last 3 decades this
heart through the internal jugular vein. Caves designed a modified society has been proliferating exponentially. Now it has multiple
Seldinger technique using a Mylar sheath which allowed repeated disciplines involved related to the heart and lung transplantation,
passage of bioptome. Many modifications were done in this instru- mechanical circulatory support and basic sciences. International
ment. Since then transvenous endomyocardial biopsy remains the society for heart and lung transplantation holds annual meetings to
gold standard even today. Dr Margaret E Bellingham a pathologist enhance and proliferate the knowledge and formulate guidelines for
from Stanford University played a major role in defining the rejection standard practice in this field of medical science.
These pioneers and exalted surgeons lived longer and could con- devices, as bridge to transplantation, bridge to recovery or as des-
tribute a lot in the field of heart transplantation.20 Barnard died at the tination therapy. The technological evolution of these devices has
age of 78 in September 2001. James Hardy, who performed first lung gone from large, extracorporeal systems to keep the patients in hos-
transplant and first xenotransplant in human passed away in 2003. pital to development of small implantable axial-flow pumps and
Norman Shumway, the doyen of cardiac transplantation and one of magnetically suspended centrifugal pumps. This multitude of circu-
the prominent surgeons of his time had died in February 2006 due to latory assist devices in use and in experimental phase going to be the
cancer. Richard Lower, a great research partner of Shumway passed alternate of heart transplant in ever growing population of end-stage
away in early 2008. While Adrian Kantrowitz, a second surgeon to heart failure.
transplant human heart died in November 2008.
THE FUTURE OF HEART TRANSPLANT
MECHANICAL CIRCULATORY SUPPORT
Though heart transplant has been a standard practice since long,
The history of mechanical circulatory support dated back to the there are several limitations which are difficult to overcome. The
development of heart lung bypass machine in 1953 by Gibbon from countries where transplant is routine, availability of donor hearts
Jefferson Medical College, Philadelphia.21 This pioneering work and cost are the major limiting factors. For many reasons, individu-
was the beginning of the modern era of cardiac surgery. Since then als and families refuse to donate organs that could be life saving to
substantial efforts have been made in the development of effective others. Sometimes, even when an organ is available, there is no good
mechanical circulatory devices. Kolff and Akutsu tried total artificial match. Other times, there is no way to get the heart for a suitable
heart in animals in 1958. Adrian Kantrowitz and associates devel- recipient in time for the organ to still be viable. In some countries due
oped the intra-aortic balloon pump in 1962 to support failing heart.22 to religious reasons organ donation is not permitted.
In 1963, Spencer made a roller pump for failure to wean from bypass. There are several ways to help patients with end-stage heart dis-
In 1964, DeBakey established the artificial heart research program ease. One is to get more donors for heart transplant. This will require
funded by National Institute of Health. In 1969, Cooley used first time teaching people the benefits of transplantation in hope of changing
in human a mechanical circulatory support, a Liotta heart as a short- society’s attitudes. Better methods of preserving organs and prevent-
term device.23 Since the first clinical utilization in human, the field ing and treating rejection are constantly being developed. However,
has gone from the stage of clinical experimentation to that of valid there will never be enough donor hearts. Indeed, ventricular devices
and effective heart failure treatment alternatives. In 1982 Barney and total artificial hearts already exist but have a limited life-span.
Clark became the first patient to be implanted with a total artificial Also, patients with mechanical support are at high-risk of developing
heart, the Jarvik 7 by DeVries.24 For the first few years of development infection and device-related complications. There has always been
of mechanical support several devices were designed and tried but a search of developing an ideal device. Though newer generation
no device could keep the patient alive from more than few days to few devices have become good alternatives as bridge to transplantation
weeks. So usage of devices was discouraged. With time heart trans- or as destination therapy, further technical advances are required
plantation became a standard treatment for end-stage heart failure. to develop an ideal device. Xenotransplantation has been still in the
The increasing prevalence of heart failure and shortage of donor experimental phase as these organs are too “foreign” and thus the
organs for heart transplantation led to the re-emergence of ventricu- problems with rejection are currently insurmountable. Another area
lar assist devices due to shortage of donor pool. This fuelled the in- of development is genetic engineering, where researchers manipu-
terest of development of durable pumps which can keep the patient lated a gene linked to cell reproduction and growth, enabling this way
alive till they get new heart. As a bridge to transplantation volume the animal model to produce new cells replacing those dead cells as
displacement pumps also known as first generation devices were heart cells do not divide in the mammal heart. This is another step
developed for the clinical use. In 1998, REMATCH (Randomized toward applying the newer technique in treating the end-stage heart
Evaluation of Mechanical Assistance for the Treatment of Conges- disease. Heart transplantation could conceivably benefit innumer-
tive Heart failure) was started for these long-term devices.25 Results able number of patients, but the actual number of persons who will
of this trial were very encouraging compared to the medical treat- benefit is severely constrained by donor supply. Though donor sup-
ment. After this a plethora of devices developed for clinical use and ply is the most critical determinant of the future of heart transplanta-
being used as short-term or long-term support, as extracorporeal or tion, the nature of the legal and ethical issues involved are not less
implantable as right, left or biventricular, as partial or full-support important.
REFERENCES
1. Eisenberg I. A history of rhinoplasty. South Afr Med J. 1982;62(9):286-92.
2. Carrel A, Guthrie CC. The transplantation of veins and organs. Am Med. 1905;10(1):101-2.
3. Mann FC, Priestley JT, Markowitz J, et al. Transplantation of the intact mammalian heart. Arch Surg. 1933;26:219-24.
Chapter 83  History of Heart Transplantation and Its Future 709
4. Shumacker HB. A surgeon to remember: notes about Vladimir Demikhov. Ann Thorac Surg. 1994;58(4):1196-8.
5. Neptune WB, Cookson BA, Bailey CP, et al. Complete homologous heart transplantation. AMA Arch Surg. 1953;66(2):174-8.
6. Marcus E, Wong SN, Luisada AA. Homologous heart grafts. Technique of interim parabiotic perfusion. II. Transplantation of the heart in dogs.
AMA Arch Surg. 1953;66(2):179-91.
7. Hardy JD Webb WR, Dalton ML, et al. Lung homotransplantations in man. JAMA. 1963;186:1065-74.
8. Blumenstock DA, Hechtman HB, Collins JA, et al. Prolonged survival of orthotopic homotransplants of the heart in animals treated with metho-
trexate. J Thorac Cardiovasc Surg. 1963;46:616-25.
9. Lower RR, Shumway NE. Studies on orthotopic homotransplantation of the canine heart. Surg Forum. 1960;11:18-9.
10. McRae D. Early history of heart transplantation. History of international heart and lung transplantation. Philadelphia: Elsevier; 2010. pp. 1-36.
11. Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape
Town. S Afr Med J. 1967;41(48):1271-4.
12. Kantrowitz A, Haller JD, Joos H, et al. Transplantation of the heart in an infant and an adult. Am J Cardiol. 1968;22(6):782-90.
13. Stinson EB, Dong E, Schroeder JS, et al. Initial clinical experience with heart transplantation. Am J Cardiol. 1968;22(6):791-803.
14. Borel JF. The history of Cyclosporine A and its significance. In: White DJG (Ed). Cyclosporin A. Amstredam: Elsevier Biomedical Press; 1982. pp.
5-17.
15. Calne RY, White DJ, Thiru S, et al. Cyclosporine A in patients receiving renal allografts from cadaver donors. Lancet. 1978;2(8104-5):1323-7.
16. Caves PK, Schulz WP, Dong E, et al. New instrument for transvenous cardiac biopsy. Am J Cardiol. 1974;33(2):264-7.
17. Ballingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung
rejection. J Heart Transplant. 1990;9(6):587-93.
18. Bailey LL, Nehlsen-Cannarella SL, Concepcion W, et al. Baboon-to-human cardiac xenotransplantation in neonate. JAMA. 1985;254(23):3321-9.
19. Kushner T, Belliotti R. Baby Fae: a beastly business. J Med Ethics. 1985;11(4):178-83.
20. McRae D. Every second counts: the race to transplant the first human heart. New York: G.P. Putnam’s sons; 2006.
21. Gibbon JH. The development of heart-lung apparatus. Am J Surg. 1978;135(5):608-19.
22. Kantrowitz A, Tjonneland S, Freed PS, et al. Initial clinical experience with intra-aortic balloon pumping in cardiogenic shock. JAMA.
1968;203(2):113-8.
23. Cooley DA, Liotta D, Hallman GL, et al. Orthotopic cardiac prosthesis for two-staged cardiac replacement. Am J Cardio. 1969;24(5):723-30.
24. DeVries WC, Anderson JL, Joyce LD, et al. Clinical use of total artificial heart. N Engl J Med. 1984;310(5):273-8.
25. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):
1435-43.
84 The History of Congenital
Heart Surgery
Iyer KS
lung collapse. However, it was many years before this was incorporat-
INTRODUCTION
ed into routine anesthetic practice and it was not till the 1920s that any
Surgery for congenital heart disease (CHD) as it exists today largely major breakthrough took place. As early as 1902, Sir Thomas Lauder
developed in the latter half of the 20th century. Unlike other organs Brunton had suggested mitral valvotomy as a possible treatment for
of the body which were amenable to surgical therapy without need mitral stenosis and in 1907, John Munro of Boston had suggested liga-
for mechanical control of circulation, surgery within the heart had tion of the patent ductus arteriosus (PDA). However, not only were
to await the development of cardiopulmonary bypass (CPB) that their suggestions rejected, they were also subjected to ridicule. As his-
allowed safe entry into the heart to permit “direct vision intracar- tory would later prove, they were obviously well ahead of the times. In
diac repairs”. The development of CPB was the single most important 1923, Elliot Cutler of the Harvard Medical School a ttempted to relieve
landmark in the history of cardiac surgery and the timeline of cardiac mitral stenosis by cutting the valve with a tenotomy knife introduced
surgery is often divided into the pre-CPB era and the post-CPB era. through the left ventricle (LV) and producing mitral regurgitation, the
rationale being the observation that mitral regurgitation was better
THE PRE CARDIOPULMONARY BYPASS ERA tolerated than mitral stenosis. His first patient survived, but the sub-
sequent six died, understandably. In 1925, Henry Souttar in London
In the 19th century, the heart was believed to be a hallowed or- passed a finger through the left atrial appendage and opened a sten-
gan, not to be desecrated by the surgeon’s knife. However, cardiac otic mitral valve with his finger. Although the patient lived and im-
wounds continued to trouble surgeons because of their inevitable proved symptomatically, the operation was not considered appropri-
fatal outcomes and in 1896 Ludwig Rehn of Frankfurt, Germany fi- ate by the physicians and Souttar never got another patient referred to
nally dared to suture a stab wound in the right ventricle (RV) and him for surgery. It was not until the end of the second world war that
saved the patient. The heart was no longer sacrosanct and the era in 1948 Charles Bailey from Philadelphia, Dwight Harken from Bos-
of cardiac surgery began. Progress over the next few years centered ton and Lord Russell Brock from London reported successful closed
around treatment of cardiac injuries and diseases of the pericardi- mitral valvotomy. It is evident that early attempts at cardiac surgery
um, notably constrictive pericarditis. Rehn in 1917 and Sauerbruch were met with great resistance from the physicians and progress was
in 1925 described pericardial resection as a treatment for constric- for a long period of time only in fits and starts.
tive pericarditis. Another area that caught the attention of surgeons By the early 30s major improvements had occurred in anesthe-
was pulmonary embolism. Frederick Trendelenberg devised a surgi- sia, mechanical ventilation, blood transfusion and postoperative
cal procedure to remove emboli from the pulmonary artery (PA) of care. A lot of experimental work was also being done in the animal
patients dying of pulmonary embolism. However, since the patients laboratories, which would have major bearing on the subsequent
were in extremis and no cardiopulmonary support was available, development of cardiac surgery. Notable amongst them was the
there were few survivors. In 1937, John Gibbon estimated that only 9 work on vascular anastomosis and organ transplantation by Alexis
of 142 patients survived the Trendelenberg operation and these dis- Carrel, a French researcher working at the Rockefeller Institute,
mal results provided the stimulus for his work on the development which subsequently earned him the Nobel Prize in 1912. The discov-
of a pump-oxygenator that could support the circulation during the ery of heparin by Jay Maclean in 1915, when he was still a medical
procedure. student and its subsequent purification by Charles Best in Toronto in
A major impediment to the further development of cardiac sur- 1933 was also crucial to the development of CPB.
gery was the inability to expose the heart through a thoracotomy Supported by these developments, Robert Gross at the Boston
whilst the patient was breathing spontaneously. The development of Children’s Hospital created history on April 16th, 1938 by success-
endotracheal insufflation by Meltzer and Auer in 1909 allowed sur- fully ligating a PDA in a 7-year-old girl. This was the first successful
geons to open the chest and access the heart without life-threatening surgical correction of a congenital heart defect and this day became
Chapter 84  The History of Congenital Heart Surgery 711
a landmark in the history of congenital heart surgery. This credit was A different type of systemic to pulmonary shunt was described
unfortunately missed by John Streider, also from Boston, who had by William Glenn of Yale University in 1958, wherein he anastomo-
actually performed a ligation of a PDA in a patient with associated sed the superior vena cava to the right PA. Although initially used as
endocarditis in 1937. Unfortunately, the patient died 4 days later and palliation for any cyanotic lesion with decreased pulmonary blood
although Streider was technically successful in ligating the PDA, his flow, it later became part of the management protocol for patients
patient did not live to tell the tale and he missed a place in history. with single ventricle, in a modified form—the bidirectional Glenn
Soon followed successful correction of coarctation of aorta shunt. Although the operation is still popularly referred to as the
which was reported by both Clarence Crafoord in Sweden in 1944 Glenn shunt, it is now known that it was first performed in April 1956
and Robert Gross in 1945, each being unaware of the other’s work by Meshalkin in Russia.
because of the second world war. Both surgeons used the technique In 1946, T Holmes Sellors in London relieved PS in a patient
of resection of the narrowed segment and reanastomosis of the aorta. by passing a tenotomy knife through the RV and cutting through
Again in 1945, Gross reported repair of a vascular ring compressing the stenosed pulmonary valve. Russell Brock also of London devel-
the trachea. oped an instrument to resect infundibular muscle and this became
The year 1944 was also notable for the ground breaking Blalock- for some time a popular palliative operation known as the Brock’s
Taussig shunt. Dr Helen Taussig, a cardiologist at the Johns Hopkins procedure. Thus, within a period of 7–8 years, corrective surgery for
Hospital in Baltimore had a keen interest in children with cyanotic PDA, coarctation and vascular ring had been established and ways to
CHD. She had observed that patients of tetralogy of Fallot (TOF) were palliate cyanotic CHD had been discovered.
less likely to be severely cyanosed if they had a PDA. She suggested Two other palliative procedures were important in the his-
to Alfred Blalock, the chief of cardiothoracic surgery that creating tory of surgery of CHD. In 1948, Blalock and Hanlon described an
an artificial ductus might be a way of surgically relieving cyanosis in ingenious method to create an atrial septal defect (ASD) to palliate
such patients. In his earlier position at Nashville, Tennessee, Blalock children born with transposition of great arteries (TGA). This opera-
had unsuccessfully tried to create a model of pulmonary hyperten- tion remained in practice till 1966 when Rashkind described balloon
sion in dogs by constructing a systemic to PA shunt. That experience atrial septostomy—a procedure that dramatically altered the natural
in the lab allowed him to bring Helen Taussig’s idea to fruition. On history of TGA. Banding of the PA was described in 1952 by Mull-
November 29th 1944, the first Blalock-Taussig shunt was performed er and Dammon to restrict blood flow in patients with left to right
on a 15-month-old girl with TOF and severe cyanosis. A stormy post shunts and heart failure. Even after open heart surgery became avail-
operative course ensued, but she was discharged home 2 months able, PA banding was widely practiced in young infants to allow them
later, much improved. Credit for this operation also needs to go to to be operated at an older age, when operative mortality was lower.
Vivien Thomas—Blalock’s laboratory assistant, who had operated Today the PA band remains in use, in single ventricles with increased
on hundreds of dogs in the laboratory to perfect the technique of pulmonary blood flow, multiple muscular ventricular septal defect
subclavian artery to PA anastomosis and who stood by Blalock’s side (VSD) and for LV training in TGA and corrected TGA.
while the historical first operation was being performed. Although many of the surgical procedures performed on a beat-
When Blalock published his report on the outcomes of this ing heart were ingenious, the next phase of CHD surgery was de-
operation in three patients in 1945, there was world-wide acclaim pendent on the ability of the surgeon to have direct vision of the in-
and surgeons from far and wide visited the Johns Hopkins Univer- side of the heart.
sity to learn this new operation. By 1949, Blalock and his team had
performed 878 such operations in children with pulmonary steno- Intracardiac Surgery Before the Era of
sis (PS) and cyanosis. Apart from providing relief to a large number
Cardiopulmonary Bypass
of patients, the operation was recognized as a palliative operation
based on surgically created physiologic alterations to the circulation. Even in early days surgeons knew that circulation could be stopped
This stimulated widespread interest in the study of the pathophysiol- under normothermic conditions for only 2–3 minutes before irre-
ogy of CHD. Soon afterwards, other forms of systemic to PA shunts versible brain damage occurred. This did not allow adequate time for
were described—the Pott’s descending aorta to left PA shunt in 1946 any worthwhile intracardiac procedures. In 1952, Gross described
and the Waterston (1962) and Cooley (1966) ascending aorta to right a technique known as the Gross’s ink-well technique, where a rub-
PA shunt. These shunts however were difficult to regulate, often re- ber cone was sutured to the right atrial wall and allowed to fill with
sulted in pulmonary overcirculation and were soon abandoned. blood. An opening at the bottom of the cone allowed blind access
The Blalock-Taussig shunt continues to be used today, although in a to the right atrial cavity and under guidance of finger palpation, an
much more restricted subset of patients. The sole modification to the ASD could be closed or created. Work on hypothermia and its effects
original operation (DeLeval, 1981), was the use of a synthetic graft on metabolic rate by Bigelow et al. in Toronto in the early 50s raised
between the subclavian artery and PA, which allowed subclavian ar- the possibility that circulation could be stopped for longer periods of
tery continuity to be maintained and allayed fears of limb ischemia time. On September 2, 1952, J Lewis and M Taufic at the University of
resulting from division of the subclavian artery. Minnesota closed an ASD successfully in a 5-year-old girl. In the next
3 years, they had operated on 60 patients with ASD using moderate In the early years, use of CPB in children was limited because the
hypothermia and inflow occlusion with six operative deaths. The dis- equipment and cannulae available were too bulky for use in small
covery of the pump-oxygenator put an end to this technique, how- babies. The use of hypothermia and circulatory arrest allowed more
ever, it is still practiced in some parts of the world like Siberia and complex intracardiac repairs in infants and neonates without bulky
Mongolia. Principles of hypothermia continued to play a significant cannulae cluttering the surgical field. In 1961, Kirklin et al. reported
role in cardiac surgery, especially in the development of infant and on the results with the use of hypothermic circulatory arrest using
neonatal cardiac surgery. the pump-oxygenator in 29 of them. Horiuchi et al. from Japan re-
ported 16 survivors out of 18 infants undergoing VSD closure using
THE ERA OF CARDIOPULMONARY BYPASS the technique of surface-induced cooling to 25°C and circulatory ar-
rest. Dillard et al. extended the duration of circulatory arrest to 60
Depressed by the poor outcomes of the Trendelenberg operation for minutes by lowering body temperature to 17–20°C allowing success-
pulmonary embolism, John Gibbon worked furiously on developing ful repair of total anomalous venous connections in four infants. In
a pump-oxygenator for temporary mechanical support of the cir- 1970, Barratt-Boyes from Auckland described the use of circulatory
culation. His efforts finally resulted in the first successful closure of arrest with the combination of surface-induced hypothermia and
an ASD in an 18-year-old girl using a pump-oxygenator on May 6th, further cooling on CPB. In 1973, Hamilton et al. reported 18 infants
1953. Gibbon, however, failed to have any more survivors after this in whom cooling for circulatory arrest was done entirely on CPB.
initial success and abandoned further work on the pump-oxygenator. With improved ability to perform repairs in infancy safely, there
Meanwhile, Walton Lillehei at the University of Minnesota was was a move away from palliative surgery to early primary surgery.
working on a novel technique of controlled cross-circulation. At- Neonatal surgery received a boost with the introduction of neona-
tempting to mimic the support of fetal circulation by the maternal tal arterial switch in 1984. In 1985, Leonard Bailey from Loma Linda
circulation, he interconnected the circulations of two dogs using tub- University performed the first neonatal heart transplant. As safety
ings and roller pumps and used one dog to support the circulation of of cardiac surgery improved, newer techniques evolved, improved
the other while its heart was stopped temporarily and demonstrated management strategies evolved and more and more complex lesions
the feasibility of the technique to perform direct vision intracardiac were brought under the surgically correctable category. Surgery for
surgery. He used the technique clinically for the first time to close a congenital heart surgery remains in constant evolution, but none of
VSD in a 12 month old child using the child’s father as the donor. By what is done today would be possible, but for the groundbreaking
July 1955, Lillehei and his colleagues had operated on a remarkable work of the pioneers and the foundations laid by them.
series of 45 patients using this technique. Although most of the chil-
dren were very sick and “high-risk” and 15 were less than 1-year-old, LANDMARK MOMENTS IN THE
28 of them survived the surgery. This remarkable series of patients
DEVELOPMENT OF SURGERY
included the first successful open heart correction of VSD, TOF, atrio-
ventricular (AV) communis (AV septal defect). In 2009, 20 of these Some landmark moments in the development of surgery for some of
patients were reported alive after 53 years of follow-up—a remark- the common lesions are reviewed here.
able outcome for procedures performed at the dawn of open heart
surgery. This period also marked the discovery of surgically induced Atrial Septal Defect
heart block and means to correct it by cardiac pacing.
Even as Gibbon abandoned his work with the pump oxygenator, • 1948: Attempts at external closure, Murray’s external suturing,
other groups continued with their efforts. Notable among them were Bailey’s atrioseptopexy, Sandergard’s purse-string suture clo-
Clarence Dennis in Minnesota, J Jongbloed in Utrecht, Clarence sure.
Crafoord in Stockholm, Forrest Doddril in Detroit and Mario Digli- • 1953: Lewis and Taufic, first successful closure using hypother-
otti in Turino. By 1955, two teams led the race—Walton Lillehei and mia and inflow occlusion
his group at the University of Minnesota using the DeWall pump- • 1953: Gibbon, first successful closure using pump-oxygenator
oxygenator system and John Kirklin’s group in the neighboring Mayo • 1974:King and Mills, first percutaneous closure with occlusion
Clinic in Rochester using the Mayo-Gibbon pump-oxygenator devel- device
oped by them. Rapid refinements in CPB—a name coined by Denton
Cooley of Houston, occurred in the next few years with the develop- Ventricular Septal Defect
ment of disposable bubble and membrane oxygenators, introduc-
tion of hemodilution, use of hypothermia, introduction of cardio- • 1952: Mueller and Dammon, PA banding for palliation
plegia and many more innovations and open heart surgery became • 1954: Lillehei and Varco, first successful closure using controlled
available in hundreds of institutions world-wide. cross-circulation
Chapter 84  The History of Congenital Heart Surgery 713
• 1956: Kirklin and DuShane, first series of closures using mechan- • 1966: Rashkind and Miller, balloon atrial septostomy
ical pump-oxygenator • 1959: Senning, first successful atrial switch operation
• 1957: Lillehei, right atrial approach for closure • 1963: Mustard, atrial switch using intra-atrial pericardial baffle
• 1969: Okamoto, Barratt-Boyes, use of deep hypothermia and cir- • 1969: Rastelli, repair of TGA, VSD and PS using extracardiac con-
culatory arrest for closure and superiority of primary closure in duit
infancy over PA banding • 1975: Jatene, first successful arterial switch in TGA with VSD
• 1988: Lock et al. transcatheter device closure • 1977: Yacoub, two-stage arterial switch for TGA with intact ven-
tricular septum
Atrioventricular Septal Defect • 1984: Castaneda et al. Radley-Smith and Yacoub, Quegabaur
et al. primary arterial switch in neonatal period
• 1955: Liillehei, first successful repair by direct closure using • 1989: Jonas, rapid two-stage arterial switch for TGA with re-
controlled cross-circulation gressed LV
• 1962: Maloney et al. Gerbode, repair with single patch with
resuspension of AV valve leaflets Single Ventricle
• 1975: Trusler et al. two-patch technique of repair
• 1999: Nunn et al. modified single patch technique • 1971: Fontan and Baudet, first right heart bypass for tricuspid
atresia—“Fontan procedure”
Total Anomalous Pulmonary • 1973: Kreutzer, atriopulmonary connection in tricuspid atresia
• 1987: Puga et al. Fontan procedure for other forms of single ven-
Venous Connection
tricle
• 1951: Muller, partial repair by closed method anastomosing • 1988: DeLeval et al. lateral tunnel Fontan—“total cavopulmo-
common vein to left atrial appendage nary connection”
• 1956: Lewis and Varco, first total repair using hypothermia and • 1990: Marceletti, extracardiac Fontan
inflow occlusion • 1990: Bridges et al. fenestrated lateral tunnel Fontan
• 1956: Burroughs and Kirklin, first total repair using CPB • 1993: Norwood and Jacobs, two-stage Fontan
• 1967: Dillard, repair in infancy using surface cooling and circula-
tory arrest ORIGINS OF CONGENITAL
• 1971: Barratt-Boyes et al. repair in neonates and infants using
HEART SURGERY IN INDIA
surface cooling and limited CPB
The first congenital heart surgery to be performed in India was a PDA
Tetralogy of Fallot ligation done by BR Billimoria at the Masina Hospital in Bombay. The
first palliation for TOF was done in 1951 by Reeve H. Betts in Chris-
• 1945: Blalock and Taussig, first successful palliation with subcla- tian Medical College, Vellore in the form of a Pott’s shunt. He also
vian artery to PA shunt performed the first pulmonary valvotomy under inflow occlusion in
• 1948: Sellors, Brock, palliation by closed pulmonary valvotomy 1953. Also in 1953, PK Sen performed the first repair of coarctation
• 1954: Lillehei et al. first successful repair without prosthetic ma- of the aorta in Bombay and followed that up with the first successful
terial using controlled cross-circulation direct vision closure of an ASD under hypothermia and inflow occlu-
• 1955: Kirkiln et al. first successful closure using pump-oxygenat- sion in 1956.
or Open aortic valvotomy under surface-induced hypothermia
• 1957: Warden and Lillehei, patch enlargement of RV infundibu- and inflow occlusion was performed by AK Basu in Calcutta in 1959.
lum The first open heart operation to be done using cardiopulmonary
• 1963: Hudspeth et al. transatrial approach for repair bypass was an ASD closure by KN Dastoor at BYL Nair Hospital
• 1966: Ross and Somerville, RV to PA extracardiac homograft con- in Mumbai on Feb. 16th 1961. In May 1961, N. Gopinath success-
duit for TOF with pulmonary atresia fully closed a VSD using a pump-oxygenator in CMC, Vellore, Ta-
• 1969: Barratt-Boyes et al. primary repair in infancy mil Nadu, India. The first total correction for TOF was done by R
Padhi in 1963 at the Wanless Chest Hospital in Miraj. Other pioneer-
Transposition of Great Arteries ing surgeons in those early years included Dr NA Shah from Bom-
bay Hospital and Dr Stanley John from Christian Medical College,
• 1950: Blalock and Hanlon, closed atrial septectomy for palliation Vellore, Tamil Nadu, India. Dr KM Cherian from Railway Hospital
• 1953: Lillehei and Varco, Baffes, partial atrial switch also known contributed greatly to the development of infant cardiac surgery
as “Baffes procedure” in the late 70s and is credited with the first Senning operation in
1979 and arterial switch in 1984. Other surgeons actively pursuing DK Saksena in Mumbai. The first successful rapid two-stage arterial
congenital heart surgery during this period were P Venugopal and switch was performed by KS Iyer (the author) in 1991 at AIIMS, New
IM Rao at the All India Institute of Medical Sciences (AIIMS), New Delhi and the first successful double switch operation was also per-
Delhi, MR Girinath at Southern Railway Hospital, Perambur and formed by him there in 1993.
BIBLIOGRAPHY
1. Cooley DA. Early development of congenital heart surgery: open heart procedures. Ann Thorac Surg. 1997,64(5):1544-8.
2. Karaskov AM, Kitchlu CS, Lomivorotov VN. Cardiac surgery under perfusionless hypothermia: Siberian experience. Asian Cardiovasc Thorac Ann.
2002:10(1);3-7.
3. Kouchoukos NT, Blackstone EH, Doty DB, Hanley FL, Karp RB, Eds. Kirklin/Barratt-Boyes—Cardiac Surgery. Philadelphia: Churchill Livingston;
2003.
4. Litwak RS. Cardiac surgery: from a stabbing in the chest to the artificial heart. Dialogues in cardiovascular medicine. 2006;2(2)141-7.
5. Moller JH, Shumway SJ, Gott VL. The first open-heart repairs using extracorporeal circulation by cross-circulation: a 53-year follow-up. Ann
Thorac Surg. 2009;88(3):1044-6.
6. Naidu KV. Fifty years of cardiac surgery in India. Ind J Thorac Cardiovasc Surg. 1996;12:1-2, 1-6.
7. Schumacker HB. The evolution of cardiac surgery. Bloomington, Ind: Indiana University Press; 1992.
8. Stephenson LW. History of cardiac surgery. In: Cohn LH, Edmunds LH Jr (Eds). Cardiac Surgery in the Adult. New York: McGraw Hill; 2003. pp
3-29.
9. Waldhausen JA. The early history of congenital heart surgery: closed heart operations. Ann Thorac Surg. 1997;64(5):1533-9.
SECTION
Future of Cardiology
5
85. Future of Thrombolytics
86. Future of Thrombus, Thrombolytic Therapy and PCI in Cardiovascular Disorders in
India
87. Future of Balloon Valvotomy—Newer Aspects
88. History of Stem Cell Therapy and its Future in Cardiovascular Diseases
89. Future of Heart Transplant in India
85 Future of Thrombolytics
Oliveros E, Dahya Z, Ishmael A, Peña C, Mehta S
Fibrinolytic therapy, on the other hand is an attractive option

HISTORY AND EVOLUTION OF
when such facilities are not immediately available (Fig. 85.2). It
FIBRINOLYTIC THERAPY
should be recommended when primary PCI (PPCI) is not available in
The 1930s was the dawn of fibrinolytic therapy. Sherry et al. found patients presenting with an AMI of less than equal to 12 hours
fibrinolytic properties in the group C, b-hemolytic streptococci.1 Not duration, in left bundle-branch blocks (LBBB) with associated ST
far away was the development of streptokinase (SK), which held the elevation change (Grade 1B), when ECG findings are consistent with
capacity to dissolve clots and fibrinous exudates. Although originally, a true posterior MI (Grade 2B), and in high risk patients with ongoing
it was used to treat hemothoraces, soon afterwards, its potential to symptoms characteristic of AMI or hemodynamic compromise and
change the management of acute myocardial infarctions (AMIs) those patients with a duration of 12–24 hours who have persistent
was evident. Streptokinase was examined in several trials until the STE or LBBB with STE changes (Grade 2B).4 Most critically, fibrino-
mid-1980s.1 They unequivocally demonstrated with angiographic
evidence that direct intracoronary use of the drug could successfully
achieve culprit vessel recanalization and improved survival.1
A model for physiological fibrinolysis was published at the 7th
International Congress on Thrombosis and Hemostasis, establishing
the concept of the fibrin-specificity of alteplase (tPA).1 These lines of
research created the basis for the development of an alternative drug
to the non-fibrin specific plasminogen activator (PA), SK, and uroki-
nase.1 Figure 85.1 offers an overview of the development of thrombo-
lytic drugs and their role in the medical field. The fibrinolytic agents
can be grouped into direct and indirect PAs, and into first, second
and third generation agents (Table 85.1).
ROLE OF THROMBOLYTICS FOR ACUTE

MYOCARDIAL INFARCTION
Acute ST-segment elevation myocardial infarction (STEMI) is pro-
duced by a coronary plaque rupture/erosion and consequently a
thrombosis, which leads to an occluded epicardial infarct related
artery (IRA). According to the acute STEMI guidelines, a patient pre-
senting with an AMI of less than or equal to 12 hours in duration and
persistent ST elevation should undergo rapid reperfusion therapy
and have a reperfusion strategy established promptly after contact
with the health care system. The recommendation leans towards
mechanical reperfusion using percutaneous coronary intervention
(PCI) as the initial approach to management of STEMI, with the con-
Figure 85.1: Timeline of thrombolytic therapy. Source: Modified from
sideration that the center has a skilled catheterization laboratory and
Maroo A, Topol E J. The early history and development of thrombolysis
initiates therapy less than 90-minute2,3 (Fig. 85.2). in acute myocardial infarction. J Thromb and Haemost. 2004;2:1.
718 Section 5  Future of Cardiology
TABLE 85.1 Chronology of development of thrombolytic agents

First Generation Urokinase (1947), Streptokinase (1986), Anisoylated plasminogen streptokinase activator complex (APSAC) (1988)
Second Generation Single chain urokinase type plasminogen activator (scu-PA), Prourokinase-undergoing clinical trials, rscu-PA- undergoing
clinical trials, Saruplase (unglycosylated scu-PA)- rejected by the European Medical Evaluation Agency, A74187
(r-prourokinase)- undergoing Phase III clinical trials, Alteplase (1994)
Third Generation Reteplase (1995), Lanoteplase (1998)-undergoing phase III trials, Pamiteplase- undergoing trials in animals,
Staphylokinase- has completed Phase 2 clinical trials, Tenecteplase (1999)
New Thrombolytic Agents: Alfimeprase, Desmoteplase, BB10153
Phase III and II (2007)
Note: Bold indicates that the thrombolytic therapy is FDA approved.
Figure 85.2: Reperfusion strategies. Source: Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting
with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European
Society of Cardiology. Eur Heart J. 2008;29(23):2909-45.
lytic therapy administration should be within 30 minutes of arrival can be performed when needed or as a pharmacoinvasive strategy.5
or PPCI within 90 minutes of arrival. PPCI is associated with nearly If the patient is not high risk, transferring as soon as possible should
half the in-hospital mortality compared to treatment with fibrinolytic also be considered.5 The impact on the global management of acute
therapy. High risk patients (≥ 1 high-risk feature: extensive ST-seg- STEMI with fibrinolytics has transformed the therapeutic approach.
ment elevation, new-onset LBBB, previous MI, Killip class 2 or left The benefits of rapid reperfusion with a systemic intravenous bolus
ventricular ejection fraction ≤ 35% for inferior MIs; anterior MI alone or infusion are remarkable. Numerous discoveries were made over
with ≥ 2 mm of ST elevation in ≥ 2 leads) who receive fibrinolytic the past decade regarding the use of fibrinolytic therapy for acute
therapy as a primary reperfusion therapy at a non-PCI facility should STEMI, taking into consideration that early achievement of TIMI II-
be transferred as soon as possible to a PCI-capable facility, where PCI III flow in the IRA is associated with reduced infarct-size, minimized
Chapter 85  Future of Thrombolytics 719
myocardial damage, preserved left ventricular function, and reduced The timing of drug administration is also critical, and TNK-tPA
mortality and morbidity.6,7 has an advantage over other drugs. The duration of the tPA infu-
Noteworthy is the striking data supporting benefits of early sion may be either too long or too short. The timing of the second
thrombolysis, and the concept of the “golden hour”.8 A large MI will bolus of rPA at 30 minutes may occur too early or too late, or may be
compromise more viable myocardium, therefore making it more missed entirely.The bolus of rPA may be given more or less rapidly
vulnerable to subsequent ischemia and infarction.8 Most notably, over 2 minutes.12 TNK-tPA offers the potential to facilitate immedi-
myocardial salvage is time-dependent.It is closely related to suc- ate thrombolysis in a prehospital setting and thus maximizing myo-
cessful epicardial reperfusion and it can be achieved if thrombolysis cardial salvage, considering that reduced treatment time equates to
occurs within 1–2 hours of symptom onset. A better left ventricular salvage of the cardiac muscle.
function can also result from early administration of a fibrinolytic TNK-tPA is more fibrin specific than tPA.7 The “plasminogen
treatment.9 steal” phenomenon is produced by very low systemic levels of plas-
The use of SK, anistreplase, tPA, reteplase (rPA) or tenecteplase minogen leading to its diffusion out of the thrombus, depleting the
(TNK-tPA) is preferred over no fibrinolytic therapy if the electrocar- substrate and decreasing the amount of plasmin generated on the
diogram reveals ST elevation and symptoms have a duration of ≤ 12- clot surface, thereby decreasing clot lysis. In the case of double-bolus
hour (Grade 1A).4,10 Administration of tPA (Grade 1A) or TNK-tPA tPA, a lower rate of TIMI 3 flow and IRA patency is observed. Because
(Grade 1A) over SK is preferred for patients with symptom duration the double-bolus regimen can be associated with depletion of sys-
less than or equal to 6 hours (Grade 1A).11 There is still no preference temic plasminogen, a hypothesis states that plasminogen steal may
in reperfusion therapy in patients who present within 3 hours after reduce the efficacy of a more aggressive regimen. As such, the fibrin
symptom onset.6 The clinical trials’ designs were oriented to the de- specificity of TNK-tPA should permit rapid plasminogen activation in
velopment of guidelines. Initially, the purpose was to find the correct the clot to proceed, even when given as a single bolus.7
dosing of thrombolytics to achieve a successful reperfusion, while
taking into consideration the risks of dreaded complications, such as Thrombolysis in Myocardial Infarction-10B
reinfarction, intracranial and systemic hemorrhage, and the need for
a blood transfusion. The TIMI-10B was a phase II, dose-ranging angiographic study, made
Tenecteplase is the most recent drug that has received the US to compare the efficacy of TNK-tPA (different doses) with tPA (Table
FDA approval as thrombolytic agent for AMI. TNK-tPA is a mutant 85.2).13 The analysis showed that higher weight-corrected doses im-
recombinant tissue PA. It has higher fibrin specificity, and more re- proved TIMI 3 flow until a plateau was reached approximately at 0.5
sistance to inhibition from PAI-1 than tPA. TNK-tPA is compatible mg/kg of TNK-tPA. The TIMI frame count had no significant differ-
for combination with a broad range of other antiplatelets drugs like ence between TNK-tPA and tPA in the rate of less than 28 frames. The
glycoprotein (GP) IIb/IIIa, low-molecular-weight heparins, unfrac- drop in plasminogen was only 10–15% after TNK-tPA, in comparison
tionated heparin and aspirin.11 We will proceed to give a brief sum- to a 50% drop post tPA. The consumption of α2-antiplasmin, the flu-
mary of the relevant clinical trials leading to the development of id-phase inhibitor of plasmin, and a consequent increase in plasmin-
TNK. α2-antiplasmin complexes were 4–5 times greater with tPA than with
TNK-tPA at any of the three doses. Overall, 78 patients were treated
CLINICAL TRIALS RELEVANT TO THE with 50 mg of TNK-tPA plus heparin. From this group, three patients
(mean weight 77.2 kg) manifested an intracranial hemorrhage (ICH),
DEVELOPMENT OF TENECTEPLASE
so the dose was replaced with a 40-mg bolus.9,13 Therefore, adjust-
Thrombolysis in Myocardial Infarction-10A ments were made to the protocol, no additional heparin would be
given previously to diagnostic angiography, and reduced-weight-
The Thrombolysis in Myocardial Infarction (TIMI)-10A Trial was adjusted heparin doses were implemented. Rates of ICH for TNK-tPA
a phase I, dose-ranging, pilot trial designed to evaluate the phar- were 1% for the 30-mg dose, 1.9% for the 40-mg dose and 3.8% for the
macokinetics, safety and efficacy of the TNK-tPA in humans 50-mg dose. The ICH rate for tPA was 1.9%. Consequently, the rates of
(Table 85.2). Furthermore, it assessed the effects of increasing doses ICH associated with TNK-tPA treatment were diminished from 1.82%
of TNK-tPA on the coagulation parameters and evaluated efficacy of to 0.73% (p=0.046). The ICH was a critical issue, prompting consider-
using TIMI 3 flow and TIMI frame count.7 The fact that this throm- able evaluation of the data. Retrospective analysis demonstrated that
bolytic agent can be administered in a bolus brings clear benefits. the heparin dose played a far greater role than TNK-tPA dose in the
In addition to the speed and ease of use, the potential for errors is ICH incidence. Although TNK-tPA has proven to be more fibrin spe-
reduced. Mortality is increased in patients receiving incorrect doses cific compared with tPA, the trial documents that this specificity does
of other thrombolytics, such as SK and tPA, which require IV infusion not prevent ICH. It has become subsequently clear that ICH is caused
based on weight. by thrombolytics when there is lysis of microthrombi in cerebral ves-
TABLE 85.2 Clinical trials of tenecteplase

TRIAL N Trial design Results Conclusion
TIMI 10A 113 Patients with AMI presenting within TNK-tPA: CLp=151±55 mL/min. T1/2=17±7 TNK-tPA has a prolonged half-life;
12 h received a single bolus of min. Drop in systemic fibrinogen (3%) and therefore administration as a single
TNK-tPA over 5–10 seconds with plasminogen(13%). TIMI 3 at 90 min with bolus is possible. It is fibrin specific.
doses from 5 mg to 50 mg, and were 30–50 mg doses was between 59% and 64% (p
compared with a group receiving =.032). Outcome: Mortality at 30 days = 3.5%,
tPA. reinfarction = 4.4%, major hemorrhage= 6.2%.
tPA: Clp=572±132 mL/min. T1/2=3.5±1.4 min.
TIMI 10B 886 Patients with AMI presenting within TIMI 3 at 90 min = TNK-tPA 40 mg and tPA TIMI 3 flow at 40-mg dose of
12 h received a single bolus of 30 had similar rates (62.8% vs 62.7%, p=NS). The TNK-tPA was similar to that with
or 50 mg of TNK-tPA, or front- 30-mg dose was 54.3% (p = 0.035), and the the 90-minute of tPA. Weight-
loaded tPA, followed by a coronary 50-mg dose achieved 65.8% (p=0.62 vs tPA; adjustment dosing is important in
angiography. Heparin was given to p=0.03 vs TNK-tPA doses).TIMI frame count optimizing reperfusion and safety.
the discretion of the physician, until = <40 (low reperfusion) with TNK-tPA 30-mg Adjunctive heparin dosing has a
high doses showed increased ICH, vs tPA. TIMI 3 = 62-63% for doses of ≈0.5 mg/ role in bleeding complications, with
so it was weight-adjusted. TNK-tPA kg. Safety results: ICH rates= 1.0% for 30 mg a favorable safety profile when
50-mg dose was related with ICH, so TNK-tPA, 1.9% for 40 mg, and 3.8% for 50 mg, using ↓ heparin dose.
it was replaced with a 40 mg bolus, and 1.9% for tPA. Serious bleeding= 1.9%, 5.2%,
and heparin doses were reduced. and 11.5% (p=0.001) of patients treated with
the 30-, 40-, and 50-mg doses of TNK-tPA, vs
8.5% for tPA. Clinical Outcome: Mortality at 30
days was 4.9% and reinfarction was 5.4%, no
differences between TNK-tPA or tPA.
ASSENT 1 3,301 Single bolus of TNK-tPA doses: 30-, Total stroke rate at 30-day=1.5%. ICH= 0.77%; Single bolus of 30 to 50-mg TNK-tPA
40- and 50-mg. The 50-mg dose was 0.94% in the 30-mg group; and 0.62% in the is comparable in safety and efficacy
related with ICH, so it was replaced 40-mg group. Patients treated within 6 hours to that of accelerated rtPA.
with 40-mg bolus and heparin doses after symptom onset ICH were 0.56% (30-mg)
were weight-adjusted and ↓. and 0.58% (40-mg). Death, stroke, severe
hemorrhage occurred in 6.4%, 7.4%, and 2.8%,
respectively.
ASSENT 2 1,6949 In 1021 hospitals, patients with Total stroke rate was 1.78% with TNK-tPA vs TNK-tPA and tPA were equivalent
acute MI < 6 hours received a rapid 1.66% with tPA. ICH was similar (0.93% for TNK- for 30-day mortality. The simplicity
infusion with tPA or a single bolus tPA vs. 0.94% for tPA). Noncerebral bleeding in TNK-tPA administration might
weight-adjusted dose of TNK-tPA. All complications (26.1% vs 28.4%) and need for facilitate its use in and out of the
patients received ASA and heparin. transfusions (4.3% vs 5.5%) were lower with hospital.
TNK-tPA. Diastolic BP ≤ 70 mm Hg was a major
risk factor for noncerebral hemorrhage with OR
1.33 (1.14–1.54). Total mortality after 30-day
with TNK-tPA and tPA were 6.18% and 6.15%,
respectively. The group with lower mortality
had received TNK-tPA after 4 h.
ASSENT 3 6095 Patients with acute STEMI were 1° efficacy endpoint: (30-day mortality, in- Clinical outcomes after elective
randomized in 3 groups: Full dose hospital reinfarction or in-hospital refractory PCI were similar with the three
TNK-tPA + enoxaparin; Half-dose ischemia) in 11.4% of the TNK-tPA + enoxaparin antithrombotic co-therapies studied
TNK-tPA + Weight-adjusted, reduced group, 11.1% of the TNK-tPA + abciximab
dose UFH + abciximab; Full dose group and 15.4% of the TNK-tPA + UFH group
TNK-tPA + Weight-adjusted UFH. All (p = 0.0001). 1° efficacy + safety endpoint
the patients received ASA. (in-hospital ICH or in-hospital major bleeding) :
occurred in 13.7% of the TNK-tPA + enoxaparin
group, 14.2% in the TNK-tPA + abciximab group
and 17.0% of those in the TNK-tPA + UFH group
(p = 0.0081)
Contd...
Contd...
TRIAL N Trial design Results Conclusion
ASSENT 3 1,639 In 12 countries, patients presenting The median time from symptom onset until Benefits of enoxaparin used with
PLUS with STEMI within 6 hours were initiation of pre-hospital fibrinolysis was 115 TNK-tPA, but should be used with
treated with pre-hospital fibrinolysis. minutes. The group that received enoxaparin caution in elderly patients.
The patients received TNK-tPA + UFH had reduced 30-day mortality, intrahospital
or enoxaparin. reinfarction or in-hospital refractory ischemia
but augmented stroke and ICH rates (especially
in patients >75 years).
ASSENT 4 PCI 4,000 Patients with acute STEMI < 6 hours PCI median after thrombolysis = 104 min. A strategy of full-dose TNK-tPA
duration were prepared for PPCI Higher in-hospital mortality in the facilitated with antithrombotic co-therapy, as
with an anticipated delay of 1–3 (6%) than in standard PCI (3%) group used in this study and preceding
hours or preceded by full dose TNK- (p=0.0105). Primary endpoint in 19% of PCI by 1–3 h, was associated with
tPA. All patients received ASA and patients assigned facilitated PCI vs 13% of those more major adverse events than
UFH (single bolus). randomized to primary PCI (RR 1.39, 95% CI PCI alone in STEMI and cannot be
1.11-1.74; p=0.0045). Stroke increased with recommended
facilitated compared to standard PCI, 1.8%
and 0% (p < 0.0001) respectively. Major non-
cerebral bleeding complications (6% vs. 4% ,
p=0.3118), were reported with facilitated rather
than standard PCI. Reinfarction (6% vs 4%,
p=0.0279) and need for repeat of target vessel
revascularization (7% vs. 3%, p=0.0041) were
predominant in the facilitated PCI group.
TRANSFER 1,059 Patients were randomized into 2 Catheterization was performed in 88.7% of High-risk STEMI patients should
AMI groups: High risk STEMI patients that the patients receiving standard treatment undergo transfer for PCI within 6
were receiving TNK-tPA at centers (median 32.5 hours) and in 98.5% of the hours after fibrinolysis
without PCI (some underwent group that had routine early PCI (median
rescue PCI or delayed angiography) 2.8 hours). The primary end point at 30-day
or a strategy of immediate transfer (Death, reinfarction, recurrent ischemia, new
with PCI 6 hours after fibrinolysis. or worsening CHF and cardiogenic shock) was
All patients received ASA, heparin or present among 11% of the group of routine
enoxaparin and clopidogrel. early PCI vs 17.2% of the standard treatment
group (RR with early PCI 0.64; 95%CI, 0.47 to
0.87; p=0.004).
sels. This can be sustained by stating that both elderly patients and dial ischemia.4,12 The mortality rate for TNK-tPA 50 mg was 3.8%, and
those with established cerebrovascular disease are at a 5–10 times the resultant net clinical benefit (death or nonfatal intracranial hem-
greater risk of ICH, as documented in the TIMI 2 and GUSTO-I tri- orrhage) was 5.1%. Reinfarction was present in 5.4% of the patients,
als. Finally, the plasmin on the cerebral vasculature may also induce not significantly different among both drugs.
ICH.14,15 The assessment of the safety and efficacy of a new thrombolytic
Non-ICH bleeding rates are as follows: serious bleeding rates for (ASSENT)-1 was a phase II trial conducted at the same time as the
TNK-PA were 1.9% for the 30-mg dose, 5.2% for the 40-mg dose and TIMI-10B study (Table 85.2).16 TNK-tPA doses of 0.5-mg/kg were
11.5% for the 50-mg dose. The serious bleeding rate for tPA was 8.5%. selected based on the results on the TIMI-10B and the ASSENT-1
It also appears that the bleeding rates are higher than those generally leading to comparisons with the front-loaded tPA in a phase III trial.
observed in large-scale safety trials and in clinical practice, most like-
ly because of the need for vessel instrumentation in the angioplasty, ASSENT-2
and the higher heparin dosing used in these trials due to adjunctive
or rescue percutaneous coronary intervention within 12 hours after The ASSENT-2 was a phase III, double-blind, randomized, controlled
failed fibrinolysis for patients with continuing or recurrent myocar- trial, which compared TNK-tPA to tPA in 16,949 patients with STE-
MI worldwide, presenting within 6 hours of symptom onset (Table increase in noncerebral bleeding complications.11,18 They
85.2).17 These results may translate into greater cost effectiveness, i.e. helped sustain the concept that a more potent antiplatelet agent
taking into account fewer days in the intensive care unit, the costs of increases flow in the IRA. The benefits of the drugs were achieved
imaging studies to determine the site of bleeding, the cost of thera- in the GUSTO V and in the ASSENT-3, but this also brought higher
peutic modalities, such as endoscopy, among others.12 Females had rates of thrombocytopenia, major bleeding complications and
a higher risk of noncerebral major bleeds and those with body weight blood transfusions. The combination of full dose TNK-tPA and
less than or equal to 67 kg had higher manifestations of ICH.15 Di- long-term administration of enoxaparin (7-day course) was the
astolic blood pressure (BP) below or equal to 70 mm Hg was a ma- most successful of this trial. The benefits are the simplicity of the
jor risk factor for noncerebral hemorrhage with OR 1.33 (1.14–1.54), medication regimen and the lack of need for monitoring antico-
similar to the findings in the GUSTO-I study with OR 0.94 for diasto- agulation.
lic BP 90 versus 80 mm Hg, 95% CI, 1.12–1.57.15 Total mortality after
30-day with TNK-tPA and tPA were almost identical, 6.18% and 6.15%, ASSENT-3 PLUS
respectively. The only group that manifested lower mortality had
received TNK-tPA after 4 hours.17 Prehospital fibrinolysis has shown to significantly reduce time to
The improved safety profile of TNK-tPA may reflect only minimal treatment around the world, particularly in rural or congested urban
depletion of fibrinogen and weight-adjusted dosing. The rates were areas where transportation times are long or when PCI facilities are
also similar to those observed in the GUSTO-III study, which com- not readily available. This is the preference over no therapy (Grade
pared rPA with tPA (i.e. 0.91 % for rPA and 0.87% for tPA), leading 1A).4,6,19 The comparison of angioplasty to prehospital throm-
to state that the higher the fibrin specificity of TNK-tPA, the better bolysis trial in myocardial infarction (CAPTIM) and PRAGUE (Pri-
dissolution of the older fibrin clot and, consequently, an improved mary angioplasty in patients transported from general community
clinical outcome. In general, the ASSENT-2 study confirmed that hospitals to specialized PTCA Units with or without emergency
weight-optimized dosing of TNK-tPA could be utilized to treat pa- thrombolysis)-2 trials showed that primary percutaneous coronary
tients with AMI effectively and safely.12 intervention (PPCI) had no survival advantage as compared with
rapid pharmacological reperfusion in the pre-hospital setting.6,19 The
ASSENT-3 patients stratified according to treatment within 2 hours of symptom
onset. The 30-day survival favored fibrinolysis.19 The ASSENT-3 PLUS
Suboptimal macroperfusion and microperfusion, recurrent ischemia, is a randomized trial in AMI that studied 1,639 patients with STEMI
reinfarction and ICH were still major challenges to overcome with within 6 hours in 12 countries, who were treated with pre-hospital
the use of TNK-tPA in patients with acute STEMI (Table 85.2). In fibrinolysis (Table 85.2). The patients received TNK-tPA plus UFH
all the previous trials, unfractionated heparin (UFH) was routinely or enoxaparin. The marked differences found among the different
given to most patients. More recently low-molecular-weight heparin countries enrolled in the study may help explain delays in time to
(LMWH) has been combined with fibrinolytics. LMWH has more treatment and time from symptom onset to first medical contact.
predictable kinetics, is less protein-bound, has less potential for Simple things not even related to the health system, such as traffic,
platelet activation, and requires no monitoring—all features that will alter the outcome of the patient. The presence of a physician
provide a strong rationale for potentially better outcomes when given in the prehospital setting was associated with greater adherence to
in combination with fibrinolytics. Several studies show lower rates protocol mandated treatments and procedures but created delays in
of reocclusion, late patency of the IRA, or a reduction in reinfarction time to treatment. In other countries, the evaluation is made by EMS
rate when compared with UFH.18 units with physicians, and the limitation is the insufficient number
The introduction of platelet GP IIb/IIIa inhibitors as adjunctive of units.19
therapy with fibrinolytic agents has demonstrated better patency of
the epicardial IRA and signs of improved tissue reperfusion. ASSENT-4 PCI
Considering all the knowledge recollected from previous works,
the ASSENT-3 trial randomized 6,095 patients with STEMI into three The ASSENT-4 PCI study made a review in the administration of a
groups receiving: full-dose of TNK-tPA plus enoxaparin; half-dose full-dose of TNK-tPA before a delayed PCI (Table 85.2). Early phar-
of TNK-tPA plus weight-adjusted, reduced-dose of UFH plus abcixi- macological approaches prior to mechanical intervention were a
mab; or full-dose of TNK-tPA plus weight-adjusted UFH. key point to be studied. Current, prospective randomized trials that
The use of abciximab or enoxaparin reduces ischemic complica- have assessed facilitated angioplasty in patients with STEMI are
tions of AMI treated with TNK-tPA.18 ASSENT-4, FINESSE (Facilitated intervention with enhanced reper-
GUSTO V was a phase III trial that studied half-dose rPA and fusion speed to stop events) and CARESS AMI (Combined abcixi-
abciximab, compared with full-dose rPA. They were unsuccessful mab reteplase stent study in acute myocardial infarction).11 Delays
in demonstrating a decrease in 30-day mortality and showed an in transfer between health facilities, to provide PPCI as reperfusion
strategy, has become the cornerstone of providing proper manage- appropriate reperfusion therapy with PPCI challenging. Strategies
ment. There is controversy as to whether treatment delays in PPCI are for initial reperfusion with fibrinolytic administration followed by
less important than those in fibrinolytic therapy.20 immediate transfer to a facility capable of timely catheterization
improves mortality and remains one of the points to be further stud-
OTHER RELEVANT TRIALS ied.8,11 In the study conducted by Gibson et al. the National Registry
of MI in the US was recompiled and showed a significant decline in
In the GRACIA-2 study, they found delays in treatment was associ- mortality with improved door-to-needle (D2N) and door-to-balloon
ated with higher 6-month mortality in patients with STEMI receiv- (D2B) times, relative adjustments of 16.3% and 7.5% respectively.
ing reperfusion therapy. Furthermore, this relationship appeared The proper D2N time is in a range in which small changes in the
to be less steep in patients undergoing PPCI than in those receiving myocardium have happened; thereby there will be greater myo-
fibrinolytic therapy. The efficacy of fibrinolytic therapy at re-estab- cardial salvage.8 Fibrinolysis is preferred when there is a delay to
lishing TIMI 3 flow diminishes with longer treatment delays lead- implementing an invasive strategy such that D2B time minus D2N
ing to worse clinical outcomes. This is potentially due to enhanced time exceeds 1 hour.6 Even when PPCI has proven superiority over
thrombus organization over time within the IRA. PPCI mechanically fibrinolytic therapy in mortality, it is important to recognize that the
disrupts the thrombus, and therefore its ability to re-establish TIMI statement is not applicable for all patients. In these situations, TNK-
3 flow is less time-dependent.20 STEMI patients can go through a tPA may be a better alternative for reperfusion therapy, considering
routine stent-angioplasty within 3–12 hours of fibrinolysis and it can age, the infarct-related artery or delays in the system of activating the
be considered safe and equivalent to primary stenting in preserving catheterization laboratory.8,22
myocardial function.20 What about the use of PCI after early administration of lytic
The difference between ASSENT-4 and the GRACIA-2 trial was therapy? As corroborated by GRACIA-2 and WEST trials, routine
that in the latter study, primary and facilitated cases had to re- fibrinolysis followed by angioplasty within 3–12 hours seems to be
ceive intervention within an identical short delay: 1–3 hours from cost-effective and most suitable for developing countries. Further-
randomization. PPCI was considered to be superior to facilitated more, early use of thrombolysis can treat the infarction and it can
angioplasty when the intervention is performed with a similar de- dramatically reduce mortality when given during the first 1–2 hours
lay.20 Primary and facilitated PCI had a low and identical incidence of onset.3 Pre-hospital treatment might be the key. TNK is the ideal
of ischemic events and 6-week angiographic reocclusion. In spite of agent to pursue this strategy; it is delivered rapidly, in a single bolus
the longer intervention delay, postfibrinolysis intervention resulted and without interaction with other drugs. In addition, TNK has high
in an equivalent infarct size and ventricular outcome when com- fibrin specificity, which results in higher reperfusion rates. The as-
pared with primary stent-angioplasty under abciximab protection.20 sociation with other agents, such as eptifibatide, might bring better
The time window between fibrinolysis and angioplasty can be safely results in reperfusion.
widened up to 6 hours after first medical contact.20 Nevertheless, new questions are raised; who should initiate lytic
therapy? For many years there has been much debate concerning the
FUTURE HORIZONS OF dispensation of the thrombolytic drug therapy in a prehospital set-
ting. In the past, out of hospital fibrinolytic drug therapy was used
THROMBOLYTICS THERAPY
if the duration of the patient transport time was greater than 1 hour.
When reviewing the use of thrombolytic therapy, the critical points On the other hand, more recent studies have indicated the opposite
to review are the promptness of thrombolysis and the actual strategy. and have shown that out-of-hospital fibrinolysis is a safe and practi-
In doing so, one is confronted with the troublesome statistics that be- cal option. This procedure can be done by an experienced, qualified
tween 25% and 40% of patients, worldwide, who present with clinical paramedic, nurse or physician given that it is performed under pre-
signs of acute STEMI, do not receive any reperfusion therapy at all. A cise protocols. If emergency medical system (EMS) has fibrinolytic
formidable challenge in the contemporary era is to extend the use of giving capacity and the patient meets the requirements for therapy,
reperfusion therapies to all who are likely to benefit. Longer times to pre-hospital fibrinolysis should be initiated within 30 minutes upon
treatment are inversely related to mortality with both thrombolytic arrival at the patient scene.
therapy and PPCI. Cantor et al. compared the strategy of prompt inter-hospital
Most hospitals do not have on-site PCI capability; therefore, transfer for early PCI after fibrinolysis with a standard strategy of
thrombolysis is used as the primary mode of therapy at the time transfer for PCI only in cases in which fibrinolytic therapy had failed
of presentation or before transferring to facilities able to perform (Table 85.2). The first group showed significantly lower rate of death,
PCI. This strategy of routine early PCI after thrombolysis may be reinfarction, recurrent ischemia, congestive heart failure and car-
most beneficial in higher risk STEMI patients.21 Despite the signifi- diogenic shock. The strategy was PCI performed within 6 hours after
cant improvements made in D2B time, many hospitals settings lack fibrinolysis (not the same meaning of a facilitated PCI) and showed
catheterization laboratories, and this has made efficient and timely an important beneficial outcome among high-risk patients.21
Fibrinolysis is followed by increased platelet activation and aggre- The ideal thrombolytic agent should restore normal epicardial
gation and stent implantation early after fibrinolysis. Inadequate and tissue level perfusion very rapidly, be easily administered as a
antiplatelet therapy may be associated with increased rate of acute bolus, have a prolonged half-life, slow plasma clearance and mini-
stent thrombosis. When the delay between fibrinolysis and PCI is too mal bleeding complications. It should also be highly fibrin specific
long, patients are exposed to the risk of reinfarction and recurrent with little or no systemic fibrinogen depletion. The ideal thrombo-
ischemia while they await PCI, and patients in whom reperfusion lytic agent has yet to be discovered. Administrating an optimal lytic
after fibrinolysis is not successful may not be able to undergo res- therapy might narrow the gap between primary PCI and thrombo-
cue PCI quickly enough to salvage myocardium.21 Transfer should lytic agents. This might be achieved by an early administration of the
be considered when fibrinolysis has failed and can probably wait drug and using the ideal agent.
until the day after fibrinolytic therapy is given. Fibrinolysis should
be followed by an early invasive approach. Rescue PCI occurs after CONCLUSION
failed fibrinolysis in patients with large infarcts if performed within
12 hours after onset.23 PCI when executed within 90 minutes of a pa- STEMI remains a killer of mankind whose scourge is felt more in
tient’s arrival has shown to be a better option to fibrinolysis in com- developing nations such as in India. Although PPCI demonstrates
bined end points of death, stroke and reinfarction in many studies. clinical superiority over thrombolytic therapy, wide-spread adop-
The reality is that PCI is not widely available at acute care hospitals. tion of this strategy remains hampered by its high-cost and by oth-
In the United States, of the nearly 5,000 acute care hospitals, 2,200 er daunting hurdles. Thrombolytic therapy, in particular the use of
have catheterization laboratories. Among those, only 1,200 (< 25%) newer fibrin-specific agents, remains a viable alternative provided
are capable of performing PCI.11 the appropriate agent is delivered urgently.
REFERENCES
1. Collen D, Lijnen HR. The tissue-type plasminogen activator story. Arterioscler Thromb Vasc Biol. 2009;29(8):1151-5.
2. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a
report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999
Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110(9):e82-292.
3. Fernandez-Aviles F, Alonso JJ, Pena G, et al. Primary angioplasty vs. early routine post-fibrinolysis angioplasty for acute myocardial infarction with
ST-segment elevation: the GRACIA-2 non-inferiority, randomized, controlled trial. Eur Heart J. 2007;28(8):949-60.
4. Goodman SG, Menon V, Cannon CP, et al. Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines, 8th edition. Chest. 2008;133(6 Suppl):708S-75S.
5. Kushner FG, Hand M, Smith SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial
infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (up-
dating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23):2205-41.
6. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contem-
porary management options. J Am Coll Cardiol. 2007;50(10):917-29.
7. Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myo-
cardial Infarction (TIMI) 10A dose-ranging trial. Circulation. 1997;95(2):351-6.
8. Gibson CM, Pride YB, Frederick PD, et al. Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality
among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006. Am
Heart J. 2008;156(6):1035-44.
9. Armstrong PW, Collen D. Fibrinolysis for acute myocardial infarction: current status and new horizons for pharmacological reperfusion, part 1.
Circulation. 2001;103(23):2862-6.
10. Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart. 2003;89(11):1358-62.
11. Mehta S. Textbook of STEMI Interventions. 1st edition. Miami: HMP Communications; 2008.
12. Gibson CM, Marble SJ. Issues in the assessment of the safety and efficacy of tenecteplase (TNK-tPA). Clin Cardiol. 2001;24(9):577-84.
13. Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarc-
tion: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation. 1998;98(25):2805-14.
14. Armstrong PW, Granger C, Van de Werf F. Bolus fibrinolysis: risk, benefit, and opportunities. Circulation. 2001;103(8):1171-3.
15. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Phy-
sicians Evidence-Based Clinical Practice Guidelines,8th edition. Chest. 2008;133(6 Suppl):257S-98S.
16. Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocar-
dial infarction: the ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J. 1999;137(5):786-91.
17. Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the AS-
SENT-2 double-blind randomised trial. Lancet. 1999;354(9180):716-22.
18. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in com-
bination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet.
2001;358(9282):605-13.
19. Welsh RC, Chang W, Goldstein P, et al. Time to treatment and the impact of a physician on prehospital management of acute ST elevation myocar-
dial infarction: insights from the ASSENT-3 PLUS trial. Heart. 2005;91(11):1400-6.
20. Nallamothu B, Fox KA, Kennelly BM, et al. Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percu-
taneous coronary intervention. The Global Registry of Acute Coronary Events. Heart. 2007;93(12):1552-5.
21. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med.
2009;360(26):2705-18.
22. Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) eve-
rything? Am J Cardiol. 2003;92(7):824-6.
23. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation:
the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J.
2008;29(23):2909-45.
Future of Thrombus, Thrombolytic
86 Therapy and PCI in Cardiovascular
Disorders in India
Iyengar SS
“We should all be concerned about the future because we will have to spend the rest of our lives there.”
—Charles E Kettering
and third generation reteplase and tenecteplase appeared on the

INTRODUCTION
scene. The third generation fibrinolytics have prolonged plasma
The origin of mammalian blood coagulation could be traced back to clearance and can be administered as a bolus rather than infusion
400 million years, but only the last few years have witnessed rapid or double bolus and infusion. Tenecteplase is a mutant of tissue plas-
strides of advances in understanding the intricacies of bleeding and minogen activator (tPA), and was compared with tPA in Assessment
clotting, paving the path for safer and more effective therapeutic of the safety and efficacy of a new thrombolytic (ASSENT-2), a phase
strategies in the field of thrombolytic therapy. 3 equivalence trial.2 Tenecteplase was superior in a sub-group of pa-
Clot as a culprit plays havoc in various vascular territories of tients who were treated after 4 hours of onset of symptoms, with a
the human body, leading to considerable morbidity and mortality. mortality rate of 7.0% with tenecteplase and 9.2% with tPA (p = 0.018).
The blood clot as it blocks the vascular lumen cuts the life line of the Thrombolytic therapy has several potential limitations, like
organ supplied by the artery, interferes with the drainage of the area contraindications to thrombolysis, failed reperfusion, and residual
if in a vein and also acts as source for thromboembolic showers. stenotic lesion in the infarct related artery. Also the hemorrhagic
Infrequently, it might cause choking of a prosthetic valve and its dys- events undermine the safety of thrombolytic therapy. Moreover, in
function. reperfusion therapy for acute STEMI, it has a stronger opponent, i.e.
The role of thrombolytic therapy has been established in the primary percutaneous coronary intervention (PCI). But, intravenous
following clinical situations: thrombolysis is easy to administer and widely available and thus
• ST elevation myocardial infarction (STEMI) continues to be the treatment of choice for initial therapy in most pa-
• Acute pulmonary embolism tients of STEMI eligible for thrombolytic therapy.
• Stroke
• Others: Peripheral arterial disease, deep vein thrombosis, Future
clotted prosthetic valve.
Thrombolytic Therapy
ST ELEVATION MYOCARDIAL INFARCTION
For years to come, thrombolytic therapies will continue to be the
So Far choice of initial reperfusion strategy in patients with STEMI, for
economic and logistic reasons.3 Tenecteplase with its ease of bolus
Early thrombolysis restores flow, salvages myocardium and reduces administration and affordable pricing will be used more often. How
mortality in patients with STEMI. With the results of the first Italian quickly the reperfusion therapy can be delivered is more important
group for the study of the survival of myocardial infarction (GISSI) than which reperfusion therapy is offered and this principle will be
trial studying more than 11,000 patients with intravenous strepto- the guiding factor in therapeutic strategies in managing STEMI.
kinase in 1986, the role of thrombolytic therapy in STEMI was well
established. The collaborative overview of results from nine trials Pre-hospital Thrombolysis
of thrombolytic therapy showed a significant 18% reduction in 35-
day mortality.1 After streptokinase, which is antigenic and produces In a meta-analysis of all the available trials,4 a very impressive mor-
marked systemic fibrinogen depletion, second generation alteplase tality reduction was seen amongst patients treated within the first
Chapter 86  Future of Thrombus, Thrombolytic Therapy and PCI in Cardiovascular ... 727
2 hours of onset of STEMI. This prompts us to plan practicing pre- TABLE 86.1 Characteristics of the ideal thrombolytic agent
hospital initiation of thrombolytic therapy. Well-equipped ambu- • Rapid reperfusion
lance services with well-trained paramedical personnel with facili-
• 100% thrombolysis in myocardial infarction (TIMI) grade 3 flow
ties of tele-transmission of electrocardiograms (ECGs), and a legal
reperfusion
support would make pre-hospital thrombolysis a reality.
• Administration as an intravenous bolus
• Fibrin specific
Thrombolysis Followed by PCI
• Low incidence of systemic bleeding
We also need to overcome another limitation of the thrombolytic • Low incidence of intracranial hemorrhage
therapy, and that is “reocclusion” of the infarct related artery lead- • Resistant to plasminogen activator inhibitor-1 (PAI-1)
ing to reinfarction and poor outcome. The reocclusion rate following
• Low reocclusion rate
thrombolysis is 10% in-hospital and 30% during the first year.5 Apart
• No effect on blood pressure
from the adjunctive therapy with antiplatelets and antithrombot-
ics, a routine PCI after 3 hours and before 24 hours is an attractive • No antigenicity
option.6 It is preferable to avoid early PCI during the prothrombotic • Reasonable cost
period following thrombolysis on the one hand and to minimize the
risk of reocclusion on the other hand, and hence a time window of
3–24 hours following successful thrombolysis is recommended. In
combined abciximab reteplase stent study (CARESS) trial7 a more efit and minimize the risk. However, an ideal thrombolytic agent is
conservative strategy (i.e. angiogram only in cases of failed throm- yet to emerge. Staphylokinase and vampire bat plasminogen activa-
bolysis) was associated with a worse clinical outcome than the tor are undergoing evaluation.
strategy of rescue angioplasty in all cases following thrombolysis.
The limitations of this study are that it was an open label study of a
small number of patients and the optimal timing of PCI is not clear. Health Policy
TRANSFER-AMI study8 showed that with optimal pharmacotherapy Development of a regional system of STEMI care is a matter of
and 6 hours cut-off, pharmacoinvasive strategy is better than rescue great importance and is required to utilize the local resources in an
PCI or selective PCI postlysis. There was a clear benefit at 30 days optimal fashion. Local cardiologists and cardiological societies
when early transfer for PCI after receiving thrombolysis at a non-PCI should collaborate with the local health authorities and develop a
hospital was compared to the standard approach and also there was system that cares for STEMI patients. Apart from health education
no excess bleeding. to improve awareness, institution of preventive measures and early
recognition of the disease, the collaboration should evolve a triage
Intra-coronary Low Dose Thrombolysis During PCI system and networking of PCI-capable and PCI-noncapable hospi-
tals to manage STEMI patients.
In primary PCI, distal embolization and microvascular dysfunc-
tion remain a problem. Distal embolization is evident at coronary THROMBOLYTIC THERAPY IN
angiogram in as many as 15% of patients presenting with STEMI.9
ACUTE ISCHEMIC STROKE
In postmortem studies, as many as 80% of patients with STEMI have
evidence of microembolization.10 Will intracoronary administration So Far
of low-dose thrombolytic solve this problem? There is a randomized
study using intracoronary low-dose streptokinase (2.5 lac units) giv- Based on 21 completed randomized clinical trials of 7,152 patients,
en immediately after primary PCI.11 There was significant benefit in thrombolytic therapy is of proven value for select patients with acute
terms of long-term infarct size and left ventricular function. This is to cerebral ischemia.13,14
be seen whether this strategy will be utilized in future regularly and “Time lost is brain lost”. Use of alteplase for acute ischemic stroke
that would depend on more data. has been approved by Food and Drug Administration (FDA) in 1996
and subsequently approved for use in Canada, Europe, South Africa
An Ideal Thrombolytic Agent and Asia. And the time window specified was 3 hours. However, in
2007 American Heart Association and American Stroke Association
The future will also see the scientific community in search of an “ide- extended the time window to 4.5 hours with a few more exclusion cri-
al thrombolytic agent” (Table 86.1).12 An ideal thrombolytic agent teria. Streptokinase was tried with a time window between 4.5 hours
has to be effective, safe and affordable. It should maximize the ben- and 6 hours and was found to be of no benefit.
Future report from Pathak et al.17 and Becattini et al.18 showed the benefit of
tenecteplase therapy in 58 hemodynamically stable patients of pul-
Third generation thrombolytic agent, tenecteplase, was studied with monary embolism with right ventricular dysfunction.
a time window of 3 hours. Its safety and benefit ratio was found to be
greater than or equal to tPA.15 Lager studies have to be carried out THROMBOLYTIC THERAPY
before tenecteplase finds its place in the treatment of acute ischemic
IN OTHER SITUATIONS
stroke.
With imaging facilities like magnetic resonance imaging (MRI) Thrombosis of cardiac prosthetic valves is one of the most serious
and multimode computerized tomography (CT) scan, it is possible complications of cardiac valve replacement. Thrombolytic therapy
to identify salvageable brain tissue and extend the time window up to in these situations avoids re-operation related risks.19 Thrombolytic
9 hours. Intra-arterial prourokinase has been tried in acute ischemic therapy also has its role in other thrombotic conditions like occluded
stroke. dialysis access grafts, occluded bypass grafts, acute arterial embolism
and acute arterial occlusions. Here again, third generation thrombo-
THROMBOLYTIC THERAPY IN ACUTE lytic agents will be utilized more often in future.20
PULMONARY EMBOLISM
CONCLUSION
So Far
• Thrombolytic therapy will continue to be the initial choice of
Thrombolytic therapy with streptokinase/alteplase has been ap- reperfusion therapy in STEMI for a long time to come
proved for use in patients of acute pulmonary embolism categorized • Third generation thrombolytic agents in general and tenect-
as “high risk”. The use of thrombolytic agent in patients with interme- eplase in particular will be utilized more often for thrombolysis in
diate risk is at the clinician’s discretion. STEMI
• However, our efforts should be to switch over to primary PCI for
Future all patients of STEMI
• We will probably transit through “pre-hospital thrombolysis” and
Third generation thrombolytic agents (reteplase and tenecteplase) “thrombolysis followed by routine PCI” before the switch over
are more likely to be used more frequently and by more clinicians in • The search for an ideal thrombolytic agent will continue.
future. European Society of Cardiology Guidelines mentions tenect- “I know not what the future holds, but I know who holds the
eplase as an off-label indication for thrombolysis in acute pulmonary future”
embolism. There are a few clinical studies documenting the use of The scientists in the field of thrombosis and the clinicians
tenecteplase in case of acute pulmonary embolism16 including a case involved in the care of patients of STEMI hold the future.
REFERENCES
1. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collabora-
tive overview of mortality and major morbidity results from all randomized trials of more than 1,000 patients. Lancet. 1994;343(8893):311-22.
2. Van De Werf F, Adgey J, Ardissino D, et al. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) investigator, Single-bo-
lus tenecteplase compared with front loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet.
1999;354(9180):716-22.
3. Sharma S. Coronary angiography and percutaneous coronary intervention after fibrinolytic therapy: when and to whom? Indian Heart J.
2009;61(5):443-7.
4. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and pre-hospital thrombolysis for acute myocardial infarction: a meta-analysis. JAMA.
2000;283(20):2686-92.
5. Gibson CM, Kartha J, Murphy SA, et al. Early and long-term clinical outcome associated with reinfarction following fibrinolytic administration in
the Thrombolysis in Myocardial Infarction trials. J Am Coll Cardiol. 2003;42(1):7-16.
6. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation:
the Task Force on the management of ST-Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):
2909-45.
7. Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Com-
bined Abciximab Reteplase Stent study in Acute Myocardial Infarction (CARESS-in-AMI): an open, prospective, randomized, multicentre trial.
Lancet. 2008;371(9612):559-68.
8. Cantor WJ. TRANSFER-AMI presented at American College of Cardiology 2008 Scientific Sessions/i2 Summit-SCAI Annual Meeting.
9. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolisation during primary angioplasty for acute myo-
cardial infarction. Eur Heart J. 2002;23(14):112-7.
Chapter 86  Future of Thrombus, Thrombolytic Therapy and PCI in Cardiovascular ... 729
10. Saber RS, Edwards WD, Bailey KR, et al. Coronary embolisation after balloon angioplasty or thrombolytic therapy: an autopsy of 32 cases. J Am
Coll Cardiol. 1993;22(5):1283-8.
11. Sezer M, Cimen A, Aslanger E, et al. Effect of intracoronary streptokinase administered immediately after primary percutaneous coronary inter-
vention on long-term left ventricular infarct size, volumes, and function. J Am Coll Cardiol. 2000;54(12):1065-71.
12. Van de Werf FJ. The ideal fibrinolytic: can drug design improve clinical results? Eur Heart J. 1999;20(20):1452-8.
13. Wardlaw JM, Murray V, Sandecock PAG. Thrombolysis for acute ischemic stroke: an update of the Cochrane thrombolysis meta-analysis. Int J
Stroke. 2008:3(Suppl 1):50.
14. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;369(13):1317-29.
15. Haley EC, Lyden PD, Johnston KC, et al. A Pilot dose escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005;36(3):607-12.
16. Kline JA, Hernandez-Nino J, Jones AE. Tenecteplase to treat pulmonary embolism in the emergency department. J Thromb Thrombolysis.
2007;23(2):101-5.
17. Pathak L, Patil S, Parikh AP, et al. Tenecteplase in acute pulmonary embolism. Indian Heart J. 2010;62(4):342-3.
18. Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embo-
lism. Thromb Res. 2010;125(3):82-6.
19. Roudaut R, Serri K, Lafitte S. Thrombolysis of prosthetic heart valves: diagnostic and therapeutic considerations. Heart. 2007;93(1):137-42.
20. Hull JE, Hull MK, Urso JA, et al. Tenecteplase in acute lower-leg ischemia: efficacy, dose, and adverse events. J Vasc Interv Radiol. 2006;17(4):
629-36.
87 Future of Balloon Valvotomy—
Newer Aspects
Arora R
is, mechanical dilatation without visualization, balloon dilatation by

INTRODUCTION percutaneous technique was introduced by Inoue in 19846 and Lock
After the introduction of percutaneous balloon valvuloplasty by Kan et al. in 19857 by using two different types of balloons. Subsequent
in 1982 for the pulmonary valve, there has been major breakthrough progress has been at a frenetic pace as scores of operator’s adopted this
in the management of stenotic heart valves.1 The ideal requirements simple and effective means of treatment. Al Zaibag in 1986 intro-
of any new procedure are a user friendly technique, optimum suc- duced the techniques of double balloon mitral valvulplasty.8 Simi-
cess rate, minimal morbidity and mortality as well as comparability larly, in 1990 Stefanadis reported the technique of retrograde left
or superiority to the existing conventional mode of therapy. With var- atrial catheterization via the ventricle.9 Finally, Cribier introduced a
ious advancements in cardiac imaging and balloon designs coupled percutaneous metallic valvotomy device which was basically similar
with improvements in the quality of catheters, delivery sheath, guide to Tubb’s dilator used by surgeons for CMC.9 After various modifi-
wires, assisted systems and superior noninvasive imaging, balloon cations in the procedural techniques and experience when the im-
dilatation procedures became widely accepted therapeutic modality mediate and long-term results of percutaneous transvenous mitral
worldwide in all age groups both for congenital and acquired lesions. commissurotomy (PTMC) were found to be similar to CMC, it be-
With increasing experience there has been tremendous procedural came the preferred form of therapy for relief of MS.
safety, effectiveness, low cost and thus the decreasing demographic
trends of surgical management. Selection of Patients
By the late 1980s when it was possible to diagnose many congen-
ital malformations in fetal life including aortic valve stenosis with left Percutaneous transvenous mitral commissurotomy is indicated for
ventricular dysfunction and that of those fetuses going to term there all symptomatic patients [New York heart association (NYHA) Class
were rare survivors of surgery or postnatal balloon valvuloplasty, led II] who have moderate and severe MS [mitral valve area (MVA) ≤ 1.5
to explore the possibility of balloon dilatation during fetal life.2 cm2]. The procedure is not without risk and should not be routinely
indicated in asymptomatic patients. Exceptions to the rule are those
MITRAL STENOSIS with severe MS who require other major noncardiac surgery, young
women in the reproductive period and patients at high risk of throm-
Rheumatic heart disease (RHD) is still one of the commonest car- boembolism (history of thrombotic phenomenon, dense spontane-
diovascular ailments in India and many other developing countries. ous contrast in left atrium and recurring atrial fibrillation).10
Mitral valve is afflicted in almost all cases of RHD and mitral steno- Patient selection is fundamental in predicting immediate and
sis (MS) is the commonest lesion followed by multivalvular lesions.3 follow-up results. This requires a detailed echocardiography—two-
Attempts to open the mitral valve is the story of more than 100 years dimensional, Doppler and cardiac function index (CFI) for assess-
when in 1898 it was recognized that opening the mitral valve will ment of morphologic characteristics of mitral valve apparatus, he-
help the patients. In 1925, Henry Suttar relieved MS with his finger modynamic significance of the stenosis and regurgitation, other
through the apex of the left ventricle (LV). However, reports were associated valvular lesions and pulmonary artery pressure estima-
treated with skepticism and it took nearly 50 years for three surgeons: tion. Wilkins et al. described morphologic changes of the mitral
Bailey, Harken and Block to perform the successful closed mitral valve, i.e. leaflet motility, leaflet thickening, valve calcification and
commissurotomy (CMC).4 This was the preferred method of treat- involvement of subvalvular apparatus each of them classified in 0–4
ment for more than 3 decades because of satisfactory immediate and scale.11 Palacious et al. have established that among its components,
long-term results (excellent symptomatic improvement in 80% at the the only one that correlates with an absolute change in MVA after
end of 15 years), as well as being more economical and available at valvuloplasty is thickening of the valve.12 This score does not take
many cardiovascular centers.5 Based on the same mechanisms that into account other factors, that are important in predicting results
Chapter 87  Future of Balloon Valvotomy—Newer Aspects 731
such as asymmetry of fused commissures and their degree of calci- Techniques of PTMC
fication and it fails to predict severe mitral regurgitation.10 Bilateral
commissural calcification is the predictor of suboptimal results and The different techniques by which PTMC can be performed are given
should be taken as relative contraindication of valvuloplasty. In pres- below.
ence of mild to moderate (central jet) MR, PTMC can be done while
the presence of severe MR is conventionally considered a contraindi- Transfemoral Transvenous Antegrade Approach
cation, but in the pediatric age group when it is not possible to deploy
prosthetic mitral valve of proper size, PTMC needs to be attempted It is most commonly practiced, as septal approach from inferior vena
in symptomatic patients.13 Another important aspect assessed by cava (IVC) to fossa ovalis is direct, but not easy for balloon catheter to
echocardiography in the presence of thrombus in the left atrium or cross the mitral valve, almost bends at 180°, yet with various complex
left atrial appendage (LAA). While the mobile thrombus on the in- maneuvers the procedure can be safely performed. Percutaneous
teratrial septum and left atrial cavity is an absolute contraindication transvenous mitral commissurotomy can be accomplished by using
for transseptal puncture, there are reports of the procedure being Inoue balloon, double balloon (Mansfield), bifoil or trifoil balloon,
performed with caution after anticoagulation with clots localized in Joseph balloon, multi-track technique or metallic valvulotome15
LAA14 (Figs 87.1A and B). (Figs 87.2A to D).
Transjugular Transvenous Antegrade Approach

It finds indication in thrombosed femoral veins, presence of IVC
webs or filters, azygous continuation of IVC, distorted atrial anatomy
and operators preference.16 Although approach of balloon catheter
to mitral valve (MV) is direct, but septal puncture with long and un-
wieldy brockenbrough needle is difficult and operator gets more ra-
diation. There is possibility of less dislodgement of LAA clot and less
radiation to pregnant patient.
Retrograde Non-transseptal Aortic Approach

(Femoral or Brachial Artery)
It is indicated in IVC obstruction or anomalies and inability to per-
form transseptal puncture, but is contraindicated in severe aortic
stenosis, prosthetic aortic valve and peripheral arterial disease.9
A Stefanadis designed a catheter that enters the left atrium easily but
catheter requires 8-9F sheath for its introduction. Although success
rate is more than 90%, but large sheath and arterial damages made
the technique less attractive especially in juvenile MS.
Percutaneous transvenous mitral commissurotomy is per-
formed during pregnancy on an elective basis after 20 weeks of gesta-
tion when organogenesis is complete but in emergency at any stage.
Radiation exposure has been found within safety limits and should
be minimized by adequate abdominal shielding, short fluoroscopy
time, user friendly Inoue balloon technique and the procedure to be
performed by experienced operators. To avoid the risk of radiation
induced teratogenicity, procedure can be attempted under echocar-
diography guidance (Figs 87.3A to C).17
Comparison of PTMC, CMC and OMC

B
Several studies compared the immediate and early follow-up results
Figures 87.1A and B: Transthoracic echocardiogram (TEE) showing of PTMC versus CMC in optimal patients. The results have shown
thrombus. (A) On interatrial septum; (B) In left atrial appendage either superior outcome from PTMC or no significant difference
A B
C D
Figures 87.2A to D: Percutaneous transvenous mitral commissurotomy techniques. (A) Inoue balloon across stenosed MV;
(B) Fully inflated Inoue balloon at MV; (C) Double balloon (Mansfield); (D) Metallic valvulotome
between both groups.18 Long-term follow-up results shown by Ben free survival at long-term follow-up between the two techniques. The
Farhat et al.19 were similar for PTMC and open mitral commissurot- use of double balloon technique is limited by the fact that the pro-
omy (OMC) and significantly superior to CMC. Though the results cedure is more complex. In comparison, the Inoue balloon is more
of PTMC and OMC were quite comparable, but for OMC the need user-friendly, requiring less procedure and fluoroscopy time plus
for cardiopulmonary bypass, thoracotomy, higher cost, longer length cost-effective. This has important implications in developing coun-
of hospital stay and longer period of convalescence made PTMC the tries with large number of patients, as well as for emergency high risk
procedure of choice. Since mitral commissurotomy is a palliative and pregnant patients.
procedure, the likelihood that thoracotomy might be needed at some
point later in the course of the disease, the complications of repeat Therapeutic Results of PTMC
thoracotomy can also be avoided.
Excellent acute hemodynamic results have consistently been
Comparison of Double Balloon reported in numerous clinical studies involving a large number
of patients.12,20,21 In author’s series of 4,838 cases, success-
and Inoue Balloon
ful valvuloplasty was achieved in 99.8%, while optimal results
With experience post PTMC MVA (1.9 ± 0.6 vs 1.7 ± 0.6 cm2, p = 0.008) were obtained in 91% only (defined as MVA ≥ 1.5 cm2, MVEDG
and success rate were significantly higher in the Inoue group as well < 5 mm Hg and ≤ 2 + MR). Among the various factors analyzed
as there was a lower incidence of severe MR is more than or equal for determining the success of PTMC (age, valve morphol-
to 3 + (6.8% vs 12%, p = 0.16).12 Despite the differences in the im- ogy and baseline MVA), none predicted the outcome in these
mediate outcome, there were no significant differences in the event patients.21 In patients with calcified vs noncalcified valves and
mitral restenosis after previous commissurotomy (CMC, OMC

or PTMC) vs native valve, there was less increase in MVA, but
not statistically significant. The overall complications were
low—hemopericardium in 2%, severe MR requiring mitral valve
replacement (MVR) in 1.4%, systemic arterial embolization and
infective endocarditis in 0.1%, persistent left to right shunt in
0.02% and mortality in 0.15%. At a follow-up of 12–166 months,
more than 90% of cases were in functional class I or II, restenosis
resulted in 4.8% and elective MVR was required in 1% due to symp-
tomatic functional deterioration of severity of MR.21
Newer Applications
Over the conventional CMC indications, PTMC is being performed
A for restenosed valves, as treatment of choice during pregnancy,
juvenile cases of MS and even those with central jet of severe MR,
nonpliable and calcified valves, few select cases with documented
left atrial thrombus, associated moderate regurgitation, multivalvu-
lar stenosis, coexistent coronary artery disease and as an emergency
life-saving procedure in acute pulmonary edema with hypoxia/
hypotension.12,21
Role of Surgery in MS
At present CMC is only recommended in technically unsuccessful
PTMC or if this facility is not available. Direct vision OMC is the pro-
cedure of choice only in patients with associated left atrial thrombus
especially mobile and close to the interatrial septum. Mitral valve
replacement is reserved for adult patients with severe MR, acute
severe MR, symptomatic patients with suboptimal balloon valvulo-
B plasty with densely calcified valve, restenosis of a bioprosthesis, in
the presence of organic tricuspid regurgitation, associated significant
aortic disease or coronary artery disease requiring bypass surgery.
TRICUSPID STENOSIS
It is an uncommon disease, almost always of rheumatic origin and
virtually never occurs as an isolated lesion. Its incidence may be
underestimated because it is commonly overlooked and particularly
when associated with MS. Tricuspid valve pathology is present at
autopsy in about 15% of patients with RHD and is of clinical signifi-
cance in only about 5% of cases.22 The clinical diagnosis of Tourette
syndrome (TS) is difficult and there is no perfect diagnostic method.
The characteristic clinical features are of low cardiac output—fatigue,
edematous feet, ascites and anasarca out of proportion to the degree
of dyspnea. The absence of symptoms due to pulmonary congestion
C
(hemoptysis, paroxysmal nocturnal dyspnea and acute pulmonary
Figures 87.3A to C: Percutaneous transvenous mitral commissuro edema) in a patient with obvious MS should suggest the possibility of
tomy under TTE guidance. (A) Arrow showing tenting of fossa ovalis
TS. Like other valvular lesions, echocardiography provides an accurate
by septal puncture needle within Mullin’s dilator; (B) Balloon across
MV into LV; (C) Inflated balloon at MV with arrow heads showing noninvasive tool and compares very well to catheterization in the quan-
constriction by fused commissures tification of TS.
After balloon valvuloplasty emerged as an alternative procedure continuous relief of stenosis after 3–24 months in four patients. The
for pulmonic, aortic or MS, an attempt was made to dilate the tricus- specific impact of TS on pregnancy is not known, but Gamra et al.
pid valve concomitantly to obviate surgery and the improvement in found recurrent miscarriages in a patient with TS and that patient
valve area and symptoms were found to be similar to surgical com- had a normal pregnancy after successful dilatation.27 The mecha-
missurotomy.23,24 nism by which TS could be the cause of miscarriages has been as-
cribed to low cardiac output, resulting in an impairment of uterine
Selection of Patients blood flow and elevated venous pressure may have adverse effects
on venous drainage of the uterus/placenta and thus reduce both pla-
Those with suspected clinical features should be screened by cental and fetal viability.
detailed echocardiography (2D, Doppler and color flow imaging).
Apical four-chamber and parasternal long-axis inlet views are the PULMONARY VALVE STENOSIS
most useful as all three leaflets can be visualized by taking these
two views.25 Patients taken up for valvuloplasty are those with (1) an The first valve to be attempted in children with successful balloon
echocardiographic mean tricuspid valve diastolic gradient of 2 mm dilatation for the relief of pulmonary valve stenosis by Kan et al.1
or more and a tricuspid valve area (TVA) of less than or equal to 2 cm2 facilitated this technology to all age groups. Being less invasive, safe
(2) in the presence of a grade I-II/III tricuspid regurgitation mean tri- and effective with very minimal complication rate has become the
cuspid valve diastolic gradient of 5 mm or more and TVA of less than procedure of choice avoiding the need for surgical intervention in
or equal to 2 cm2. the majority.
Techniques of Tricuspid Valve Dilatation Selection of Patients

It can be performed by percutaneous transvenous femoral or tran- The majority of patients is asymptomatic and is detected on routine
sjugular route by using double balloon or Inoue balloon.23,26 In examination for the presence of a cardiac murmur. Neonates with
patients with combined mitral and tricuspid stenosis, the mitral critical pulmonary stenosis (PS) can present in emergency with
valve is usually dilated first. This is especially relevant to patients heart failure or cyanosis because of right to left shunt. The indica-
with pre-existing tricuspid regurgitation as dilating the mitral tions for balloon pulmonary valvotomy (BPV) are similar to those
valve first provides the opportunity to confirm a satisfactory split used for surgical pulmonary valvotomy, i.e. peak to peak gradient of
of the mitral valve and a fall in pulmonary artery pressure before above or equal to 50 mm Hg with normal cardiac index or echocar-
dilating the tricuspid valve. Because of the high right atrial pres- diographic peak gradient of above or equal to 60 mm Hg.28 Prena-
sure, a close watch should be kept for hypoxemia developing due tal diagnosis is possible and helps in planning balloon dilatation
to right to left shunt across the interatrial septum.25 In such an before ductal closure. Pulmonary valve dysplasia is a relative con-
event tricuspid valve has to be dilated as quickly as possible. If traindication, but if the pulmonary annulus is more than 75% of the
attempted before the mitral valve, to prevent right to left shunt age and body surface area (BSA) of predicted normal, valvuloplasty
and clinical compromise, there is a possibility of worsening the will usually be effective.
pulmonary congestion due to the increase in blood flow, given
the high left atrial pressures and transmitral gradient. If there is Techniques of Balloon Pulmonary Valvotomy
associated pulmonary or aortic valve, dilatation of these valves is
attempted first. The percutaneous femoral venous route is the most preferred
entry site and should be used routinely. If required transhepat-
Therapeutic Results of Total Blood Volume ic, jugular or axillary or umbilical access can be considered. A
5–7F venous and 3–5F arterial hemostatic sheaths are inserted.
Following tricuspid balloon valvuloplasty, satisfactory immediate Pulmonary valve is crossed by using tip-hole catheters like bal-
hemodynamic results have been consistently reported in various loon wedge, Goodale lubin, multipurpose Judkins right coronary
case and small serious reports.23,25 Most of the cases of total blood with the help of soft tipped guidewire. The neonates and young
volume (TBV) apart from bioprosthesis have been performed con- infants may require 0.014” coronary guidewire than 0.035” guide
comitantly with mitral, aortic or pulmonary valve balloon dilatation. wire. Over an extra stiff guidewire, low profile balloon catheter is
The criteria for optimal valvuloplasty are taken to be the same as for positioned across the pulmonary valve and balloon is inflated till
PTMC. Among 10 cases of Sharma et al. hemodynamic parameters the disappearance of the waist (Figs 87.4A and B). Commercially
revealed an increase in TVA from 1.11 ± 0.41 to 2.52 ± 0.69 cm2, p < available balloons are XXL, Ultrathin, Power flex diamond, Tyshak
0.005), and a fall in the mean valve gradient from 11.80 ± 4.70 to 4.14 I, II, 2-Med, Mullins X, bifoil, trefoil, etc. and the balloon diameter
± 3.40 mm Hg along with an increase in cardiac index.25 There was should be 1.2–1.4 times the annular size and 1.4–1.5 times when
A B
Figures 87.4A and B: (A) Right ventricular (RV) angiogram lateral view in a neonate showing severe pulmonary valve stenosis; (B) Balloon
across the pulmonary valve showing the waist at the stenotic site with guide wire across the patent ductus arteriosus (PDA) into descending aorta
dilating dysplastic valves. Length of the selected balloon is 20, 30 tic valve having pulmonary annulus diameter less than 70% of the
or 40 mm for neonates children and adults respectively. Try not normal or severe infundibular narrowing which has not regressed
to inflate at the infundibulum and tricuspid valve. Pre- and post- after successful BPV.
transvalvular gradients are obtained with multi-track catheter, so
that the guidewire is in place, cine angiography is not routinely AORTIC STENOSIS
performed.29
Percutaneous balloon aortic valvuloplasty (BAV) was introduced
Results and Problems by Lababidi in 1983 and because of the effectiveness of the method
in gradient reduction, the procedure was documented in children
UACA registry reported 0.24% death rate and 0.35% major complica- with congenital aortic stenosis.34 The anatomic types of aortic
tion rate from 822 BPV procedures but with increasing experience, valve stenosis include unicuspid, bicuspid, tricuspid, quadricus-
the complication rate should even be lower.30 Complete right bun- pid and undifferentiated valve, but majority of the stenotic valves
dle branch block, permanent heart block, cerebrovascular accident, are bicuspid. There are two types of bicuspid valves: (1) balanced
cardiac arrest, convulsions, rupture of tricuspid papillary muscle and or anatomically bicuspid and (2) unbalanced or functionally bi-
pulmonary artery tears though rare have been reported. Develop- cuspid, the concept of which is important with regard to progno-
ment of severe infundibular obstruction can occur in nearly 30% of sis of valvuloplasty.35 The balanced one is composed of two equal
patients, the older the age and higher the severity of obstruction; the sized cusps with two sinuses of valsalva. The functionally bicuspid
greater is the prevalence of infundibular reaction.3 When the residual also opens as bicuspid but has three sinuses, two of them adja-
infundibular gradient is more than 50 mm Hg, β-blocker therapy is cent to fused cusp which is actually formed by two unequal cusps
given. This obstruction usually regresses at follow-up and surgical conjoined by an unopened commissure. In the balanced bicuspid
intervention is very rarely required.31 Pulmonary insufficiency may valve, the orifice is enlarged by splitting of the functioning com-
increase on follow-up, but usually pulmonary valve replacement is missures while in unbalanced bicuspid valve the fused cusp is
not required. Although, Berman et al. reported severe pulmonary often torn aside from the rudimentary commissure and causes
insufficiency in 6% of patients requiring pulmonary valve replace- severe aortic regurgitation.
ment following oversize balloon in small infants.32 In neonates,
Hanley et al. reported success rate of 92% and in 74% no reinterven- Selection of Patients
tion was required after the first procedure with survival rate of more
than or equal to 89% at 1 month and 81% at 4 years.33 Surgical valvot- Based on clinical and echocardiographic criteria, BAV is indicated
omy may be required in patients with hypoplastic annulus, dysplas- in:36
• All patients with a Doppler peak systolic gradient is above or

SPECIAL SITUATIONS
equal to 75 mm Hg
• In patients with left ventricular strain on electrocardiogram Neonates with Critical Valvular Aortic Stenosis
(ECG) and a peak gradient is above or equal to 60 mm Hg
• Regardless of the gradient in all patients presenting with synco- These children present with congestive heart failure and cardiogenic
pe, low cardiac output or severe left ventricular dysfunction shock secondary to poor left ventricular function and/or mitral in-
• In borderline cases an exercise test is performed and, if suben- sufficiency. Outcome is usually fatal in the majority within the first
docardial ischemia or a hypotensive reaction occurs, treatment few weeks of life despite medical treatment. When the diagnosis is
is indicated. made prenatally, arrangements should be made so that the baby
In patients with moderate to severe aortic regurgitation, surgical is born in the center with facility for balloon or surgical dilatation.
treatment is preferred to valvuloplasty. These children usually require mechanical ventilatory support,
inotropic agents, correction of acidosis and prostaglandin E (PGE),
Techniques of BAV is started to augment cardiac output in the setting of a failing and
obstructed LV. Closed or open surgical valvotomy was the only tech-
The procedure is usually performed from femoral artery by retro- nique available although with decline in mortality from 86% to 9%,
grade approach, occasionally it may be impossible to pass the guide till 1986 when balloon valvuloplasty for aortic stenosis was success-
wire from the retrograde approach to LV, in such cases the proce- fully performed in a newborn.39 Transthoracic echocardiography
dure can be completed from the femoral venous access. First, the is the imaging method for selection of patients for BAV. Results are
foramen ovale patency is explored and if not possible, transseptal good if left ventricle end-diastolic diameter (LVED) is more than 17
puncture is done. Simultaneously recording of the procedure in mm and aortic annulus diameter 6–8 mm, but if LVED is less than
the LV and aorta just above the valve or pullback gradient can be 14 mm, surgical procedures like Noorwood operation are performed.
measured by using multi-track catheter. Balloon catheter with low Vascular access can be from umbilical vessels. Optimal valvuloplasty
profile, fast inflation and deflation, noncompliant, and of diameter is achieved in around 70% and 85% are alive on follow-up at 5 years
80–90% of the annulus size should be used. The optimum ratio of and 60% free of reintervention.40
balloon length to balloon diameter is more than 3 and it should
never be less than 2. When it is not possible to hold the inflated Balloon Aortic Valvuloplasty
balloon steady in proper position, the adenosine administration or
for the Elderly Patients
rapid ventricular pacing are almost 100% effective in the prevention
of balloon movement. Degenerative changes of the aortic valve occurs with age and are
The major pitfall is the mitral valve injury if the guidewire is often observed in those more than 70 years of age, but patients with
threaded through the anterior mitral leaflet chordae. Occasionally bicuspid or rheumatic pathology can present earlier in life. Once
transient left anterior hemiblock or left bundle branch may occur. symptomatic [angina, syncope or congestive heart failure (CHF)] the
prognosis is poor, without intervention and surgical valve replace-
Results ment was the standard treatment. Balloon aortic valvuloplasty has a
special role:41,42 (1) those in cardiogenic shock require as a bridge to
A reduction of more than 50% gradient have been demonstrated high risk aortic valve replacement and (2) patients who need urgent
in a large cohort of children in a multicentric study.37 Long-term noncardiac surgery or those without surgical option for aortic valve
results of valvuloplasty at the age of 5 weeks—23 years, with a medi- replacement.
an follow-up of 7.5 years showed a restenosis rate of 15% and severe No doubt BAV is a palliative procedure, not an alternative
aortic insufficiency in 20%.36 While the restenosis can be success- to valve replacement but today, it is safe in experienced hands,
fully treated by a repeated valvuloplasty, but aortic regurgitation is low-cost procedure and can be performed at any age as a thera-
progressive in the long-term perspective and surgery is required peutic modality to relieve symptoms in those at high risk for valve
in late childhood or early adulthood.38 The actuarial probability of replacement.
survival is 0.93 in infants and 0.98 in older patients, but the proba-
bility of surgery-free survival is only 0.52 in infants and 0.65 in older FETAL BALLOON DILATATION
patients. The functionally bicuspid aortic valve is an independent
predictor of severe post valvuloplasty aortic insufficiency and the It was attempted in fetal life at Guy’s hospital in London for se-
need for surgery. vere valvular aortic stenosis with left ventricular dysfunction.2 At
present, clinical work in fetal interventions centers on three major perforate the pulmonary valve. The guide wire was passed across the
aspects: (1) the treatment of fetal aortic stenosis arouses interest pulmonary valve into the arterial duct and 3–4 mm coronary balloon
for survival and to prevent the possibility of development of hy- were used for dilatation. Both babies had postnatal balloon dilata-
poplastic left heart syndrome (HLHS), (2) the possible role of fetal tion and there was significant increase in right ventricle and tricus-
atrial septostomy in improving the ultimate survival of fetus with pid valve in fetal life. Subsequently, the results have not been very
established HLHS and (3) the possible utility of intervention in fe- encouraging.
tus with critical PS or atresia with intact ventricular septum. At present there are clinical limitations as the equipment is not
ideal and the imaging is still suboptimal.
Aortic Stenosis with Left
Ventricular Dysfunction CONCLUSION
In 2004, Tworetzky published a series of fetal balloon aortic valve dil- During the past three decades, balloon valvotomy has revolutionized
atations with the aim of preventing the evolution from aortic stenosis the approach to stenotic heart valves and has become the standard
(AS) to HLHS to provide a two ventricular circulation in postnatal treatment modality in all age groups in most centers demonstrating
life.43 The selection criteria are: (1) mid-trimester fetus with domi- optimal clinical outcomes with evolving techniques. Psychologically
nant AS and (2) in fetus going to progress to HLHS (LV length not also, there is more acceptability as there is no thoracotomy scar, no
more than 2SD below the mean for gestational age with little forward general anesthesia, no regular use of blood transfusion, less hospi-
flow through the aortic valve). talization, lesser morbidity and mortality, as well as possibility of re-
Technique: Once selected, the procedure is carried out with light peat valvuloplasty for restenosis avoiding risk of thoracotomy. The
general anesthesia to the mother and the fetus is paralyzed using maximum application is in the developing countries as the major-
transabdominal ultrasound with 19 gauge cannula and stylet are ity of the valvular lesions are of rheumatic origin and MS, which is
inserted from the maternal skin passing through the uterine wall, the commonest lesion, has found balloon dilatation as the first line
puncturing the fetal thorax and LV. A 0.014” coronary guidewire is therapeutic procedure with superior or equal results to surgical val-
passed across the aortic valve and dilatation is done using 3–4 mm votomy. There is no longer controversy regarding the nonsurgical
coronary balloon. Various modifications are done if fetal lie is un- catheter dilatation as one of the best approach in the neonates and
favorable including minilaparotomy. Although, success rate is 80% elderly patients especially for aortic stenosis with high operable risk,
but only 25% are alive with two ventricle circulation while all without till the newer techniques of percutaneous valve replacement find ap-
dilatation of aortic valve developed HLHS, showing a significant implication as the treatment of first choice. It is not yet ideal to perform
provement over the natural history. fetal cardiac interventions routinely, but those having the requisite
equipment and expertise should continue to investigate in this field.
Pulmonary Atresia or Critical PS Above all, the choice of initial intervention should depend on mor-
phological factors, local expertise, ability to obtain vascular access
with Intact Ventricular Septum
and resource utilization. The prerequisite of availability for closed
The first report of fetal intervention was in 2002 by Tulzer et al. in two and opened heart surgery should be kept in mind even with expe-
cases44 under local anesthesia to the mother. The right ventricle was rienced operators and in centers performing balloon valvuloplasty
perforated with a 16 gauge needle and the same needle was used to on routine basis.
REFERENCES
1. Kan JS, White RI, Mitchell SE, et al. Percutaneous balloon valvuloplasty: a new method for treating congenital pulmonary-valve stenosis. N Eng J
Med. 1982;307(9):540-2.
2. Maxwell D, Allan L, Tynan MJ. Balloon dilatation of the aortic valve in the fetus: a report of two cases. Br Heart J. 1991;65(5):256-8.
3. Padmavati S. Present status of rheumatic fever and rheumatic heart disease in India. Indian Heart J. 1995;47(4):395-8.
4. Bailey CP. The surgical treatment of mitral stenosis (mitral commissurotomy). Dis Chest. 1949;15(4):377-97
5. John S, Bashi VV, Jairaj PS, et al. Close mitral valvotomy: early results and long-term follow-up of 3,724 consecutive patients. Circulation.
1983;68(5):891-6.
6. Inoue K, Owaki T, Nakamura T, et al. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc
Surg. 1984;87(3):394-402.
7. Lock JE, Khalilullah M, Shrivastava S, et al. Percutaneous catheter commissurotomy in rheumatic mitral stenosis. N Engl J Med. 1985;313(24):1515-
8.
8. Al Zaibag M, Ribiero PA, Al Kasab S, et al. Percutaneous double-balloon mitral valvotomy for rheumatic mitral-valve stenosis. Lancet.
1986;1(8484):757-61.
9. Stefanadis C, Kourouklis C, Stratos C, et al. Percutaneous balloon mitral valvuloplasty by retrograde left atrial catheterization. Am J Cardiol.
1990;65(9):650-4.
10. Arora R, Kalra GS, Murty GS, et al. Percutaneous transatrial mitral commissurotomy: immediate and intermediate results. J Am Coll Cardiol.
1994;23(6):1327-32.
11. Wilkins GT, Weyman AE, Abascal VM, et al. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related
to outcome and mechanism of dilatation. Br Heart J. 1998;60(4):299-308.
12. Palacious IF. Percutaneous mitral balloon valvuloplasty: book of percutaneous interventions for congenital heart disease. In: Sievert H, Qureshi
SA, Wilson N, Hijazi ZM (Eds). Publisher Informa Healthcare; 2007. pp. 177-84.
13. Arora R, Mukhopadhyay S, Yusuf J, et al. Technique, results, and follow-up of interventional treatment of rheumatic mitral stenosis in children.
Cardiol Young. 2007;17(1):3-11.
14. Chen WJ, Chen MF, Liau CS, et al. Safety of percutaneous transvenous mitral commissurotomy in patients with mitral stenosis and thrombus in
left atrial appendage. Am J Cardiol. 1992;70(1):117-9.
15. Cribier A, Eltchanioff H, Koning R, et al. Percutaneous mechanical mitral commissurotomy with a newly designed metallic valvulotome: immedi-
ate results of the initial experience in 153 patients. Circulation. 1999;99(6):793-9.
16. Joseph G, Baruah DK, Kuruttukulam SV, et al. Transjugular approach to transseptal balloon mitral valvuloplasty. Cathet Cardiovasc Diagn.
1997;42(2):219-26.
17. Arora R, Lal P. Valvular heart disease in pregnancy: problems and practice. Cardiol Today. 2008;12:207-14.
18. Arora R, Nair M, Kalra GS, et al. Immediate and long-term results of balloon and surgical closed mitral valvotomy; a randomized comparative
study. Am Heart J. 1993;125(4):1091-4.
19. Ben Farhat M, Ayari M, Maatouk F, et al. Percutaneous balloon versus surgical closed and open mitral commissurotomy; seven-years follow-up
results of a randomized trial. Circulation. 1998;97(3):245-50.
20. Chen CR, Cheng TO. Percutaneous balloon mitral valvuloplasty by the Inoue technique: A multicenter study of 4,832 patients in China. Am Heart
J. 1995;129(6):1197-203.
21. Arora R, Kalra GS, Singh S, et al. Percutaneous transvenous mitral commissurotomy: immediate and long-term follow-up results. Cathet Cardio-
vasc Intervent. 2002;55(4):450-6.
22. Kitchin A, Turner R. Diagnosis and treatment of tricuspid stenosis. Br Heart J. 1964;26:354-79.
23. Khalilullah M, Tyagi S, Yadav BS, et al. Double-balloon valvuloplatsy of tricuspid stenosis. Am Heart J. 1987;114(5):1232-3.
24. Arora R. Tricuspid valve stenosis: book of percutaneous interventions for congenital heart disease. In: Sievert H, Qureshi SA, Wilson N, Hijazi ZM
(Eds). Publishers Informa Healthcare; 2007. pp. 201-6.
25. Sharma S, Loya YS, Desai DM, et al. Percutaneous double-valve balloon valvotomy for multivalve stenosis: immediate results and intermediate-
term follow-up. Am Heart J. 1997;133(1):64-70.
26. Patel TM, Dani SI, Shah SC, et al. Tricuspid balloon valvuloplasty: a more simplied using Inoue balloon. Cathet Cardiovasc Diagn. 1996;37(1):86-8.
27. Gamra H, Betbout F, Ayari M, et al. Recurrent miscarriages as an indication for percutaneous tricuspid valvuloplasty during pregnancy. Cathet
Cardiovasc Diagn. 1997;40(3):283-6.
28. Rao PS. Indications for balloon pulmonary valvuloplasty. Am Heart J. 1988;116(6 Pt 1):1661-2.
29. Rao PS. Balloon pulmonary valvuloplasty in children. J Invasive Cardiol. 2005;17(6):323-5.
30. Stranger P, Cassidy SC, Girod DA, et al. Balloon pulmonary valvuloplasty: results of valvuloplasty and angioplasty of congenital anomalies registry.
Am J Cardiol. 1990;65(11):775-83.
31. Thapar MK, Rao PS. Significance of infundibular obstruction following balloon valvuloplasty for valvular pulmonic stenosis. Am Heart J.
1989;118(1):99-103.
32. Berman W, Fripp RR, Raiser BD, et al. Significant pulmonary valve incompetence following oversize balloon pulmonary valvuloplasty in small
infants: a long-term follow-up study. Cathet Cardiovasc Interven. 1999;48(1):61-5.
33. Hanley FL, Sade RM, Freedom RM, et al. Outcomes in critically ill neonates with pulmonary stenosis and intact ventricular septum: a multi-
institutional study. Congenital Heart Surgeons Society. J Am Coll Cardiol. 1993;22(1):183-92.
34. Lababidi Z, Wu JR, Walls JT. Percutaneous balloon aortic valvuloplasty: results in 23 patients. Am J Cardiol. 1984;53(1):194-7.
35. Reich O, Tax P, Marek J, et al. Long-term results of percutaneous balloon valvuloplasty of congenital aortic stenosis: independent predictors of
outcome. Heart. 2004;90(1):70-6.
36. Reich O. Aortic valve congenital aortic stenosis in book of percutaneous interventions for congenital heart disease. In: Sievert H, Qureshi SA,
Wilson N, Hijazi ZM (Eds); 2007. pp. 153-62.
37. Rocchini AP, Beekman RH, Ben Shachar G, et al. Balloon aortic valvuloplasty: results of Valvuloplasty and Angioplasty of Congenital Anomalies
Registry. Am J Cardiol. 1990;65(11):784-9.
38. Balmer C, Beghetti M, Fasnacht M, et al. Balloon aortic valvuloplasty in paediatric patients: progressive aortic regurgitation is common. Heart.
2004;90(1):71-81.
39. Lababidi Z, Weinhaus L. Successful balloon valvuloplasty for neonatal critical aortic stenosis. Am Heart J. 1986;112(5):913-6.
40. Pass RH, Hellenbrand WE. Catheter intervention for critical aortic stenosis in the neonate. Cathet Cardiovasc Interven. 2002;55(1):88-92.
41. ACC/AHA guidelines for the management of patients with valvular heart disease, a report from the American College of Cardiology/Ameri-
can Heart Association, Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Disease). J Am Coll Cardiol.
1998;32(5):1486-588.
42. Cribier A, Remadi F, Koning R, et al. Emergency balloon valvuloplasty as initial treatment of patients with aortic stenosis and cardiogenic shock.
N Engl J Med. 1992;326(9):646.
43. Tworetzky W, Wilkins-Haug L, Jennings RW, et al. Balloon dilatation of severe aortic stenosis in the fetus: potential for prevention of hypoplastic
left heart syndrome, candidate selection, technique and results of successful intervention. Circulation. 2004;110:2125-31.
44. Tulzer G, Arzt W, Franklin RC, et al. Fetal pulmonary valvuloplasty for critical pulmonary stenosis or atresia with intact septum. Lancet
2002;360(9345):1567-8.
88 History of Stem Cell Therapy and its
Future in Cardiovascular Diseases
Shah VK, Shalia KK
INTRODUCTION of using stem cells as tools in the hands of mankind for regenerating
myocardium. Although their findings were subsequently challenged
Coronary artery disease remains major cause for morbidity and by Murry and colleagues in 2004,4 the journey of stem cells in regen-
mortality despite the recent advances in its management. Irrevers- erating the myocardium had already begun. Experimental evidences
ible myocyte injury begins immediately after 20 minutes of coronary such as regenerative potential of native human myocardium, exist-
occlusion leading to loss of myocardial systolic function and scar for- ence of cardiac stem cells (CSC), evidences of endogenous cell re-
mation. This loss of viable myocardium initiates a process of adverse cruitment from the systemic circulation within the myocardium and
ventricular remodeling and a downward spiral leading to congestive evidences that not only exogenously administered cell population
heart failure (CHF). This is followed by repeated hospitalization and home to the injured heart but they can also reconstitute infarcted
increased economic burden on the society with 50% of the patients myocardium, were some of the preclinical findings that gave a way to
dying within 5 years of the diagnosis. animal experiments.
However, a veritable revolution is now unfolding in the field of
cardiac biology where a fundamental principle that “the heart is a PRECLINICAL DATA EVIDENCE TOWARDS
terminally differentiated (postmitotic) organ incapable of regenera-
REGENERATION
tion” has come under attack of late. According to this dogma, “the
number of cardiomyocytes we are born with is all we will have for the Report by Kajstura et al. (1998)5 in control human hearts by confocal
rest of our lives. If myocytes die they cannot be replaced as they have microscopy demonstrated 14 × 106 myocytes in mitosis. Subsequent-
withdrawn from the cell cycle and have ceased to proliferate”. This ly, Beltrami et al.6 in 2001 reported 4% of myocyte nuclei undergoing
bleak doctrine has been challenged by the discovery of “myocytes in mitosis in the infarct border of postmortemed hearts. These findings
mitosis” and the hypothesis that “adult stem cells which have been gave evidence of regenerative potential of native human myocar-
used to restore blood and immune system since last 50 years can also dium. Evidence of existence of resident CSC in mice were given by
regenerate myocytes”.1 Hierlihy et al. (2003)7 and subsequently by Beltrami et al. (2003)8 who
Every single cell in the body originates from stem cell. They are demonstrated that these lineage-negative (Lin–) c-Kit positive (Lin−
the primitive, undifferentiated, undefined, pluripotent, multilineage C-Kit+) cells were able to differentiate in vitro into all three main cell
cells that retain the ability to renew themselves through mitotic divi- types—myocardial, endothelial and smooth muscle cell types. These
sion and can divide and create a cell more differentiated than itself as findings encouraged reconsideration of traditional beliefs concern-
per their anatomical surroundings. Stem cells are usually classified ing cardiac self-regeneration.
according to the following criteria: origin (fetal/adult), type of organ It has been known for many decades that myocardial infarction
or tissue from which the cells are derived, surface markers and final (MI) is an inflammatory disease which results first in the homing of
differentiation fate. The cells which are known to have cardiogenic neutrophils and later monocytes from the circulation (Malloy et al.
potential are listed in Table 88.1. Myocardium with vessels, valves 1939).9 However, only recently it has been appreciated that marrow-
and even conducting systems has become an attractive target of stem derived progenitor cells circulate and home to injured tissues similar
cell therapy. Regenerating the myocardium requires differentiation to leukocytes where they contribute to the formation of new tissues
of stem cells into myocardial, endothelial and smooth muscle cells (Jackson et al. 2001).10 In an interesting experiment by Laflamme
giving rise to myocytes, capillary microcirculation and extracellular et al. (2002)11 and Quaini et al. (2002)12 of sex-mismatched cardiac
matrix. transplantations, homing of recipient’s progenitor cells in the myo-
Since last 12 years, history of science has witnessed certain path cardium was demonstrated. In their procedure, Y-chromosome in-
breaking findings demonstrating the role of stem cells in healing the situ hybridization was used to track the male cells in the female allo-
heart.2 The revolutionary paper by Orlic et al. in 20013 gave a hope grafts coupled with immunostaining to define the identity these cells
TABLE 88.1 Major cell types with potentials for cardiac cell therapy
Type Markers Advantages Disadvantages
Embryonic stem cells (ESC) — Totipotent and highly expandable Immunosuppression required, ethical
Blastocysts debate, lack of availability and tumor
(Inner cell mass) potential
Umbilical cord blood cells CD34+, CD133+ Pluripotent and highly expandable Immunosuppression required
Umbilical Cord
Adult/Fetal Isl+, Lin− c-Kit+ Sca-1+ Multipotent Cardiomyocyte phenotype Immunosuppression required, ethical
cardiosphere cells, SP cells debate, short survival and limited
supply
Cardiomyocytes Electrophysiologically compatible
Skeletal myoblasts satellite cells CD56+ Autologous transplantation, lack of Electrophysiologically incompatible-
immunogenicity and high yield and fatigue- lack of gap junction, arrhythmogenic
resistant, slow-twitch fibers
Hematopoietic stem cells bone CD34+, CD45+, CD133+ Multipotent, lack of immunogenicity and Quantum of cell population not
marrow/Peripheral blood autologous transplantation-different lineage adequate
of cells
Endothelial prognitor cells bone CD133+ Autologous transplantation Need for expansion because of limited
marrow/Peripheral blood Monopotent supply
Lack of immunogenicity
Mesenchymal stem cells bone Adhesion molecules Allogenic/autologous transplantation, lack Requires expansion
marrow stromal/Muscle, skin, and (ALCAM/CD44) of immunogenicity, (Lack of MHCII and B7
adipose tissue Antigens expression), pluripotent and cryopreservable
(SH2/SH3/SH4/ STRO-1) for future use
Induced pluripotent cell (IPS) Pluripotent indistinguishable from ESCs Tumorigenesis
Fibroblast at the epigenetic and functional levels.
(By reprogramming adult somatic Embryonic stem cell like autologous adult
cells with genes regulating ESC cells for cell therapy
pluripotency)
had acquired. Quanni et al.12 further hypothesized that the donor In addition to tracking endogenous cells, several exogenous ad-
hearts harbor a population of resident primitive cells and also attract ministered cell populations were also shown to home in the injured
a second population of progenitor cells from the recipient. This gave heart after intravenous injection. Kocher et al. (2001)15 demonstrated
evidence for endogenous cell recruitment from the systemic circula- EPCs isolated from blood or marrow to harbor in myocardium. Bel-
tion within the myocardium. At least three major compartments can trami et al. (2003)8 demonstrated that when Lin−-c-Kit+ cells from
be thought of to regulate this complicated orchestra of “Homing the myocardium were injected into an ischemic heart, these cells or
Cells”—the injured myocardium, the bone marrow and the periph- their clonal progeny reconstituted well-differentiated myocardium
eral circulation. The injured myocardium is responsible for releasing formed of new blood vessels and myocytes with the characteristics of
the signals via peripheral blood to mobilize the extra-CSC from the young cells, encompassing approximately 70% of the ventricle.
bone marrow into peripheral circulation. Following mobilization,
these cells follow a specific signal, exit the circulation and home ANIMAL EXPERIMENTS
into injured sites to initiate the cardiac repair process (Fig. 88.1).13
Despite the existence of cardiac stem/progenitor cells or evidence The in vitro findings of bone marrow stem cells (BMSCs) or circulat-
of recruitment of stem cells from bone marrow at the site of injury, ing progenitor cells (CPCs) to transdifferentiate into cardiomyocytes
it is well recognized that this endogenous capacity for regeneration and their abundance made many to choose them for myocardial
is insufficient to mediate repair following severe cardiac injury. It regeneration in small animal MI models.
has to be replenished exogenously by infusion of stem cells to repair In 1999, Tomita et al.16 documented transplantation of autolo-
the damage. However, studies like Werner et al.14 have provided evi- gous BMSCs to stimulate angiogenesis in the recipient ischemic
dence of increased survival following acute MI in patients with great- myocardium. In their experiments, cryoinjuries were created
er number of circulating endothelial progenitor cells (EPCs) (Fig. 3 weeks earlier. Bromodeoxyuridine (BrdU) positive BMSCs were
88.2). then transplanted into myocardial scar. These labeled cells were
Chapter 88  History of Stem Cell Therapy and its Future in Cardiovascular Diseases 741
Figure 88.1: A schematic representation of cell-based myocardial repair. Signals for mobilization and homing must work in an integrated fashion
among the myocardium, peripheral blood, and bone marrow to achieve functionally significant stem cell-mediated repair and regeneration. Source:
Adapted from Liao R, Pfister O, Jain M, et al. The bone marrow—cardiac axis of myocardial regeneration. Prog Cardiovasc Dis. 2007;50(1):18-30
Figure 88.2: Circulating endothelial progenitor cells and cardiovascular outcomes. Source: Adapted from Werner N, Kosiol S, Schiegl T, et al.
Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999-1007.
found in hearts examined 8 weeks post-transplantation. Not only et al.3 with a very provocative finding. They suggested that directly
there was increased capillary density in comparison to control group injecting hematopoietic stem cells resulted in extensive myocardial
but these cells were present within the wall of the newly formed regeneration. They sorted Lin−-c-Kit+ stem cells from the bone mar-
vessels. Functional improvement was observed only in recipients row of transgenic mice expressing green fluorescent protein (GFP).
of the mesenchymal stem cells (MSCs) that had been treated with After 3–5 hours of induction of MI through coronary ligation, these
5-azacytidine. Two years later came the revolutionary paper of Orlic cells were injected into the infarct border zone. After 9 days, newly
formed (green-fluorescing) myocardium reportedly occupied 68% created intrinsic genetic marker that can be recognized without
of the infarcted protein of the ventricle. Analysis of developing tis- antibody staining to identify transplanted cells. No bone marrow
sue reportedly showed proliferating myocytes and vascular struc- cell-derived myocytes were identified. While as discussed above
tures, prompting the authors to suggest that autologous BMSCs may Orlic and colleagues3 relied on detecting BMSCs derived myocytes
able to generate myocardium de novo. Further mice receiving stem using fluorescently tagged antibodies. The increased fluorescence
cells injection showed reduced ventricular dilatation and increased observed in their study could be due to nonspecific antibody reac-
fractional shortening by echocardiography. This article generated tion of muscle specific contractile protein, potentially leading to the
tremendous excitement in both the basic and clinical research com- misinterpretation of this fluorescent signal as transdifferentiation.20
munities. At the same time Jackson and colleagues17 reported simi- Meanwhile, fueled in part by hopes for cardiac transdifferentiation as
lar finding with side population cells (SP cells, CD34−/low c-Kit+, well as by the considerable body of data supporting angiogenic activ-
Sca-1+). Kocher et al.15 demonstrated that systemic infusions of hu- ity, clinicians became bullish and bone marrow studies had already
man bone marrow-derived endothelial cell precursors were able to moved from small animals to human trials.
intercept the remodeling process of the left ventricle. The observed
neovascularization prevented apoptosis of hypertrophied myocytes HUMAN TRIALS
reduced collagen deposition, subsequent scar formation and im-
proved postinfarction left ventricle (LV) function. In all the above Skeletal myoblasts, often called as “Satellite Cells”—found beneath
studies, cell administration was performed by direct intramyocardial the basal membrane of muscle tissue, lie dormant till stimulated to
injection and, therefore, this technique was limited for open heart proliferate by muscle injury or disease. These cells were the first to
surgery. Wang et al.18 delivered MSCs suspension 2 weeks after coro- enter the clinical arena after completion of a decade of experimen-
nary artery ligation under direct vision in briefly occluded ascend- tal testing resulting in at least 40 studies. These studies consistently
ing aortas. Injected cells could be identified after 3 weeks as cardio- showed differentiation of implanted myoblasts into multinucleated
myocytes or fibroblasts. Thus, it was concluded that cells migrated myotubes (not cardiomyocytes) with the lack of connexin activity
through the coronary circulation to sites of injury under the direct and absence of electromechanical coupling with host cardiomyo-
effect of the local microenvironment and transdifferentiated into re- cytes. Despite these apparent shortcomings, a definite improvement
quired phenotypes. This attempt demonstrated possibility of deliv- in regional and global LV function was demonstrated. These data
ering stem cells through intracoronary route in the catheterization along with the clinically appealing characteristics of skeletal myo-
laboratory without surgical intervention to more critical patients. blasts (a high in vitro scalability of the initial biopsy, an advance
Orlic et al.19 further hypothesized and demonstrated that mo- stage of differentiation virtually eliminating tumorigenicity and a
bilization of animal’s own bone marrow with granulocyte colony- high resistance to ischemia) paved the way for the initial human tri-
stimulating factor (G-CSF) before and after MI resulted in growth of als which started in June 2000.21
new cardiomyocytes in the infarct zone, improved ventricular func- Autologous myoblasts were isolated enzymatically from muscle
tion and substantial decreased mortality by 68%. This finding initi- biopsies and were expanded for several weeks in culture by using
ated parallel studies to know the regulatory mechanisms that control fetal bovine serum (tested free from bovine spongiform encephalop-
the homing and holding of stem cells to injured tissues. The precise athy prion as a mitogen). All studies focused on patients with severe
time course, kinetics and factors stimulating bone marrow mobiliza- LV dysfunction caused by MI and cell injections were targeted to dis-
tion have remained the subject of intense investigation. Myocardial crete akinetic and metabolically inactive scars. Four of these studies
ischemia is known to induce several classical “mobilizing cytokines” were surgical,22-25 i.e. myoblasts were implanted at the time of coro-
such as G-CSF, granulocyte/macrophage colony-stimulating factor nary artery bypass graft (CABG) or with left ventricular assist device
(GM-CSF), stem cell factor (SCF), vascular endothelial growth factor implantation and remaining were catheter-based procedures and
(VEGF), stromal derived factor (SDF-1), and erythropoietin (EPO) used either an endoventricular26 or a coronary sinus transvenous
which may be responsible for the observed homing of BMSCs fol- approach.27 At 18 months, myoblasts were observed aligned paral-
lowing MI.2 Several more experiments on smaller and larger animal lel to the host cardiomyocytes embedded in scar tissues. However,
models nearing similarity to humans investigating a variety of cell 4 out of 10 patients developed serious ventricular arrhythmias soon
types in conjunction with various cytokines were initiated and have and required implantable defibrillators.22 Disorganized myocardial
been published. architecture, difference in the activation kinetics of the ion chan-
However, the spark that had ignited fire, the Orlic et al.’s find- nels between skeletal and cardiac muscles as well as inflammatory
ing3 was itself challenged by Murry and colleagues in the year 2002.4 responses against the dead myoblasts were coined for the arrhythmo-
They used different method of tracking the fate of transplanted cells. genesis observed in these trials. No meaningful conclusion could be
A transgenic mouse cell line with a cardiac specific-myosin heavy drawn regarding efficacy in restoration of function in the injected
chain promoter that drives expression of a LacZ reporter was used areas. These results indicated that Phase II randomized controlled
to monitor cardiomyogenic transdifferentiation events. Thus, they trials are needed which include common culture processes, variable
TABLE 88.2A Summary of major cell-based clinical trials
Study Method of Patients Treated/ Placebo/ Control Cell Type Cell/ Time of Cell Results
Delivery Control Number or dose Delivery (Days
post-MI)
Strauer et al. 200228 IC 20/10 Case controlled BM-MNC 7 Improved contractility
(Germany) 9−28 x 106 and reduced infarct size
at 6 months
TOPCARE-AMI IC 30/29 Control BM-MNC 3 to 7 Improved LVFE and reduced
Assmus et al. 200229 nonrandomized 2.4 x 108 infract size at 4−12 months
open-labeled CPC
BOOST IC 30/30 Control BM-MNC 6 Improved EF at 6 months,
Wollert et al. 200431 24 x 109 increased regional
Meyer et al. 200632 contractility,
(Germany) No difference at 18 months
REPAIR-AMI IC 102/102 Placebo BM-MNC 4 Improved EF and reduced
Schachinger et al. 200633 2.4 x 108 infarct size at 4 months
(Germany)
Fernandez et al. 200434 IC 20/13 Control BM-MNC 10 to 15 Significant functional
11−90 x 106 improvement and reduced
infarct size
Janssens et al. IC 33/34 Placebo BM-MNC 1 Decrease scar size but no
200535 3.0 x 108 cells improvement in LVEF at 4
(Belgium) months
ASTAMI IC 50/50 Control BM-MNC 5 to 8 No difference at 6 months
Lunde et al. 200636 randomized + 8.7 x 107
(Norway) placebo controlled
Shah et al. 200737,38 IC 20/10 Control BM-MNC 6 to 8 Improved LV function at 6
(India) Open-label 13.4 x 107 months and sustained at 24
nonrandomized months
Chen et al. 200444 IC 34/35 Placebo controlled MCSs 18 Inc LVEF, Inc regional
(China) 48−68 x 1010 contractility, increase viability
of infarct zone/wall after 3
and 6 months
Hare et al. 200945 IV 39/21 Double blind MSCs 0.5, 1.6, 5 1, 2, 3, 6 Improved LVEF, and reverse
(USA) placebo controlled million cells/kg months follow modeling
up
Keywords: IC—Intracoronary; IV—Intravenous; BM-MNC—Bone marrow mononuclear cell; CPC—Circulating progenitor cells; MCSc— Mesenchymal
stem cells
end points to judge efficacy [stress echocardiography, nuclear angio- patients and had a control group comprising 10 patients who refused
grams, cardiac magnetic resonance imaging (MRI), positron emis- the treatment. This method resulted in significantly improved myo-
sion tomography (PET)] and the variable baseline functions of the cardial perfusion and wall motion indexes. In the transplantation of
engrafted regions that range from hypokinetic to dyskinetic areas. progenitor cells and regeneration enhancement in acute MI (TOP-
Simultaneously further research on skeletal engraftment into cardio- CARE-AMI) study;29,30 59 patients after acute MI were randomized to
myocyte and improving its myocardial viability is warranted. receive either infusion of BMSCs or ex vivo expanded CPCs into the
Because animal studies demonstrated that tissue damage in infarct-related artery 4 days after MI. They showed improvement in
MI resulted in BMSCs homing to the infarcted myocardium, several LV ejection fraction (LVEF) from 51% to 58% (P < 0.001), myocardial
trials were carried out using mononuclear cell (BMMNC) fraction viability and regional wall motion in the infarct area. However, there
of autologous BMSCs (Table 88.2A). The first published trial of was no difference between the two active cell treatment groups. In
Strauer et al.28 in the year 2002, carried out intracoronary delivery of the BOne marrOw transfer to enhance ST-elevation infarct regenera-
autologous BMSCs in the infarct-related artery 7 days after MI in 20 tion (BOOST)31 trial, Wollert and coworkers randomized 60 patients
after successful percutaneous coronary intervention (PCI) for acute and further to show improvement in LV function (Table 88.2A). Car-
MI to receive either intracoronary BMSCs or standard therapy. They diac function analysis at 6 months of 18 patients and 10 controls by
demonstrated an improvement in LVEF of 6.7% in the treatment 2D ECHO, LV angiography and cardiac MRI demonstrated signifi-
group and 0.7% in the control group at 6 months (P = 0.0026). In the cant rise in LVEF by 4–8%, significant fall in LV end-systolic volume
18-month follow-up,32 the improvement in LVEF in the cell therapy (LVESV) of 10–25% and marginal fall in LV end-diastolic volume
group was sustained. However, the control group also had improved (LVEDV) as compared to controls who demonstrated rise in LVEF
by this time and the difference between the two groups was no long- of 1–3% and moderate rise in ESV and EDV (Shah et al. 2007).37 The
er significantly different. This catch-up phenomenon in the control 24-month follow-up showed sustained improvement in the LV func-
group suggests that the cell therapy may in fact accelerate the postin- tion as seen at 6 months by 2D ECHO.38 Clinical follow-up demon-
farction LV functional recovery that is achievable with standard med- strated arrhythmias in none although one patient and two controls
ical therapy. In an interesting study, reinfusion of enriched progeni- demonstrated history of angina. Repeated hospitalization was seen
tor cells and infarct remodeling in acute MI (REPAIR-AMI) trial,33 in one subject from patients and three from controls whereas r epeat
which is the largest, double blind randomized, placebo controlled, intervention was required in four patients and three controls. So-
clinical trial involving 204 patients, showed a significant improve- nography of abdomen and pelvic organ, chest X-rays and some rou-
ment in angiographically calculated LVEFs (5.5%) compared with tine pathological tests carried out after 24 months in patients who
placebo (3.0%) at 4 months. Cell-therapy-treatment group was given had received bone marrow therapy demonstrated no detrimental
intracoronary infusion of BMSCs suspended in medium while place- long-term effects of bone marrow infusion on any organ. This study
bo group received only medium, 3–7 days after undergoing success- showed that intracoronary infusion of autologous BMSCs was safe,
ful PCI. Those with lower baseline LVEF seemed to benefit more from feasible after acute MI and there was a favorable trend towards im-
the cell therapy and it was associated with a reduction of prespecified provement of LV function and prevention of ventricular remodeling
clinical end point of death, MI and revascularization at 1 year. Fer- which determines long-term survival.
nandez et al.34 labeled human BMSCs, seeded on top of cryoinjured Mesenchymal stem cells are a particularly interesting type of
mice heart slices and cultured. These cells showed the ability to graft progenitor cells whose differentiation capabilities have been recog-
into the damaged mouse cardiac tissue. After 1 week, they acquired nized since 1999.16 These cells which represent about 0.01% of the
a cardiomyocyte phenotype and expressed cardiac proteins, includ- mononuclear cell fraction of the bone marrow are also studied in
ing connexin 43. In a simultaneous clinical trial, 20 patients were human trials (Table 88.2A). Chen and colleagues39 randomized 69
transplanted with autologous BMSCs to see their e ffect on postin- patients after MI to receive intracoronary autologous MSCs or pla-
farction LV remodeling. At 6 months, MRI showed improved global cebo. They demonstrated a significant improvement in global as
LV function and increased thickness of the infarcted wall, whereas well as regional LV function and protection against LV remodeling.
coronary restenosis was only 15%. No changes were found in a non- Another study by Hare et al. (2009)40 also demonstrated that intra-
randomized contemporary control group. No major cardiac events venous allogenic MSCs were safe in patients after acute MI with in-
occurred up to 11 ± 5 months. Thus, they demonstrated that BMSCs creased LVEF and reverse remodeling. Currently, several studies have
were capable of nesting into the damaged myocardium and acquire been undertaken for allogenic MSCs in clinical trials for myocardial
a cardiac cell phenotype in vitro which may have benefited ventricu- regeneration in the United States under the sponsorship of Osiris
lar remodeling in vivo. However, there are contradictory reports as therapeutics. Taken together these studies suggested that BMSCs are
well. Janssens and colleagues35 (Table 88.2A) did not find any im- safe and may improve cardiac function by a substantial and clinically
provement in LVEF (P = 0.36) after intracoronary transfer of BMSCs meaningful degree following MI. Simultaneously several trials were
although they demonstrated a significant reduction in scar size and also being conducted wherein G-CSF was used to mobilize endog-
an improvement in regional function. Their patient population dif- enous bone marrow cells41-45 but with lack of benefit (Table 88.2B).
fered from the BOOST trial in that they were reperfused earlier and In contrast to the acute MI setting, patients with chronic
may, therefore, have gained only a small benefit from cell therapy, ischemic heart disease (IHD) are unlikely to release signals from
as maximal benefit may have been derived from earlier reperfusion. damaged myocardium to induce stem cell homing (Table 88.2B).
Another trial by Lunde et al. in ASTAMI trial36 (Autologous stem cell However, Strauer et al.46 broadened the revolution by describing
transplantation in acute MI) demonstrated no significant LV im- positive results of intracoronary administration of autologous BM-
provement at 12 months after intracoronary infusion of cells 6 days SCs in 18 chronic IHD patients. They found increased regional and
after MI. The reason given for lack of benefit may be the method of global LV function. Other studies by Perin et al.,47,48 Stamm et al.49
cell separation they used. and Patel et al.50 (Table 88.2B) used myocardial injection of cells to
We, in India, initiated a trial in June 2005 for treating acute deliver to the exact location where the effect was required for chronic
anterior MI (AMI) patients with autologous BMSCs in addition to the IHD patients. Perin et al.48 enrolled 14 IHD patients under treat-
standard therapy. The aim was to demonstrate safety and feasibility ment group and 7 IHD patients under control group. The treatment
of harvesting autologous BMSCs, implanting into the coronary artery group received endomyocardial injection of approximate 30 million
TABLE 88.2B Summary of major cell-based clinical trials
Study Method of Patients Treated/ Placebo/ Cell Type/Cell Time of Cell Delivery Results
Delivery Controlled Control Number or Dose (Days post-MI)
Ince et al. 200539 Mobilization of 15/15 Randomized + BM-MNC CD34+ 1–6 After 4 and 12 months
First line-AMI G-CSF Controlled follow-up improved
(Germany) LVEF and systolic wall
thickness
Rippa et al. 200640 Mobilization of 39/39 Randomized BM-MNC CD34+ 1–6 After 6 months follow-up
STEMMI (Denmark) G-CSF + Placebo systolic wall thickness
controlled ↑ viability of infarct zone/
wall
Zohlnhofer et al. Mobilization of 56/58 Randomized BM-MNC CD34+ 1–6 After 4 and 6 months
200641 G-CSF + Placebo follow-up
Ince et al. 200742 controlled No effects
REVIVAL
(Germany)
Engelman et al. Mobilization of 22/22 Randomized + BM-MNC CD34+ 1–5 After 4 and 6 months
200643 G-CSF Placebo follow up
G-CSF-STEMI controlled No effects
(Germany)
Strauer et al. IC 18/18 Chronic MI BM-MNC 5–102 After 3 months increase
200546 > 5 months LVEF, decreased infarct
IACT Controlled size and increased
(Germany) velocity of infarct wall
Perin et al. Intramyocardial 14/7 Post-MI BM-MNC 103/mm2 Not mentioned After 2, 4, 6 and 12
200347,48 injection IHD, CHF Infarct area months increase LV
(USA) Endocardial functions
Stamm et al. Intramyocardial 12 Post-MI IHD, CD133+ 27 ± 31 After 3 and 10 months
200349 injection CHF 1.5 x 106 Increased LVF, and
(Germany) Epicardial increased perfusion in
infarct zone
Patel et al. 200550 Intramyocardial 10/10 Post-MI IHD, BM-MNC CD34+ Not mentioned After 1, 3 and 6 months
(USA) Injection CHF increase LV functions
Epicardial
Keywords: IC—Intracoronary; IV—Intravenous; BM-MNC—Bone marrow mononuclear cell
BMSCs. They showed a significant improvement in overall LV func- Thus, results from these clinical trials suggest that therapy with
tion. Notably, they enrolled subjects with significant LV dysfunction adult BMSCs reduces infarct size, improves LV function and perfu-
at baseline; therefore, their results may be more clinically relevant to sion. An extensive meta-analysis by Latiff et al.52 on 18 eligible studies
the CHF patient group than previous studies that enrolled patients (n = 999 patients) involving adult BMSCs such as BMNNC, MSCs and
with normal or mildly impaired LV function after MI. Currently, a EPCs measuring the same outcomes demonstrated that as compared
number of Phase II studies are ongoing with BMSCs. In addition to to controls, bone marrow transplantation improved LVEF [pooled
TOPCARE study that used EPCs, Erb and colleagues51 randomized difference of 3.66%, 95% confidence interval (CI), 1.93% to 5.4%,
patients with recanalized, chronically occluded coronary arteries to P < 0.001]; reduced infarct scar size (−5.49%, 95% CI: −9.1% to −1.8%,
receive intracoronary progenitor cells or placebo. They mobilized P = 0.003); and reduced LVESV (−4.8% ml, 95% CI: −8.2 to −1.41 ml,
BMSCs using G-CSF, harvested them from peripheral blood, ex- P = 0.006). The available evidence suggests that BMC transplantation
panded them ex vivo, and reinfused them via the coronary artery. is associated with modest improvements in physiologic and anatom-
This treatment resulted in significant improvement in coronary flow ic parameters in patients with both acute MI and chronic IHD, above
reserve, cardiac function and reduction in infarct size. Specialized and beyond conventional therapy. This further suggests carrying out
centers for cell-based therapy program also plan to conduct clinical multicenteric randomized large trials targeted to address the impact
trials of MSCs for patients with CHF. of intracoronary cell therapy on important outcomes and long-term
event free survival as compared to the conventional therapy. Latif FUTURE DIRECTIONS
et al.53 also carried out meta-analysis of clinical trials (Table 88.2B)
wherein BMSCs were mobilized with G-CSF. The analysis revealed Future research may focus on two major aspects. The first is to under-
that G-CSF therapy in unselected patients with acute MI appeared stand the genetic and cellular mechanisms that initiate the transdif-
safe but did not provide benefit. Subgroup analyses suggest that ferentiation of transplanted cells into cardiomyocytes. The second is
G-CSF therapy may be salutary in acute MI patients with severe LV to improve the evaluation of the efficacy of cardiac cell therapy in the
dysfunction and when started early. Larger randomized studies may clinical scenario by understanding cell tracking with various imaging
be conducted to evaluate the potential benefits of early G-CSF therapy modalities.
in acute MI patients with LV dysfunction.
Studies on the Mechanisms
Safety Issues of the Stem Cell Therapy
Although clinical human trials in general have been heterogeneous There is so far little evidence suggesting transdifferentiation of im-
as far as the protocols concerned regarding types of cells, time of de- planted bone marrow-derived cells into any cardiac cell lineages in
livery, routes of delivery, and most importantly with respect to the vivo. Accumulating evidences have attributed the clinical benefits to
end points selected for analyzing the data, they have all demonstrat- several other effects apart from transdifferentiation such as parac-
ed safety. However, there are safety issues which were known to be rine effects—perhaps preventing apoptosis and promoting healing of
of concern such as oncogenic transformation, multiorgan seeding, myocytes, angiogenic effects, cell fusion, passive mechanical effects,
unintended cell differentiation, ventricular arrhythmias, accelerated and activating endogenous responses of CSC which are residing in
atherogenesis and coronary thrombosis. Our own trial demonstrated specific niches (Fig. 88.3). Thus, studies on the complicated mecha-
that infusion of these cells did not have any adverse effect on cardiac nisms of stem cell therapy may lead to novel or optimized therapies
or extra-cardiac organ on long-term follow-up of 24 months.38 targeting CSCs for their role in cardiomyogenesis and angiogenesis.
Figure 88.3: Proposed mechanism of myocardial repair Source: Adapted from Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of
myocardial infarction. Arterioscler Thromb Vasc Biol. 2008;28:208-16
For example, a cocktail of small molecules, such as of growth factors

SPECIFIC SET-UP REQUIRED FOR CLINICAL
or cytokines, may be developed and injected into the affected myo-
CELL THERAPY TO ENSURE QUALITY
cardium with or without cell transplantation.2,54
CONTROL AND SAFETY
Development of Safe and Effective-Cell Despite the uncertain outcomes research and development in stem
cell therapy worldwide is moving rapidly towards clinical appli-
Tracking Modalities
cation. At the moment, there are close to 50 ongoing clinical trials
In cardiac cell therapy, safe cell tracking modalities with high sensi- registered with ClinicalTrials.gov. Before being safely administered
tivity and spatial resolution are required. Safe and effective cell track- to patients, bone marrow-derived cells need to be isolated and pro-
ing in turn is necessary for a better understanding of the fate of im- cessed in the laboratory. While processing BMSCs takes only a few
planted cells in vivo and their roles in cardiac repair. To date there is hours, the procedure for preparing BM derived MSCs takes 3 weeks
no satisfactory cell tracking procedure applicable to human subjects. (from isolation of BMSCs to cell expansion and differentiation). Thus,
Implanted cells are directly labeled with contrast agents that have application of BM-derived cells to patients is a complicated process
already been approved for clinical applications. For instance, super- starting from the operating theater, then moving to the laboratory,
paramagnetic iron oxide (SPIO) in MRI, Indium-111 (In) Oxin, Tech- and finally returning to the operating theater or cardiac catheteri-
netium (Tc) and fluorodeoxyglucose (F18-FDG) for direct labeling zation laboratory. In today’s clinical practice, such a process must
of cells by radionuclide imaging and PET scanning. However, direct comply with good manufacturing practice (GMP) to reduce risks to
labeling only facilitates short periods of tracking since the labeling the eventual recipients. Accordingly, cell therapy centers should be
materials would be diluted during cell division, diffused or degraded GMP accredited, wherein trained personnel operates under specific
over time. Additionally genetic labeling with reported genes which facilities (clean room and cell culture laboratory facilities) follow-
can be traced with imaging probes have been introduced that will aling the GMP standards. Similar set-ups for hematopoietic stem cell
low for repeatable tracking of cellular and subcellular function over therapy are adopted in many hospitals worldwide. Cell processing
a long period of time. Also whenever possible, tissue-based analyses may inadvertently expose human cells with a variety of hazards and
should be included in clinical trial design, either by evaluation of ex- contaminations. The major concern is zoonotic contamination, as
planted hearts at the time of transplantation or by autopsy of patients animal-derived materials (e.g. fetal calf or bovine serum) are com-
who die following cell therapy. Thus, further pharmacological and monly used in cell cultures. This problem could be overcome by
genetic strategies that seem to offer insight into the enhancement using commercially-available serum-free media (with growth sup-
of stem cell retention, engraftment, differentiation and paracrine plements). In the meantime, autologous human serum may be con-
capability, deserves further exploration.2 The research on these two sidered as a replacement to animal serum. Finally, prior to the deliv-
aspects may help in finding solutions to following various unresolved ery in patients, cell supernatants must be tested for infectious agents
issues. at different time points dependent on the specific protocol.55
Unresolved Issues CONCLUSION

The ultimate aim of the cellular transplantation remains the regen- The Orlic trial which fueled excitement of using stem cells for car-
eration of lost heart muscle along with the reversal of the remodeling diac regeneration was itself under criticism. However, often “science
process. In order to achieve this, few crucial points to be considered profits from mishaps.” many of the bigger discoveries and inventions
are: (1) Which cell populations should be delivered? (2) What num- have followed such traumatic experiences. Had Andreas Gruentzig
ber of cells should be delivered? (3) When cells should be transplant- not embarked on clinical applications after experimenting on just
ed? (4) Which application method is the most efficient? (5) What 8 dogs, a new field of interventional cardiology would not have
should be the clinical end points? So far both in animal and human emerged. Therefore, the risk of exposing patients to possible adverse
experiments research MSCs have emerged as most promising cell outcome of any new treatment must be weighed against the risk
population with their inherent property of transdifferentiating into of depriving all patients of new treatment to alleviate sufferings or
cardiomyocytes and to be tolerated by the immune system giving us prolong the life. The argument that these trials should be delayed
the most convenient “off the shelf” reagent. For better engraftment till mechanisms are further understood will prevent large number
and bioavailability of these cells, NOGA has emerged as one of the of patients from therapeutic approaches that may improve their
technique for transplanting the cells directly into the myocardium clinical outcome. There is a wealth of preclinical and early clini-
by electromechanical mapping during transendocardial approach to cal data showing safety, feasibility and early efficacy of adult cell-
discriminate between the ischemic or viable regions and for targeted based therapy. Now only clinical trials can lead to optimization of it.
delivery of cells2. Adult stem cell therapies should therefore proceed to randomized,
placebo-controlled double blind clinical trials. Another compelling to advance. The ongoing rigorously designed trials will contribute
argument for initiating clinical research is that the results of these greatly to this emerging and exciting new therapeutic approach for
investigations often provide pivotal insights that allow a new field diseases of the cardiovascular system.
REFERENCES
1. Gatti RA, Meuwissen HJ, Allen HD, et al. Immunological reconstitution of sex-linked lymphopenic deficiency. Lancet. 1968;2:1366-68.
2. Shah VK, Shalia KK. Regeneration of myocardium-dawn of a new era. J Phys India. 2009;57:312-31.
3. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701-5.
4. Murry CE, Soonpa MH, Reinecke H, et al. Hemopoietic stem cells do not transdifferentiate into cardiomyocytes in myocardial infarcts. Nature.
2004;428:664-8.
5. Kajstura J, Leri A, Finato N, et al. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci USA. 1998;95:8801-5.
6. Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. 2001;344:1750-7.
7. Hierlihy AM, Seale P, Lobe CG, et al. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002;530:239-43.
8. Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763-76.
9. Mallory GK, White PD, Salcedo-Salgar J. The speed of healing of myocardial infarction a study of the pathologic anatomy in 72 cases. Am Heart J.
1939;18:647-71.
10. Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest.
2001;107:1395-402.
11. Laflamme MA, Myerson D, Saffitz JE, et al. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts.
Circ Res. 2002;90:634-40.
12. Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med. 2002;346:5-15.
13. Liao R, Pfister O, Jain M, et al. The bone marrow—cardiac axis of myocardial regeneration. Prog Cardiovasc Dis. 2007;50:18-30.
14. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999-1007.
15. Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents
cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430-36.
16. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999;100:II247-
56.
17. Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest.
2001;107:1395-402.
18. Wang JS, Shum-Tim D, Chedrawy E, et al. The coronary delivery of marrow stromal cells for myocardial regeneration: pathophysiology and thera-
peutic implications. J Thorac Cardiovasc Surg. 2001;122:699-705.
19. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci
USA. 2001;98:10344-9.
20. Gulati R, Simari RD. Cell therapy for acute myocardial infarction. Med Clin N Am. 2007;91:769-85.
21. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet. 2001;357:279-80.
22. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am
Coll Cardiol. 2003;41:1078-83.
23. Herreros J, Prosper F, Perez A, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with nonacute
myocardial infarction. Eur Heart J. 2003;24:2012-20.
24. Pagani FD, DerSimonian H, Zawadzka A, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histo-
logical analysis of cell survival and differentiation. J Am Coll Cardiol. 2003;41:879-88.
25. Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: Phase I
clinical study with 12 months of follow-up. Am Heart J. 2004;148:531-7.
26. Smits PC, van Geuns RJ, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of
ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol. 2003;42:2063-9.
27. Siminiak T, Fiszer D, Jerykcwska O, et al. Percutaneous transvenous transplantation of autologous myoblasts in the treatment of postinfarction
heart failure. The POZNAN trial. Eur Heart J. 2004;25 (Abstract suppl):264.
28. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation
in humans. Circulation. 2002;106:1913-8.
29. Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOP-
CARE-AMI). Circulation. 2002;106:3009-17.
30. Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction:
final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004;44:1690.
31. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomized con-
trolled clinical trial. Lancet. 2004;364:141-8.
32. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the
randomized, controlled BOOST (Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration) Trial. Circulation. 2006;113:1287-94.
33. Sachachinger V, Erbs S, Elasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J. Med.
2006;355:1210-21.
34. Fernández-Avilés F, San Román JA, García-Frade J, et al. Experimental and clinical regenerative capability of human bone marrow cells after myo-
cardial infarction. Circ Res. 2004;95:742-8.
35. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial in-
farction: double-blind, randomized controlled trial. Lancet. 2005;367:113-21.
36. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med.
2006;355:1199-209.
37. Shah VK, Tanavde V, Desai AJ, et al. Bone marrow cells for myocardial repair—a new therapeutic concept. Indian Heart J. 2007;59:482-90.
38. Shah VK, Vasvani JB, Payannavar SS, et al. Shalia Stem cell therapy for acute myocardial infarction-long-term 24 months follow-up: Short title:
follow-up of ABMSCs therapy in AMI. Ind Heart J. 2007;59:394.
39. Chen Sl, Fang WW, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem
cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92-5.
40. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mes-
enchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54:2277-86.
41. Ince H, Petzsch M, Kleine HD, et al. Prevention of left ventricular remodeling with granulocyte colony-stimulating factor after acute myocardial
infarction: final 1-year results of the front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by granu-
locyte colony-stimulating factor (FIRSTLINE-AMI) Trial. Circulation. 2005;112:I73-80.
42. Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac
regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo controlled stem cells in myocardial
infarction (STEMMI) trial. Circulation. 2006;113:1983-92.
43. Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a
randomized controlled trial. J Am Med Assoc. 2006;295:1003-10.
44. Ince H, Nienaber CA. Granulocyte-colony-stimulating factor in acute myocardial infarction: future perspectives after FIRSTLINE-AMI and RE-
VIVAL-2. Nat Clin Pract Cardiovasc Med. 2007;4:S114-8.
45. Engelmann MG, Theiss HD, Hennig-Theiss C, et al. Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating
factor after subacute ST-segment elevation myocardial infarction undergoing late revascularization: final results from the G-CSF-STEMI (granu-
locyte colony-stimulating factor st-segment elevation myocardial infarction) trial. J Am Coll Cardiol. 2006;48:1712-21.
46. Strauer BE, Brehm M, Zeus T, et al. Regeneration of humaninfarcted heart muscle by intracoronary autologous bone marrow cell transplantation
in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol. 2005;46:1651-8.
47. Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart
failure. Circulation. 2003;107:2294-302.
48. Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autolo-
gous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation. 2004;110:II213-8.
49. Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361:45-6.
50. Patel AN, Geffner L, Vina RF, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective
randomized study. J Thorac Cardiovasc Surg. 2005;130:1631-8.
51. Erb S, Linke A, Adams V, et al. Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first
randomized and placebo-controlled study. Circ Res. 2005;97:756-62.
52. Abdel-Latif A, Bolli R, Tleyjeh IM, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern
Med. 2007;167:989-97.
53. Abdel-Latif A, Bolli R, Zuba-Surma EK, et al. Granulocyte colony-stimulating factor therapy for cardiac repair after acute myocardial infarction: a
systematic review and meta-analysis of randomized controlled trials.. Am Heart J. 2008;156:216-26.
54. Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol. 2008;28:208-16.
55. Wei HM, Wong P, Hsu LF et al. Human bone-marrow derived adult stem cells for post-myocardial infarction cardiac repair: current status and
future directions. Singapore Med J. 2009;50:935-42.
89 Future of Heart Transplant in India
Shad S
Fourteen years of estimated conditional half-life is a dramatic

HEART TRANSPLANT AS THE DEFINITIVE
improvement of survival in patients who otherwise are destined to
TREATMENT FOR HEART FAILURE
die within 1–2 years of advanced heart failure (HF).
History of Surgical Developments
INDIAN SCENARIO
Heart transplantation started in 1964 in Mississippi Medical Centre
in Jackson when a chimpanzee heart was transplanted into a dying
History of Heart Transplant in India
patient. The heart only beat for 90 minutes before it stopped irre-
versibly; but it paved the way for human heart transplantation and Prof. Venugopal at All India Institute of Medical Sciences com-
defined the surgical procedure. menced cardiac transplantation in India in 1994. Since then heart
The first human to human heart transplant by Prof. Christiaan transplantation has been performed in 14 centers of the country and
Barnard in South Africa was performed in December 1967. Dr Bar- most of those centers performed only one or two cardiac transplants
nard did ten conventional heart transplants and almost 45 hetero- before uniformly poor results forced program foreclosures. Only
topic (piggyback) heart transplants. Other than one conventional AIIMS and the Frontier Hospital at Chennai continue to hold the
heart transplant recipient who survived 24 years most others died beacon of hope for the over 8,000 patient per annum in India who
under 2 years. After an initial euphoric opening of over 100 trans- potentially require and aspire for a heart transplant. We too have tak-
plant centers around the globe in the early 70s, cardiac transplant en a lead by providing the only heart transplant facility in the private
worked but stopped the world over following uniformly poor results. sector in North India.
The Director General of Health Services of course applies very
Landmarks stringent standards before any hospital is approved to perform cardi-
ac transplantation. These operations can only be carried out in very
The dogged work of Prof Norman Shumway at Stanford and others large super-specialty hospitals, which must satisfy certain important
led to understanding of transplant immunology, or how one body criteria like superb cardiac surgery and cardiology services, large
reacts to the tissues of others. This understanding led to better treat- intensive care unit (ICU) that is fully equipped, excellent neurology
ments and better outcomes. Presently nearly 4,000 hearts are trans- and neurosurgery and top class laboratory services that are available
planted worldwide per annum, more than 90% of patients survive round the clock. It is essential also that cardiac surgery staff be fully
the first month after operation and more than 85% of patients are updated about the nuances of modern therapy, advanced surgical
alive for one year. Ten years later more than 50% of transplant pa- technique and be committed to look after the very sick patients who
tients are alive and leading healthy lifestyles. Nowadays, transplant require much more personalized care than can be provided in rou-
heart half-life is being increasingly recognized as a better measure of tine cardiac centers.
survival. The half-life is the estimated time point at which 50% of all
of the recipients have died; presently this is almost 11 years. A new The Burden of Heart Failure
measure is called the conditional half-life of the transplanted heart.
This is the estimated time point at which 50% of the recipients who In the absence of a surveillance program to track incidence, preva-
survive to at least 1 year have died. Presently this stands at 14 years. lence, outcomes and key causes of HF it is not possible to come with
Because the decline in survival is greatest during the first year follow- an accurate estimate of HF in India. Nevertheless, is accepted that
ing transplantation, the conditional survival provides a more realistic the incidence and prevalence rates of HF are rising due to popula-
expectation of survival time for recipients who survive the early post- tion, epidemiological and health transitions. In addition to tradi-
transplant period. tional risk factors for cardiovascular disease (CVD) like coronary
Chapter 89  Future of Heart Transplant in India 751
heart disease (CAD), hypertension, obesity; India is burdened by the to an implant. A good tissue match will make the immune modula-
persistence of diseases like tubercular pericardial disease, endomyo- tion that much easier.
cardial fibrosis as well as rheumatic heart disease. Conservative esti- Along with that the donor heart must be retrieved at perfect
mates of the prevalence of HF in India due to coronary heart disease, physiological conditions, atarumatically with good cardioplegia and
hypertension, obesity, diabetes and rheumatic heart disease range cold myocardial preservation techniques. The transport should be
from 1.3 million to 4.6 million, with an annual incidence of 491, 600– swift and timing of recipient surgery should be such as to minimize
1.8 million.1 Unlike western countries where HF is predominantly a the ischemic time.
disease of the elderly, in India it affects younger age group.2 The high
prevalence of hypertension and diabetes among South Asians may The Recipient
predispose to diastolic HF. Additionally, systolic HF tends to manifest
earlier among South Asians3 and with frequent hospital admissions. An ideal heart transplant recipient is someone with isolated HF with-
Numerous drug, revascularization, valve repair or replacement out pulmonary hypertension, native lung disease, renal dysfunction,
as well as interventional therapies do indeed improve the symptoms ongoing infection, previous mediastinal surgery, osteoporosis, inac-
and prognosis of HF. However, there remains a sizable subset of pa- tivity, cachexia and so on. One can see that a recipient that has no
tients who are desperately ill and nothing short of a heart transplant other major comorbidities would stand a much better chance of sur-
or an implanted ventricular assist device would improve their life viving a rather large operation with a somewhat prolonged recovery.
which is otherwise limited to oxygen, diuretics, bed rest and repeated
admissions to ICUs before a lonely death intervenes. The Operation and Aftercare
Specific Indications for Heart Transplant The operation itself is the most important predictor of survival for
any surgery. Not only in terms of accuracy of dissection and anasto-
• Dilated cardiomyopathy 50–60% moses, but also in terms of the limited time available from the time
• Ischemic cardiomyopathy 40% of retrieval from the donor to completion of all the anastomoses and
• Congenital heart disease for which no conventional therapy ex- reperfusion in the recipient. Obviously the patient would require
ists or that conventional therapy has failed extremely close monitoring and immunomodulation in the early re-
• Ejection fraction less than 20% covery period as well as for the lifetime.
• Intractable angina or malignant cardiac arrhythmias for which
conventional therapy has been exhausted FACTORS LIMITING MODERN
• Late stage hypertrophic obstructive cardiomyopathy (HOCM)
THERAPIES IN INDIA
with severe systolic HF
• Pulmonary vascular resistance of less than two Wood units Despite good results, heart transplant is not an easy option for HF
• Age younger than 65 years patients in India. While many factors do interplay in the patient
• Ability to comply with medical follow-up care. selection, recipient maintenance, donor family counseling and ulti-
mate donation from a cadaveric donor; the prime limitation remains
ESSENTIALS OF GOOD RESULTS the lack of coordinated effort. Individually certain major limitations
we should look at closely are:
OF HEART TRANSPLANT
One of my colleagues once said that a heart transplant is like making Healthcare Governance
a good car. You only need to get a good engine into a good chassis ac-
curately. For a transplant to be good one needs to place a good heart Health is a state subject. Therefore there is an absence of uniform
into a rather healthy individual with surgical precision. policies across the country to guide organ retrieval from potential
donors. On top of it there are stringent guidelines that need to be
The Heart followed before carrying out retrieval procedures like a complicated
consent procedure, availability of brain death declaration team, as
A good heart would necessarily come from a young individual, who well as police indifference for medicolegal cases. All these factors
is known not to be hypertensive, diabetic or suffering from CVD. hamper organ donation.
The heart should be known to have a good function in the absence
of inotropes, though vasoconstrictors are not contraindicated. Obvi- Hospital Administration
ously one needs to know the global systolic and diastolic functions,
presence of septal defects or valvar lesions. Pulmonary hypertension Lack of trained transplant coordinators/social workers; lack of spe-
in the donor is helpful for the post-transplant recovery period. Obvi- cific guidelines regarding organ transplants and lack of ICU facilities
ously transmissible infections and cancers should be excluded prior to maintain brain dead donors at major quaternary center of health-
care in our country are cause of major concern. Most successful OPPORTUNITIES AND THE WAY FORWARD
transplant teams are led by single dynamic individuals who over-
come institutional apathy and conduct transplants. A more involved The obvious way forward is to be setting up more cardiac centers in
management in any hospital would undoubtedly advance the cause the country, with more and more cardiac surgeons, cardiologists as
of transplantation. well as physicians teaming up to define risk factors for HF and treat-
ing pre HF effectively. For the patients with established HF more
Recipient Factors and more effective medical therapies must be applied with appro-
priate evidence base. Early treatment of acute coronary syndromes,
Heart failure patients often get used to their level of exercise intol- myocardial infarction and viral myopathies is essential. Shortly, we
erance and hope as with any other chronic condition that it would would see a surge in the number of cardiac surgeons willing to un-
not get worse. At times during a period of relative symptom control, dertake transplant and device therapies.
end stage HF patients are known to have declined transplant, only to
deteriorate and die shortly thereafter. CONCLUSION
We all know that HF is an incessantly progressive disease with
periods of plateauing symptoms followed by periods of rapid dete- Heart transplantation is not just a complicated operative exercise;
rioration. However, it is a rather difficult task to counsel a patient for surgery is but one aspect of the big picture and is the beginning of a
surgery when they are not desperately ill. Unfortunately, an organ long period of commitment and dedication on part of the transplant
would almost never be available for patients when they are gravely team. It is mandatory that the patient is aware and understands the
ill; primarily because donations are few and far between. complex issues related to immunosuppression and cardiac function.
They also need to be acutely aware of their propensity to develop in-
Finance fective complications and their early recognition. A close coopera-
tion between the operating team, various other specialists, hospital
A transplant procedure can be expensive in a private hospital, and administration as well as the patient is mandatory so that compli-
there is also the expense of regularly medication, testing, admissions cations can be recognized early and effectively treated so that the
for surveillance and treatments. However, various charitable agen- patients are able to benefit from a trying experience and enjoy their
cies can be brought together to help such patients. second lease of life.
REFERENCES
1. Huffman MD, Prabhakaran D. Heart failure: epidemiology and prevention in India. Natl Med J India. 2010;23(5):283-8.
2. Reddy S, Bahl A, Talwar KK. Congestive heart failure in Indians: how do we improve diagnosis and management? Indian J Med Res. 2010;132:549-60.
3. Shantsila E, Lip GY, Gill PS. Systolic heart failure in South Asians. Int J Clin Pract. 2011;65(12):1274-82.
Index
Page numbers followed by f refer to figure and t refer to table
A Adaptation of cardiac periods 352 inhibitors 23, 60, 81, 84f, 153, 163,
Abciximab 39 Adenosine 117 213, 613
reteplase stent study 727 deaminase 331 II receptor 59
Abdominal aortic aneurysm 300, 367 diphosphate 32, 109 subtypes 61
Abiotrophia defectiva 242 myocardial perfusion imaging 521 receptor 59, 60
Abnormal Adenovirus 229, 233 blockers 23, 59, 65, 152, 203, 408
communications 274 Adipocyte role in insulin resistance 199f Anglo-Scandinavian cardiac outcomes trial-
ductus venosus 489f Adrenocorticotropic hormone and lipid lowering arm 52
immune response 224 cortisone 258 Anitschkow’s rabbits 182
tricuspid valve flow 490f Advanced heart failure 750 Anterior
Abnormalities of tricuspid valve 558 Advent of sport aerobics 144 mitral leaflet 457, 658
Absent Age of cerebral protection 640 thoracotomy incision 657
atrioventricular connection 481 Ahlquist’s report 116 Anterolateral myocardial
pulmonary valve syndrome 481 Akira Endo and era of statins 190 ischemia 514f
Accelerated Albuminuria 152 segments 514f
atheroma 582 Alcohol septal ablation 217 Anthracyclines 229
idioventricular rhythm 343f A-lipoic acid 321 Antibiotic
Acetylsalicylic acid 367t Aloka 880 color Doppler system 420f era 241
Acorn Corcap device 661 Ambulatory blood pressure monitoring 162 in cardiology 76
Acquired American prophylaxis 241
immunodeficiency syndrome 82, 296 College of Antideoxyribonuclease-B 77
valvular dysfunction 78 Cardiology 11, 71, 83 Antihypertensive
Action potential duration 117, 343f Chest Physicians 9 and lipid lowering treatment to prevent
Active inflammatory destruction 233 Heart Association 11, 71, 83, 142, 158, 195, heart attack trial 52, 105
Acute 577, 588, 658 drugs 163
arthritis 249 Society of Nuclear Cardiology 532 therapy 203
cor pulmonale 284 Amiodarone 50, 115, 117 Anti-inflammatory drugs 77
coronary syndrome 36, 55, 71, 81, 87, 88, Amlodipine 104, 105 Antinuclear antibody test 236
141, 367t, 534 Amount of blood sugar 316 Antiobesity drugs 201
infarction ramipril efficacy 165 Amprenavir 50 Antioxidant properties of lycopene 131
myocardial Amyloidosis 405, 535 Antiplatelet
infarction 5, 6, 8, 10, 65, 89f, 92, 94, Ancillary therapy 13 agents 31, 84
107, 121, 158, 244, 309t, 366, 439, Androgenetic alopecia 405 therapy 107, 109
577, 596, 683, 717, 717f Angina Antipsychotics 230
infection 299 and chronic heart failure 99 Antistreptolysin O 77
pericarditis 233 pectoris 21, 92, 101, 209 Anti-tobacco
pulmonary Anginal disease 140 movements and sentiments 298
embolism 726 Angiocardiography 432 policies 301
thromboembolism 247 Angioplasty for Antituberculosis
rheumatic fever 76, 404 aortoiliac occlusive diseases 641 chemotherapy 331, 332
rheumatism 249, 251, 253, 255 infrainguinal peripheral vascular disease 641 treatment 331
ST-segment elevation myocardial infarc- Angiotensin 59, 65 Aortic
tion 717 converting enzyme 65, 73, 163, 203, 213, dissections 700
unexplained dyspnea 284 225, 323, 408 homograft 670
754 Textbook of Cardiology: A Clinical and Historical Perspective
insufficiency 499 Atenolol 85, 117 B

regurgitation 78 Atheroma progression 22
root dilation 659 Atherosclerosis 89, 180 Babylonian clay tablets 270
stenosis 457, 481, 499, 660, 735, 737 Atherosclerotic Bailey’s atrioseptopexy 712
valve 457, 669 cardiovascular disease 180 Balloon
regurgitation with surgical repair heart disease 310 angioplasty 582
technique 659t A-tocopherol 132 aortic
repair 658, 672 Atorvastatin evaluation and infection valvotomy 475
replacement 658 therapy 56 valvuloplasty 736
valvuloplasty 627 Atrial atrial septostomy 278, 467
Aortocoronary saphenous vein graft 581 fibrillation 292, 421f, 576, 608, 616, 645 pulmonary valvotomy 734
Aortopulmonary window 481 ablation 645 valvuloplasty 648
Application and stroke 292 Bare metal stents 582, 591
of cardiac MRI 495 in WPW syndrome 354f Baroreceptor sensitivity 345t, 351, 352
software architecture 543f surgery 693 Bazett’s formula 346
ARB and isomerism 481 B-carotene cancer prevention 132
coronary artery disease 410 septal defect 78, 271, 463, 463t, 496, 511, Benidipine 104
nephropathy 410 626, 645, 711, 712 Benign
stroke 410 closure 647f neoplasms 505
Arbutamine two-dimensional stress echocar- Atrioventricular PVC 357
diography 454 concordance with ventriculoarterial Benzathine penicillin 77, 260
Arginine-glycine-asparate 38 discordance 481 Beta-blocker
Armchair treatment of MI 157 defect 559 and heart failure 26
Arrhythmia 10, 22, 336 discordance with ventriculoarterial and left ventricular hypertrophy 26
of sudden cardiac death 342f discordance 481 distribution coefficients 19t
Arrhythmogenic right ventricular nodal hemodynamic values 18t
cardiomyopathy 501 ablation 616 in hypertension 23
dysplasia 632 tachycardia 631 therapy 24t
Arterial pathway 631 Bicuspid aortic valve 417
aneurysmal disease 697 septal defect 481, 713 Bicycle ergometer two-dimensional stress
blood pressure 318 valve anomalies 481 echocardiography 450
natriuretic peptide 314 Atropa belladonna 116f Big chief of heart 274
occlusive disease 699 Atropine two-dimensional stress echocardiog- Biomarkers of stress 312
Arteriosclerotic diseases 315 raphy 455 Birth of
Arteriovenous fistula 650 Autoimmune blood culture 239
Articular rheumatism 249 diseases 230, 402 polypill 80
Artificial heart valve 669 disorders 230, 397t Blade atrial septostomy 650
Asia Heart Foundation Southern India Automated Blasting
Project 551 endoscopic system for optimal positioning gelatin 101
Aspirin 31, 36, 109 657, 674, 692 oil 99
development 34t external defibrillators 390 Blastocysts 740
in secondary prevention 84f Autonomic Bleeding bowls 241
Assessment of nervous system 342 Blocks
chest pain 12 tone and reflexes after myocardial potassium efflux 117
ischemia 495 infarction 349 slow calcium channels 117
pulmonary regurgitation severity 566 AV nodal reentrant tachycardia 607 Blood 148, 239
Association of Heart Disease 250 Azeotropic nitric acid 100 cholesterol 136, 136, 180, 191
Asymptomatic carotid atherosclerotic Azimilide 118 clotting 326
disease 132 Azithromycin 78 pressure 73, 81, 105, 160, 367t
Atazanavir 50 Azol anti-fungal 50 pumps 663
Index 755
Body mass index 23, 367t Candesartan cilexetil 62 Cardiotropic viral genome 233
Boerhaave’s aphorisms 252 Capsule’s relation to adherence 264 Cardiovascular
Borderline lesions in coronary angiography Carbohydrates 157 and pulmonary rehabilitation 158
517, 517f Cardiac chest pain 235
Bouillaud’s endocarditis 238 abnormalities with normal four-chamber disease 28, 31, 49, 80, 82t, 83t, 122, 131,
Bourneville’s disease 400 view of heart 483t 132, 156, 160, 168, 170t, 173, 175,
Brachial measurement 163 amyloidosis 220 177, 180, 195, 296, 300, 360, 370,
Bradykinin potentiating arrhythmia 650 380, 383t, 384t, 541, 750
factor 73 pilot study 117 dysmetabolic syndrome 195, 199t
peptides 74 suppression trial 116, 348 epidemic and cholesterol wars 180
Brain 128, 153, 172t beta-myosin heavy chain 216 illnesses 99
death 706 biomarkers 231 infections 76
heart connection 306 catheterization 597 protection 62
Branches of coronary artery 680f death system 76, 327
Brazilian picture 376 and systolic murmur 215 and liver 199
B-receptor blockers 163 in heart failure trial 344 Cardioverter defibrillator 225
Bretylium 115, 117 device Carney complex 400
British Hypertension Society Guidelines 178 endocarditis 78 Carotid angioplasty 639
Brock procedure 277 infection 78 Carvajal syndrome 402f
Broken heart syndrome 311 electrophysiology 605 Carvedilol prospective randomized cumulative
Bronchodilatation 16 enzymes and biomarkers 12 survival 165
Bronchospasm 521 events with perindopril 84 Catecholaminergic polymorphic ventricular
Bruce’s method of exercise tolerance function index 730 tachycardia 342, 354
testing 446f insufficiency bisoprolol study 27 Catechol-O-methyltransferase 535
Brugada irradiation 679 Categories of medical information 542t
criteria 632 ischemia 365 Catharina serafin 93, 94f
syndrome 354 magnetic resonance imaging 12, 743 Catheter ablation of atrial fibrillation 576
Bundle masses 495 Catheterization techniques 277
branch MRI at Causes of hyperhomocysteinemia 380
block 631 3tesla 494 Cefazolin 78
re-entrant tachycardia 634f 7tesla 495 Ceftriaxone 78
of His 337 occupational therapy 361 Celiac disease 230
Burden of perforation 650 systemic lupus erythematosus 230
cardiovascular disease 163 procedures 76, 78 Cell 103
heart failure 750 rehabilitation 143 based clinical trials 743, 745t
Burns 100, 283 services 143 membranes 371
resynchronization transplantation 662
C heart failure 615 types with potentials for cardiac cell
therapy 613, 661, 662 therapy 740t
Calafiore’s left anterior small thoracotomy therapy in patients with severe Cellular membrane 252
operation 656 systolic heart failure 614t Central
Calcium therapy trials 614t blood pressure measurements 163
antagonist 104 Society and Foundation 3 committee for food standards 377
blockers 116, 141 stem cells 739 nervous system 494
channel tumors 501 obesity 200
blockers 152, 163 Cardio pulmonary resuscitation 390 Cephalexin 78
blocking drugs 105t Cardiocutaneous diseases 396 Cephalosporins 230
heteromeric complex 103f Cardiomyocytes 740 Cerebrovascular accident 384, 367t, 592
Calf muscles 245 Cardiomyopathies 456, 495, 500 Cervicothoracic denervation surgery 677
Canadian American Ticlopidine Study 35 Cardiopulmonary bypass 655, 710 Chagas disease 229, 661
Cancer 105, 283, 297 Cardiorenal connectors 314f CHD in fetus 483, 484t
Chemical structure of Clostridia 229 Contractile dysfunction 10

catecholamine and β-blocker 17f Clotted prosthetic valve 726 Contraction of myocardium 235
sildenafil 393f Clozapine 229, 230 Contrast venography 245
Chest Coarctation of aorta 476, 477t, 481, 497, 699 Control of arterial pressure 150
pain 360, 363 Coat hypertension 162 Conventional Doppler ultrasound 417
tumor 93 Coburn’s suggested schedule 262 Co-operative new scandinavian enalapril
X-ray 235 Cocaine 229 survival study 165, 213
Chlamydia pneumoniae 333 Coconut oil 187 Cor triatriatum 481
Cholesterol 81, 362 Cognitive behavioral therapy 312 Coronary
awareness survey 190 Cohnheim’s assessment 93 and peripheral artery disease and arrhyth-
lowering medications 188 Cold pressor test 447, 457 mias 28
Cholesteryl ester transfer protein 371 Collaborative atorvastatin diabetes study 52 artery 92
Chordae 555 Color flow bypass graft 120, 124t, 141, 174, 518,
Chorea 249 Doppler 557, 559, 563, 566, 569 518f, 579, 581, 588, 684
Chromium 684 imaging 566 disease 78, 84, 87-89, 92, 93, 120, 124t,
Chronic Combination therapy 80 180, 181, 189, 297, 307, 322, 340,
alcohol intake 380 Comparison of ice catheters 645 359, 361, 367t, 370, 374t, 380, 443,
heart failure 615 Complete 457, 510, 522, 536, 546, 547, 597,
kidney disease 367t blood count 236 622, 655, 663t
myofascial pain 211 thyroidectomy 678 disease with intake of trans-fats 372
obstructive Complications of intracardiac echocardio stenting 640
airway disease 297 graphy 650t surgery study 346, 360, 589f
pulmonary disease 512 Components of polypill 82 atheromatous volume 23f
sinoatrial block 337 Computed tomography 494, 623 cameral fistula 471, 471t
thromboembolic pulmonary hypertension scan 285 care unit 95, 141
247 Concept of heart disease 49, 81, 81t, 130-133, 135,
total occlusion 595 adrenoceptor 15 299, 325, 360, 380, 383, 384, 541
vascular disease 599 coronary care units 95 MR angiography 505
Chronical distempers 209 rheumatic activity 256 primary prevention trial 189
Chronicle of hypertension 160 β-blockade 15 sinus 464, 648, 649
Chronology of development of thrombolytic Concomitant cardiovascular 160 procedures 680
agents 718t Congenital thrombolysis 366
Cilnidipine 104 cardiac disease 274 thrombosis 89
Cinchona succirubra 113f heart vascular disease 359f
Cinnarizine 104 block 490 vasospasm 457
Circulating progenitor cells 740 defects 489 venous ligation 678
Clarithromycin 50, 78 disease 78, 463, 480, 481t, 495, 496, Coxsackie virus 229, 231
Classification of 546, 547, 597, 710, 751 C-reactive protein 77, 131, 333
antiplatelet drugs 107, 108f Congestive Creatine kinase 50, 231, 602
cardiocutaneous diseases 397t cardiac failure 221 Cross-section of ascending aorta 485f
endocarditis 240 heart failure 122, 165, 211, 283, 341, 367t, Current
hypertension 171, 174, 175, 176t 613, 739 controversies and future direction 205
tachycardias 631 Connective tissue diseases 234 indications of statins 52
Clindamycin 78 Conquering valvular lesions 278 trends in fetal cardiology 486
Clofibrate 188 Consequences of pulmonary regurgitation 567 Cut section of cardiac rhabdomyoma 483f
Clopidogrel 109 Constrictive pericarditis 504 Cutis laxa 402, 403
aspirin stent international cooperative Continuous Cyanose tardive 274
study 109 medical education 545 Cyanotic spells 272
in unstable angina 36 wave 472 Cyclic
Closed Doppler 558, 560, 567 adenosine monophosphate 109
circulation of man 88f Doppler signal across pulmonary guanosine monophosphate 393
mitral commissurotomy 730 valve 473f Cyclosporin 50
Index 757
D Diabetic nephropathy 165 Disorders of

Diagnosis of chest 140
da Vinci system set-up 674f coronary thrombosis 94 keratinization 397t, 401
Daptomycin 242 deep venous thrombosis and pulmonary lipid metabolism 397t, 403
Decrease embolism 283 Distal
functional capacity 141 Tourette syndrome 733 embolic protection devices 583, 640
of blood pressure 101 tubercular myocarditis 332 embolization 583
Deep Diastolic filter device 584
hypothermic circulatory arrest 699 blood pressure 176, 722 filtration 584
transgastric view 557 dysfunction 507 occlusion device 584
vein thrombosis 5, 69, 95, 244, 283, 284, hypertensives 24t Dobutamine 365, 448, 455
726 tissue velocity 457 atropine stress echocardiography 454, 457
Defects of cardiac septa 273 trans mitral velocity 457 myocardial perfusion imaging 522
Defibrillators in nonischemic cardiomyopathy two-dimensional stress echocardiography stress echocardiography 451, 457
treatment evaluation 345 457 two-dimensional stress echocardiography
Degenerative velocity 123 451
aortocoronary saphenous venous graft Dichloroisoprenaline 116 Docosahexaenoic acid 372
623 Diet heart Donald Fredrickson and classification of lipo-
valve diseases 241 disease 185 proteins 184
Demonstrate tricuspid regurgitation 485 hypothesis 137 Doppler
Density lipoproteins 183 Dietary derived myocardial performance index
Dental procedures 76 deficiency 380 126
Deoxyribonucleic acid 131, 321 fat intervention trials 137 echocardiography 236, 433
Depression and heart disease 308 intervention trials 186 features of aortic coarctation 477
Dermatomyositis 400f Different classes of glycoprotein IIB/IIIA interrogation 472
Development of inhibitors 37t Dotter technique 599
antiplatelet agents 39t Digital Double
blood tests 90 imaging and communication system 542, apex beat and ejection systolic murmur
cardiology in India 3 546f 216
cardiopulmonary bypass 710 two-dimensional stress echocardiography blind primary intervention trial 180
clinical cardiac ultrasound 414 450 inlet atrioventricular connection 481
coronary angiography 90 Dihydropyridines 104, 105 outlet
current robotic technology 688 Dilated right ventricle 483
intravascular ultrasound 622 cardiomyopathy 211, 224, 500, 535, 751 ventricle 481
lovastatin 49 inferior vena cava 565 vessel disease 592f
robotic cardiac surgery 689 Diphtheria 229 Down’s syndrome 401, 401f
safe and effective-cell tracking modalities Dipyridamole 37, 109, 365, 448 Drug eluting stent 578, 582, 590
747 myocardial perfusion imaging protocol Duct dependent
saralasin 61 519 pulmonary blood flow 470
streptokinase 717 transesophageal 448 systemic blood flow 471
systemic arterial hypertension 73 Direct Ductal stenting 470
thrombolytic therapy 5 attached storage 544 Ductus venosus 489
tissue valves 671 implantation of vessels into myocardium Dynamic cardiac myoplasty 662
vascular grafts 700 680 Dyslipidemia 199, 199t
venous thromboembolism 283f renin inhibitors 163 Dyspnea 235, 363
Devices beyond balloon 600 Directional coronary atherectomy 578 Dyssynchrony and cardiac resynchronization
Dextrothyroxine 188 Discipline of interventional cardiology 602 therapy 617
Diabetes 156, 171, 360, 362, 535 Discovery of
mellitus 124, 172 compactin 49 E
and CVD 197 estrogen 326
on diet 202 streptokinase 5 Ebstein anomaly 481, 487, 497, 559
prevention program 201 Disopyramide 117 of tricuspid valve 561, 561f
Echo of pulmonic valves 568 Enzyme linked immunosorbent assay 285 External loop recorder 337
Echocardiography 241, 285, 365, 413 Epicardial Exudative pleural effusion 237
of pulmonic valve 565 and myocardial reperfusion 12
Echo-dobutamine international cooperative reperfusion 10 F
451, 457 Epiloia disease 400
Echo-persantine international cooperative Epithelial internalization 264 Fabry’s disease 221, 404, 405f
451, 457 Eptifibatide 39 Factors
Ehlers-Danlos syndrome 402, 403 Era of influencing prognosis 175t, 177t
Ejection fraction 232, 457, 751 cardiopulmonary bypass 712 limiting modern therapies in India 751
Elderly systolic hypertension 25t electrocardiography 93 Fallot’s tetralogy 28
Electrocardiogram 437, 457, 631, 727 Forssmann and Cournand 597 False positive echocardiograms 236
diagnosis 631 randomized trials 613 Familial hypercholesterolemia 135, 182
QRS duration 346 Sones and Judkins 598 Fan-shaped chordae 555f
transmission 539 unlocking left heart 598 Fatal heart attacks 188
Electrocardiograph device 549f Erectile dysfunction 393 Fatty
of hypertrophic cardiomyopathy 353f Ergometer exercise testing 444 acids 321
transmission 547 Erythema marginatum 404f degeneration 92
Electrocardiography 177 Erythromycin 50, 77 diseases of heart 92
Electronic medical record 545 Escherichia coli 45 Felodipine 104, 105
Electrophysiology of ventricular tachycardia Established vein graft disease 582 Femoral artery 120
631 Estrogen 188 Fetal
Embolic therapy 283 balloon dilatation 736
phenomena 239 European cardiac intervention 491
protection devices 581 cooperative acute stroke study 589f heart block 490
Embryonic stem cells 740 myocardial infarction amiodarone trial Fibrin split products 285
Emergency medical system 723 348 Fibromas 502
End society of First
diastolic ventricular volumes 661t cardiology 157, 176 alcohol septal ablation 215
stage diabetes 380 hypertension 176 degree AV block 337
Endocarditis 239, 249 Evaluation of line β-blockers (atenolol) perform 25t
Endocrine steroid cardiopathy 311 acute coronary syndrome 89 pass radionuclide angiocardiography 511
Endocrinological disorders 398t aortic valve stenosis 475t septal myectomy 215
Endomyocardial atrial septum by transesophageal echocar- trimester
biopsy 229 diography 465 echocardiography 487
fibrosis 219 cardiac tricuspid regurgitation and congenital
in India 220 resynchronization therapy 457 heart defects 490
Endoscopic transplant 495 Five-chamber view of heart 484t
assisted coronary artery bypass 657 coarctation of aorta 477t Fixed dosed combination pills 85
coronary artery bypass 657, 685, 693 coronary arteries 495 Flecainide 115, 117
Endothelial prognitor cells bone 740 losartan in elderly study 65 Fleischner’s sign 245
Endothelium derived relaxing factor 393 myocardial oxygenation 495 Flexible explosive 101, 421f
Endovascular Ewart sign 235 Flow convergence method 567
interventions for aortoiliac occlusive Excessive urination 209 Fluoroscope 432
disease 641 Exclusion of intracardiac thrombus 648 Foam cells 135
repair of aortic aneurysm 641 Exercise Folic acid 380, 384t
valve edge-to-edge repair study 660 capacity and NYHA class 350 Food
Endoventricular patch plasty 661t induced mitral regurgitation 449 and drug administration 45, 74
End-stage renal disease 314, 367t stress echocardiography 457 standards agency 376
Enhanced external counterpulsation 120, 127 Exertional dyspnea 229 Foot pressures 149
Enigma of endomyocardial fibrosis 219 Experimental reproduction of endocarditis Fosamprenavir 50
Enteroviruses 229, 233 240 Fossa ovalis 643
Index 759
Four-chamber view of heart 483t Health statistics in India 541t History of

Fragmin in coronary artery disease 70 Heart 104, 128, 751 ACE-inhibitors 73
Framingham heart study 23t, 185 and coronary vessels 87 acute coronary syndrome 87
Francis fontan 281f attack 65, 89 AMI 92
Fraxiparine in ischemic syndromes 70 block 336, 650 angiography 625
Free fatty acid 199, 527 contractions 148 angiotensin receptor blockers 59
Functional tricuspid regurgitation 559 disease 142 antiarrhythmic drugs 113
Future of of children 281 aortic surgery 697
balloon valvotomy 730 failure 29, 95, 124, 160, 172, 535, 536, 619, balloon atrial septostomy 626
heart transplant in India 750 661f beta-blockers 15
thrombolytics 717 primary prevention 27 blood pressure
lung machine 279 amplification 149
G outcomes prevention evaluation 84, 203, measurement 162
384t calcium channel blockers 103
Galderisi cardiovascular ultrasound 123 protection study 333 cardiac
Ganglionic blocking drugs 163 rate turbulence 345t, 349 fitness programs 140
Gangrene senilis 290 transplantation 662, 663, 751 imaging 432
Gastrointestinal bleeding 105 Heavy chain myosin 232 interventions and future directions
Gaucher’s disease 221 Hellerstein’s original 142 597
Gelignite 101 Hematogenous route 332 rehabilitation 156
Gene therapy 97, 662 Hematopoietic stem cells bone 740 syncope 336
Genetics of dilated cardiomyopathy 212 Hemochromatosis 501 cardiorenal connectors 314
German diabetes and dialysis study 56 Hemodynamic cardiovascular disease protection 321
Giant cell myocarditis 212, 230 stress 224 catheter ablation 605
Global cardiovascular disease 80 two-dimensional stress echocardiography coil closure 629
Gluconeogenesis 16 456 coronary artery disease 92
Glutathione peroxidase 321 Hemodynamically significant tricuspid deep vein thrombosis and pulmonary
Glycerin’s nucleophilic oxygen atoms 100 stenosis 565t thromboembolism 244
Glyceryl trinitrate 101 Hemorrhagic stroke 290 development of angiotensin receptor
Glycogenolysis 16 Heparin 42, 68, 286 blockers 408
Goldstein brown and LDL receptor 182 and thrombosis of veins 69 device closure 628
Gonorrheal vaginitis 327 in cardiovascular disease 70 drugs in acute rheumatic fever 256
Grading of induced thrombocytopenia 70 endomyocardial fibrosis 219
pulmonary regurgitation 567t Hepatic vein flow 562 fetal cardiology 480
tricuspid regurgitation 562t Hepatitis C virus 229, 230 four-chamber view 480
TS 565t Hepatojugular reflux 235 heart
Grading pulmonic stenosis 569 Herbal tea 241 transplant in India 750
Granulocyte colony-stimulating factor 742 Heterozygous familial hypercholesterolemia transplantation 705
Green 49 heparin and cardiovascular disease
fluorescent protein 741 High protection 68
telepresence surgery system 690 blood hormone replacement therapy and heart
Grönblad-Strandberg syndrome 403 cholesterol 140 325
Group streptococcus 76, 258 pressure 140, 199t, 326 infective endocarditis and future
Gruentzig cholesterol 136 directions 238
and coronary angioplasty 600 coronary disease risk 171 interventions for congenital heart disease
balloon 599 density lipoprotein 17, 130, 173-175, 177, 625
323, 362, 374 intravascular ultrasound 622
H cholesterol 195, 367t IVC filters 642
His bundle electrogram 606 left main percutaneous coronary
Hampton’s hump 245 Historic milestones in antiplatelet therapy 107, intervention 588
Headache 326 108t markers of sudden cardiac death 340
MRI 508 Hypersensitivity 229 Inhibition of

myocardial contrast echocardiography Hypertensinases 318 cannabinoid 201
436 Hypertension 28, 80, 156, 172t, 360, 362 insulin release 16
nitrates 99 and stroke 291 lipolysis 16
nuclear cardiology 509 and target organ damage 160 smooth muscle cell 578
oxidative stress 321 Hypertensive heart disease 547 Injections of penicillin 259
pediatric cardiology 270 Hypertrophic Inner wall of blood vessels 132
peripheral vascular interventions 638 cardiomyopathy 78, 215, 350, 353, 500, Insulin
pulmonary embolism 283 535, 649 receptor in
restrictive cardiomyopathy 219 obstructive cardiomyopathy 28, 216 adipocytes 198
robotically assisted cardiac surgery 688 Hypoplastic left heart syndrome 470, 481, 491 muscle 198
sildenafil 393 resistance 199
statins 49 I Intact ventricular septum 737
stem cell therapy 739 Integrating indices of severity 567
stent use 630 Idiopathic Intensive care unit 750
stress dilated cardiomyopathy 212 Interatrial
and heart disease relationship 306 orthostatic hypotension 28 communication 474
echocardiography 442 Iliac artery aneurysms 641 septum 643, 646f
stroke in cardiac patients 289 Immune system 103 Internal
surgery for ischemic heart disease 676 Immunoglobulin complexes 236 cardioverter defibrillators 337
tobacco in India 298 Immunological and infective disorders 399t, jugular vein 90
ultrasound 413 404 mammary artery 656
valvular heart surgery 667 Implantable International
valvuloplasty 627 cardioverter defibrillators 78, 221, 341, business machines 692
warfarin 40t 615 collaboration on endocarditis 242
women and heart disease 359 defibrillators 341 maritime satellite 539
HIV-infection 234 Importance of randomized evaluation 71
Holmium 684 atrioventricular dissociation 631 Interpretation of metaiodobenzylguanidine
Homocystinuria 404 epicardial reperfusion 10 images 534f
Honolulu heart study 136 Inadequacy of public health programs 261 Interrupted aortic arch 481
Hormone replacement therapy 325, 326, 363 Inborn errors of metabolism 399, 404 Interventricular
and cancer 328 Incidence and management of cardiac-device septal 457
and heart disease 327 infection 78 septum 554f, 632
and stroke 328 Increase of heart rate 101 Intima-media thickness 132
and thromboembolic disease 328 Indian Intra-aortic balloon pumping 661
Human council of medical research 4, 77, 220 Intracardiac
aortic endothelial cells 131 defence service 550 echocardiography 236, 643, 646f, 649f,
heart 87 hypertension guidelines 171 650t
immunodeficiency virus 229, 296, 331 Indinavir 50 extension 502
serum albumin 509 Induced pluripotent cell 740 intracoronary ultrasound 433
Hybrid procedures 478 Infective endocarditis 77, 238, 241, 404 Intracoronary shunts and coronary occlusion
Hydraulic systems 121 Inferior 656
Hydrogen peroxide 321 gastric artery 656 Intracranial hemorrhage 719
Hydroxymethyl glutaryl-coenzyme 49 vena cava 464, 605, 607 Intractable angina 751
Hyperbaric oxygen 97 Infiltrative disorders 399, 405 Intraprocedure role of echocardiography 465
Hypercholesterolemia 80, 189 Inflamed heart 250 Intravascular ultrasound 478, 579, 590, 622
Hyperhomocysteinemia 387 Inflation of balloon 648f Intravenous immune globulin 233
Hyperkeratotic vascular skin lesions Influenza 229 Invasive coronary surgery 656
angiokeratomas 405f Infundibular stenosis 474 Irbesartan diabetic nephropathy trial 65, 165
Hyperkinetic heart syndrome 28 Inherited disorders of Irreversible injury 10
Hyperlipidemia 88, 156, 360 collagen and elastin 399 Ischemic
Hyperproliferative disorders 380 elastin and collagen 402 cardiomyopathy 351, 751
Index 761
heart disease 3, 71, 81, 83f, 101, 120, 310, bundle branch block 617, 717 dose dobutamine echocardiography 451,
333, 382, 433, 495, 685, 744 heart syndrome 737 457
lower extremity 8 main coronary artery 588, 591 HDL cholesterol 172t
mitral regurgitation 659 disease 591 molecular weight 286
Isosorbide stenting 591 heparin 38, 43, 70, 225, 286, 722
dinitrate 101 ventricle end-diastolic diameter 736 triglycerides 16
mononitrate 101 ventricular 152, 219, 230, 311, 341, 613 Lowenbereg’s sign 245
Isovolumetric contraction time 123 aneurysmectomy 661, 661t Ludwig’s kymograph 147
Isovolumic relaxation time 123 assist device 457 Lung perfusion scans 285
Isradipine 104, 105 diastolic dysfunction 122 LV end-diastolic volume 495
Itraconazole 50 dysfunction 737 Lycopene in food 133
ejection fraction 65, 122, 225, 232, Lyme carditis 229
J 343-345, 367t, 511, 591, 613, 661
end diastolic pressure 447, 457 M
Jeremiah Stamler and American Heart endomyocardial fibrosis 219
Association 188 hypertrophy 122, 172t, 174 Macrolide antibiotics 50
Jerky pulse 216 mass 123 Magnetic resonance
John gibbon with heart-lung machine 279f mass index 123, 177 cholangiopancreatography 77
Joint national committee on prevention 168 systolic dysfunction 224 imaging 246, 494, 728
Jones criteria for diagnosis of rheumatic fever Legacy of young branch 270 Mahomed’s study 149
258 Leiomyomatosis 502 Main pulmonary artery 485f
Jugular venous distension 235 Leopard syndrome 396, 400f Major clinical trials of glycoprotein IIB/IIIA
Lercanidipine 104 inhibitors 39t
K Level of residual obstruction 472 Malignant
Lidocaine 114, 117 cardiac arrhythmias 751
Kanyini-guidelines adherence with polypill 85 Lidoflazine 104 hypertension 315
Kawasaki Ligation of internal mammary artery 656 nephrosclerosis 316
disease 78, 404 Light’s criteria 331 pericardial neoplasms 505
syndrome 404 Limitations of tumors 503
Ketoconazole 50 echocardiographic imaging of duct 470 Mammalian skeletal and cardiac muscle 103
Kidney 128 polypill 85 Management of
Kissing balloon technique 595 radial approach 595 acute
Knockout of insulin receptor in liver 197 Linezolid 242 coronary syndrome 90
Kuopio ischemic heart disease 132 Lipid myocardial infarction 718
hypothesis 135, 182 arrhythmias 95
L lowering therapy 95 atherothrombosis 110
Lipomas 502 blood pressure 157
Lacidipine 104 Lipomatous hypertrophy of interatrial septum CDS 200t
Lack of international recognition 4 503 end stage heart failure 662f
Lactic acid dehydrogenase 237 Lippmann capillary electrometer 93 hypertension 312
Laennec’s tube 147 Livedo reticularis 401f pulmonary embolism 285
Landline vs mobile transmission 549t Liver cirrhosis or suicide 192 wide QRS tachycardia 635
Landmark Long QT syndrome 342 Manidipine 104
in aortic surgery 702 Long-term ambulatory ECG recording 348 Manifestations of
moments in development of surgery 712 Lopinavir 50 coronary artery disease 92
trials across ARBS 66t Losartan intervention for endpoint 203 target-organ damage 170t
Laparoscopic surgery 689 reduction in hypertension 23, 65, 165 Marfan’s syndrome 559, 699
Large blood vessels 153 Low Markers of sudden cardiac death 344, 345f
Lazy sinus syndrome 336 blood cholesterol levels 192 Mean pressure drop 565
Left density lipoprotein 81, 138, 173, 175, 177, Measurement of vena contracta 561
anterior descending 457, 656, 677 226, 322, 371, 374t Measures of epicardial reperfusion 11
atrial appendage 645, 731 cholesterol 49, 180, 181, 367t Mechanical scanning 622
Mechanism of Monday morning headache 102 muscle 229

action of Monoamine oxidase 535 opacification 437f
dipyridamole 521 Monocyte cells 131 perfusion 510, 512, 514
streptokinase 5 Monotherapy to combination therapy 164 imaging 516
insulin resistance 198f Moricizine 115 scan 520
Mediastinal lymph node 330 Morphology of pediatric cardiology 277 retroperfusion 680
Members of ARB class 408 Mortality statistics 541 stunning and hibernation 511, 528
Membranous septum 555f Moses’s sign 245 T2 quantification 506
Menopause 363 Mucocutaneous lymph node syndrome 404 T2 signal intensity 506
Mental stress-induced ischemia 309 Mullin’s dilator 733f Myocarditis 224, 229
Mesenchymal stem cells bone 740 Multicenter Myotomy-myectomy 215
Metabolic insync randomized clinical evaluation 615 Myxomas 502
disorders 28 oral carvedilol heart failure assessment
syndrome 124f, 195, 197, 199f 213 N
in Indian urban population 196f unsustained tachycardia trial 344
status 202f Multimode computerized tomography scan Nation’s health care system 297
Methionine 380, 381 728 National
Methylene tetrahydrofolate reductase 380 Multiparameter device 549f Cholesterol Education Program 180, 181,
Methylglutaryl-coenzyme 182 for primary health center 547 190, 195
Mexiletine 117 Multiple institute for health and clinical excellence
Miconazole 50 lentigines syndrome 396 376
Microalbuminuria 172t muscular ventricular septal defect 711 Natural blood channels 128
Microscopic cardiac rhabdomyoma 483f neurofibromas of face 402 Nature of
Midesophageal Multisite stimulation in cardiomyopathies 614 atrioventricular 219
four-chamber view 555 Multivessel small thoracotomy 657 vein graft disease 581
long axis view 557 Murray’s external suturing 712 Naxo’s disease 402, 402f
right ventricular inflow-outflow 556, 556f Muscle Nefazodone 50
Migraines 326 contraction 16 Neonate with critical pulmonary stenosis 474t
Mild fiber 92 Neoplastic diseases 505
coarctation of aorta 483 Muscular ventricular septal defect 467 Nervous system 199
semilunar valves stenosis 483 Myalgias 229 Neurochemistry of brain 318
tricuspid regurgitation 78, 560f Mycobacterium tuberculosis 331 Neurovisceral diseases 306
Minimal tricuspid regurgitation 555 Myocardial New York
Minimally invasive mitral valve surgery 658 apoptosis imaging 511 Heart Association 345
Mitral blood flow 436, 518f trans-fat scenario 375
insufficiency 499 contrast echocardiography 436, 454, 457 Niacin 188
regurgitation 457, 660, 669 disease 481 Nicardipine 104, 105
stenosis 444, 457, 499, 660, 730 function, systolic and diastolic 510 Nicotiana
and stroke 291 hypoxia imaging 511, 536 rustica 297
valve 78, 667 infarct imaging 511, 528 tabacum 297
repair 672 infarction 6, 10, 21, 31, 52, 60, 88, 92, 107, Nicotinamide adenine dinucleotide phosphate
surgery 693 114, 132, 137, 140, 170, 173-175, 321
valvuloplasty 627 180, 217, 283, 359, 367, 383, 384, Nicotinic acid 188
Mixed carotenoids 321 457, 510, 521, 591f, 599, 632, 722 Nifedipine 104, 105
M-mode and breast cancer 130 Nimodipine 104, 105
recording of pulmonic valve 568 and stroke 82, 291 Nisoldipine 104, 105
stress echocardiography 444 trial 109 Nitrendipine 104, 105
Mode of action of ARB 408 ischemia 55, 495, 521 Nitric
Molecular imaging 525 acid 100
fatty matter 92 metabolism 510, 527 oxide 101, 102, 314, 381
structure of all-trans lycopene 130f microcirculation 583 Nitrogen 101
Index 763
Nitroglycerin 99, 100-102, 104, 457 P left atrial appendage occlusion 648
tablets 102 mitral valve repair 648
Nitrolingual pump spray 101 Pacemaker PFO and ASD closure 646, 650
Nitrospan 101 infection 78 saphenous vein grafts intervention 582
Nitrostat 101 lead-induced severe tricuspid valve transluminal
Nivadipine 104 stenosis 565 angioplasty 638
Non-angiotensin-converting enzyme pathway Pacing coronary angioplasty 141, 365, 577,
61f catheter perforation 418f 581, 594
Non-cardiac surgery 22f transesophageal two-dimensional stress renal angioplasty 640
Non-insulin dependent mellitus 205 echocardiography 456 transvenous mitral commissurotomy 730
Non-invasive cardiology 411 Paget-Schroetter syndrome 245 techniques 732f
Non-Q-wave myocardial infarction 534 Palmoplantar keratoderma 402f under TTE guidance 733f
Non-ST segment elevation 70 Panconductional disease 337 valve repair and replacement 660
myocardial infarction 10, 107 Papillary muscle 555, 561 valvular procedures 647
Non-steroidal anti-inflammatory drugs 109, Para-aminobenzoic acid 617 ventricular septal defect 649
234 Parasitic infection 239 Pericardial
Non-tubercular pericarditis 505 Paravertebral injection of alcohol in dorsal cyst 504
Noonan’s syndrome 401 nerve roots 677 disease 547f
Normal Parent-teacher association programs 261 effusion 650
ductus venosus 489f Paroxysmal atrial fibrillation 22 fluid analysis 237
heart 238 Partial friction rub 235
sestamibi myocardial perfusion scan 516f left ventricular resection 661 inflammation 504
sinus rhythm 421f, 634f perfusion 11 injury syndromes 234
tricuspid valve pressure of oxygen in arterial blood 284 tumors 503
flow 490f thromboplastin time 70 Pericardiocentesis 478
motion 557 Parvovirus 229, 233 Pericarditis 233, 249
Norwegian vitamin trial 384t Patau syndrome 399t Perimembranous ventricular septal defect 469
Nuclear cardiology procedures 510 Patent Peripartum cardiomyopathy 224
ductus arteriosus 78, 276, 469, 471t, 497, Peripheral
O 511, 735f and coronary tree 577
foramen ovale 466, 643 arterial
Obesity 172, 199, 363 visualization 646f disease 21, 22, 367t, 736
and cardiovascular disorder 209 Pathogenesis of pulmonary embolism 283 occlusion 8
and diabetes 140 Pathophysiology of atherothrombosis 107 pulmonary stenosis 481
and syndrome X 210 Peabody’s sign 245 vascular disease 300
Obstructive disorders 497 Peak Persistent ductus arteriosus 481
Off-pump coronary artery bypass surgery 684 dose dobutamine echocardiography 451, Pet myocardial ischemia 510
One-dimensional echocardiography 413f 457 Pharmacological stress perfusion imaging 518,
Opacifying myocardium 436 filling rate 511 522
Open mitral commissurotomy 732 Pediatric cardiology 4, 270, 277 Phenytoin 114, 117
Operative treatment of angina pectoris 677 Penicillin 229, 230, 259, 260 Pheochromocytoma 28
Optimal epicardial artery patency 12 and public health programs 261 Pioneers in stress echocardiography 448t
Oral prophylaxis 262 Placebo-controlled heart-failure trials 27t
anticoagulants 39, 286 Penicillium citrinum 49 Plasminogen activator inhibitor 205
D-sotalol 117 Pentasaccharides 44 Platelet function 81
Organic anion transporting polypeptide 50 Percutaneous Polymerase chain reaction 230
Origins of congenital heart surgery in India annuloplasty 660 Polypill
713 balloon aortic valvuloplasty 735 in cardiovascular disease 80
Orthostatic hypotension 101, 338 closure of ductus arteriosus 470 trials 83t
Osteoporosis 326 coronary intervention 10, 70, 109, 581, Polyunsaturated fats 136
Oxidative stress 321 590f, 591f, 595, 717, 744 Poor ventricular function 95, 96
Oxygen 101 intervention of vein grafts 586t Portal hypertension 28
Positron emission tomography 221, 495, 510, Pseudosinuses 658 Q

523, 525, 535, 743 Pseudoxanthoma elasticum 403
Post heart-lung machine era 681 Psoriasis 309, 406 QRS
Posterior Pulmonary axis in frontal plane 632
descending artery 656 and tricuspid valves 672 complex of electrocardiogram 618
mitral leaflet 658 angiography 246, 285 duration 342
Postmenopausal estrogen 364 annulus 554f Quantification of myocardial blood flow 436
Potassium nitrates 101 arterial hypertension 547 Quantifying myocardial perfusion 438
Potential arteriovenous fistula 481 Quinidine 113, 117
CMR correlates of heart transplant rejec- artery 554f, 569f, 710
tion 507 anomalies 481 R
molecular mechanisms of cardiovascular catheter 570f
effects of trans-fatty acids 371 pressure tracing 416f Radial artery 656
Pratt’s sign 245 systolic pressures 558 Radionuclide ventriculography 511
Pravastatin in ischemic disease 55 atresia 474, 481, 497 Ramipril 85
Pre-cardiopulmonary bypass era 710 blood flow 470 global endpoint trial 65
Pre-heart-lung machine 679 commissures 554f Randomized carotid endarterectomy 640
Predicting left ventricular 12 cusps 554f Rauwolfia serpentina 115, 115f
Predictors of diastolic hypertension 23t embolism 5, 95, 244, 283 Reactions of different β-blockers 15
Pregnancy induced heart disease 360 hypertension 512, 535, 751 Recombinant
Pre-hospital thrombolysis 726 and right heart failure 416f deoxyribonucleic acid 31
Premature ventricular contraction 342 infarction and hemorrhage 284 tissue plasminogen activator 286
Prevention of heart disease in women 367t regurgitation 565, 568 Red blood cell 147
Previous venous thromboembolism 283 stenosis 481, 568, 734 Re-emergence of beating heart surgery 684
Primary thromboembolism 8, 245 Regional wall motion
cerebral type 337 valve 565, 570 abnormality 443, 457
coronary intervention 13 echo tracing 416f score index 454, 457
hypertension 23 stenosis 474, 734 Relative wall thickness 123
myocardial disease 215 valvuloplasty 627 Renaissance period 270
PCI 717 vascular resistance 751 Renal
percutaneous coronary intervention 8, veins 464, 643 angioplasty 640
595, 722, 726 venous vasodilator 60
prevention trials of aspirin 35t flow 464 Renin
Procainamide 113, 117 systolic 124 angiotensin
Progesterone 326 Pulmonic aldosterone system 203
Progress in echocardiography 415f regurgitation 568, 568f cascade 61
Propafenone 117 valve 553, 567 pathway 59f
Properties of statins 51t implantation 649f system 62, 73
Prophylaxis for deep venous thrombosis 287 Pulsatile and nonpulsatile pumps 663t release increase 16
Prosthetic Pulse Requiring enormous energy 147
cardiac valve 78 pressure 151 Resolution of
heart valve 658t wave Doppler 557, 560, 561f chest pain 11
and stroke 292 Pulsed Doppler demonstration of various heart ST elevation in ECG 11
Protease inhibitors 50 valves 486f Resting electrocardiograms 141
Proteins 321 Pulseless electrical activity 341 Restrictive cardiomyopathy 501
Prothrombin time 40 Pulsus paradoxus 235 Reteplase plasminogen activator 7
Prothrombotic state 205 Purified protein derivative 236 Retinopathy 170
Protozoal infection 229 Purkinje fibres 337 Retrograde
Proximal occlusion device 584 Pyroglycerine 99 lymphatic 332
Pseudoaneurysm formation 650 Pyruvate dehydrogenase kinase 197 non-transseptal aortic approach 731
Index 765
Retroperitoneal bleeding 650 S Small

Rheumatic atrial septal defects 483
and nonrheumatic valvular heart disease 76 Safety of ultrasound contrast agents 439 blood vessels of brain and kidney 153
carditis 256 Sandergard’s purse-string suture closure 712 ventricular septal defects 483
fever 249, 250, 257f, 263, 275 Saphenous vein grafts intervention 584t Smokeless powder 101
and invasive gas disease 264 Sarcoidosis 221, 405 Smooth muscle 16
fascinates 264 Sarothamnus scoparius 114, 114f Sodium 101
heart disease 4, 76, 77, 249, 263, 292, 541, Saturated fatty acid 186 Sorbitrate 99
730 Saturation phenomenon 186 Sotalol 117
Rheumatism Second Spectroscopy 507
in 18th century 249f generation prosthetic valves 671 St elevation myocardial infarction 726
of heart 249 hand smoke and cardiovascular diseases Stable coronary heart disease 55
Rheumatoid diseases 230 300 Staphylococcus aureus 241
Ribonucleic acid 321 Secondary prevention of myocardial Starvation diet 241
Right infarction 22f Statins in special populations 56
and left heart catheterization 575 Secundum atrial septal defect 481 Stem cell therapy 97, 662
bundle branch block 338, 346, 617, 632 Senile vaginitis 327 Stenting of saphenous vein grafts 582
coronary artery 457 Septal Stentless valves 672
internal mammary artery 656 dilatation 467 Stimulation of lipolysis 16
ventricle 272, 283, 413 leaflet of tricuspid valve 554f and thermogenesis 16
function 474 remodeling 661t Story of single pump 279
ventricular 219 Septolateral annular cinching 660 Strawberry tongue 404f
aneurysm 418 Serpiginous margin 404f Streptococcal
ejection fraction 511 Serum infection 229, 249
endomyocardial fibrosis 219 β-carotene concentrations 133 tonsillitis 260
infarction 418f homocysteine 81 Streptococcus 240, 261, 263
outflow tract 355, 427f, 647 Sestamibi 515 equisimilis 6
pressure tracing 416 Severe mitior seu viridians 240
systolic function 472 pulmonary valve stenosis 735f Streptokinase 5, 31
Ringer’s solution 316 tricuspid regurgitation 560f Stress
Ritonavir 50 Severity of and cardiovascular diseases 307
Robotic stenosis 475 and sudden death 310
cardiac surgery 692 tricuspid insufficiency 560t cardiomyopathy 311
coronary artery bypass 693 Short-term heart rate variability 348 cardiovascular magnetic resonance 496
valve surgery 673 Shrunken kidneys 152 echocardiography 443, 457
Role of Shunt induced cardiac dysfunction 311
ARB in hypertension 409 and valve repairs 499 Stroke 289, 300, 726
echocardiography in lesions 463, 496 volume 457
catheter intervention 463t Sick sinus syndrome 336 Structure of
congenital heart disease 463 Sideris device 628 antithrombin binding site of heparin 44f
exercise echocardiography 567 Signal-averaged electrocardiogram 342 cis- and trans-fatty acids 371f
oxidation in pathogenesis of coronary Simple atrial septal defect 78 ST-segment elevation myocardial infarction
heart disease 131 Single 71, 595
surgery in MS 733 photon emission computed tomography Studies of left ventricular dysfunction 165, 213
thrombolytics for acute myocardial 312, 437, 454, 457, 510 Subaortic stenosis and hypertrophied nondi-
infarction 717 vessel disease 592f lated left ventricle 215
trans-fatty acids in cardiac arrhythmias Sir thomas bevill peacock 273 Subclavian origin 470
374 Sjögren syndrome 230 Subitaneis mortibus 292
Rotational angioplasty catheter system 600 Skeletal Success story of sildenafil 394
Routine electrocardiogram 510 muscle 104, 199 Sudden cardiac death 340, 341
RV outflow tract 553 myoblasts satellite cells 740 in heart failure 616
Sulfinpyrazone 109 Teboroxime 516 therapy 96, 286, 726

Sulfonamides 229, 230 Tecadenoson 118 in acute ischemic stroke 727
Sulfur trioxide 100 Technetium-99m labeled annexin V 529 in acute pulmonary embolism 728
Sulfuric acid 100 Techniques of Thrombus 503
Sulphadiazine 77 balloon pulmonary valvotomy 734 Thulium 684
Superficial femoral artery 638 BAV 736 Thyroid-stimulating hormone 236
Superior vena cava 464, 485f, 496 enhanced external counterpulsation 127f Tick anticoagulant peptide 38
Super-paramagnetic iron oxide 747 PTMC 731 Tigecycline 242
Supporting structure of tricuspid valve 555 tricuspid valve dilatation 734 Time
Supraventricular tachycardia 605-607, 631 Telemedicine in cardiology 541 line of landmark trials with ARBS 65
Surgery for Telepresence surgery 690 velocity integral 456, 457
aortic stenosis 668 Teleradiology Timeline of interventions of congenital heart
heart failure 661 and cardiac imaging solutions 551 disease 630
mitral stenosis 667 solutions 551 TIMI
rheumatic fever 264 Telithromycin 50 grading system for coronary 11t
Surgical Tenecteplase 7 myocardial perfusion grade 12
strategy to repower failing heart 662t Tests for diagnosis of Tip of iceburg 340f
treatment of ischemic heart disease 677 deep venous thrombosis 284 Tipranavir 50
Survival of myocardial infarction 726 pulmonary embolism 284 Tirofiban 39
Sutureless anastomotic devices for coronary Tetralogy of Fallot 474, 481, 483, 498, 711, 713 Tissue
artery bypass 657t palliation 277 disease 230
SVG disease 582 Tetrofosmin 516 Doppler
Sweep technique 483 after stress injection 516f and speckle tracking imaging 423
Switzerland model 374 Therapeutic imaging 123
Systemic results of engineered heart valves 673
arteriovenous fistula 481 PTMC 732 factor pathway inhibitor 70
hypertension 160 total blood volume 734 plasminogen activator 7, 45, 726
lupus erythematous 380 studies of intravascular ultrasound 623 synchronization imaging 618
sclerosis 230, 406f Therapy TNF-alpha 225
vasodilatation 521 for rheumatism in early 19th century 255 Tobacco 296
Systolic of infections 76 and CVDS 303
anterior movement 216 Thiazide 85 Tombstone of Paget’s views 275
blood pressure 160, 168, 176 Thiazolidinediones 205 Tongue 102
hypertension 23t, 152 Thienopyridines 35, 109 Torsade de pointes 341
velocity 123 Thin layer of skin 93 Total
Third degree AV block 337 anomalous pulmonary venous
T Thomas Bevill peacock 273f connection 481, 713
Three return 498
Tachycardia 235, 634f dimension of PS 570 arterial revascularization 656
QRS narrow than sinus QRS 632 dimensional artificial heart 662
Tachypnea 235 echo in pulmonic regurgitation 568 blood volume 734
Tailor made approach 356f echocardiography 423, 457, 565 Toxins 229
Takayasu arteritis 230 generation of ventricular assist devices Tracers of myocardial perfusion 523
Takotsubo cardiomyopathy 311 663t Transapical aortic valve implantation 660
Target Thrikarana shuddhi 390 Transcatheter
lesion revascularization 591f Throat infection 76 pulmonic valve implantation 649f
of antiplatelet drugs 108f Thromboembolism 650 valve implantation 648
organ damage 168, 174 Thrombolysis in myocardial infarction 36, 109, Transesophageal
Taxus and cardiac surgery 592 111, 583, 719 echo examination of tricuspid valve 555
Tc-99m flow 11 echocardiography 236, 423, 463, 465f,
labeled glucarate 528 Thrombolytic 466f, 553, 563, 643, 660
pyrophosphate 528 agent 45, 727t stress echocardiography 449f
Index 767
Trans-fat Tricuspid U
in Australia 376 and pulmonic valve disease 500
in Canada 376 atresia 497 Ultrasound angioplasty 579
in United States of America 375 leaflets 553 Umbilical cord 740
intake with coronary artery disease 373t regurgitation 490, 558 blood cells 740
Trans-fatty acids 370, 374t stenosis 562, 564, 564f, 733 Unfractionated heparin 38, 70
Transfemoral transvenous antegrade approach valve 418f, 553, 557f, 562, 645 Uniaural stethoscope 147
731 anatomy 553 United State Public Health Science Hospital
Transgastric disease 659 605
basal short axis view 556 Triggers of Unlocking
right ventricular inflow 556f SCD 343f coronary arteries 598
Transient ischemic attack 31, 107, 174, 521 ventricular arrhythmias 350 right heart 597
Transitional devices 628 Trimetazidine 455 Unprotected left main trunk intervention
Transjugular transvenous antegrade approach Trinipatch 455 multicenter assessment 590
731 Trinitrin 99 Unravelling coronary vasculature 576
Transluminal extraction catheter 600 Triple vessel disease 592f Unstable
Transmural myocardial strain profile 457 Tropheryma 242 angina 10, 31, 110, 534
Transmyocardial Truncus arteriosus 481, 498 arrhythmias 439
laser revascularization 120, 683, 684 Tubercle bacilli 332 heart failure 439
revascularization 579 Tubercular pericarditis 505 Upper silesia in prussia 93
Transplanted heart 506 Tuberculosis 229, 296 Urokinase 7, 31
Transposition of great arteries 483, 498, 711, and atherosclerosis 333 pulmonary embolism trial 8, 45, 286
713 and heart 330 Use of tobacco 298
Transseptal puncture 645 and myocardium 332
and catheterization 650 and pericardium 330 V
Transthoracic echocardiography 562, 643 in heart transplant recipients 333
Trauma 283 of heart 330 Valsalva maneuver 448
Treadmill exercise Tuberculous pericarditis 331 two-dimensional stress echocardiography
testing 443 Tuberous sclerosis 399t, 401f 446
two-dimensional stress echocardiography complex 400 Valsartan
447 Tumor 400 antihypertensive long-term use
Treatment of markers 237 evaluation 65
acute myocardial infarction 683 necrosis factor 230 heart failure trial 65
cardiovascular diseases 103 Turner’s syndrome 399t in acute myocardial infarction trial 65, 165
coronary disease 597 T-wave alternans 340, 345t, 351 Value of electrocardiogram during sinus
high blood pressure 168 Two-dimensional rhythm 634
hypertension 164f and three-dimensional echocardiography Valve
obesity in early days 210 in non-coronary heart diseases diseases 238
wide-QRS tachycardia with 456 repair 78
irregular rhythm 635f echocardiography 414f, 417, 433, 559, 562, surgery 657
regular rhythm 635f 566, 569 Valvular
Trials of stress echocardiography 445 aortic stenosis 736
cardiac resynchronization therapy with cold pressor test 447 damage 238
with defibrillator 615 Type D pattern and heart disease 308 dysfunction 78
without defibrillator 614 Types of heart disease 456, 495, 535, 673
coronary artery bypass graft for left main ASD device used 629f lesions 499
revascularization 589f heart blocks 337 pulmonary stenosis 471
intensive statin therapy 52t ice catheters and transducers 643 regurgitation 497
statins with clinical endpoints 53t idiopathic ventricular tachycardia 633f stenosis 497
tenecteplase 720t Typical atrial flutter 607 vegetations 238
Valvuloplasty 471, 647 tachycardia 340, 521, 605, 608, 631, 632 Warn about dangers of tobacco 302f
Vascular and fibrillation 310 Wartime production rates 99
bleeding and hematoma 650 wall thickness and systolic function 507 Water-bottle heart 235
circular stapling apparatus 682 Verapamil 50, 104, 105, 117 Weight gain, salt and fluid retention 326
headaches 101 Veratrum alkaloids 163 Wells and rheumatism of heart 252
Vaso-depressor type 337 Vertical duct 470 West of Scotland coronary prevention study 52
Vasodilatation 16 Very Whipple’s disease 229, 230
Vasospastic angina 534 early days 15 Wide pulse-pressure 25t
Vaughan Williams antiarrhythmic classifica- low density lipoprotein 183 Wolff-Parkinson-White syndrome 354
tion 117t Vessel Women’s
Velocity vector imaging in two-dimensional in hyperhomocysteinemia 380 health
stress echocardiography 455 lesion on coronary angiography 517 initiative 327
Vena contracta 557, 559, 561 wall 148 study 132
width 567 Veterans ischemia syndrome 363
Venous administration cooperative surgery study Wood pulp 101
blood of intact kidney 318 589f Woolly hair 402f
ligation and inferior vena cava filters 286 heart failure trial II 213 World health organization 3, 77, 195
thromboembolism 283 Vierordt’s counter pressure 147 Worth of steroid hormones 262
Ventak-congestive heart failure 615 Vineberg operation 680
Ventilation perfusion scan 246, 285 Viral infection 229 X
Ventricular Virchow’s triad 283
assist devices 662 Viruses 229 Xanthine oxidase 323
assist devices biventricular 662 Visualization of aortic stenosis jet 422f Xylocaine 114
left 662 Vitamin
right 662 B1 323 Y
total artificial heart 662 B12 380
ectopy and NSVT 345t, 348 B6 380 Yphilitic carditis 76
fibrillation 153, 340, 605 intervention for stroke prevention 384 Yttrium aluminum garnet 579, 684
function 469 von Willebrand factor 108
hypertrophy 632 Z
septal defect 78, 467, 468t, 497, 712 W
device 469t Zeus system set-up 674f
septum 413, 418f Wall motion score index 447 Zinc 321
tachyarrhythmias 650 Walter reed army medical center 539 Zohman’s program 141

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Textbook of

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

Jaypee Brothers Medical Publishers (P) Ltd.

© 2013, Jaypee Brothers Medical Publishers

Inquiries for bulk sales may be solicited at: [email protected]

Textbook of Cardiology: A Clinical and Historical Perspective

First Edition : 2013

Evaluation of Acute Coronary Syndrome 89

Reducing the Burden of Cardiovascular Disease 163

Infective Endocarditis and Stroke 292

ARB and Diabetes 410

SECTION 2: NONINVASIVE CARDIOLOGY

Grading Pulmonic Stenosis 569

SECTION 3: INTERVENTIONAL CARDIOLOGY

SECTION 4: CARDIAC SURGERY

SECTION 5: FUTURE OF CARDIOLOGY

FUNDING OF HEALTH CARE PREVENTIVE PROGRAMS

Chopra HK, Sambi RS, Krishna CK

adsorb the fibrinogen and prevent the formation of a clot. However,

The Discovery of Streptokinase

Tissue Plasminogen Activator Tenecteplase

Chopra HK, Sambi RS, Krishna CK

The importance of early reperfusion therapy in reducing the

MEASURES OF EPICARDIAL REPERFUSION Resolution of ST Elevation in ECG

TABLE 3.1 TIMI-Grading system for coronary flow9

Combined Indicator for Reperfusion

Beta-Receptor Occupancy, Selectivity

Figure 4.2A: Agonist activity and the β-1 receptor

Figure 4.2B: Agonist activity and the β-2 receptor

TABLE 4.2 Some of the older β-blocker hemodynamic values

Figure 4.6: Effects of different β-blockers on airways function in labile asthmatics

TABLE 4.3 Beta-blocker distribution coefficients in octanol/water (high

TABLE 4.4 Pharmacokinetic profiles of some commonly used β-blockers

Relating to β-1 Blockade

All β-blockers on the market possess, to a greater or lesser extent,

Relating to β-2 Blockade

Peripheral Arterial Disease Thus, exercise/stress-induced supraventricular arrhythmias,

All this was to change in 2006 when [primarily as a result of two

TABLE 4.8 Placebo-controlled heart-failure trials involving β-blockers–effects on all-cause death

ders (antiplatelet agents, anticoagulants and thrombolytics) is rich in

making acetylsalicylic acid but, again, it was ignored. In 1860, Kolbe

In concert with the two accompanying papers, the paper of

TABLE 5.2 Primary prevention trials of aspirin

TABLE 5.4 Major clinical trials of glycoprotein IIb/IIIa inhibitors

TABLE 5.6 Brief history of warfarin

Hirudin and Its Analog

Manchanda SC, Makhija A, Sharma MK

acted via competitive inhibition of the enzyme HMG CoA reductase.

In 1991, pravastatin, derived by a biotransformation of compac-

Dose in severe renal 20 mg 10 mg 5 mg Dose unchanged Dose unchanged 5 mg

and serum transaminase levels should be measured in the first few

(hscRP)39 Revascularization Person/y vs 0.69)

4D (diabetes + 2005 Atorvastatin Placebo 1,255 4 72 120 41 All-cause 37 vs 38 0.92 (0.77-

TABLE 7.1 Angiotensin II receptors and their functions and location

Figure 7.3: Non angiotensin-converting enzyme (ACE) pathway

This development was laborious and expensive work and it is ap-

Figure 7.4: Discovery and development of angiotensin receptor blockers (ARBs)

(FDA) in October 2009 has approved a new indication for ARB-tel-

INTRODUCTION first water-soluble anticoagulant discovered.3 Neither Howell nor

was instrumental in demonstrating the possibility of the therapeu-