Current News in Cardiology

To my beloved wife Luisa
Someone said Love, pleasant folly,

I say Love, lunatic happiness...
True love doesnt know how to speak!
Michele M. Gulizia (Editor)
Current News
in Cardiology
Proceedings of the
Mediterranean Cardiology Meeting
(Taormina, May 20-22, 2007)
13
Michele M. Gulizia, MD
Chief of Cardiology Division
Garibaldi-Nesima Hospital
Catania, Italy
Library of Congress Control Number: 2007927712

ISBN 13: 978-88-470-0635-5 Springer Milan Berlin Heidelberg New York
e-ISBN 13: 978-88-470-0636-2
This work is subject to copyright. All rights are reserved, whether the whole or part of the
material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under
the provisions of the Italian Copyright Law in its current version, and permission for use
must always be obtained from Springer. Violations are liable to prosecution under the
Italian Copyright Law.
Springer is a part of Springer Science+Business Media

Springer-Verlag Italia 2007
Springer.com
The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general
use.
Product liability: The publisher cannot guarantee the accuracy of any information about
dosage and application contained in this book. In every individual case the user must
check such information by consulting the relevant literature.
Cover design: Simona Colombo, Milan, Italy
Typesetting: Graphostudio, Milan, Italy
Printing: Grafiche Porpora, Segrate, Italy
Printed in Italy
Springer-Verlag Italia S.r.l. Via Decembrio 28 I-20137 Milan
Preface
It is said that the true essence of the progress is the constant verification of
that which is certain.
Clinical practice is evolving at a rapid pace, nowhere more so than in the
field of cardiology.
Acute Coronary Syndromes, Sudden Cardiac Death, Heart Failure, Atrial
Fibrillation, Syncope, and Prevention of Global Cardiovascular Risk are the
main emerging pathologies, on which many investigators are focusing their
research. Less than 10 years ago, some of them were considered of relevance
only to internists, and some others as common benign arrhythmias or ineluctable illnesses. Today, their prevalence amongst the population represents a
major public health problem at the beginning of the third millennium.
The need for a state-of-the-art overview of the epidemiology, physiopathological and electrogenetic mechanisms, diagnosis, pharmacological or electrical treatment, prognosis, patient management in and out of hospital, organisational and economical implications of these emerging pathologies, and the
great success of the previous editions, inspired us to organise the third edition
of this biannual International Meeting, to give you the Current News in
Cardiology.
This book contains the Proceedings of the Mediterranean Cardiology
Meeting held in Taormina, Italy, 20-22 May 2007. Like the previous volumes, it
boasts the participation of many nationally and internationally renowned
speakers in the field of clinical and interventional cardiology who will interact
actively with delegates.
The exceptional novelty of this edition is that all participants to the
Meeting will receive a password for a free pdf download of all chapters of the
book, which can, be found on the website of the Mediterranean Cardiology
Meeting (www.mcmweb.it) via SpringerLink.
The book is divided into 8 sections, 11 sub-sections, and a total of 54 chapters, each devoted to a different topic: Atrial Fibrillation and Atrial Flutter;
Hear t Failure; Sy ncope; Sudden Cardiac Death; Cardiac Pacing;
Electrocardiography; Acute Coronary Syndromes; Global Cardiovascular Risk
Prevention.
VI
Preface
It aims to provide the latest information on the most recent and modern
aspects of the above mentioned pathologies. It is intended not only for cardiologists, but also for those who are actively interested in the evidence-based
approach to clinical care, such as internists, emergency and critical care clinicians, physicians of general medicine, fellows, students, nurses, and technicians. It may also be helpful for individuals engaged in the development and
coordination of research strategies in biological engineering, industry, and
regulatory affairs, who have a strong interest in the overall management of
these cardiac pathologies.
A Faculty selected from leading Italian and International experts ensures
the highest quality of this volume: the publications of many of them have contributed to the scientific progress in cardiology and influenced many of our
professional considerations and decisions. I am most indebted to all these
authors, who have devoted the invaluable time and effort without which this
book would not have been completed.
I also wish to thank the staff of Springer, and in particular Donatella Rizza,
Executive Editor, who has facilitated the publication of this book since the
first edition of the Mediterranean Cardiology Meeting, and who has kindly
assisted me throughout this project together with her staff member Eleonora.
Special and deep thanks are addressed to Rita Reggiani, professional, tireless,
and wonderful Project Leader of Adria Congrex, who has helped and supported me in achieving the best possible organisation of this International
Meeting, together with her staff members Silvana, Sara and Elisa.
I cannot forget to acknowledge the role of my two teachers, Antonio Circo
and Salvatore Mangiameli, who encouraged my passion for cardiology and
particularly for arrhythmology and clinical management.
In addition, I would like to thank my co-workers Cacia, Cardillo, Francese,
Mangiameli, Portale, Raciti, Ragusa, the chief of nursing Salpietro and the
entire staff of my Cardiology Division at the Garibaldi-Nesima Hospital of
Catania for their active collaboration and support during these years of work
and for the organisation of this Meeting.
Finally, a special mention goes to my dear wife Luisa, my daughters Alice
and Raffaella, and my parents Raffaele and Cettina. I am especially and deeply
grateful to them. Without their love and patience I could not have spent so
many nights and weekends preparing the Meeting and this volume.
Michele M. Gulizia
Table of Contents
ATRIAL FIBRILLATION AND ATRIAL FLUTTER

PHARMACOLOGICAL THERAPY
Anti-arrhythmic Drugs in Atrial Fibrillation: Historical Perspectives
and New Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Berndt Lderitz
Pill-in-the-Pocket Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Paolo Alboni
Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic Treatment . . . . . . . . . . 17
Gianluca Botto, Mario Luzi, Giovanni Russo, Barbara Mariconti
RADIOFREQUENCY ABLATION
Radiofrequency Ablation of Atrial Fibrillation and Atrial Flutter:
Who and When? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Josef Kautzner, Dan Wichterle
Cryocatheter Ablation for Atrial Flutter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Peter Andrew, Annibale Sandro Montenero
Clinical Profile, Electrophysiological Characteristics, and Outcome after
Radiofrequency Catheter Ablation of Atypical Atrial Flutter . . . . . . . . . . . . . . . 41
Golmehr Ashrafpoor, Amir-Ali Fassa, Henri Sunthorn, Haran Burri,
Pascale Gentil-Baron, Dipen Shah
The Impact of New Imaging, Mapping and Energy Delivery Technology
on the Current Approach to Ablation of Atrial Fibrillation . . . . . . . . . . . . . . . . 43
Andrea Colella, Marzia Giaccardi, Luigi Padeletti, Gian Franco Gensini
Trigger vs Substrate Ablation for the Treatment of Atrial Fibrillation . . . . . . . 49
Atul Verma
VIII
Table of Contents
Complications of Atrial Fibrillation Ablation: How To Prevent Them . . . . . . . 57

Giuseppe De Martino, Giovanna Rodio, Carmine Mancusi, Stefano De Vivo
PACING IN THE PREVENTION AND THERAPY OF ATRIAL ARRHYTHMIAS

Pacing in Atrial Fibrillation: Is It Still Viable? . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Oscar Oseroff, Gustavo Iralde, Enrique Retyk
Traditional or Device Approach for the Management of Atrial Fibrillation
in Patients with Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Aurelio Quesada, Mnica Gimnez, Victor Palanca, Javier Jimnez, Jos Roda
PRACTICAL ISSUES IN MANAGING ATRIAL FIBRILLATION PATIENTS

Conversion of Persistent Atrial Fibrillation to Sinus Rhythm by DC Shock:
Is It Still in Use Two Years After AFFIRM? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Valeria Calvi, Salvatore Timineri
Lone Atrial Fibrillation and Sports Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Francesco Furlanello, Giuseppe Inama, Claudio Pedrinazzi,
Luigi De Ambroggi, Riccardo Cappato
HEART FAILURE
Heart-Failure Management: Focus on Heart-Failure Practice Guidelines . . . . 101
Eugene Crystal, Rajneesh Calton
MANAGING PATIENTS WITH IMPLANTABLE CRT DEVICES FOR HEART FAILURE

Determination of Left Ventricular Contractile Reserve by Dobutamine
Stress Echocardiography To Predict the Response to CRT . . . . . . . . . . . . . . . . . 117
Carmine Muto, Bernardino Tuccillo
Focus on Optimization of Cardiac Resynchronization
Therapy Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Maurizio Lunati, Yann Poezevara, Andrea Boncompagni
Evaluation of the Clinical State of Cardiac Resynchronization Therapy
Patients by Continuous Heart-Failure Monitoring . . . . . . . . . . . . . . . . . . . . . . . 125
Henri Benkemoun, Bertrand Colombo, Jean Sacrez, Philippe Lagrange,
Philippe Cabrol, Gabriel Robert, Marc Moulichon
Table of Contents
IX
Predicting Heart Failure Events in CRT Patients: Future Challenges . . . . . . . . 129

Roberto Mantovan, Danilo Contardi, Vittorio Calzolari,
Martino Crosato, Zoran Olivari
Use of Fluid Accumulation Monitoring in HF Patients . . . . . . . . . . . . . . . . . . . . 137
Saverio Iacopino, Rossella Alemanni, Antonella Talerico,
Gennaro Fabiano, Sergio Canonaco, Francesco Borrello
SYNCOPE
DIAGNOSTIC EVALUATION OF PATIENTS WITH RECURRENT SYNCOPAL EPISODES
Performing Carotid Sinus Massage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Roberto Maggi, Michele Brignole
Performing Tilt Testing and Physical Countermaneuvers Training . . . . . . . . . 153
Giuseppina M. Francese, Michele M. Gulizia
Implanting a Loop Recorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Michele Brignole
SUDDEN DEATH
NONINVASIVE SUDDEN DEATH RISK STRATIFICATION
Noninvasive Sudden Death Risk Stratification: Heart Rate
Variability and Turbulence, and QT Dynamicity . . . . . . . . . . . . . . . . . . . . . . . . . 167
Antonio Vincenti, Stefano Pedretti
Noninvasive Risk Stratification of Sudden Death: T-Wave Alternans . . . . . . . . 179
Roberto F.E. Pedretti, Simona Sarzi Braga, Raffaella Vaninetti,
Antonio Laporta, Sergio Masnaghetti, Rossella Raimondo, Mario Salerno,
Francesco Santoro
Risk Stratification for Sudden Death in Hypertrophic Cardiomyopathy . . . . . 191
Domenico Catanzariti, Massimiliano Maines, Giuseppe Vergara
Managing Hypertrophic Cardiomyopathy: Screening in Young Subjects . . . . 197
Maurizio Santomauro on Behalf of the AIAC Task Force of Risk Management,
Gianluca Botto, Corrado Diaco, Michele M. Gulizia, Giuseppe Marceca,
Francesco Melandri, Franco Naccarella, Carla Riganti, Massimo Santini
Table of Contents
PHARMACOLOGICAL THERAPY
The Prevention of Sudden Death: New Perspectives . . . . . . . . . . . . . . . . . . . . . . 205
Savina Nodari, Marco Metra, Alessandra Manerba, Silvia Frattini,
Giuseppe Seresini, Livio Dei Cas
CURRENT NEWS IN PREVENTION OF SUDDEN DEATH BY IMPLANTABLE

CARDIAC DEFIBRILLATORS
Which Patient and when Should Receive an ICD? Evolving
New Indications on the Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Roberto Verlato, Maria Stella Baccillieri, Pietro Turrini
Implantable Cardiac Defibrillators: Is Defibrillation Threshold
Testing Still Necessary in all Patients? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Franco Naccarella, Fabio Iachetti, Angela Wang, Cristina Felicani,
Giovannina Lepera, Elvira Moccia, Leilei Sun, Luca Casari, Giorgio Morselli,
Patrizia Capogreco, Gerald Naccarelli
Current Practice in Italy of VF Testing at Implant:
What Do We Know and Where Do We Go From Here? . . . . . . . . . . . . . . . . . . . . 231
Michele Brignole, Giovanni Raciti, Maria Grazia Bongiorni,
Giuseppe De Martino, Stefano Favale, Maurizio Gasparini,
Raffaele Luise, Eraldo Occhetta, Alessandro Proclemer
How To Choose Between Single-Chamber and Dual-Chamber ICD . . . . . . . . 239
Maurizio Del Greco, Lorena Gramegna, Massimiliano Marini,
Marcello Disertori
Which Patients Should Receive Dual Defibrillators? Results of DATAS . . . . . . 245
Aurelio Quesada, Mnica Gimnez, Victor Palanca, Javier Jimnez,
Alfonso Valle, Jos Roda
Prevention of Sudden Death in Patients with Genetic Arrhythmias . . . . . . . . 255
Pietro Delise
Cost-Effectiveness of ICD Therapy in the Prevention of Sudden
Death in CAD and/or HF Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Andrea Pozzolini
Table of Contents
XI
CARDIAC PACING
HEMODYNAMIC ISSUES AND PRACTICAL APPLICATIONS IN CARDIAC PACING
Hemodynamic Impact of Right Ventricular Pacing . . . . . . . . . . . . . . . . . . . . . . 279
Ral Chirife, G. Aurora Ruiz, M. Cristina Tentori
Hemodynamics in Standard Cardiac Pacing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Milos Taborsky
Hemodynamic Assessment with an Implanted Pacing Device . . . . . . . . . . . . . 303
Maria Grazia Bongiorni, Ezio Soldati, Giuseppe Arena, Giulio Zucchelli,
Andrea Di Cori, Alberto Barbetta, Franco Di Gregorio
Hemodynamic Optimization of Pacing Configuration
in Bradyarrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Gianfilippo Neri, Rolando Zamprogno, Diego Vaccari,
Giuliano Masaro, Alberto Barbetta, Franco Di Gregorio
Applications of TVI Sensing in Cardiac Stimulation . . . . . . . . . . . . . . . . . . . . . 317
Eraldo Occhetta, Miriam Bortnik, Franco Di Gregorio,
Alberto Barbetta, Paolo Marino
The Ideal Pacemaker for Complete AV Block . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
I. Eli Ovsyshcher
The Ideal Pacemaker for Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Gulmira Kudaiberdieva, Bulent Gorenek
ELECTROCARDIOGRAPHY
WHAT IS NEW IN 12-LEAD ELECTROCARDIOGRAPHY?
Update on ACC/ESC Criteria for Acute ST Elevation
Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Peter W. Macfarlane
ECG-MRI based Localization of Myocardial Infarction . . . . . . . . . . . . . . . . . . . 347
Henrik Engblom, Olle Pahlm
XII
Table of Contents
Electrocardiographic Predictors of Arrhythmias In CCU Patients . . . . . . . . . . 355

Afshin Parspour, Alparslan Birdane, Bulent Gorenek
The Routine ECG as a Marker of Sudden Cardiac Death . . . . . . . . . . . . . . . . . . 365
Luigi De Ambroggi
ACUTE CORONARY SYNDROMES

International Guidelines on Acute Coronary Syndrome:
Practical Application and Current News in Cardiology . . . . . . . . . . . . . . . . . . . 375
Giacomo Chiarand, Giuseppa Strano, Angela Lazzaro, Marta Chiarand
Is There a Limit to PTCA in Elderly Patients? . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Francesco Bovenzi, Roberto Lorenzoni, Mauro Lazzari,
Andrea Boni, Cristina Gemignani
When Should Patients with Ischemic Mitral Regurgitation
Undergo Cardiac Surgery? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Scipione Carerj, Concetta Zito, Giuseppe Dattilo, Grazia Di Bella,
Carmelo Nipote, Annalisa Lamari, Rossella Garufi, Salvatore Micciulla,
Francesco Arrigo
Minimally Invasive Techniques in Cardiac Surgery:
An Opportunity for All Patients? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Leonardo Patan, Alfio Cavallaro
GLOBAL CARDIOVASCULAR RISK PREVENTION

Cardiovascular Risk Management: An Overview . . . . . . . . . . . . . . . . . . . . . . . . 407
Andrea Boni, Roberto Lorenzoni, Mauro Lazzari,
Cristina Gemignani, Francesco Bovenzi
Is Arterial Pressure Self-Measurement Better Than Ambulatory
24-Hour Pressure Monitoring? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
Carlo Fernandez
Role of Angiotensin-Receptor Blockers in the Prevention
of Cardiovascular Risk: Clinical Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Pasquale Perrone-Filardi, Pierluigi Costanzo, Antonio Marzano,
Paolo Cesarano, Paola Gargiulo, Enrico Vassallo, Caterina Marciano,
Teresa Losco, Massimo Chiariello
Table of Contents
XIII
New Evidence about the Beneficial Effects of Angiotensin-Receptor

Blockers on the Heart and the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Claudio Borghi, Marco Manca
Lercanidipine, Enalapril, and Their Combination in the Treatment
of Elderly Hypertensive Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Juan Garcia Puig, Carlos Calvo, Olavi Luurila, Harri Luurila,
Sakari Sulosaari, Arto Strandberg, Cristina Ghezzi
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
List of Contributors
ALBONI P., 11
ALEMANNI R., 137
ANDREW P., 29
ARENA G., 303
ARRIGO F., 391
ASHRAFPOOR G., 41
BACCILLIERI M.S., 215
BARBETTA A., 303, 309, 317
BENKEMOUN H., 125
BIRDANE A., 355
BONCOMPAGNI A., 119
BONGIORNI M.G., 231, 303
BONI A., 383, 407
BORGHI C., 433
BORRELLO F., 137
BORTNIK M., 317
BOTTO G., 17, 197
BOVENZI F., 383, 407
BRIGNOLE M., 145, 159, 231
BURRI H., 41
CABROL P., 125
CALTON R., 101
CALVI V., 87
CALVO C., 441
CALZOLARI V., 129
CANONACO S., 137
CAPOGRECO P., 221
CAPPATO R., 93
CARERJ S., 391
CASARI L., 221
CATANZARITI D., 191
CAVALLARO A., 395
CESARANO P., 425
CHIARAND G., 375
CHIARAND M., 375
CHIARIELLO M., 425

CHIRIFE R., 279
COLELLA A., 43
COLOMBO B., 125
CONTARDI D., 129
COSTANZO P., 425
CROSATO M., 129
CRYSTAL E., 101
DATTILO G., 391
DE AMBROGGI L., 93, 365
DE MARTINO G., 57, 231
DE VIVO S., 57
DEI CAS L., 205
DEL GRECO M., 239
DELISE P., 255
DI BELLA G., 391
DI CORI A., 303
DI GREGORIO F., 303, 309, 317
DIACO C., 197
DISERTORI M., 239
ENGBLOM H., 347
FABIANO G., 137
FASSA A-A., 41
FAVALE S., 231
FELICANI C., 221
FERNANDEZ C., 417
FRANCESE G.M., 153
FRATTINI S., 205
FURLANELLO F., 93
GARGIULO P., 425
GARUFI R., 391
GASPARINI M., 231
GEMIGNANI C., 383, 407
GENSINI G.F., 43
GENTIL-BARON P., 41
XVI
GHEZZI C., 441

GIACCARDI M., 43
GIMNEZ M., 75, 245
GORENEK B., 331, 355
GRAMEGNA L., 239
GULIZIA M.M., 153, 197
IACHETTI F., 221
IACOPINO S., 137
INAMA G., 93
IRALDE G., 63
JIMNEZ J., 75, 245
KAUTZNER J., 23
KUDAIBERDIEVA G., 331
LAGRANGE P., 125
LAMARI A., 391
LAPORTA A., 179
LAZZARI M., 383, 407
LAZZARO A., 375
LEPERA G., 221
LORENZONI R., 383, 407
LOSCO T., 425
LDERITZ B., 3
LUISE R., 231
LUNATI M., 119
LUURILA H., 441
LUURILA O., 441
LUZI M., 17
MACFARLANE P.W., 341
MAGGI R., 145
MAINES M., 191
MANCA M., 433
MANCUSI C., 57
MANERBA A., 205
MANTOVAN R., 129
MARCECA G., 197
MARCIANO C., 425
MARICONTI B., 17
MARINI M., 239
MARINO P., 317
MARZANO A., 425
MASARO G., 309
MASNAGHETTI S., 179
MELANDRI F., 197
METRA M., 205
MICCIULLA S., 391
MOCCIA E., 221

MONTENERO A.S., 29
MORSELLI G., 221
MOULICHON M., 125
MUTO C., 117
NACCARELLA F., 197, 221
NACCARELLI G., 221
NERI G., 309
NIPOTE C., 391
NODARI S., 205
OCCHETTA E., 231, 317
OLIVARI Z., 129
OSEROFF O., 63
OVSYSHCHER I.E, 325
PADELETTI L., 43
PAHLM O., 347
PALANCA V., 75, 245
PARSPOUR A., 355
PATAN L., 395
PEDRETTI R.F.E., 179
PEDRETTI S., 167
PEDRINAZZI C., 93
PERRONE-FILARDI P., 425
POEZEVARA Y., 119
POZZOLINI A., 263
PROCLEMER A., 231
PUIG J.G., 441
QUESADA A., 75, 245
RACITI G., 231
RAIMONDO R., 179
RETYK E., 63
RIGANTI C., 197
ROBERT G., 125
RODA J., 75, 245
RODIO G., 57
RUIZ G.A., 279
RUSSO G., 17
SACREZ J., 125
SALERNO M., 179
SANTINI M., 197
SANTOMAURO M., 197
SANTORO F., 179
SARZI BRAGA S., 179
SERESINI G., 205
SHAH D., 41
SOLDATI E., 303

STRANDBERG A., 441
STRANO G., 375
SULOSAARI S., 441
SUN L., 221
SUNTHORN H., 41
TABORSKY M., 293
TALERICO A., 137
TENTORI M.C., 279
TIMINERI S., 87
TUCCILLO B., 117
TURRINI P., 215
VACCARI D., 309
XVII
VALLE A., 245

VANINETTI R., 179
VASSALLO E., 425
VERGARA G., 191
VERLATO R., 215
VERMA A., 49
VINCENTI A., 167
WANG A., 221
WICHTERLE D., 23
ZAMPROGNO R., 309
ZITO C., 391
ZUCCHELLI G., 303
ATRIAL FIBRILLATION AND ATRIAL FLUTTER
Anti-arrhythmic Drugs in Atrial Fibrillation:

Historical Perspectives and New Developments
BERNDT LDERITZ
Introduction
The treatment of atrial fibrillation (AF) remains challenging in everyday
practice. Even with the introduction of catheter ablation, decision-making
about the type of therapy has become more complex. The recently published
guidelines of the American College of Cardiolog y, American Hear t
Association, and the European Society of Cardiology clearly show the therapeutic approaches for the different types of AF (Fig. 1).
Minimal Heart Disease

LVH, Hypertens. Heart Disease
No Heart Disease
Flecainide
Propafenone
Sotalol
Amiodarone
(Dofetilide)
Catheter
ablation
Fig. 1. From guidelines to individual treatment and maintenance of sinus rhythm.

Adapted from [1]. LVH, Left ventricular hypertrophy
Department of Medicine - Cardiology, University of Bonn, Bonn, Germany
Berndt Lderitz
The fear of thromboembolism in a patient compels the physician to

restore sinus rhythm and obtain perfect anticoagulation. Factors affecting
the overall management strategy of AF are the type and severity of AF, the
corresponding symptoms, associated cardiovascular disease, patients age,
associated medical conditions, and treatment options.
AF is the most frequently experienced cardiac arrhythmia, affecting an
estimated 2.2 million people in the USA, and approximately 6 million in
Europe. Approximately 1.2 million patients suffer from paroxysmal AF, and
about 1 million from persistent AF. The conversion rate from paroxysmal AF
to persistent AF is estimated to be 30% [2]. The prevalence of AF increases
with age [3], ranging from less than 1% at 5059 years to nearly 9% at 8089
years [4]. In addition to palpitations, patients with AF have an increased risk
of stroke and can develop decreased exercise tolerance and left ventricular
dysfunction [5]. All of these problems may be reversed by the restoration
and maintenance of sinus rhythm. Thus, the treatment of AF is warranted in
the hope of eliminating symptoms, preventing complications, and possibly
decreasing the excess mortality associated with this arrhythmia [6]. The primary intervention for maintaining sinus rhythm after restoration is use of
anti-arrhythmic drugs (Tables 1, 2).
However, many of the existing drugs have only limited efficacy and are
associated with considerable undesirable adverse effects. Current treatment
is therefore still suboptimal [7].
The features of an ideal anti-arrhythmic drug for the treatment of AF are:
namely effective suppression of symptoms, low incidence of pro-arrhythmia,
low incidence of side effects and drug interactions, good cardiac safety, effective rhythm control, ease to use, simple dosing regimen, ability to initiate in
an outpatient setting, and cost-effectiveness.
Table 1. Introduction of antiarrhythmic drugs: chronological overview

1918
Quinidine
1964
Propafenone
1936
Procainamide
1982
Flecainide
1948
Lidocaine
1982
Amiodarone
1950
Phenytoin
1994
Adenosine
1954
Disopyramide
1995
Ibutilide
1958
Ajmaline
1999
Dofetilide
1962
Beta receptor
blocking agents
Anti-arrhythmic Drugs in Atrial Fibrillation: Historical Perspectives and New Developments
Table 2. New class III antiarrhythmic drugs

Drug
Effect
Ibutilide
Blocks IKr
Azimilide
Blocks IKr
and IKs
Tedisamil
Blocks I
and ITo
Ersentilide
b-Blockade
Application
Indication
i.v.
Atrial fibrillation,
atrial flutter
i.v. and p.o.
atrial flutter,
SVT, VT/VF,
SCD-prophylaxis
(+)
i.v. and p.o.
Atrial fibrillation
Blocks IKr
and 1
i.v. and p.o.
Atrial fibrillation
atrial flutter,
SVT, VT/VF,
SCD-prophylaxis
Dofetilide
Blocks IKr
i.v. and p.o.
atrial flutter, SVT
Trecetilide
Similar to
Ibutilide
i.v. and p.o.
atrial flutter
i.v. and p.o.
atrial flutter,
VT, VT/VF,
SCD-prophylaxis
Dronedarone Multiple effects

like amiodarone
SVT, Supraventricular tachycardia; VT, ventricular tachycardia; VF, ventricular fibrillation; SCD, sudden cardiac death
Concerning pharmacological rate control, we recommend digitalis as the

first choice in patients with congestive heart failure; amiodarone can also be
considered. Beta-receptor blocking agents, e.g., Sotalol, provide first-line
treatment in ischemic heart disease. Class 1c drugs (propafenone, flecainide)
are very effective for rate control; however, they are contraindicated in
patients with structural heart disease. Calcium channel antagonists (verapamil, diltiazem) are first-line drugs in active patients and also in those with
congestive heart disease or lung disease. Amiodarone is the drug of choice in
patients with compromised left ventricular function. The pharmaceutical
management strategy or decision tree in paroxysmal AF (PAF) is shown in
Fig 2. If there is a first episode, observation is appropriate. If frequent
episodes of PAF are observed, asymptomatic PAF requires rate control. In
symptomatic PAF and structural heart disease, amiodarone is drug of first
choice. In those patients without structural heart disease, 1c anti-arrhythmic
drugs, such as propafenone or flecainide, are particularly suitable.
Berndt Lderitz
PAF
First Episode
Observe
Frequent PAF
Asymptomatic
Rate Control
Symptomatic
No Structural Heart
Disease
Structural Heart
Disease
1c AA
(Propafenone,
Flecainide)
Amiodarone
Fig. 2. Paroxysmal atrial fibrillation (PAF): pharmacological management
Rhythm Control or Rate Control and Anticoagulation

Clinical categorization relating to the quality of life of patients who present
with AF is a major determinant of the most appropriate strategy for rhythm
management. For patients with recurrent AF that has not become permanent, the two available strategies are: (1) rhythm control and anticoagulation, and (2) rate control and anticoagulation. Our knowledge about the efficacy and safety of various therapeutic strategies is insufficient, especially
with respect to the direct comparison of re-establishment of sinus rhythm by
drugs with rate control [8].
Which patients with AF will benefit from rhythm control? Patients with
intolerable symptoms due to AF; those with AF lasting longer than 1 year;
young, physically active individuals; patients suffering from paroxysmal AF;
those with good response to therapy; patients with significant left ventricular (LV) hypertrophy and LV dysfunction; those with left atrial diameter > 50
mm; and patients with contraindications to anticoagulation. In concise
terms, in a given patient, normal sinus rhythm is an appropriate goal if the
advantages of treatment (pharmacologically or electrically) outweigh the
disadvantages.
In AF patients, restoration and maintenance of sinus rhythm are the primary therapeutic goals. Once sinus rhythm is maintained, physiological rate
control is restored and LV ejection fractions, cardiac output, and exercise
capacity are increased. This improved cardiovascular performance enhances

the patients ability to perform the functions of normal daily life. Effective
treatment of AF is based on these objective criteria, but subjective criteria
such as quality of life are also important. Rigorous yet practical approaches
are needed to enable a comprehensive understanding of quality of life in
patients with AF [9]. For example, it has been shown that pharmaceutical
treatment can enhance quality of life in patients with AF [1]. The data are
shown in Table 3, in which the components of a health-related quality of life
(SF-36 categories) were assigned scores. Higher score indicates higher quality of life.
Table 3. Medical Therapy Estimates by scoring points of health-related quality of life
(SF-36 categories)
SF-36 category
Baseline
Medical therapy
Follow-up
Physical function
71 26
81 24
< 0.05
Physical role
54 41
65 38
< 0.05
Bodily pain
67 17
63 245
ns
General health
68 19
69 21
ns
Vitality
50 16
55 21
ns
Social function
68 24
78 26
< 0.01
Emotional role
74 40
78 36
ns
Mental health
69 15
73 19
< 0.05
ns, Not significant
Discussion
The pharmacological treatment of AF continues to challenge physicians in
everyday practice. Despite the introduction of catheter ablation, the choice of
the most appropriate therapy has become increasingly complex. Recently
published guidelines delineate the therapeutic approaches for different types
of AF. The need to avoid thromboembolism in an AF patient underlines the
physicians need to restore sinus rhythm and perform a perfect anticoagulation.
The history of anti-arrhythmic therapy of AF is long and fascinating.
Initially, not only the anatomy and physiology of the heart but also an analysis of the pulse, which indicates the electric and hemodynamic activity of the
Berndt Lderitz
heart, were important considerations. The analysis of the (peripheral) pulse

as a mechanical expression of heart activity goes back several millennia.
Digitalis, probably the oldest anti-arrhythmic agent, was discovered as a
cardiac active substance in the 16th century, by Leonhart Fuchs, and clinically introduced by William Withering, in Birmingham, England. Modern-day
anti-arrhythmic drugs came into use at a much later stage than the cardiac
glycosides. Quinidine, an optical isomer of quinine, became available as antiarrhythmic agent in 1918. Today, the most widely used anti-arrhythmic
drugs were developed in the 1960s and 1970s (e.g., disopyramide, beta-receptor blocking agents, propafenone, flecainide, amiodarone, adenosine, and
ibutilide). Candidate drugs for the treatment of AF include azimilide,
dofetilide, dronedarone, tedisamil, trecetilide, and ambasilide. Further nonpharmaceutical developments consist of radiofrequency ablation, atrioventricular defibrillators, and advanced anti-arrhythmic surgery. Advances in
the development of pharmacological and electrical tools as well as alternative strategies, including gene and cell therapy, will continue as rapidly as
before, thus equipping clinicians with a broad palette of possibilities with
which to care for their patients.
References
1.
2.
3.
4.
5.
6.
7.
Fuster V, Ryden LE, Cannom DS et al (2006) 2006 Guidelines for the Management
of Patients with Atrial Fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice Guidelines (Writing
Committee to Revise the 2001 Guidelines for the Management of Patients With
Atrial Fibrillation): developed in collaboration with the European Heart Rhythm
Association and the Heart Rhythm Society. Circulation 114:700752
Feinberg WM, Blackshear JL, Laupacis A et al (1995) Prevalence, age distribution,
and gender of patients with atrial fibrillation: analysis and implications. Arch
Intern Med 155:469473
Benjamin EJ, Levy D, Vaziri SM et al (1994) Independent risk factors for atrial
fibrillation in a population-based cohort: the Framingham Heart Study. JAMA
271:840844
Kannel WB, Wolf PA, Benjamin EJ et al (1998) Prevalence, incidence, prognosis,
and predisposing conditions for atrial fibrillation: population-based estimates. Am
J Cardiol 82:2N-9N
Krahn AD, Manfreda J, Tate RB et al (1995) The natural history of atrial fibrillation:
incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J
Cardiol 98:476484
Benjamin EJ, Wolf PA, DAgostino RB et al (1998) Impact of atrial fibrillation on
the risk of death: the Framingham Heart Study. Circulation 98:946952
Lderitz B, Jung W (2000) Quality of life in patients with atrial fibrillation. Arch
Intern Med 160:17491757

8.
9.
Wyse DG (2000) The AFFIRM trial: main trial and substudies what can we
expect? J Interv Card Electrophysiol 4:171176
Jung W, Lderitz B (1998) Quality of life in patients with atrial fibrillation. J
Cardiovasc Electrophysiol 9(Suppl 8):S177-S186
Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic

Treatment
GIANLUCA BOTTO, MARIO LUZI, GIOVANNI RUSSO, BARBARA MARICONTI
Introduction
Atrial fibrillation is a common arrhythmia and the cause of substantial morbidity [1, 2]. Management strategies for its control are far from satisfactory
[3]. Most importantly, whether by restoring sinus rhythm or by controlling
ventricular rate, arrhythmic strategies bring with them a proarrhythmic or
arrhythmogenic risk [4]. In such cases, the basic arrhythmia may be aggravated or new and more devastating arrhythmia may be produced.
The question of long-term anti-arrhythmic medication for the treatment
of lone atrial fibrillation often arises. In individuals with frequent recurrences of rapid and symptomatic atrial fibrillation, prophylactic therapy is
clearly indicated. In those with less frequent or asymptomatic recurrences
with controlled heart rate, the major concern becomes the risk of proarrhythmic events [2]. The risk of therapy must be balanced by the known
adverse effect of anti-arrhythmic medication and the benefit from its utilization.
Where to initiate anti-arrhythmic therapy is another important issue.
There are two major reasons to initiate drug therapy in-hospital: to observe
the effects of anti-arrhythmic agents on the arrhythmia being treated, and to
permit surveillance for adverse reaction to the drugs. However, the actual
risk of proarrhythmia in patients undergoing treatment for atrial fibrillation
is not yet well-defined [2].
Department of Cardiology, SantAnna Hospital, Como, Italy
18
Defining the Risk of Proarrhythmic Events

Most studies of ventricular proarrhythmia include patients undergoing
treatment for ventricular tachyarrhythmias [5], not supraventricular tachycardia. While most patients with ventricular arrhythmias have underlying
structural heart disease, this is not the case for many patients with supraventricular tachycardia. In a review of the literature of ventricular proarrhythmia in patients treated with anti-arrhythmic drugs for supraventricular
tachycardia, almost all cases occurred in patients with heart disease [6].
Thus, it is important to define more precisely which patients with
supraventricular tachycardia, undergoing treatment for maintaining sinus
rhythm, are at risk for proarrhythmia (particularly, ventricular proarrhythmia), and possibly sudden death.
Many of the studies assessing the proarrhythmic risk of anti-arrhythmic
drugs are related to the prophylactic indication of a specific drug [7]. The
assumption that proarrhythmia will occur during the initial day of therapy,
when it can be detected while the patient is still under surveillance, has not
been well-documented for different types of anti-arrhy thmic agents.
Nonetheless, in-hospital initiation of drug therapy would be unwarranted if
the time from initiation of treatment to proarrhythmic event took several
weeks or longer.
Types of Proarrhythmia
Proarrhythmia occurs with anti-arrhythmic drug therapy when the drug has
an adverse interaction with one or more types of cardiac tissue. The various
forms of proarrhythmia are reported in Table 1.
Ventricular proarrhythmia is far from being a rare event. Drugs that prolong repolarization can cause torsade de pointes, and drug-associated ven-
Table 1. Various forms of proarrhythmic events

Sinus node dysfunction with marked bradycardia
Increase in the frequency or duration of atrial arrhythmias
Slowing atrial tachycardia rate during drug therapy, facilitating rapid atrioventricular
conduction
Atrioventricular nodal or His-Purkinje block
Ventricular proarrhythmia
Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic Treatment
19
tricular fibrillation has been reported with most anti-arrhythmic agents,

regardless of their anti-arrhythmic action [8].
However, the type of ventricular proarrhythmia depends to some degree
on the anti-arrhythmic drug used. In a review of 51 papers in the literature,
quinidine was most commonly implicated, but this may be due in part to the
sole use of quinidine for many years [7].
Torsade de pointes is the most frequently reported proarrhythmic event,
probably for the above-mentioned reason. However, it has also been
observed during chronic treatment with drugs that block potassium channels, such as sotalol [9], or the relatively new class III anti-arrhythmic drugs
[10]. Ventricular hypertrophy appears to predispose to torsade de pointes,
favoring the development of early after-depolarization. For this reason, the
risk for ventricular arrhythmias is increased in patients with left ventricular
hypertrophy [11].
Torsade de pointes may occur as an idiosyncratic reaction at low, even
subtherapeutic plasma concentrations of drugs like quinidine [12]. For other
drugs, such as sotalol, the condition is related to drug dose, with an
increased incidence at doses > 320 mg per day [9].
There is little information regarding ventricular arrhythmia with class IC
drugs. Heart disease is present in most patients with ventricular proarrhythmia who are on flecainide treatment, and the proarrhythmic effect was
reported to occur most often during exercise [6].
The most common proarrhythmic effect during treatment with class IC
drugs is atrial flutter due to regularization of atrial waves together with a
slowing of tachycardia atrial rate. This facilitates atrioventricular nodal conduction, leading to a more rapid ventricular rate. An example is conversion
of atrial fibrillation to a relatively slow atrial flutter with the possibility of
1:1 atrioventricular conduction, particularly during adrenergic drive (e.g.,
during effort). This phenomenon is more frequent with flecainide than with
propafenone [13].
More than half of the proarrhythmic events that occur with drugs such as
quinidine, procainamide, or dysopiramide happen within the first 3 days of
therapy [6]. However, when the time from onset of therapy to the proarrhythmic event was documented for quinidine, the duration was within a few
weeks of treatment [6]. Torsade de pointes was observed to occur during the
first 3 days of treatment with sotalol, dofetilide, or ibutilide [10]. Atrial
proarrhythmic events occurring during acute administration of class IC
drugs to convert recent-onset atrial fibrillation were observed within 6 h
from the onset of therapy [13]. Proarrhythmia with amiodarone often occurs
during the first week of drug therapy, during the loading phase [14].
20
What Is the True Incidence of Proarrhythmia in Atrial Fibrillation?

Recently, a large prospective study comparing treatment strategies
(AFFIRM) designed to achieve either rate or rhythm control in patients with
atrial fibrillation demonstrated that patients randomized to the rhythm-control arm did not have lower all-cause mortality than those randomized to the
rate-control approach. There was a trend toward a higher death rate in the
rhythm-control arm [3]. In this study, the percentage of patients with lone
atrial fibrillation was fairly low (16%). A few years later, the AFFIRM investigators published a further study describing the cause-specific modes of
death in the main study with respect to treatment approach [15]. It was concluded that the excess mortality in the rhythm-control arm may have been
associated with an increased non-cardiovascular (pulmonary and cancer)
death rate instead of the more-expected increase in proarrhythmia-related
deaths. In the AFFIRM study, there were 3,030 exposures to anti-arrhythmic
drugs in 2,023 patients; in a 6-year follow-up 96 (3.16%) arrhythmic adverse
events were detected, w ith an annual incidence of 0.53% per year.
Furthermore, 12 episodes of torsade de pointes occurred, all of them related
to the use of class III drugs and/or to coexistent favorable factors
(hypokalemia, interaction with other drugs). The authors thus concluded
that the overall risk of adverse arrhythmic events upon exposure to antiarrhythmic drugs was reasonably low in the AFFIRM study [16].
Which Drugs Maintain Sinus Rhythm in Lone Atrial Fibrillation?

Very recently, the Italian Association of Arrhythmia and Cardiac Pacing
(AIAC) published its national guidelines on the treatment of patients with
atrial fibrillation, with particular attention given to patients with lone atrial
fibrillation [17].
In patients without structural heart disease there is a trend to prescribe
class 1C anti-arrhythmic drugs (propafenone or flecainide) or sotalol. These
agents appear to have similar efficacies with good long-term tolerance [18].
Amiodarone and quinidine are second-choice drugs in the treatment of this
subset of patients.
Unfortunately, restoration and maintenance of sinus rhythm are sometimes not possible or only attainable with high-dose medications. In these
circumstances radiofrequency ablation is becoming increasingly popular.
The use of radiofrequency energy is particularly safe and well-tolerated in
patients without structural heart disease and could become an alternative to
anti-arrhythmic drug administration [19].
Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic Treatment
21
Out-of-Hospital Administration of Anti-arrhythmic Drugs

Patients are hospitalized to receive anti-arrhythmic drug therapy for safety
reasons, typically to prevent proarrhythmic events. Thus, whenever in doubt,
in-patient initiation of therapy is acceptable. However, the low frequency of
proarrhythmia suggests that in-hospital initiation of therapy may not be
cost-effective [20]. Instead, there are data to support out-patient antiarrhythmic drug treatment in patients who have no or minimal ventricular
dysfunction.
In conclusion, the following strategies are recommended:
1. The first episode of atrial fibrillation or supraventricular tachycardia
must be treated in-hospital to observe the effects of any anti-arrhythmic
agents on the arrhythmia being treated, and to permit surveillance for
adverse reactions to the drug.
2. Patients must be treated in-hospital, when quinidine, dysopiramide, procainamide, sotalol, or new class III agents are prescribed. Observation
should be extended for at least 4872 h after initiation of the drug.
3. Amiodarone loading can be initiated out-of-hospital, even in patients
with structural heart disease; monitoring of multiple possible adverse
events related to drug administration is mandatory in the first 2 weeks of
drug loading.
4. Initiation of therapy with flecainide or propafenone should be discouraged in patients with structural heart disease, particularly when ischemic
heart disease or ventricular dysfunction is present.
5. Patients without structural heart disease, sinus node dysfunction, or atrioventricular conduction abnormalities who have a normal basal QTc
interval do not usually need to be hospitalized when treated with class IC
drugs.
References
1.
2.
3.
4.
Feinberg WM, Blackshear JL, Laupacis A et al (1995) Prevalence, age distribution,

and gender of patients with atrial fibrillation. Analysis and implications. Arch
Fuster V, Ryden LE, Cannom DS et al (2006) ACC/AHA/ESC 2006 guidelines for the
management of patients with atrial fibrillation. Circulation 114: e257-e354
Wyse DG, Waldo AL, DiMarco JP et al (2002) A comparison of rate control and
rhythm control in patients with atrial fibrillation. The Atrial Fibrillation Follow-up
Investigation of Rhythm Management (AFFIRM) Investigators. N Engl J Med
347:18251833
Falk RH (1992) Proarrhythmia in patients treated for atrial fibrillation. Ann Int
Med 117:141150
22
5.
The Cardiac Arrhy thmia Suppression Trial (CAST) Investigators (1989)

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med
321:406412
Prystowsky EN (1996) Proarrhythmia during treatment for supraventricular tachycardia: paradoxical risk of sinus rhythm for sudden death. Am J Cardiol 78:3541
Coplen SE, Antman EM, Berlin JA et al (1990) Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta analysis of randomized, controlled trial. Circulation 82:11061116
Minardo JD, Heger JJ, Miles WE et al (1988) Clinical characteristics of patients with
ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med
319:257262
Capucci A, Villani GQ, Aschieri D et al (1998) Effects of class III drugs on atrial
fibrillation. J Cardiovasc Electrophysiol 9:109120
Camm AJ, Yap YG (1999) What should we expect from the next generation of
antiarrhythmic drugs ? J Cardiovasc Electrophysiol 10:307317
Levy D, Anderson KM, Savage DD et al (1987) Risk of ventricular arrhyhtmia in left
ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 60:560565
Roden DM (1994) Risk and benefit of antiarrhyhtmic therapy. N Engl J Med
331:785791
Botto GL, Bonini W, Broffoni T et al (1994) Regular ventricular rhythms before
conversion of recent onset atrial fibrillation to sinus rhythm. Pacing Clin
Electrophysiol 11:21142117
Capucci A, Villani GQ, Aschieri D et al (2000) Oral amiodarone increase the efficacy of DC-cardioversion in restoration of sinus rhythm in patients with chronic
atrial fibrillation. Eur Heart J 21:6673
Steinberg JS, Sadaniantz A, Kron J et al (2004) Analysis of cause specific mortality
in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM)
study. Circulation 109:19731980
Kaufman ES, Zimmermann PA, Wang T et al (2004) Risk of proarrhythmic events
in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM)
study. J Am Coll Cardiol 44:12761282
Disertori M, Alboni P, Botto GL et al (2006) Linee guida AIAC 2006 sul trattamento
della fibrillazione atriale. Giornale Italiano di Aritmologia e Cardiostimolazione
9:171
Reimold SC, Cantrillon CO, Friedman PL et al (1993) Propafenone versus sotalol in
suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 71:558563
Cappato R, Calkins H, Chen SA et al (2005) Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation
111:11001105
Naccarelli GV, DellOrfano JT, Wolbrette DL et al (2000) Cost-effective management
of acute atrial fibrillation: role of rate control, spontaneous conversion, medical
and direct current cardioversion, transesophageal echocardiography, and anti
embolic therapy. Am J Cardiol 85:36D-45D
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Pill-in-the-Pocket Approach
PAOLO ALBONI
In the clinical setting, some patients with recurrent atrial fibrillation (AF)
present with episodes that are not frequent (< 1 per month) and are hemodynamically well-tolerated, but which are long enough to require emergency room (ER) intervention or hospitalization. These patients need treatment, but long-term oral prophylaxis or catheter ablation may not be the
most appropriate first-line therapy. Rather, in this group of patients the
pill-in-the-pocket approach, consisting of a single-dose oral ingestion of
an anti-arrhythmic agent at the time and place of palpitation onset, may
offer a more appropriate treatment strategy. The pill-in-the-pocket has
already been investigated in studies carried out in hospital, in patients with
recent-onset AF. The oral drugs that have been used to convert recent-onset
AF to sinus rhythm are class IA, class IC, and class III anti-arrhythmic
agents [17]. The class IC agents flecainide and propafenone have the
advantage of being conveniently administered in a single oral dose that
acts rapidly and causes minimal side effects [1, 6, 816]. The efficacy of a
single oral loading dose of flecainide and propafenone in converting
recent-onset AF to sinus rhythm has been documented by several placebocontrolled trials [1, 6, 8, 9, 11, 13, 16]. The two drugs showed similar efficacy, and their success rate varied from 58 to 95% [1, 6, 813], depending on
the duration of AF and the observation period after drug administration.
In all controlled studies, a low incidence of adverse effects has been reported [16, 813, 15, 16], the most of which is the appearance of a transient
atrial flutter with high ventricular rate owing to 1:1 atrioventricular (AV)
conduction (in about 1% of patients).
Division of Cardiology and Arrhythmologic Center, Ospedale Civile, Cento (FE), Italy
12
Paolo Alboni
Very recently, out-of-hospital treatment with the pill-in-the-pocket

approach was investigated in an Italian multicenter study [17]. Inclusion criteria were as follows: (1) patients between the ages of 18 and 75 years requiring ER intervention for recent onset (< 48 h) AF; (2) a history of palpitation
with abrupt onset but hemodynamically well-tolerated (absence of symptoms such as dyspnea, presyncope, or syncope); (3) number of episodes in
the last year < 1 per month; (4) absence of cardiologic symptoms apart from
the arrhythmic episodes. Patients with contraindications to class IC agents
were excluded. The patients could be treated either in the ER or in the cardiology ward. For AF conversion, oral propafenone and flecainide were administered in a single dose according to the weight of the patient: flecainide 300
mg for patients weighing 70 kg, or 200 mg otherwise; propafenone, 600 mg
for patients weighing 70 kg, or 450 mg otherwise. Treatment was considered successful if the conversion time to sinus rhythm was < 6 h after drug
administration, without severe side effects.
An in-hospital oral loading dose of flecainide and propafenone was
administered to 268 patients with recent-onset AF. Of these, 58 were excluded from the out-of-hospital treatment: in three (1%), findings included in the
exclusion criteria emerged during echocardiographic recording, in 41 (14%)
the drug was not effective in restoring sinus rhythm within 6 h, and in 14
(6%) the drug induced side effects (transient hypotension in four, atrial flutter in seven, including one with 1:1 AV conduction, and slightly symptomatic
bradycardia in three). The remaining 210 patients (age 59 11 years) were
discharged on flecainide or propafenone for pill-in-the-pocket treatment of
recurrent AF. Of these, 118 had no signs of heart disease and the remaining
92 (43%) had mild heart disease. The mean follow-up was 15 5 months;
four patients were lost just after enrollment. Of the remaining 206 patients,
41 (20%) did not experience any arrhythmic recurrences during the followup period and 165 reported 618 episodes of palpitation with abrupt onset,
569 of which were treated with flecainide (64 patients) or propafenone (101
patients). The drug was effective in 534 out of 569 arrhythmic episodes
(94%). Similar results on the efficacy of class IC drugs were recently reported
by Capucci et al. [16], who investigated in hospital the reproducibility of efficacy of an oral loading dose of propafenone in restoring sinus rhythm in
patients with recurrent AF. Efficacy was evaluated by electrocardiographic
monitoring and was reproducible in 93% of the patients. In the Italian multicenter study, time to symptom resolution after drug ingestion was 113 84
min (median 98). Sixteen arrhythmic episodes were interrupted in a time > 6
h without the patients contacting the ER. Twenty-six episodes (5%) required
ER intervention, ten of which (2%) resulted in hospitalization. Out of the 618
13
episodes, 49 were not treated, mainly because of drug unavailability and five
(10%) of these required ER intervention. Therefore, during the follow-up
period, there were 31 (5%) ER contacts among the treated and untreated
arrhythmic episodes, ten of which led to hospitalization. Out of the 31 calls
for ER intervention, 19 were due to AF lasting > 6 h, one to acceleration of
heart rate after drug ingestion (atrial flutter with 1:1 AV conduction), and 11
to anxiety (request for ER intervention although palpitation had ceased).
During follow-up, the number of calls for ER intervention per month was
significantly lower than in the year before the target episode (4.9 vs. 45.6, p <
0.001). Even the number of hospitalizations per month during the follow-up
period was significantly lower (1.6 vs. 15, p < 0.001). Adverse effects during
one or more arrhythmic episodes were reported in 12 out of the 165 patients
(7%) who used the drug during follow-up. One (0.7%) felt a marked acceleration of heart rate after drug ingestion and contacted the ER; electrocardiogram showed atrial flutter with 1:1 AV conduction. This implies that successful in-hospital treatment does not completely prevent the appearance of atrial flutter at a high rate during follow-up. The remaining 11 patients reported
non-cardiac side effects, such as nausea, asthenia, or vertigo.
These results show that out-of-hospital treatment of recurrent AF with
the pill-in-the-pocket approach is feasible and safe, in view of the high rate
of patient compliance and the very low incidence of adverse effects. Data
from the Italian study show that the pill-in-the-pocket strategy with flecainide or propafenone is effective in treating over 90% of arrhythmic
episodes, after patient selection on clinical grounds and on the basis of the
results of in-hospital treatment. Episodic treatment minimizes the need for
ER and hospital admission during the acute event. It is noteworthy that
about one-third of ER contacts were due to anxiety. Therefore, psychological
management of these patients (particularly reassurance) may further reduce
calls for ER intervention. The marked reduction in ER and hospital admissions, in addition to the avoidance of prophylactic treatment, will help to
reduce the economic impact of AF, although in a rather small group of
patients with this tachyarrhythmia. The safety of this approach without previous evaluation of in-hospital treatment remains to be investigated; therefore, at present, oral flecainide or propafenone must be tested once in hospital before it can be prescribed for the out-of-hospital treatment.
Contraindications to class IC drugs must always be considered. If the
patient is treated over the long-term with anti-arrhythmic drugs, the loading
dose of flecainide or propafenone cannot be used, but if the patient appears
suitable for pill-in-the-pocket treatment, long-term therapy can be suspended and the loading dose administered during the next AF relapse.
Paolo Alboni
14
Atrioventricular nodal blockers (beta-blockers, verapamil, diltiazem) for the

treatment of hypertension or other diseases can be chronically administered.
Before discharge, patients should receive the following recommendations:
They must take the drug 510 min after any subsequent onset of typical palpitation; after ingestion of the drug, the patient should rest (supine or sitting
position) until the palpitation has stopped or for at least 4 h have passed; the
patient must contact the ER if palpitation has not ceased 8 h after ingestion
of the drug, if he/she has symptoms that have not occurred during previous
arrhythmic episodes (e.g., dyspnea, presyncope, or syncope) or if he/she
senses a marked increase in heart rate after ingestion of the drug; the patient
must not take more than one oral dose during a 24-h period; the patient
must not self-reduce the prescribed dosage of the drug. The practical management of patients suitable for out-of-hospital treatment with the pill-inthe-pocket approach is summarized in Fig. 1. In the recent ACC/AHA/ESC
guidelines for the management of patients with AF, this form of treatment is
a class IIA recommendation [18].
Patients with mild heart disease or none, requiring emergency room (ER) intervention for an
episode of recent onset (< 48 h) atrial fibrillation (AF), with a history of palpitations with an
abrupt onset, seldom ( 1 per month), hemodynamically well-tolerated but long enough to
require hospital intervention, in the absence of contraindications to class IC drugs after
clinical and electrocardiographic evaluation
In-hospital treatment (ER or ward) with a loading dose of flecainide (300 mg or 200 mg if
body weight < 70 kg) or propafenone (600 mg or 450 if body weight < 70 kg)
If successful AF interruption within < 6 h, without severe side effects, an echocardiogram and
laboratory tests (thyroid hormones, creatinine, transaminases, potassium) must be requested
If contraindications do not emerge, the drug used in hospital, can be prescribed

at the same dose for out-of-hospital interruption of AF episodes
Fig. 1. Practical management of patients suitable for the pill-in-the-pocket approach

to treating atrial fibrillation
15
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Villani GQ, Rosi A, Piepoli M et al (1990) The efficacy of oral treatment with flecainide for paroxysmal atrial fibrillation: correlation with plasma concentration. G
Ital Cardiol 20:564568
Capucci A, Lenzi T, Boriani G et al (1992) Effectiveness of loading oral flecainide
for converting recent-onset atrial fibrillation to sinus rhythm in patients without
organic heart disease or with only systemic hypertension. Am J Cardiol 70:6972
Botto GL, Bonini W, Broffoni T et al (1994) Regular ventricular rhythms before
conversion of recent onset atrial fibrillation to sinus rhythm. Pacing Clin
Capucci A, Boriani G, Botto GL et al (1994) Conversion of recent onset atrial fibrillation by a single oral loading dose of propafenone or flecainide. Am J Cardiol
74:503505
Capucci A, Boriani G, Rubino I et al (1994) A controlled study on oral propafenone
versus digoxin plus quinidine in converting recent-onset atrial fibrillation to sinus
rhythm. Int J Cardiol 43:305313
Boriani G, Capucci A, Lenzi T et al (1995) Propafenone for conversion of recentonset atrial fibrillation; a controlled comparison between oral loading dose and
intravenous administration. Chest 108:355358
Halinen MO, Huttunen M, Paakkinen S et al (1995) Comparison of sotalol with
digoxin-quinidine for conversion of acute atrial fibrillation to sinus rhythm (the
sotalol-digoxin-quinidine trial). Am J Cardiol 76:495498
Botto GL, Bonini W, Broffoni T et al (1996) Conversion of recent onset atrial fibrillation with single oral dose of propafenone: is in-hospital admission absolutely
necessary? Pacing Clin Electrophysiol 19:19391943
Azpitarte J, Alvarez M, Baun O et al (1997) Value of single oral loading dose of propafenone in converting recent onset atrial fibrillation: results of a randomized,
double-blind, controlled study. Eur Heart J 18:16491654
Boriani G, Biffi M, Capucci A et al (1997) Oral propafenone to convert recent-onset
atrial fibrillation in patients with and without underlying heart disease: a randomized, controlled trial. Ann Intern Med 126:621625
Botto GL, Capucci A, Bonini W et al (1997) Conversion of recent onset atrial fibrillation to sinus rhythm using a single loading oral dose of propafenone: comparison of two regimens. Int J Cardiol 58:5561
Botto GL, Bonini W, Broffoni T et al (1998) A randomized, crossover, controlled
comparison of oral loading versus intravenous infusion of propafenone in recentonset atrial fibrillation. Pacing Clin Electrophysiol 21:240244
Blanc JJ, Voinov C, Maarek M for the PARSIFAL Study Group (1999) Comparison of
oral loading dose of propafenone and amiodarone for converting recent-onset
atrial fibrillation. Am J Cardiol 84:10291032
Kishikawa T, Maruyoma T, Kaji Y et al (1999) Effects of oral disopyramide on
acute-onset atrial fibrillation with concurrent monitoring of serum drug concentration. Int J Cardiol 68:5762
Khan IA (2001) Single oral loading dose of propafenone for pharmacological cardioversion of recent onset atrial fibrillation. J Am Coll Cardiol 37:542547
Capucci A, Villani GQ, Piepoli MF (2003) Reproducible efficacy of loading oral propafenone in restoring sinus rhythm in patients with paroxysmal atrial fibrillation.
Am J Cardiol 92:13451347
16
Paolo Alboni
17.
Alboni P, Botto GL, Baldi N et al (2004) Outpatient treatment of recent-onset atrial

fibrillation with the pill-in-the-pocket approach. N Engl J Med 351:23842391
ACC/AHA/ESC (2006) Guidelines for the management of patients with atrial fibrillation Executive summary : a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice Guidelines (Writing
Atrial Fibrillation). J Am Coll Cardiol 48:854906
18.
Clinical Profile, Electrophysiological Characteristics, and

Outcome after Radiofrequency Catheter Ablation of Atypical
Atrial Flutter
GOLMEHR ASHRAFPOOR, AMIR-ALI FASSA, HENRI SUNTHORN, HARAN BURRI,
PASCALE GENTIL-BARON, DIPEN SHAH
Although radiofrequency (RF) catheter ablation is well accepted as the treatment of choice for typical atrial flutter, there is limited experience with its
use in the treatment of atypical atrial flutter (AAF).
A study at our institution consisted of patients who underwent RF
catheter ablation for an AAF pattern on the electrocardiogram between 2002
and 2006. Conventional and electroanatomic mapping were performed in
most cases (90%). The ablation strategy involved delineation of the individual circuit, followed by ablation of the narrowest isthmus(es). Procedural
success was defined as arrhythmia termination during RF delivery.
The 58 patients (67% males, mean age 57 14 years) included in the
study underwent 70 RF catheter ablation procedures (12 patients underwent
a single repeat intervention) for 109 AAF types. A high proportion of
patients had a history of atrial fibrillation (57%), stroke (16%), cardiac
surgery (47%), previous RF catheter ablation (57%), and pulmonary-vein
isolation (41%). Mean cycle length was 282 58 ms. The reentrant circuit
was located in the left atrium in 43 patients (74%) and in the right atrium in
13 patients (22%). In two patients (3%), a circuit dependent on both atria
was identified. A pseudo-AAF (cavotricuspid isthmus dependent) was found
in four patients (7%). The mean number of RF lesions was 28 25.
Fluoroscopic and procedure duration times were, respectively, 45 19 and
185 67 min. Success was achieved in 80% of the procedures, and in 79% of
the patients after 1.2 procedures. Complications occurred during four procedures (6%): regressive stroke (1%), heart block requiring pacemaker implantation (1%), and local bleeding requiring intervention (1%). There were no
fatalities.
Geneva University Hospitals, Geneva, Switzerland
42
Golmehr Ashrafpoor, Amir-Ali Fassa, Henri Sunthorn,Haran Burri, Pascale Gentil-Baron, Dipen Shah
The results indicated that patients with AAF usually have a complex substrate, characterized by significant heart disease, previous cardiac surgery, or
catheter ablation. This results in a wide and variable range of reentrant circuits. Despite this complexity, an individualized strategy of catheter ablation
for AAF is a safe and effective treatment in a majority of patients.
Suggested Reading
1.
2.
3.
Shah DC, Jais P, Haissaguerre M et al (2000) Dual loop intra-atrial reentry in man.
Circulation 101 (6):631639
Jais P, Shah DC, Haissaguerre M et al (2000) Mapping and ablation of left atrial
flutters. Circulation 101(25):29282934
Shah DC, Sunthorn H, Burri H et al (2006) Narrow, slow-conducting isthmus
dependent reentry developing after ablation for atrial fibrillation: ECG characterisation and elimination by focal ablation. J Cardiovasc Electrophysiol 17:508515
Complications of Atrial Fibrillation Ablation:

How To Prevent Them
GIUSEPPE DE MARTINO1, GIOVANNA RODIO2, CARMINE MANCUSI1, STEFANO DE VIVO3
Introduction
In recent years, increasing surgical experience in high-volume centers,
greater consistency in surgical technique, and the support of sophisticated
electromedical navigation tools have increased the success treatment of atrial fibrillation ablation to 80% after the first procedure and to > 90% after the
second procedure. Moreover, these results are associated with a progressive
decrease in the incidence of complications. According to the data in Table 1,
taken from a study published in 20032004 [1], major complications associated with the ablation of all pulmonary veins outside the tubular segment
occurred in 2.9% of cases, as reported by the six leading centers that have
adopted this approach. This compares favorably with the 5.9% reported in a
worldwide survey of such procedures performed between 1995 and 2002 [2].
Table 1. Complication rates compiled from 1,033 patients
Events (n) Rate (%) Range in studies (%)
Transient ischemic attack
0.4
03
Permanent stroke
0.1
01
Severe PV stenosis (> 70%, symptomatic)
0.3
03
Moderate PV stenosis (4070%, asymptomatic) 13
1.3
05
Tamponade/perforation
0.5
03
Severe vascular access complication
0.3
04
1Arrhythmology and Decompensation Division, Santa Maria Hospital, Bari; 2Cardiology

Division, Altamura Hospital, Altamura (BA); 3Cardiology Division, Monaldi Hospital,
Naples, Italy
58
Cerebrovascular Events
The prevalence of permanent stroke and of transient ischemic attack is,
respectively, 0.1 and 0.4%. The main cause is embolism from thrombus mobilization. Common sites of thrombus formation are the left atrial appendage,
adjacent to the catheter tip and, in most cases, at the transseptal sheath.
Prevention includes: (1) pre-ablation visualization of a thrombus in the left
atrial appendage by transesophageal electrocardiography (TEE); (2) avoidance of thrombus formation on the ablation catheter by using irrigated-tip
catheters and intracardiac echocardiography imaging (ICE) of the amount of
micro-bubble formation, which allows titration of the radiofrequency (RF)
energy output; (3) avoidance of thrombus formation at the transseptal sheath
by high-flow perfusion (180 ml/h) and by pulling back the sheath in the right
atrium; (4) aggressive anticoagulation to obtain an ACT > 300 s.
Pulmonary Vein Stenosis

The prevalence of this complication, which manifests within the first 6
months after ablation, is rapidly decreasing and was estimated at around 1.6
0.3% in a recent survey [1]. Severe (> 70%) and symptomatic stenosis
occurs in 0.3% of patients, and mild to moderate and asymptomatic stenosis
in 1.3% of patients. The significant reduction in the incidence was obtained
by adopting the technique of ablation outside the pulmonary veins, reducing
the radiofrequency energy output, and by using ICE and electromedical navigation tools.
Stenosis of one pulmonary vein is frequently asymptomatic. Severe
stenosis of more than one pulmonary vein may manifest as exertional dyspnea or, less frequently, dyspnea at rest, pleuritic-type chest pain, cough, and
hemophthisis. Chest X-ray may reveal parenchymal consolidation and pleural effusion, which are not diagnostic. An increased pulmonary flow velocity,
detected by TEE, reinforces the diagnostic suspicion. Direct diagnosis may
be obtained by spiral computed tomography (CT) scanning, magnetic resonance imaging (MRI), ICE, or pulmonary-vein angiography. Percutaneous
angioplasty is a proven and effective treatment of this currently very rare
complication.
Cardiac Tamponade
The latest data from high-volume laboratories report the occurrence of this
serious complication in < 0.51% of patients [1, 3]. Cardiac tamponade must
Complications of Atrial Fibrillation Ablation: How To Prevent Them
59
be immediately diagnosed when arterial hypotension (< 90 mmHg) occurs,

as visualized by motionless cardiac borders on fluoroscopy or by the presence of pericardial fluid on echocardiography. Percutaneous drainage is successful in most patients; rarely, surgical drainage is needed.
Tamponade occurs mostly because of tissue boiling and subsequent
endocardial rupture (associated with a typical popping noise), due to excessive RF power and a high catheter-tip temperature during linear ablation of
the atrial wall, especially if the tip is positioned perpendicular to the wall. In
a minority of patients, mechanical perforation is responsible for this complication.
Prevention is mainly based on the use of externally irrigated tip catheters
and by reducing the delivered power to 30 W or, certainly, to 40 W, which
minimizes the risk of popping. The power reduction often implies an
increased duration of RF delivery especially during mitral isthmus ablation.
The risk of mechanical perforation has been addressed by the use of non-fluoroscopic three-dimensional mapping systems, which enable better visualization of the atrial chambers and thus facilitate catheter manipulation. ICE
is another option for obtaining the same information to appropriately guide
the catheter.
Severe Vascular-Access Complications

These are mainly femoral pseudoaneurysm and arteriovenous fistula. The
prevalence is 0.3% in patients treated in high-volume centers and it correlates inversely with surgical skill level.
Two complications not listed in Table 1 are atrioesophageal fistula and
diaphragmatic paralysis from phrenic nerve injury (PNI). While both are
currently very rare, they are clinically relevant because the first is almost
always fatal and in the second there is a possibility of permanent impairment
of respiratory function.
Atrioesophageal Fistula
Although very infrequent, atrioesophageal fistula is the more devastating
complication and is almost always fatal. This was confirmed in a recent
series obtained from leading high-volume centers (0.05%) [4].
The occurrence of atrioesophageal fistula depends on the variable and
sometimes minimal distance (< 5 mm) between the esophagus and the posterior wall of the left atrium. Surgical intervention is the only effective treat-
60
ment; early diagnosis is mandatory and the condition must be suspected as

soon as a clinical picture of endocarditis following ablation develops. Others
symptoms include dysphagia, gastrointestinal bleeding, and neurological or
cardiac symptoms related to ischemia from embolism. The final picture is
that of cardiogenic shock. Among the diagnostic procedures, TEE and
esophagoscopy must be avoided because of the danger of aggravating the
lesion. Noninvasive imaging, such as MRI, transthoracic echocardiography
(TTE), and thoracic CT scan with water-soluble contrast, are the most useful
diagnostic tools.
Prevention is based on the following techniques: (1) ICE [5] allows detection of both the amount of echogenicity changes and accelerated bubble formation at the ablated site, indicating rapid development of a lesion and possible wall necrosis. These changes indicate the necessity to reduce the power
( 50 W) and RF duration ( 20 s). (2) CT-based and electroanatomic
CARTO-derived imaging [6] give a more-defined visualization of the
anatomical relationships between the esophagus and posterior wall of the
left atrium. When used in association with imaging fusion software, they
allow navigation with the ablation catheter according to a map in which both
structures are simultaneously displayed. However, since the esophagus is a
mobile structure that can readily migrate in the time interval between CT
acquisition and the ablation time or during the ablation procedure, these static images may be of limited value. (3) Electroanatomic reconstruction
obtained with the NavX system [7, 8] is an easy and accurate approach for
visualizing the left atrium and esophagus, and it overcomes some of the limitations of the previously described method. The course and relationship of
the two structures are recorded and displayed in real time, so that even modest movements of the esophagus due to the mechanical pressure of the ablation catheter may be detected.
Phrenic Nerve Injury

The currently reported prevalence of PNI is 0.110.48% [9]; however, it may
be asymptomatic in around one-third of patients. The main symptom is dyspnea; other symptoms include cough or hiccup. The diagnosis is made on
chest X-ray, which shows hemidiaphragmatic paresis or paralysis with paradoxical movement. The outcome is often favorable, with complete or partial
recovery after 7 7 months, but some patients fail to recover. Pulmonary
rehabilitation may play a role in improving recovery. In rare cases, surgical
diaphragmatic plication has been performed.
Complications of Atrial Fibrillation Ablation: How To Prevent Them
61
PNI is related to the close proximity of the right phrenic nerve to the postero-septal part of the superior vena cava and to the antero-inferior part of
the right superior pulmonary vein and of the left phrenic nerve to the left
atrial appendage roof. The risk at these critical areas is independent of the
type of ablation catheter or energy source employed.
To reduce the risk at these critical areas, high-output pacing should be
done before the ablation procedure is started and, in the case of diaphragmatic stimulation, energy application should be avoided. Early diagnosis of
PNI during RF application, suggested by cough, hiccup, or a reduction of the
diaphragmatic excursion, necessitates immediate interruption of energy
delivery.
Case reports describe the possible complications as including transient
paralysis of the vocal cords from recurrent laryngeal nerve injury, pyloric
spasm and gastric hypomotility, and vasospastic angina.
References
1. Verma A, Natale A (2005) Should atrial fibrillation ablation be considered first-line
therapy for some patients? Why atrial fibrillation ablation would be considered
first-line therapy for some patients. Circulation 112:12141231
2. Cappato R, Calkins H, Chen SA et al (2005) Worldwide survey on the methods, efficacy and safety of catheter ablation for human atrial fibrillation. Circulation
111:11001105
3. Hsu LF, Jais P, Hocini M et al (2005) Incidence and prevention of cardiac tamponade complicating ablation for atrial fibrillation. Pacing Clin Electrophysiol 28(Suppl
1):S106-S109
4. Pappone C, Oral H, Santinelli V et al (2004) Atrio esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation
109:27242726
5. Ren JF, Lin D, Marchlinski FE et al (2006) Esophageal imaging and strategies for
avoiding injury during left atrial ablation for atrial fibrillation. Heart Rhythm
3:11561161
6. Good E, Oral H, Lemola K et al (2005) Movement of the esophagus during left
atrial ablation for atrial fibrillation. J Am Coll Cardiol 46:21072110
7. Packer DL (2005) Three dimensional mapping in interventional electrophysiology:
techniques and technology. J Cardiovasc Electrophysiol 16:11101116
8. De Martino G, Capuano N, Mennella S et al (2006) Real-time electroanatomical
visualization of the esophagus during pulmonary vein ablation. Europace 8(Suppl
1):131
9. Sacher F, Jais P, Stephenson K et al (2007) Phrenic nerve injury after catheter ablation of atrial fibrillation. Indian Pacing Electrophysiol J 7:16
Cryocatheter Ablation for Atrial Flutter

PETER ANDREW1, ANNIBALE SANDRO MONTENERO2
Overview of Atrial Flutter

Atrial flutter (AFl), a common supraventricular tachyarrhythmia (SVT),
results in the atria beating up to five times faster than normal, i.e., 240 to 400
beats per minute [1]. A 2:1 relation between atrial and ventricular contractions is typically observed by electrocardiogram (ECG) [2], and under these
conditions of accelerated and mismatched contractile activity of the heart
chambers there is ineffective pumping of blood to the systemic circulation.
While AFl is usually a non life-threatening arrhythmia, it can be a chronic,
life-long condition that is episodic and transient. It can cause hypotension,
impair cardiac output, exacerbate pulmonary congestion, initiate myocardial
ischemia, and in rare cases may lead to a tachycardia-mediated cardiomyopathy [2]. Symptoms commonly experienced by individuals with AFl include
palpitations, dizziness, chest tightness, shortness of breath, and fatigue.
However, some individuals are asymptomatic.
Management of Patients with AFl

Essentially, the treatment of AFl involves treating the fast heart rate, converting to or maintaining normal sinus rhythm, and reducing the risk of thromboembolic events that predispose to stroke. Nonetheless, there are many factors to be considered when selecting the appropriate treatment approach for
any given patient. Presenting symptoms, symptom history (e.g., frequency,
duration, and severity), risk assessment, previous response to alternative
1 ATLAS Medical Research Inc, Miami (FL), USA; 2 Cardiology Department and
Arrhy thmia Center of Cardiovascular Research Institute, IRCCS Policlinico
MultiMedica, Sesto S. Giovanni (MI), Italy
30
treatment options, convenience and patient preference for a specific treatment option, and cost-effectiveness of a treatment option are among the
many factors that should be considered.
Correct diagnosis, termination of any episode in the presenting patient if
they are hemodynamically unstable, and identification of the cause of the
arrhythmia are typical immediate actions to be taken. Treatment of predisposing factors (e.g., hyperthyroidism, alchoholism, and obesity) can yield
significant clinical benefit, and oral coagulation is recommended for patients
with recurrent or chronic AFl. The goal of controlling the ventricular rate
while attempting to restore sinus rhythm and prevent recurrences may be
achieved by various treatment strategies that are available in clinical practice
(Table 1).
Table 1. Treatment options for atrial flutter commonly available in clinical practice
Electrical cardioversion
External electrical cardioversion
Internal (implantable) electrical cardioversion
1. Pharmacological therapy
2. Catheter ablation
Radiofrequency catheter ablation
Cryocatheter ablation
Catheter Ablation
Catheter ablation is a minimally invasive, non-surgical procedure that has
moved from being an experimental technique to an accepted treatment
option for AFl. The procedure involves insertion of a catheter into the
femoral vein, where it is subsequently advanced to within the heart. Once
placed endocardially, the ablation catheter is directed to cardiac tissue conducting the signals that cause the heart to beat abnormally [36]. The traditional ablation method involves destroying the reentry circuit, which is commonly (but not always) within the region of the cavotricuspid isthmus (CTI),
so as to create a bi-directional conduction block (BCB) across the isthmus
(Fig. 1). Although the traditional ablation method is the standard approach
that is used in clinical practice, preliminary evidence from a recent study
documented the successful use of a non-traditional ablation method to treat
AFl [7]. This latter method relies on the specific electrogram characteristics
31
Fig. 1. The right atrium, in a 45 left anterior oblique projection, with presentation of the
anatomical boundaries that demarcate the cavotricuspid isthmus (CTI), which is the
target area for creation of a line of conduction block. CCA, Cryocatheter ablation; CS os,
coronary sinus os; IVC, inferior vena cava; RFCA, radiofrequency catheter ablation; SVC,
superior vena cava
of the targeted cardiac tissue to identify the site for ablation, rather than creating a continuous line of block across the CTI.
The catheter ablation procedure involves several key steps. First, the
arrhythmia is mapped in order to determine whether the AFl is isthmusdependent, non-isthmus-dependent, or atypical. This is necessary to define
the conduction boundaries w ithin the reentrant circuit. Second, the
macroreentrant circuit is interrupted by creating either focal or linear
lesions within the critical zone of slow conduction that extends to anatomical borders. Finally, termination of the arrhythmia is verified by demonstrating BCB within the AFl circuit post-ablation by electrophysiological study
(EPS). A number of endpoints used to assess the safety, efficacy, and procedure characteristics of catheter ablation have been reported in clinical studies of AFl (Table 2).
32
Table 2. Endpoints commonly reported in studies concerning catheter ablation of atrial

flutter (AFl)
1. Safety outcomes
Procedure-related adverse events and complications
Device-related adverse events and complications
Discomfort on energy delivery to cardiac tissue
2. Efficacy outcomes
Bi-directional conduction block across the isthmus
Non-inducibility of AFl post-ablation
Double potentials
Symptom recurrencea
Conduction recurrenceb
3. Procedure characteristics
Procedure time
Fluoroscopy time
aSymptom
recurrence may be documented by subjective methods (e.g., patient diary

records) or objective methods (e.g., ECG, Holter monitoring, etc.). The general experience is that most cases of symptom recurrence occur within the first 6 months post
ablation
bOnly a few studies have measured persistency of bi-directional conduction block by
performing a repeat electrophysiological study at 1 to 3 months post ablation
When Should Catheter Ablation Be the First-Line Treatment for AFl?

The high efficacy and outstanding safety record reported by many studies
are strong evidence to support catheter ablation as the first-line treatment
for many patients with AFl [816]. Catheter ablation should not be reserved
as a last resort treatment for patients with AFl, but should be considered, in
some patients, as first-line therapy [17]. These are likely to include patients
with AFl who have heart disease and/or who have had cardiac surgery. AFl
also arises in some patients due to the presence of initiating factor(s), such
as metabolic imbalance and overexposure to cardiac stimulants. However,
addressing the underlying initiating factor(s) is the most prudent approach
to managing these patients prior to any consideration of catheter ablation. In
general, suitable candidates for catheter ablation includes those patients who
experience an unacceptably high frequency of recurrences, patients administered pharmacological therapy that is neither particularly effective nor welltolerated, and patients who have contraindications for other therapeutic
options for managing AFl. Natale and colleagues also suggested that catheter
ablation should be the first-line treatment for patients with AFl who have a
33
normal or mildly enlarged left atrium [8]. Catheter ablation should not be
considered as first-line treatment in all episodes of AFl. For example, this
procedure is not suitable for patients with rhythm disturbances that are likely to spontaneously resolve or unlikely to recur [18].
Some questions concerning catheter ablation treatment of AFl remain.
First, ablation and interruption of isthmus conduction do nothing to the disease mechanisms that cause the arrhythmia in the first place [19]. Hence,
catheter ablation across the CTI is considered by some to not be a curative
procedure, because it does not address the cause of flutter, and is only a necessary link in the circuit, i.e., the electrophysiologic and/or anatomic abnormalities within the atria persist after catheter ablation [18]. Second, there is
evidence of an increase in the occurrence of atrial fibrillation following ablation treatment for AFl [20], although evidence to the contrary also exists [21,
22]. Despite a high proportion of patients developing atrial fibrillation after
catheter ablation for AFl, a majority of treated patients consider the intervention beneficial due to improved quality of life [23]. But this benefit may
be restricted to those patients without predominant AFl prior to ablation for
AFl [23]. Third, there has been a narrow range of patient characteristics
(e.g., cardiac function, associated comorbidities, prior ablation status, previous failure on AA drugs, etc.) associated with individuals enrolled in clinical
studies investigating catheter ablation treatment for AFl. Consequently, it is
difficult to clearly identify those patients who are likely to achieve the best
results with catheter ablation over the long term. However, variation in the
success rate of catheter ablation for patients with different types of AFl has
been reported [14, 24].
The costs associated with catheter ablation, although not trivial, are less
over time than the cost of alternatives [25, 26]. Catheter ablation requires an
experienced electrophysiologist and comprehensive catheterization facilities,
both of which may be resource impediments to the widespread use of this
treatment option.
Cryocatheter Ablation
Cryocatheter ablation (CCA) has been reported to offer a number of potential advantages compared to radiofrequency catheter ablation (RFCA) (Table
3). Despite these many advantages, the lengthier procedure time, limitation
to point-by-point focal ablation, and lack of investigator familiarity with the
technology have dampened the canabalization of the AFl ablation market by
cryocatheters. There are a number of recent clinical studies involving CCA
for treatment of AFl (Table 4) [11, 14, 15, 2730]. Acute success rates reported
34
Table 3. Advantages and disadvantages of cryocatheter ablation (CCA) versus radiofrequency catheter ablation (RFCA) for the treatment of AFl (data from [11, 14, 15,
2740])
Advantages
1. Safety benefits
Ability to create reversible (transient) conduction block at a target site prior
to creation of permanent irreversible conduction block
Greater catheter stability (cryoadhesion) enabling shorter fluoroscopy exposure
Less patient discomfort on energy delivery during the ablation procedurea
Fewer complications e.g., less thrombogenic, less endothelial cell disruption,
and less collagen shrinkage
2. Efficacy benefits
High long-term success e.g., symptom recurrence rates relatively low in
most studies
Disadvantages
1. Longer procedure time and possibly fluoroscopy exposure
2. Cryocatheters are limited to point-by-point ablation across the CTI whereas RF
catheters can use both point-by-point and the drag-and-burn ablation methods
CCA, Cryocatheter ablation; CTI, cavotricuspid isthmus; RFCA, radiofrequency
catheter ablation
aA recent study demonstrated that RFCA-treated patients administered nitrous oxide
had reduced anxiety and discomfort with RF energy delivery [41]
with CCA range from 87 to 100%. Greater short-term success and procedure
benefits (e.g., shorter procedure time) are delivered with larger-tipped cryo
catheters [15]. Most studies report a relatively low rate of symptom recurrence over a reasonably lengthy period of follow-up.
The lack of large randomized controlled trials comparing CCA to RFCA
for treatment of AFl has impeded a valid determination of which ablation
energy is superior in a head-to-head comparison. This issue is now being
addressed by a few ongoing clinical studies. The general consensus among
users of both CCA and RFCA for treatment of AFl appears to be recognition
of a superior safety profile for CCA, an equivalent effectiveness, but a longer
procedure time.
Conclusions
Since its availability in clinical practice in the 1990s, CCA has rapidly
become a curative option for AFl. This is not surprising given the excellent
Cryocatheter
type
CryoBlator
CryoBlator
CryoBlator
CryoBlator
CryoBlator
CryoBlator
Reference
[29]
[30]
[37]
[28]
[11]
[32]
Traditional
Traditional
Traditional
Traditional
Traditional
Traditional
Ablation
methodsa
48
35
40
73
15
No. of patients
treated with CCA
64
53
56
52
55
48
Mean age
(years)
One serious procedurerelated complication

(femoral hematoma).
Otherwise, CCA was welltolerated with no discomfort
on cryo energy delivery
No major AEs; no
thromboembolic
complications
No complications during
procedure or follow-up
No AEs reported
Pain score less with cryo

than RF (p < 0.05)
No AEs reported
Safety outcomes
for CCAb
Table 4. Summary of results from recent clinical studies involving CCA treatment for patients with AFl
94% short-term success;

25% symptom recurrence

98% short-term success; 5%

symptom recurrence
99% short-term success


Efficacy outcomes
for CCAc
continue
17.6
11.7
15
~3
Mean follow-up
(months)

35
Cryocatheter
type
Freezor Xtra
Freezor MAX
Freezor Xtra
vs Freezor
MAX
Freezor MAX
vs RF
Reference
[14]
[27]
[15]
[31]
Table 4 continue
94
Non-traditional
Traditional
77
45
No. of patients
treated with CCA
Non-traditional
Non-traditional
Ablation
methodsa
NR
60
60
62
Mean age
(years)
No procedural
complications and pain
score less with cryo than RF
(p = 0.0002)
No AEs or discomfort
reported with cryo energy
delivery
delivery
delivery
Safety outcomes
for CCAb


~32% conduction
recurrence at 3 month
repeat EPS; 0% symptom
recurrence at 9 month
follow-up

30% conduction recurrence
at 3 month repeat EPS; 0%
symptom recurrence at 6
month follow-up

at 3 month repeat EPS; 0%
symptom recurrence at 9
month follow-up
Efficacy outcomes
for CCAc
~3
Mean follow-up
(months)
36
FreezorMAX
vs RF
Montenero
(unpublished)
26
20
Non-traditional
Non-traditional
63
60
delivery
delivery
~3

at 3-month repeat EPS;
4.5% symptom recurrence
c Symptom
recurrence rate was calculated over the mean length of follow-up
b To date, there have been no reports of permanent AV conduction block in the many hundreds of patients that have been treated by CCA for various cardiac arrhythmias,
including AFl
Traditional ablation method with a cryocatheter refers to the point-by-point ablation technique with creation of a continuous line of block across the isthmus. The
CryoBlator cryocatheter (CryoCor)comes in three tip lengths: 6.5,10, and 15 mm. CryoCor's CryoBlator cryocatheters are currently under investigational use for the treatment of AFl and AF within the USA. The CryoBlator cryocatheters are CE-Mark approved and commercially available for use in the EU. The Freezor Xtra cryocatheter
(CryoCath Technologies) is a 7Fr unidirectional catheter with a 6-mm ablation segment, 108-cm working length, with 4 mapping electrodes with 2-5-2 spacing, and is
available in three reach lengths (short, medium, and long). The Freezor MAX cryocatheter (CryoCath Technologies)is a 9Fr unidirectional catheter with an 8-mm ablation
segment, 90-cm working length, with four mapping electrodes with 3-5-2 spacing, and is available in two reach lengths (medium, and long). Both Freezor Xtra and Freezor
MAX cryocatheters are CE-Mark approved and commercially available for use in the EU, and are also commercially available for use in the USA
AE, Adverse event; CCA, cryocatheter ablation; EPS, electrophysiological study; NR, data not reported in abstract
Freezor MAX
[7]
Table 4 continue

37
38
safety and effectiveness profile associated with regulatory-approved CCA

technologies. A possible ceiling on its use is that it requires an experienced
cardiac electrophysiologist plus comprehensive catheterization facilities.
However, the long-term cost-effectiveness of CCA versus alternative treatment options will likely support the wider use of this curative option.
Acknowledgements
All data were analyzed by an independent organization (ATLAS Medical Research,
Miami, FL, USA). For disclosure purposes, this organization has previously analyzed
data and compiled biomedical and regulatory documentation for medical device, pharmaceutical, and biotech companies, as well as university groups involved in various
areas of medical research.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Lee KW, Yang Y, Scheinman MM (2005) Atrial flutter: a review of its history, mechanisms, clinical features, and current therapy. Curr Probl Cardiol 30(3):121167
Wellens HJ (2002) Contemporary management of atrial flutter. Circulation
106(6):649652
Foldesi C, Pandozi C, Peichl P et al (2003) Atrial flutter: arrhythmia circuit and
basis for radiofrequency catheter ablation. Ital Heart J 4(6):395403
Yee R, Connolly S, Noorani H (2003) Clinical review of radiofrequency catheter
ablation for cardiac arrhythmias. Can J Cardiol 19(11):12731284
Feld GK (2004) Radiofrequency ablation of atrial flutter using large-tip electrode
catheters. J Cardiovasc Electrophysiol 15(10 Suppl):S18-S23
Feld G, Wharton M, Plumb V et al (2004) Radiofrequency catheter ablation of type
1 atrial flutter using large-tip 8- or 10-mm electrode catheters and a high-output
radiofrequency energy generator: results of a multicenter safety and efficacy study.
J Am Coll Cardiol 43(8):14661472
Montenero AS, Bruno N, Antonelli A et al (2006 ) Low clinical recurrence and procedure benefits following treatment of common atrial flutter by electrogram-guided hot spot focal cryo ablation. J Interv Card Electrophysiol 15(2):8392
Natale A, Newby KH, Pisano E et al (2000) Prospective randomized comparison of
antiarrhythmic therapy versus first-line radiofrequency ablation in patients with
atrial flutter. J Am Coll Cardiol 35(7):18981904
Marrouche NF, Schweikert R, Saliba W et al (2003) Use of different catheter ablation technologies for treatment of typical atrial flutter: acute results and long-term
follow-up. Pacing Clin Electrophysiol 26(3):743746
Montenero AS, Bruno N, Antonelli A et al (2004) Safety and efficacy of catheter
cryoablation for the treatment of atrial flutter: acute and long term results. Ital
Heart J 5(Suppl 1):131S-137S
Manusama R, Timmermans C, Limon F et al (2004) Catheter-based cryoablation
permanently cures patients w ith common atrial flutter. Circulation
109(13):16361639
Nakagawa H, McClelland J, Beckman K et al (1993) Radiofrequency catheter ablation of common type atrial flutter. Pacing Clin Electrophysiol 16:850

13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
39
Fischer B, Jais P, Shah D et al (1996) Radiofrequency catheter ablation of common

atrial flutter in 200 patients. J Cardiovasc Electrophysiol 7(12):12251233
Montenero A, Bruno N, Antonelli A et al (2005) Long-term efficacy of cryo catheter
ablation for the treatment of atrial flutter results from a repeat electrophysiologic
Montenero AS, Bruno N, Antonelli A et al (2005) Comparison between a 7 French 6
mm tip cryothermal catheter and a 9 French 8 mm tip cryothermal catheter for
cryoablation treatment of common atrial flutter. J Interv Card Electrophysiol
13(1):5969
Calkins H, Canby R, Weiss R et al (2004) Results of catheter ablation of typical
atrial flutter. Am J Cardiol 94(4):437442
Tracy CM, Akhtar M, DiMarco JP et al (2000) American College of
Cardiology/American Heart Association Clinical Competence Statement on invasive electrophysiology studies, catheter ablation, and cardioversion: a report of the
American College of Cardiology/American Heart Association/American College of
Physicians-American Society of Internal Medicine Task Force on Clinical
Competence. Circulation 102(18):23092320
Garcia-Cosio F, Pastor A, Nunez A (1999) [Radiofrequency ablation as the first line
of treatment in patients with common atrial flutter. The arguments con]. Rev Esp
Cardiol 52(4):233236
Cosio FG (2005) Should ablation be the first line treatment for supraventricular
arrhythmias? Heart 91(1):56
Bertaglia E, Zoppo F, Bonso A et al (2004) Long term follow up of radiofrequency
catheter ablation of atrial flutter: clinical course and predictors of atrial fibrillation
occurrence. Heart 90(1):5963
De Sisti A, Leclercq JF, Fiorello P et al (1998) [The effects of the ablation of atrial
flutter in patients with and without a clinical history of paroxysmal atrial fibrillation]. G Ital Cardiol 28(11):12531260
Schmieder S, Ndrepepa G, Dong J et al (2003) Acute and long-term results of radiofrequency ablation of common atrial flutter and the influence of the right atrial
isthmus ablation on the occurrence of atrial fibrillation. Eur Heart J
24(10):956962
Anne W, Willems R, Adriaenssens B et al (2006) Long-term symptomatic benefit
after radiofrequency catheter ablation for atrial flutter despite a high incidence of
post-procedural atrial fibrillation. Acta Cardiol 61(1):7582
Della BP, Fraticelli A, Tondo C et al (2002) Atypical atrial flutter: clinical features,
electrophysiological characteristics and response to radiofrequency catheter ablation. Europace 4(3):241253
Cheng CH, Sanders GD, Hlatky MA et al (2000) Cost-effectiveness of radiofrequency ablation for supraventricular tachycardia. Ann Intern Med 133(11):864876
Bathina MN, Mickelsen S, Brooks C et al (1998) Radiofrequency catheter ablation
versus medical therapy for initial treatment of supraventricular tachycardia and its
impact on quality of life and healthcare costs. Am J Cardiol 82(5):589593
Montenero AS, Bruno N, Zumbo F et al (2005) Cryothermal ablation treatment of
atrial flutter-experience with a new 9 French 8 mm tip catheter. J Interv Card
Electrophysiol 12(1):4554
Manusama R, Timmermans C, Philippens S et al (2004) Single cryothermia applications of less than five minutes produce permanent cavotricuspid isthmus block
in humans. Heart Rhythm 1(5):594599
Rodriguez LM, Geller JC, Tse HF et al (2002) Acute results of transvenous cryoabla-
40
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.

tion of supraventricular tachycardia (atrial fibrillation, atrial flutter, WolffParkinson-White syndrome, atrioventricular nodal reentry tachycardia). J
Cardiovasc Electrophysiol 13(11):10821089
Timmermans C, Ayers GM, Crijns HJ, Rodriguez LM (2003) Randomized study
comparing radiofrequency ablation with cryoablation for the treatment of atrial
flutter with emphasis on pain perception. Circulation 107(9):12501252
Collins N, Barlow M, Leitch JW et al (2005) Cryoablation Versus Radiofrequency
Ablation in the Treatment of Atrial Flutter Trial (CRAAFT). Heart Rhythm 2005
Scientific Sessions, New Orleans, LA, USA, May 47, 2005
Daubert JP, Hoyt RH, John R et al (2005) Performance of a new cardiac cryoablation system in the treatment of cavotricuspid valve isthmus-dependent atrial flutter. Pacing Clin Electrophysiol 28(Suppl 1):S142-S145
Friedman PL (2005) Catheter cryoablation of cardiac arrhythmias. Curr Opin
Cardiol 20(1):4854
Khairy P, Chauvet P, Lehmann J et al (2003) Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation
107(15):20452050
Kuniss M, Kurzidim K, Greiss H et al (2005) Persistency of bi-directional conduction block in the cavotricuspid isthmus one month after cryocatheter ablation
(8mm-tip) of common atrial flutter. Heart Rhythm 2005 Scientific Sessions, New
Orleans, LA, USA, May 47, 2005
Lowe MD, Meara M, Mason J et al (2003) Catheter cryoablation of supraventricular
arrhythmias: a painless alternative to radiofrequency energy. Pacing Clin
Electrophysiol 26(1 Pt 2):500503
Rodriguez LM, Timmermans C (2004) Transvenous cryoablation of cardiac
arrhythmias. Technol Cancer Res Treat 3(5):515524
Skanes AC, Yee R, Krahn AD, Klein GJ (2002) Cryoablation of atrial arrhythmias.
Card Electrophysiol Rev 6(4):383388
Skanes AC, Klein G, Krahn A, Yee R (2004) Cryoablation: potentials and pitfalls. J
Cardiovasc Electrophysiol 15(10 Suppl):S28-S34
van Oeveren W, Crijns HJ, Korteling BJ et al (1999) Blood damage, platelet and clotting activation during application of radiofrequency or cryoablation catheters: a
comparative in vitro study. J Med Eng Technol 23(1):2025
Laurent G, Bertaux G, Martel A et al (2006) A randomized clinical trial of continuous flow nitrous oxide and nalbuphine infusion for sedation of patients during
radiofrequency atrial flutter ablation. Pacing Clin Electrophysiol 29(4):351357
Radiofrequency Ablation of Atrial Fibrillation and Atrial

Flutter: Who and When?
JOSEF KAUTZNER, DAN WICHTERLE
Introduction
While typical atrial flutter (AFL) is a characteristic macroreentrant atrial
tachycardia originating in the right atrium, atrial fibrillation (AF) is triggered
in most subjects by arrhythmogenic foci localized in the myocardium around
pulmonary veins and maintained by functional reentrant circuits in the left
atrial myocardium. However, there is a close relationship between the two
arrhythmias. They often coexist in the same patient and may degenerate into
each other [1]. The reasons for this coexistence are not clear. It is possible that
pulmonary venous triggers also initiate AFL or convert AFL into AF [2].
Catheter Ablation of Atrial Flutter

High procedural success rates (close to 100%) have been reported after
cavotricuspid isthmus ablation for typical AFL [3]. Two prospective, randomized studies [4, 5] compared oral anti-arrhythmic therapy to radiofrequency ablation as a first-line therapy in patients with AFL. Both studies,
irrespective of certain methodological limitations, demonstrated a significantly higher efficacy of non-pharmacological approaches; however, a substantial incidence of AF episodes was observed during follow-up [5].
Therefore, cavotricuspid isthmus ablation appears to be less successful in
those with more frequent episodes of AF. Some evidence suggests that, in
patients with AFL as the predominant clinical arrhythmia, cavotricuspid
isthmus ablation reduces recurrences of AF over a long period of time.
Patients with AF who develop AFL while receiving class IC or III anti-
Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague,

Czech Republic
24
arrhythmic drugs also seem to profit from cavotricuspid isthmus ablation,

displaying a reduced incidence of AF after AFL ablation. In these patients,
the drug that caused conversion should be continued [6]. This notion is supported by our data from a series of 126 subjects who underwent catheter
ablation for AFL and were followed for 10 8 months. While subjects with
isolated AFL presented with subsequent AF in 22% of cases and those with
IC or III AFL in only 28%, patients with documented AF and AFL developed
recurrences of AF in 71% of cases.
The above indications were summarized in the joint ACC/AHA/ESC 2003
guidelines for the management of patients with supraventricular arrhythmias [7]. According to the guidelines, catheter ablation of cavotricuspid isthmus might be the option for long-term AFL management when the first
episode of tolerated arrhythmia is documented (recommendation class I,
level of evidence B). In the case of a single episode of poorly tolerated (in
exceptional circumstances 1:1 AV conduction associated with life-threatening symptoms) or recurrent well-tolerated AFL, catheter ablation is the preferential mode of therapy (recommendation class I, level of evidence B). The
only alternative is administration of dofetilide (recommendation class IIa,
level of evidence C), whereas the usefulness or efficacy of other anti-arrhythmic drugs is even less well-established (recommendation class IIb, level of
evidence C). The same strategy applies for AFL appearing after use of class Ic
agents or amiodarone for treatment of AF; catheter ablation should be preferred to facilitate further pharmacologic management (recommendation
class I, level of evidence B) rather than substituting the current drug with
another (recommendation class IIa, level of evidence C).
Catheter Ablation of Atrial Fibrillation

Enormous progress in catheter ablation of AF has been achieved in the last
decade [8]. The goals of this therapy are elimination of symptoms, improvement in quality of life, prevention of complications and, at least theoretically,
improvement in prognosis. The current criteria for patient selection for AF
ablation are influenced by many factors, such as safety, efficacy, availability,
the risk-to-benefit ratio, and patient preference. As the ablation strategies for
elimination of AF continue to evolve, the reported efficacy varies broadly,
depending on the type of AF, ablation strategy, and the methods and duration of follow up. Although the classical definition of success has been the
maintenance of sinus rhythm in the absence of anti-arrhythmic therapy, a
significant decrease in AF burden and/or rhythm control with previously
ineffective drugs may also be clinically meaningful. In this respect, it has to
Radiofrequency Ablation of Atrial Fibrillation and Atrial Flutter: Who and When?
25
be emphasized that more extended ECG monitoring will detect a higher proportion of asymptomatic episodes and thus decreases the success rate [9].
The above advances in AF ablation have been partially incorporated in
the recent (2006) update of the ACC/AHA/ESC guidelines [10], with the
recognition that such vital details as patient selection, optimum ablation
sites, absolute rates of treatment success, and the frequency of complications
remain incompletely defined. In patients with AF likely benefiting from
maintenance of sinus rhythm and in whom no precipitating or reversible
causes of arrhythmia (such as hyperthyroidism) have been found, drugs are
typically the first choice. Left atrial catheter ablation is a reasonable secondline alternative to pharmacological therapy to prevent recurrent AF in symptomatic patients, especially in those with little or no left atrial enlargement
(recommendation class IIa, level of evidence C).
So far, the role of catheter ablation has been established in symptomatic
AF patients, whereas the appropriateness of catheter ablation in asymptomatic subjects has to be further studied. At present, asymptomatic patients
may be considered for catheter ablation when they are young or have evidence of possible tachycardia-mediated cardiomyopathy. Along the same
lines, a trial of anti-arrhythmic drugs is usually required prior to catheter
ablation. However, catheter ablation is increasingly indicated after the failure
of one or two drugs. The results of a pilot study suggested that catheter ablation may be superior to drug therapy even when applied as the first-line
treatment [11].
With the development of ablation strategies, clinical efficacy has
improved even in subjects with chronic AF. A recent trial documented that
about three fourths of patients with chronic AF may remain in sinus rhythm
with improvement of left ventricular ejection fraction and a decrease in left
atrial size [12]. Similarly, the feasibility and safety of catheter ablation for AF
have been documented even in patients with congestive heart failure and left
ventricular dysfunction [13]. Regarding patient age, catheter ablation has
been performed in those as young as 16 years up to those in their eighties.
Despite comparable efficacies documented in the elderly, some studies
reported a higher incidence of periprocedural complications [14].
Based on data from several series, a left atrial diameter > 5055 mm
appears to predict lack of procedural success [15]. Similarly, AF of long duration may be associated with a higher probability of recurrence after ablation.
Finally, in patients who require cardiac surgery for any indication, concomitant ablation for AF is appropriate. In subjects without indications for
surgery, no data are available to support surgical ablation as a stand-alone
procedure.
26
Conclusions
Catheter ablation of cavotricuspid isthmus has become the first-line therapy
in patients with typical AFL. Catheter ablation of AF, aimed at electrical isolation of pulmonary veins and various forms of substrate modification, is a
still-developing strategy that should be primarily restricted to symptomatic
subjects who have failed or have contraindications to medical treatment.
However, the indications for catheter ablation are likely to broaden in the
near future.
Aknowledgements
Supported by a Research grant MZO 00023001 of the Ministry of Health of the Czech
Republic.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Roithinger FX, Lesh MD (1999) What is the relationship of atrial flutter and fibrillation? Pacing Clin Electrophysiol 22:643654
Wazni O, Marrouche NF, Martin DO et al (2003) Randomized study comparing
combined pulmonary vein-left atrial junction disconnection and cavotricuspid
isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in
patients presenting with typical atrial flutter and atrial fibrillation. Circulation
108:24792483
Wellens HJ (2002) Contemporary management of atrial flutter. Circulation
106:649652
Natale A, Newby KH, Pisano E et al (2000) Prospective randomized comparison of
antiarrhythmic therapy versus first-line radiofrequency ablation in patients with
atrial flutter. J Am Coll Cardiol 35:18981904
Da Costa A, Thevenin J, Roche F et al (2006) Results from the Loire-ArdecheDrome-Isere-Puy-de-Dome (LADIP) trial on atrial flutter, a multicentric prospective randomized study comparing amiodarone and radiofrequency ablation after
the first episode of symptomatic atrial flutter. Circulation 114:16761681
Nabar A, Rodriguez LM, Timmermans C et al (1999) Effect of right atrial isthmus
on the occurrence of atrial fibrillation. Circulation 99:14411145
Blomstrom-Lundqvist C, Scheinman MM, Aliot EM et al (2003) AAC/AHA/ESC
guidelines for the management of patients with supraventricular arrhythmias.
Circulation 108:18711909
Riley MJ, Marrouche NF (2006) Ablation of atrial fibrillation. Curr Probl Cardiol
31:361390
Kottkamp H, Tanner H, Kobya R et al (2004) Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left
atrial lesions; trigger elimination or substrate modification: early or delayed cure? J
Am Coll Cardiol 44:869877
Fuster V, Ryden LE, Cannom DS et al (2006) ACC/AHA/ESC 2006 guidelines for the
management of patients with atrial fibrillation: full text. Europace 8:651745
Radiofrequency Ablation of Atrial Fibrillation and Atrial Flutter: Who and When?
11.
12.
13.
14.
15.
27
Wazni O, Marrouche NF, Martin DO et al (2005) Radiofrequency ablation vs

antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a
randomized trial. JAMA 293:26342640
Oral H, Pappone C, Chugh A et al (2006) Circumferential pulmonary vein ablation
for chronic atrial fibrillation. N Engl J Med 354:934941
Hsu LF, Jais P, Sanders P et al (2004) Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 351:23732383
Oral H, Hall B, Chugh A et al (2004) Age and catheter ablation of atrial fibrillation.
Circulation 110:348 (abs)
Oral H, Morady F (2006) How to select patients for atrial fibrillation ablation. Heart
Rhythm 3:615618
The Impact of New Imaging, Mapping and Energy Delivery

Technology on the Current Approach to Ablation of Atrial
Fibrillation
ANDREA COLELLA1, MARZIA GIACCARDI2, LUIGI PADELETTI1, GIAN FRANCO GENSINI1
Atrial Fibrillation
Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. It is frequently symptomatic and contributes to significant morbidity and mortality, independent of all other cardiac comorbidities [1].
Providing effective treatment of AF is one of the challenges of electrophysiology, and it is the focus of major research initiatives in the scientific community. The level of concern and interest regarding AF has increased over
the years with the advent of curative ablative techniques.
Optimal treatment of AF has yet to be achieved. Drug therapy has always
shown poor efficacy in restoration and maintenance of sinus rhythm (SR)
and reduction of AF complications (heart failure, stroke). In addition, the
potential advantage of maintaining SR with anti-arrhythmic agents is counterbalanced by their propensity to cause serious side effects, including lifethreatening pro-arrhythmic ones, and to exacerbate ischemia or heart failure
by their negative inotropic actions. Moreover, a recent AFFIRM sub-study
showed that only warfarin use and SR maintenance affect mortality, whereas
anti-arrhythmic drugs do not modify survival [2]. For this reason, the search
for therapeutic approaches effective and different from pharmacological
therapy has become an increasingly active one.
The past decade has witnessed extraordinary growth in all fields of
knowledge regarding AF. Many clinicians now agree that AF is not a unique
arrhythmia but is made up of various mechanisms in several clinical settings. These may provide optimal substrates for a tailored therapy
approach by catheter-mediated ablation of the trigger or substrate.
1Heart
and Vessels Department, Azienda Ospedaliera Universitaria Careggi, Florence;

Cardiology, Azienda A. Meyer, Florence, and Don Gnocchi Foundation,
Florence, Italy
2Pediatric
44
Ablation of Atrial Fibrillation

The remarkable results of surgical Maze procedures in treating AF [3] have
encouraged the introduction and development of the percutaneous ablation
approach in an attempt to expand this surgical technique. The therapeutic
action and target substrates of AF ablation are now understood to be more
complex than previously recognized. While catheter ablation of AF initially
focused on pulmonary vein isolation, more recently it has widened substantially to include alternative or supplementary approaches. Four different
approaches to catheter ablation of AF are emerging [4]:
1. Isolation of the triggers and perpetuating re-entrant circuits located in
the pulmonary veins (pioneered by Jais and Haissaguerre [5, 6]).
2. Disruption of the substrate for perpetuating rotors in the antra of the
pulmonary veins and the posterior left atrium (pioneered by Pappone
[7]).
3. Targeted ablation of ganglionated automonic plexi in the epicardial fat
pad (pioneered by Platt, Jackman, and Scherlag [8, 9]).
4. Disruption of the putative dominant rotors in the left and right atria as
recognized by high-frequency complex fractionated electrograms during
AF mapping (pioneered by Nadamanee [10]).
Technical Developments
As our knowledge regarding AF has grown over the last decade, AF treatment
by radiofrequency (RF) ablation has evolved. Historically, cardiac angiography represented the standard methodology to investigate the cardiac structures and to define their anatomy. In fact, angiography combined with the
electrophysiological assessment has long been used to relate cardiac anatomy to the electrical physiology of the heart. Unfortunately, this technique is
not able to provide three-dimensional (3D) information and it is inadequate
for preliminary patient evaluation. Additionally, several recently proposed
approaches for AF treatment involve a deeper knowledge of the anatomy of
the left atrium and the pulmonary veins.
New technical developments in the field of catheter ablation of AF
include greater accuracy due to reconstruction of the virtual geometry by 3D
navigation and mapping systems, and integration of 3D magnetic resonance
imaging (MRI) and computed tomography (CT) data sets with those systems. This advance allows manipulation of catheters in an anatomically
accurate 3D environment, making the procedure easier and, presumably,
safer. Approaches based on magnetic resonance or ultrasound imaging are
The Impact of New Technologies on the Current Approach to Ablation of AF
45
also expected to serve as a stepping stone to the ultimate goal of real-time

anatomical guidance of catheter ablation and potential elimination of radiation exposure. Progress is expected to be facilitated by robotic remote
catheter navigation, both mechanically and magnetically guided. Shorter
procedural times and more extensive practice of catheter ablation techniques
to cure AF will derive from the introduction of customized coil- and balloon-based catheters that make use of alternative energy sources.
Alternative Energy Sources

Nowadays, RF energy ablation remains the gold standard in clinical practice,
as most types of atrial and ventricular arrhythmias can be cured using localized ablation. Despite its widespread use, this type of ablation is commonly
known to have several limitations, i.e., risks of coagulum formation, carbonization, steam popping, crater formation, and myocardial rupture.
These limitations have motivated the evaluation of modified electrode
systems and new RF catheter designs, among which the most important is
cooling tips. Cooled RF ablation has been shown to be effective in the production of larger lesions and useful in the management of patients with
recurrent VT and AF. Even if the cooling technology does not completely
exclude the risk of increased impedance and popping, it allows the delivery
of sufficient amounts of energy to achieve a larger lesion size and depth. The
success in curing some arrhythmias using RF ablation has been, in itself, a
milestone in the field of arrhythmia management. However, some common
arrhythmias remain difficult to treat by simple ablation; thus, other forms of
ablation energy, including cryothermy, microwave, ultrasound, and laser,
have been evaluated.
Many forms of energy have been used for medical purposes. Tissue
destruction in the treatment of tumors and other tissue anomalies has been
attempted with different kinds of energy [1119]. Recently, these types of
energy have been implemented in arrhythmology as well. In the treatment of
arrhythmia, cryoablation has been used for many years, as it was found to be
effective for the ablation of any type of arrhythmia substrate, including
accessory pathways as well as the ventricular tachycardia (VT) form in
chronic ischemic heart disease. The safety and efficacy of cryoenergy ablation of myocardial tissue is well-recognized [20]. Its unique, reversible effect
was also demonstrated in a study in which AV nodal conduction resumed
after withdrawal of cooling at -45C. Permanent block was noted at temperatures below -60C applied for 90120 s [21, 22]. The other potential significant benefit with cryoablation is the absence of thrombus formation [23, 24],
46
which is a major concern when a number of RF applications are required, as

in left-sided ablation cases. The utility of cryoablation for left atrial ablation
was recently reported, and its efficacy, safety, and ease of use were confirmed. In particular, there was no occurrence of pulmonary-vein stenosis or
phrenic-nerve paralysis. Thus, cryoablation has indeed evolved as a potentially useful tool in the treatment of complex ablation, e.g., for treating large
or deep lesions. The reversible effect of this technique may also prove to be
useful for the ablation of critical areas, such as sites close to the atrioventricular node, by allowing validation of the ablation site with cryomapping
before cryoablation. At the present time, clinical investigations of new prototypes are ongoing in several countries. If the results obtained show a
decreased risk of recurrence, thus preserving the efficacy of RF ablation
while maintaining the safety profile of cryoablation, this kind of energy has
the potential to become a safe and preferred alternative to current RF techniques.
The use of laser, ultrasound, and microwave energies for ablation is currently under investigation, but applications are still in the development
phase. Both laser and ultrasound balloon delivery systems have been proposed for pulmonary-vein isolation. The laser system is still very dependent
on contact, despite the fact that the lesions created are precise with welldefined edges and excellent control of their depth is possible. Although
ultrasound must be designed to specifically control the size and depth of
lesions, its advantages are that it does not require intimate tissue contact and
it is able to generate deeper lesions than other modalities. However, longterm results have to show minimal recurrence and complications.
Finally, microwave is relatively new for AF ablation applications and still
under clinical investigation. Theoretically, this energy should provide sufficient lesions independent of contact, but distance, antenna design, and orientation are still important considerations.
Alternative forms of energy do provide some promise in terms of larger,
deeper, and complex lesions but their application is still relatively in their
early process. Nevertheless, preliminary data are promising. Clinicians and
patients will no doubt soon benefit from safe and effective forms of ablation
for treating the many other types of arrhythmias whose control remains elusive.
Stereotaxis
The advent of the Stereotaxis (Stereotaxis, St. Louis, Missouri) remote
catheter-navigation system offers the opportunity to improve the success of
The Impact of New Technologies on the Current Approach to Ablation of AF
47
complex ablation procedures while maximizing the capabilities of an

advanced 3D mapping system. By reducing the risk of catheter perforation,
limiting fluoroscopy exposure, and improving accuracy, catheter navigation
and mapping provide a unique marriage of capabilities for electrophysiological procedures. Stereotaxis technology, currently used for AF ablation,
allows magnetic navigation into the heart by remote control. In contrast to
stiffer traditional catheters, it allows very accurate catheter tip control,
avoiding the stretching of tissue and distortion of cardiac structures, which
can produce false spaces when creating chamber geometry. Beyond radiological-exposure reduction, stereotaxis technology has a shorter learning curve
than conventional ablation techniques. Early clinical results have demonstrated that stereotaxis technology is safe and effective, opening up possibilities that until now were considered to be as unlikely as remote transcatheter
ablation [25].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Benjamin EJ, Larson MG, Keyes MJ et al (2004) Clinical correlates and heritability
of flow-mediated dilation in the community: the Framingham Heart Study.
Corley SD, Epstein AE, DiMarco JP et al (2004) Relationship between sinus rhythm,
treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of
Rhythm Management (AFFIRM) Study. Circulation 109:15091513
Cox JL, Schuiessler RB, Lappas DG et al (1996) An 8?-year clinical experience with
surgery for atrial fibrillation. Ann Surg 224:267273
Keane D, Reddy V, Ruskin J (2005) Emerging concepts on catheter ablation of atrial
fibrillation from the tenth annual Boston Atrial Fibrillation Symposium. J
Cardiovasc Electrophysiol 16:10251028
Jais P, Haissaguerre M, Shah DC et al (1997) A focal source of atrial fibrillation
treated by discrete radiofrequency ablation. Circulation 95:572576
Haissaguerre M, Jais P, Shah DC et al (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med
339:659666
Pappone C, Rosanio S, Oreto G et al (2000) Circumferential radiofrequency ablation of pulmonary vein ostia: a new anatomic approach for curing atrial fibrillation. Circulation 102:26192628
Platt M, Mandapati R, Scherlag BJ et al (2004) Limiting the number and extent of
radiofrequency applications to terminate atrial fibrillation and subsequently prevent its inducibility. Heart Rhythm 1:S11 (abs)
Scherlag BJ, Nakagawa H, Jackman WM et al (2005) Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card
Electrophysiol 13(Suppl 1):3742
Nademanee K, McKenzie J, Kosar E et al (2004) A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll
Cardiol 43:20442053
48
11.
Bain C, Cooper KG, Parkin DE (2002) Microwave endometrial ablation versus

endometrial resection: a randomized controlled trial. Obstet Gynecol 99:983987
Anidjar M, Teillac P (1995) Non-surgical instrumental treatment of benign hypertrophy of the prostate. Presse Med 24:14771480
DAgostino HB, Solinas A (1995) Percutaneous ablation therapy for hepatocellular
carcinomas. AJR Am J Roentgenol 164:11651167
Miyake O, Itatani H, Itoh H et al (1995) Laser-TURP with a lateral firing fiber for
contact irradiation. Nippon Hinyokika Gakkai Zasshi 86:273278
Kigure T, Harada T, Satoh Y et al (1996) Microwave ablation of the adrenal gland:
experimental study and clinical application. Br J Urol 77:215220
Hodgson DA, Feldberg IB, Sharp N et al (1999) Microwave endometrial ablation:
development, clinical trials and outcomes at three years. Br J Obstet Gynaecol
106:684694
Korn AP (2000) Endometrial cryoablation and thermal ablation. Clin Obstet
Gynecol 43:575583
Johnson DB, Nakada SY (2001) Cryosurgery and needle ablation of renal lesions. J
Endourol 15:361368
Mitka M (2002) Tumoricidal temperature-related treatments. JAMA 287:440441
Lister J, Hoffman BF (1964) Reversible cold block of the specialized conduction tissues of the anaesthesized dog. Science 145:723725
Gallagher JJ, Sealy WC, Anderson RW et al (1977) Cryosurgical ablation of accessory atrioventricular connections: a method for correction of the pre-excitation
syndrome. Circulation 55:471479
Harrison L, Gallagher JJ, Kasell J et al (1977) Cryosurgical ablation of the A-V
node-His bundle: a new method for producing A-V block. Circulation 55:463470
Dubuc M, Roy D, Thibault B et al (1999) Transvenous catheter ice mapping and
cryoablation of the atrioventricular node in dogs. Pacing Clin Electrophysiol
22:14881498
Rodriguez LM, Leunissen J, Hoekstra A et al (1998) Transvenous cold mapping and
cryoablation of the AV node in dogs: observations of chronic lesions and comparison to those obtained using radiofrequency ablation. J Cardiovasc Electrophysiol
9:10551061
Pappone C, Vicedomini G, Manguso F et al (2006) Robotic magnetic navigation for
atrial fibrillation ablation. J Am Coll Cardiol 47:13901400
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Trigger vs Substrate Ablation for the Treatment of Atrial

Fibrillation
ATUL VERMA
Introduction
Radiofrequency ablation of atrial fibrillation (AF) has emerged as a very
effective technique for the treatment of this vexing arrhythmia. When AF
ablation was first described by Haissaguerre et al., nearly 10 years ago, the
technique focused on the elimination of focal triggers for AF emanating
largely from the pulmonary veins (PVs) [1]. In patients with predominantly
paroxysmal AF and little structural heart disease, this paradigm remained
successful, with evidence confirming that elimination of all possible triggers
via pulmonary vein isolation (PVI) would successfully prevent AF recurrence. However, the high success rates of PVI procedures were not replicated
in populations with more persistent and permanent AF. In these patients,
there is greater interest in identifying the critical elements of the atrial substrate required for maintaining AF. By targeting this substrate, it is hoped
that AF ablation will result in better cure rates in a wider spectrum of AF
patients. While markers of AF substrate have been proposed as potential targets of ablation, the efficacy of using such targets is not well known.
Furthermore, whether such targets should be eliminated alone, or in conjunction with known triggers is also not well understood.
Trigger-Based Ablation
The goal of most present-day AF ablation techniques is to electrically disconnect the PVs from the rest of the atrium by ablating around the origin of
Southlake Regional Health Centre, Newmarket, Ontario, Canada
50
Atul Verma
the veins. In their original article, Haissaguerre et al. showed that in the
majority of patients with paroxysmal, lone AF (94%), focal triggers for AF
were found in one or more of the PVs [1]. Although non-PV sites may also
trigger AF, this is less common, occurring in no more than 610% of paroxysmal AF patients [2]. Thus, most present-day techniques are focused on
ablating around the PVs. This typically involves applying lesions circumferentially around and outside of all four PVs, with the goal of achieving complete electrical disconnection between PVs and left atrium (LA) [3].
Although this technique has many names and variations, including pulmonary vein antrum isolation, circumferential PV ablation, and extraostial isolation, the lesion sets produced by the procedures are all very similar.
The success rates are also similar, with recent pooled analyses showing success in the 80% range [4].
Evidence has also suggested that the success of such ablation procedures
is directly related to eliminating conduction between the PVs and the LA.
Verma et al. studied patients post-PV antrum isolation and found that those
with successful outcomes had significantly more PVs isolated than those
who failed [5]. Furthermore, patients who were responsive to antiarrhythmic
medications had more conduction delay between the LA and PVs than those
who were not responsive. Ouyang et al. found that recurrent LA-PV conduction was the predominant finding in patients with recurrent arrhythmia
post-PV antrum isolation [6]. In both studies, patients were successfully
cured by re-isolating all of the PV antra. The majority of patients in these
studies had paroxysmal, lone AF; therefore, these results are not necessarily
applicable to more populations with persistent AF. Furthermore, wide PV
antral isolation requires very extensive lesion sets, which presents risks
including perforation and stroke. Additional or alternative lesions may be
required to modify the atrial substrate for AF maintenance beyond triggerbased ablation.
Substrate-Based Ablation
There is no general consensus on what exactly constitutes the substrate in
clinical AF, making the use of this term somewhat problematic. It seems that
when most clinicians talk about targeting the AF substrate, they are referring
to critical regions or components of the left atrial anatomy/eletrophysiology
that are responsible for allowing AF to perpetuate. Investigators have proposed different ablation targets to try and identify these critical regions,
including complex fractionated electrograms (CFEs), dominant frequencies
(DFs), and autonomic ganglionated plexi (GPs).
Trigger vs Substrate Ablation for the Treatment of Atrial Fibrillation
51
Complex Fractionated Electrograms

From early animal and human experiments, it was found that atrial regions
exhibiting very rapid activation may represent critical rotors responsible for
maintaining AF [7]. Furthermore, regions demonstrating very fragmented
potentials, to the point of almost continuous baseline activity, may represent
pivot points or regions of very slow conduction responsible for continued
fibrillatory conduction [8]. Nademanee et al. first described targeting these
types of electrograms exclusively to ablate AF [9]. They defined complex
fractionated atrial electrograms as electrograms with either: (1) two deflections or more and/or having a perturbation of the baseline with continuous
deflections from a prolonged activation complex, or (2) very short cycle
length (< 120 ms) with or without multiple potentials. These electrograms
also typically have very low voltages of 0.060.25 mV. By ablating these targets, the authors described a 76% success rate after one procedure (91% after
two). Other investigators have also shown that by adding complex atrial electrograms to ablation, success rates may be increased [10]. However, no other
centers have yet validated the CFE-alone technique. One reason is the subjectivity in identifying CFEs. To this end, mapping algorithms have been developed to automatically identify CFEs and early results have been promising
(Fig. 1) [11]. Furthermore, there is some controversy as to the relevance of
Fig. 1a, b. Examples of electrograms that have been labeled as complex fractionated electrograms (CFEs). a Low-amplitude electrograms with multiple components, to the point
of showing almost continuous deflection of the recording baseline. b Electrograms with
two or three components are regarded as fractionated. However, they are not of low
amplitude, nor is there continuous electrical activity (extensive lengths of flat lines
between electrograms), and the cycle length is not particularly short. Thus, these electrograms would not be considered as CFEs
52
Atul Verma
using CFE as a target. There is debate as to the temporal and spatial stability
of CFE and whether these electrograms represent transient regions of wavefront collision as opposed to critical, stable regions of AF perpetuation [12].
Part of the problem is that the definition of CFE varies in the literature, with
some studies defining any electrogram with more than two components as a
CFE, regardless of the cycle length or continuity of the signal (Fig. 2).
While an EGM with two or more components may technically be fractionated, only low-voltage electrograms with rapid or continuous activity have
been described as ablation targets or CFE. Perhaps complex atrial electrograms would be a better term than CFE to avoid confusion. These complex
electrograms have been reported to be spatially stable and their elimination
results in AF cycle-length prolongation, regularization, and possibly longterm AF reduction [9, 13]. Some investigators have reported searching for
such complex activity sites during sinus rhythm by examining the Fourier
transform of sinus electrograms and looking for multiple late, rightwardshifted frequencies, or fibrillar myocardium [14].
Fig. 2. Example of a three-dimensional representation of the left atrium (AP view) with
different shaded regions indicating areas of complex fractionated activity, as determined using an automated mapping algorithm (Ensite NavX, St Jude Medical, St Paul,
MN). By performing point-by-point recording of electrograms, the algorithm automatically detects the number of local electrogram peaks. By averaging the number of peaks
over a period of several seconds, an average cycle length can be calculated. Regions of
short cycle length (< 120 ms) represent regions of complex activity (either very rapid
activity, or continuous deflections of the baseline). These regions may then be targeted
for ablation
53
Dominant Frequency
Since the identification and interpretation of complex signals during AF can
be very challenging, some investigators have used DF sites to identify
regions of high-frequency atrial activity. Sanders et al., for example, reported
that AF termination or AF cycle-length prolongation during ablation was
usually seen during ablation over a DF site [15]. They also showed that the
distribution of DF may vary from patients with paroxysmal AF to those with
permanent disease, with DFs less likely to be associated with the PVs in nonparoxysmal patients. However, as with CFE, there is some question regarding
the temporal and spatial stability of DFs. Ng et al. showed that DF values
were significantly impacted by local electrogram factors, such as amplitude
variation, frequency fluctuation, and electrogram ordering or phase [16].
Thus, DF sites may not necessarily correlate with atrial regions exhibiting
the most rapid or complex atrial activity. There have not yet been any studies
validating the approach of targeting DF sites for AF ablation.
Autonomic Ganglionated Plexi

It has been suggested that autonomic inputs from ganglionated plexi surrounding the heart may contribute to both the initiation and maintenance of
AF [17]. High-frequency stimulation of epicardial autonomic plexi can
induce triggered activity from the pulmonary veins and affect the atrial
refractory periods so as to provide a substrate for the conversion of PV firing into sustained AF [17]. Elimination of vagal inputs prevented AF recurrence in animal and patient models of vagal AF [18, 19]. In AF patients,
recent data suggested that the identification and ablation of autonomic ganglia during PV isolation may improve the long-term success of treatment
[20]. However, in another report, the use of ganglionated plexus ablation
alone in vagal AF patients had a success rate of less than 30% [19]. The location of these plexi has been correlated with the presence and location of CFE
[20], but whether targeting plexi alone will ultimately prove effective
remains unclear.
The Need for Clinical Trials

Ultimately, several targets have been proposed for AF ablation, each with
their own supporting evidence and limitations. It is also quite likely that for
any given approach, there will be overlap in the targets that are ablated. The
creation of circumferential lesions around the PVs may not only isolate
Atul Verma
54
them, but may also eliminate some sites of CFE and some autonomic inputs.
However, whether we need to systematically add other targets to PVI or
move beyond PVI as a whole remains a somewhat controversial issue. The
only way to definitively determine the efficacy and utility of different
approaches is to subject them to the rigor of randomized clinical trials. One
such trial, Substrate versus Trigger Ablation for Reduction of Atrial
Fibrillation (STAR-AF) is designed to specifically look at the utility of targeting CFE vs. PVI. In this randomized, three-arm, multicenter comparison
involving AF patients with largely persistent disease, PVI will be compared
to CFE alone as well as to a hybrid procedure combining PVI and CFE. The
primary outcome will be freedom from AF at one year. Canadian and
European centers are now actively enrolling in the pilot phase of this trial
and results should be available within the next 12 years.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Haissaguerre M, Jais P, Shah DC et al (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med
339(10):659666
Finta B, Haines DE (2004) Catheter ablation therapy for atrial fibrillation. Cardiol
Clin 22(1):127145, ix
Verma A, Marrouche NF, Natale A (2004) Pulmonary vein antrum isolation: intracardiac echocardiography-guided technique. J Cardiovasc Electrophysiol
15(11):13351340
Verma A, Natale A (2005) Should atrial fibrillation ablation be considered first-line
therapy for some patients? Why atrial fibrillation ablation should be considered
first-line therapy for some patients. Circulation 112(8):12141222, discussion 1231
Verma A, Kilicaslan F, Pisano E et al (2005) Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation 112(5):627635
Ouyang F, Antz M, Ernst S et al (2005) Recovered pulmonary vein conduction as a
dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique. Circulation
111(2):127135
Morillo CA, Klein GJ, Jones DL, Guiraudon CM (1995) Chronic rapid atrial pacing.
Structural, functional, and electrophysiological characteristics of a new model of
sustained atrial fibrillation. Circulation 91(5):15881595
Konings KT, Kirchhof CJ, Smeets JR et al (1994) High-density mapping of electrically induced atrial fibrillation in humans. Circulation 89(4):16651680
Nademanee K, McKenzie J, Kosar E et al (2004) A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Amer Coll
Cardiol 43(11):20442053
Verma A, Patel D, Famy T et al (2007) Efficacy of adjuvant anterior left atrial ablation during intracardiac echocardiography-guided pulmonary vein antrum isolation for atrial fibrillation. J Cardiovasc Electrophysiol (in press)

11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
55
Verma A, Novak P, Macle L et al (2006) Effects of ablating complex fractionated

electrograms identified by a novel real-time automated mapping algorithm on
atrial fibrillation cycle length, termination, and inducibility. Can J Cardiol 22(Suppl
D):162D (abs)
Rostock T, Rotter M, Sanders P et al (2006) High-density activation mapping of
fractionated electrograms in the atria of patients with paroxysmal atrial fibrillation. Heart Rhythm 3(1):2734
ONeill MD, Jais P, Takahashi Y et al (2006) The stepwise ablation approach for
chronic atrial fibrillation. Evidence for a cumulative effect. J Interv Card
Electrophysiol 16(3):153167
Pachon MJ, Pachon ME, Pachon MJ et al (2004) A new treatment for atrial fibrillation based on spectral analysis to guide the catheter RF-ablation. Europace
6(6):590601
Sanders P, Berenfeld O, Hocini M et al (2005) Spectral analysis identifies sites of
high-frequency activity maintaining atrial fibrillation in humans. Circulation
112(6):789797
Ng J, Kadish AH, Goldberger JJ (2006) Effect of electrogram characteristics on the
relationship of dominant frequency to atrial activation rate in atrial fibrillation.
Heart Rhythm 3(11):12951305
Patterson E, Po SS, Scherlag BJ, Lazzara R (2005) Triggered firing in pulmonary
veins initiated by in vitro autonomic ner ve stimulation. Heart Rhy thm
2(6):624631
Schauerte P, Scherlag BJ, Pitha J et al (2000) Catheter ablation of cardiac autonomic
nerves for prevention of vagal atrial fibrillation. Circulation 102(22):27742780
Scanavacca M, Pisani CF, Hachul D et al (2006) Selective atrial vagal denervation
guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation.
Circulation 114(9):876885
Scherlag BJ, Nakagawa H, Jackman WM et al (2005) Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card
Electrophysiol 13(Suppl 1):3742
Pacing in Atrial Fibrillation: Is It Still Viable?

OSCAR OSEROFF, GUSTAVO IRALDE, ENRIQUE RETYK
Introduction
Atrial fibrillation (AF) is one of the most intensively studied topics in the
cardiology community due to its growing prevalence, its high morbidity and
costs, and its expanding therapeutic options following new insights into the
disease. The prevalence of AF is around 1% of the general population, and
increases to up to 4% in the population over 65 years old. Similarly, the number of patients that need a pacemaker is constantly growing, and these
patients have much in common with the AF population (elderly, coronary
artery disease, heart failure). Thus, the number of patients with a combination of AF and pacemakers is increasing [1, 2].
This article offers an analysis of the role of cardiac stimulation therapy in
the prevention and treatment of AF. The different pacing modes are compared and the impact on the incidence of AF, the alternatives that pacing
therapy offer in the prevention of AF, and the results of pacing and cardiac
resynchronization therapy (CRT) in patients who need AV nodal ablation for
heart rate control are discussed.
Physiopathologic Targets for Pacing in AF

Episodes of AF are frequently preceded by atrial premature beats (APBs),
which are the trigger for reentry mechanisms in the atrium. The combination of short atrial refractory periods, dispersion of atrial repolarization, and
slow conduct ion favor the init iat ion of AF as well as recur rences.
Pacing and Electrophysiology Division, Bazterrica Clinic, Buenos Aires, Argentina
64
Bradycardia and post-extrasystolic pauses are also associated with APBs and
increase the dispersion of atrial repolarization. Also, atrial wall distension
generated by left ventricular dysfunction or dyssynchrony favors AF [38].
AF initiation mechanisms in paced patients mostly followed a greater
density of APBs and bradycardia. In 70% of the observations, a single direct
trigger, such as frequent APBs or a short burst of atrial tachycardia, was
identified. The recurrences mostly took place after finishing a switch mode
episode (early recurrent atrial fibrillation, ERAF) [9, 10].
These observations suggest that, in a pacemaker patient with a risk of AF,
intervention can be targeted to the substratum (bradycardia, dispersion of
repolarization, long conduction times, post-extrasystolic pauses), to diminishing AF triggers (overdrive suppression of APBs, rate stabilization postAPBs, post-switch mode overdrive pacing), and to avoiding situations of
high myocardial stress (ventricular dyssynchrony, atrioventricular dissociation).
Pacing-Mode Selection
During VVI pacing, the ventricular activation pattern begets, in many
patients, atrial contraction against a closed AV valve, VA conduction, or AV
dissociation, and an abnormal pattern of ventricular contraction with
impaired LV function. This inadequate mechanical function of the heart
leads to pressure overload of the atrium, pacemaker syndrome, and AF.
In a retrospective analysis, Santini et al. observed a higher prevalence of
chronic AF in patients with VVI pacing than in patients with AAI or DDD
pacing (46.4 vs 3.7 and 12.6%). This difference was followed by a higher
stroke-related death in VVI paced patients [11].
In a randomized study that compared AAI vs VVI pacing in sinus node
disease (SND), Andersen et al. found a 46% risk reduction in AF incidence
with physiologic pacing [12].
Different studies comprising thousands of patients have shown similar
results in patients with SND, i.e., AF relative risk reductions between 18 and
46% with physiologic pacing. In patients with AV block (AVB), the results
were not as good, probably due to methodology limitations (Table 1)
[1316].
Thus, physiologic pacing is the preferred approach in SND patients due
to the higher incidence of AF in the VVI mode.
SND
SND and AVB
Tachy-Brady
SND and AVB
SND
AVB
Andersen et al. (1997)
Mattioli et al. (1998)
PAC-A-TACH (1998)
CTOPP (2000)
MOST (2001)
UKPACE (2005)
DDD vs VVI
DDDR vs VVIR
Physiologic vs VVIR
DDD vs VVI
Physiologic vs VVI
AAI vs VVI
Modes
2021
2010
2568
198
210
250
SND, Synus node disease; AVB, atrioventricular block; NS, not significant
Population
Study
Table 1. Studies comparing VVI vs Physiologic pacing modes
3y
2.7 y
3y
2y
2y
5.5 y
Mean follow up
DDD = 3% VVI = 2.8%
DDDR = 15.2% VVIR = 26.7%
Physiol. = 5.3%/y VVIR = 6.5%/y
DDD = 43%VVI = 48%
Physiol. = 20% VVI = 32%
AAI = 23.6% VVI = 34.7%
AF
0.56
0.82
0.62
0.54
RR
NS
0.001
0.05
NS
0.03
0.012

65
66
Right Ventricular Pacing and Dyssynchrony: How Can It Be Avoided?

Right ventricular pacing (RVP) begets an abnormal pattern of ventricular
contraction, with inter- and intraventricular dyssynchrony. It is therefore not
surprising that in Andersens trial, AAI pacing yielded the best results in
terms of reduction of AF episodes [12].
In a MOST (Mode Selection Trial) substudy that compared VVI vs DDD
pacing in SND, the prevalence of RVP and its effects was analyzed in a subgroup of 1339 patients with SND and normal QRS duration. The observation
was that in patients paced in DDDR mode with a nominal AV interval the
cumulative percentage of RVP was higher than in VVI paced patients (90 vs
58%, p =0.001), and it was linearly related with the number of heart failure
(HF)-related hospitalizations and AF episodes. There was a 25% increase in
AF relative risk for every 25% increase in RVP, and it was not dependent on
the pacing mode [17].
More recently, Tops et al. analyzed 55 AF patients with 100% RV pacing
after AV nodal ablation. They found that 49% of the patients had a septal to
posterior wall motion delay > 130 ms, which is a well-known left ventricular
dyssynchrony parameter. Patients with dyssynchrony showed a worsening in
their New York Heart Association functional class (NYHA FC) and a
decrease in left ventricular ejection fraction (LVEF) [18].
Different algorithms have been developed and employed to maintain a
physiologic pattern of ventricular activation, avoiding RV pacing during
DDD pacing. One option is a pacing feature to maintain AAI pacing until an
atrial event is not followed by a sensed QRS, at which point pacing shifts to a
DDD mode (Managed Ventricular Pacing-MVP, Medtronic, Minnesota, MN,
USA). In a study of this type of pacing, Sweeney et al. showed a decrease in
RV pacing from 59.1% with DDD with a long programmed AV delay to 6.5%
with MVP mode. More recently, with a similar feature (AAIsafeR, Ela
Medical, Montrouge, France), Pioger et al. found similar reductions in RV
pacing (9 vs 95%). Other devices able to search for intrinsic AV conduction
(search AV, AV hysteresis) have achieved similar results [1925].
Thus, currently, in a patient with SND and a pacemaker with the abovedescribed programmable possibilities, RV pacing and thereby the incidence
of AF can be reduced.
Special Tools for AF Prevention and Treatment

With the objective of AF prevention, different pacing algorithms have been
developed. The basic mechanism behind all of them is an increase in atrial pac-
67
ing, avoidance of post-extrasystolic pauses, prevention of ERAF, and the use of

anti-tachycardia pacing (ATP) to terminate atrial tachycardia episodes which
trigger AF. Also, and with a different focus, atrial stimulation from different
sites has been analyzed with the goal of diminishing repolarization dispersion.
AF-Prevention Algorithms
In several series of patients with DDD pacing for SND, fewer AF episodes
were observed in patients who had higher atrial-paced percentages (APP).
Thus, a rational treatment approach is to maintain atrium pacing most of the
time, with the objective of overdrive suppression of APBs [26].
Levy et al. initially tested the effect of programming the basic rate 10
beats faster than the intrinsic heart rate of the patient, in a fixed form. They
observed a modest increase in the percentage of atrial pacing but without
any effect on AF episodes [27]. Subsequently, different and more complex
algorithms were developed to dynamically maintain the atrium paced over
the rate of the patients heart rate. With this feature (APP), (atrial overdrive
pacing, atrial preference pacing, atrial pacing preference, pace conditioning
or dynamic atrial overdrive, depending on the manufacturer) an APP
between 90 and 95% was consistently maintained [2837].
Another tool available in some devices is post-switch-mode overdrive
pacing (PSOP), which is used to pace at a higher rate when an AF episode
has ended (detected as a finished switch-mode episode) to overdrive suppress atrial arrhy thmias, which frequently appear shortly after an AF
episode, while avoiding ERAF episodes. These algorithms have been shown
to reduce ERAF episodes, but are limited with respect to the time necessary
to detect sinus rhythm and begin intervention. In many episodes, the intervention starts when the AF is already in progress [33].
A third feature is the shortening in the escape interval after an APB in
order to avoid short/long sequences, which favor the initiation of arrhythmia. This feature is referred to as atrial rate stabilization or post-PAC
response, depending on the manufacturer [3437].
Finally, some devices offer overdrive pacing of certain atrial tachycardia
events in order to terminate them (anti-tachycardia pacing, ATP). This feature has excellent diagnostic accuracy and results in the termination of
> 50% of atrial tachycardia episodes. Of course, success with less-organized
rhythms such as AF is limited [28, 32, 34, 36, 37].
Despite the rationales behind these tools, there is a lack of consistency in
the results of the trials aimed at testing them and methodology limitations
(number of patients, many therapies compared in the same trial, different
68
endpoints, etc.). It is therefore premature to draw any conclusions about

these approaches. The SAFARI trial, with more than 500 patients enrolled,
might overcome some of the methodology limitations, but the results are not
yet available [38].
Multisite Pacing
A different strategy for AF prevention is to focus on substrate modification,
that is, to diminish the intra-atrial conduction delay and dispersion of repolarization by means of alternative-site or multi-site atrial stimulation [39].
Although this strategy yielded a reduction in activation times across the
atrium, manifested by a shorter duration of P waves, there was no change in
AF recurrence. The only exception was post-cardiac surgery AF, the incidence of which was reduced by biatrial transient epicardial pacing. There are
also technical issues that make this tool less attractive [4049].
Ablate and Pace: Role of Cardiac Resynchronization Therapy

In patients with permanent AF, one of the most important treatment targets
is rate control. Usually, it is accomplished with combinations of AV nodal
blocking drugs [1].
Although in most of patients, drug therapy improves symptoms, a significant number of patients do not achieve rate control objectives ; their symptoms persist or they develop tachycardiomyopathy. In the AFFIRM study, a
trial specially designed to test rate control in one of its arms, many patients
needed more than one drug for rate control, and the target of rate control
was achieved only in 70% of the patients [50].
This implies that 30% of patients with permanent AF need a non-pharmacological alternative for rate control. Ablation of AV node and RV pacing
is a well recognized alternative and has been evaluated in many small trials
with different endpoints. When analyzed together in a meta-analysis, the two
approaches brought about an improvement of symptoms as well as other
endpoints, e.g., HF-related admissions and LVEF [51].
Nonetheless, not all patients improve with this therapy or their symptoms
may even worsen. One possible explanation is the left ventricular dyssynchrony generated by RV pacing. Tops et al. found, in 55 patients with AV
nodal ablation and RV pacing, that 49% developed echocardiographic parameters of dyssynchrony, and that the presence of dyssynchrony resulted in a
worst NYHA functional class and a decrease in LVEF [52].
69
It is difficult to define a priori which patient will develop symptoms due

to LV dyssynchrony arising from right ventricular (RV) apex pacing. One
alternative is to upgrade to a CRT device in those patients whose symptoms
worsen and who experience LV dyssy nchrony in the follow-up. This
approach was tested by Leon et al., who found that the upgrade to a CRT
improved NHYA functional class in those patients with RV pacing after AV
nodal ablation who developed severe symptomatic heart failure and a
decrease in LVEF [53].
If about half of the patients will develop dyssynchrony with RV pacing,
then the implantation of a CRT device should lead to improvements in this
group. This strategy was tested in the PAVE study, which randomized 252
patients with permanent AF and AV nodal ablation, to RV or biventricular
pacing. The mean LVEF was 46%, and 70% of all patients were in NYHA
functional class III. The primary endpoint was modification of the distance
walked in the 6-min test at 6 months. In CRT patients, this distance increased
more than in RV-paced patients (31 vs 24%, p = 0.004). The improvement
with CRT was higher in the subgroup of patients with LVEF < 45% and in
those with more severe symptoms (NYHA IIIII). The differences were due
to a worsening in RV-paced patients more than an improvement in CRT
patients [54].
Thus, RV pacing after AV node ablation may be desirable for patients
with preserved LV function, with upgrade to CRT if heart failure and LV dyssynchrony ensue. CRT is recommended for patients with LVEF < 45% and
NYHA functional class IIIII.
Conclusions
In conclusion among the different therapeutic options for AF, pacing is a
useful tool in many of these patients. In SND physiologic pacing is preferred
over VVI. Better algorithms are needed prevent AF. After AV node ablation in
AF, CRT has demonstrated better outcomes with respect to rate control in
patients with lower LVEF.
References
1.
Fuster V, Rydn LE, Cannom DS et al (2006) ACC/AHA/ESC 2006 Guidelines for the
management of patients with atrial fibrillation. A Report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines and
the European Society of Cardiology Committee for Practice Guidelines (Writing
70
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.

Atrial Fibrillation). J Am Coll Cardiol 48(4):e149-e246
Gregoratos G, Gibbons RJ, Antman EM et al (2002) ACC/AHA/NASPE 2002
Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia
Devices. A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation 106:21452161
Haissaguerre M, Jais P, Shah D et al (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med
339:659666
Maurits A, Ausma J, Schotten U (2002) Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 54:230246
Waldo A (2003) Mechanism of atrial fibrillation. J Cardiovasc Electrophysiol
14:S267-S274
Nattel S (2002) Therapeutic implications of atrial fibrillation mechanisms: can
mechanistic insights be used to improve AF management? Cardiovasc Res
54:347360
Bennett MA, Pentecost BL (1970) The pattern of onset and spontaneous cessation
of atrial fibrillation in man. Circulation 41:981988
Solti F, Vecsey T, Kekesi V et al (1989) The effect of atrial dilatation on the genesis
of atrial arrhythmias. Cardiovasc Res 23:882886
Capucci A, Groppi F, Ruiter J et al, on behalf of the AF Therapy Study Group (2000)
Evaluation of re-initiation of atrial fibrillation through a pacemaker with focused
diagnostics. Pacing Clin Electrophysiol 23:722 (abs)
Hoffmann E, Janko S, Hahnewald S et al (2000) The Atrial Fibrillation Therapy
(AFT) trial: novel information on dominant triggers of paroxysmal atrial fibrillation.Circulation 102:II481-II482 (abs)
Santini M, Alexidou G, Ansalone G et al (1990) Relation of prognosis in sick sinus
syndrome to age, conduction defects and modes of permanent atrial pacing. Am J
Cardiol 65:729735
Andersen HR, Thuesen L, Baggar JP et al (1994) Prospective randomised trial of
atrial versus ventricular pacing in sick-sinus syndrome. Lancet 344:15231528
Skanes AC, Krahn AD, Yee R et al, for the CTOPP Investigators (2001) Progression
to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing.
J Am Coll Cardiol 38:167172
Lamas G, Lee K, Weeney M et al, for the Mode Selection Trial in Sinus-Node
Dysfunction (2002) Ventricular pacing or dual chamber pacing for sinus node
dysfunction. N Engl J Med 346:18541862
Lamas GA, Orav EJ, Stambler BS et al, for the Pacemaker Selection in the Elderly
Investigators (1998) Quality of life and clinical outcomes in elderly patients treated
with ventricular pacing as compared with dual-chamber pacing. N Engl J Med
338:10971104
Toff WD, Camm AJ, Skehan JD (2005) Single-chamber versus dual chamber pacing
for high-grade atrioventricular block. N Engl J Med 353:145155
Sweeney MO, Hellkamp AS, Ellenbogen KA et al, for the Mode Selection Trial
(MOST) Investigators (2003) Adverse effect of ventricular pacing on heart failure
and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation
107:29322937
Tops LF, Schalij MJ, Holman ER (2006) Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node
ablation. J Am Coll Cardiol 48:1642 1648

19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
71
Sweeney M, Ellenbogen K, Casavant D et al; The Marquis MVP Download

Investigators (2005) Multicenter, prospective, randomized safety and efficacy study
of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber
ICDs. J Cardiovasc Electrophysiol 16:811817
Pioger G, Leny G, Nitzsche R, Ripart A (2007) AAIsafeR Limits Ventricular Pacing
in Unselected Patients. PACE 30:S66-S70
Milasinovic G, Sperzel J, Smith TW et al, on behalf of The Worldwide EnPulse
Investigators) (2006) Reduction of RV pacing by continuous optimization of the
AV interval. Pacing Clin Electrophysiol 29(4):406412
Melzer C, Sowelam S, Sheldon TJ et al (2005) Induction of right ventricular pacing
in patients with sinus node dysfunction using an enhanced search AV algorithm.
Pacing Clin Electrophysiol 28:521527
Olshansky B, Day J, McGuire M, Pratt T (2005) Inhibition of unnecessary RV pacing
with AV search hysteresis in ICDs (INTRINSIC RV): design and clinical protocol.
Mayumi H, Kohno H, Yasui H et al (1996) Use of automatic mode change between
DDD and AAI to facilitate native atrioventricular conduction in patients with sick
sinus syndrome or transient atrioventricular block. Pacing Clin Electrophysiol
19:17401747
Iliev I, Yamachika S, Muta K et al (2000) Preserving normal ventricular activation
versus atrioventricular delay optimization during pacing: the role of intrinsic
atrioventricular conduction and pacing rate. Pacing Clin Electrophysiol 23:7483
Inoue N, Ishikawa T, Sumita S et al (2006) Suppression of atrial fibrillation by atrial
pacing. Circulation J 70:13981401
Levy T, Walker S, Rex S, Paul V (2000) Does atrial overdrive pacing prevent paroxysmal atrial fibrillation in paced patients? Int J Cardiol 75:9197
Friedman P, Dijkman B, Warman E et al, for the Worldwide Jewel AF Investigators
(2001) Atrial therapies reduce atrial arrhythmia burden in defibrillator patients.
Terranova P, Valli P, Terranova P et al (2006) Pacemaker Prevention therapy in
drugrefractory paroxysmal atrial fibrillation: reliability of diagnostics and effectiveness of prevention pacing therapy in Vitatron Selection Device. Indian Pacing
Electrophysiol J 6(2):6374
Puglisi A, Altamura G, Capestro F et al (2003) Impact of closed-loop stimulation,
overdrive pacing, DDDR pacing mode on atrial tachyarrhythmia burden in bradytachy syndrome. A randomized study. Eur Heart J 24:19521961
De Simona A, Senatore G, Donnici G et al (2007) Dynamic and dual-site atrial
pacing in the prevention of atrial fibrillation: The STimolazione Atriale Dinamica
Multisito (STADIM) Study. PACE 30:S71-S74
Gillis A, Unterberg-Buchwald C, Schmidinger H et al, for the GEM III AT
Worldwide Investigators (2002) Safety and efficacy of advanced atrial pacing therapies for atrial tachyarrhythmias in patients with a new implantable dual chamber
cardioverter-defibrillator. J Am Coll Cardiol 40:16531659
Prerfellner H, Doza P, Ruiter P et al, for the PMOP Investigators (2006) Reduction
of atrial tachyarrhythmia episodes during the overdrive pacing period using the
post-mode switch overdrive pacing (PMOP) algorithm. Heart Rhythm 3:11641171
Israel C, Hu B, Unterberg C et al, on behalf of the AT500 Verification Study
Investigators (2001) Pace-termination and pacing for prevention of atrial
tachyarrhythmias: results from a multicenter study with an implantable device for
atrial therapy. J Cardiovasc Electrophysiol 12:11211128
72
35.
Carlson M, Ip J, Messenger J et al, for the ADOPT Investigators (2003) A new pacemaker algorithm for the treatment of atrial fibrillation. Results of the Atrial
Dynamic Overdrive Pacing Trial (ADOPT). J Am Coll Cardiol 42:627633
Lee M, Weachter R, Pollak S et al, for the ATTEST Investigators (2003) The effect of
atrial pacing therapies on atrial tachyarrhythmia burden and frequency results of a
randomized trial in patients with bradycardia and atrial tachyarrhythmias. J Am
Coll Cardiol 41:19261932
Friedman P, Dijkman B, Warman E et al (2001) Atrial therapies reduce atrial
arrhythmia burden in defibrillator patients. Circulation 104:10231028
Gold MR, Hoffmann E, for the SAFARI Investigators (2006) Rationale and design
of a randomized clinical trial to assess the role of overdrive and triggered prevention pacing therapies in reducing atrial fibrillation: the Study of Atrial Fibrillation
Reduction (SAFARI). Am Heart J 152:231236
Misier AR, Opthof T, van Hemel NM (1992) Increased dispersion of refractoriness
in patients with idiopathic atrial fibrillation. J Am Coll Cardiol 19:15311535
DAllonnes GR, Pavin D, Leclercq C et al (2000) Long term effects of biatrial synchronous pacing to prevent drug-refractory atrial tachyarrhythmia: a 9-year experience. J Cardiovasc Electrophysiol 11:10811091
Daubert C, Leclercq C, Le Breton H et al (1997) Permanent left atrial pacing with a
specifically designed coronary sinus lead. Pacing Clin Electrophysiol 20:27552764
Saksena S, Prakash A, Hill M et al (1996) Prevention of recurrent atrial fibrillation
with chronic dual-site right atrial pacing. J Am Coll Cardiol 28:687694
Delfault P, Saksena S, Prakash A et al (1998) Long-term outcome of patients with
drug-refractory atrial flutter and fibrillation after single- and dual-site right atrial
pacing for arrhythmia prevention. J Am Coll Cardiol 32:19001908
Saksena S, Prakash A, Ziegler P et al, for the DAPPAF Investigators (2002)
Improved suppression of recurrent atrial fibrillation with dual-site right atrial
pacing and antiarrhythmic drug therapy. J Am Coll Cardiol 40:11401150
Leclercq JF, De Sisti A, Fiorello P et al (2000) Is dual site better than single site
atrial pacing in the prevention of atrial fibrillation? Pacing Clin Electrophysiol
23:21012107
Lau CP, Tse HF, Yu CM et al (2001) Dual-site atrial pacing for atrial fibrillation in
patients without bradycardia. Am J Cardiol 88:371375
Mirza I, James S, Holt P (2002) Biatrial pacing for paroxysmal atrial fibrillation. A
randomized prospective study into the suppression of paroxysmal atrial fibrillation using biatrial pacing. J Am Coll Cardiol 40:457463
Levy T, Walker S, Rex S et al (2001) No incremental benefit of multi-site atrial
pacing compared with right atrial pacing in patients with drug refractory paroxysmal atrial fibrillation. Heart 85:4852
Crystal E, Connolly SJ, Sleik K et al (2002) Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery. A meta-analysis.
Olshansky B, Rosenfeld L, Warner A et al; the AFFIRM Investigators (2004) The
Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
study. Approaches to control rate in atrial fibrillation. J Am Coll Cardiol
43:12011208
Wood M, Brown-Mahoney C, Kay G, Ellenbogen K (2000) Clinical outcomes after
ablation and pacing therapy for atrial fibrillation a meta-analysis. Circulation
101:11381144
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.

52.
53.
54.
73
Tops L, Schalij M, Holman E et al (2006) Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node
ablation. J Am Coll Cardiol 48:16421648
Leon A, Greenberg J, Kanuru N et al (2002) Cardiac resynchronization in patients
with congestive heart failure and chronic atrial fibrillation. Effect of biventricular
pacing after chronic right ventricular pacing. J Am Coll Cardiol 39:12581263
Doshi R, Daoud E, Fellows C et al for the PAVE Study Group (2005) Left ventricular-based cardiac stimulation post av nodal ablation evaluation (The PAVE Study).
J Cardiovasc Electrophysiol 16:11601165
Traditional or Device Approach for the Management of Atrial

Fibrillation in Patients with Heart Failure
AURELIO QUESADA, MNICA GIMNEZ, VICTOR PALANCA, JAVIER JIMNEZ, JOS RODA
Introduction
Atrial fibrillation (AF), the most prevalent sustained arrhythmia, is an
increasingly common risk factor in patients with severe left ventricular dysfunction. Moreover, it is associated with a poor prognosis and reduced quality of life for patients with heart failure (HF) syndrome. Trials involving HF
patients have shown that the prevalence of AF in such patients is high, over
2040% [1, 2] and increases with progressive NYHA class. AF is a relevant
factor in terms of the incidence of stroke, morbidity, refractory arrhythmic
episodes, and number of hospitalizations. Moreover, the results of the
GUSTO-III trial confirmed that AF is an independent factor for increased
mortality after myocardial infarction [3]. A retrospective analysis in the
Studies of Left Ventricular Dysfunction Prevention and Treatment Trials
showed that patients with AF at baseline, compared to those in sinus rhythm,
had significantly greater all-cause mortality (34 vs 23%), death attributed to
pump failure (16.7 vs 9.4%), and were more likely to reach the composite end
point of death or hospitalization for HF (45 vs 33%). The European GEM DR
Evaluation [4] also detected a higher early mortality of patients with
implanted cardioverter/defibrillators a population with a high prevalence
of HF and left ventricular dysfunction, related to episodes of AF.
Anatomical factors, such as stretch secondary to increased atrial pressure
and volume, are largely involved in the pathophysiology of AF in the presence of chronic heart failure (CHF). Also, the complex activation of neurohormonal pathways (bradykinin, renin-angiotensin-aldosterone system),
resulting in fibroblast proliferation, collagen accumulation, hypertrophy, and
Cardiac Electrophysiology and Arrhythmias Section, Department of Cardiology,

Hospital General Universitario de Valencia, Valencia, Spain
76
apoptosis, plays a critical role in the mechanism of AF in HF. These events

lead to loss of atrial contraction and dilatation, conduction defects, and atrial remodeling, all of which likely result in AF episodes [5].
Factors inducing anatomical and electrical remodeling make the atrium
and its surrounding structures difficult substrates to approach, such that the
t reat ment of AF in the HF populat ion is par t icularly challeng ing.
Furthermore, this group of patients has the poorest response to the traditional therapeutic approach to AF, i.e., one that is based on the use of antiarrhythmic drugs, but it is also the group most urgently requiring adequate
AF control. Thus, in this setting, non-pharmacological approaches seem
especially appropriate, even more if left ventricular systolic dysfunction is
present [6]. This article reviews the results of the use of each type of device,
including a quick look at pulmonary vein ablation as an essential part of the
armamentarium for treating patients with both AF and HF, and current
approaches to managing these difficult patients.
Pulmonary Vein Ablation

Since its introduction, ablation techniques have evolved from early attempts
to target individual and ectopic foci [79] with simple, fluoroscopy-guided
pulmonary vein isolation in focal AF to segmentary, circumferential, and
anatomical approaches. At the present time, even more complex procedures
targeting not only anatomical structures but also those producing electrophysiologically fractionated electrograms, sites of dominant frequency, and
local non-venous drivers have been proposed as possible targets for patients
with persistent and permanent AF. Although increasing success rates
(6090% free-symptoms AF, mean follow up 412 months) has been demonstrated with circumferential and anatomical isolation techniques in paroxysmal AF, worse results have been obtained with persistent AF [1012]. Even
more, the risk of complications rise according to patient age and the success
rate trends to decrease. These findings confirm the need for randomized trials to assess the wider application of ablation therapy in persistent AF, which
is the type often implicated in the heart failure population.
To date, pulmonary vein ablation for AF has been performed primarily in
patients with preserved left ventricular ejection fraction (LVEF). However as
noted above, AF and HF are frequently linked and, when associated, produce
additive deleterious effects. There are only a few investigations regarding
ablation techniques in patients with AF and low ejection fraction [13, 14]. In
a prospective study, Hsu et al. [14] showed, in 58 patients with CHF, that the
restoration and maintenance of sinus rhythm by catheter ablation in drug-
Traditional or Device Approach for the Management of Atrial Fibrillation in Patients with HF
77
refractory AF yielded significant improvement in left ventricular performance (increased ejection fraction and fractional shortening of 21 and 11%,
respectively), left ventricular dimensions (decreases in the diastolic and systolic diameters of 6 and 8 mm, respectively), exercise capacity, symptoms,
and quality of life. In terms of success rate after initial pulmonary vein isolation, AF recurrence in patients with an impaired LVEF was higher than in
subjects with normal LVEF [15]. Gentlesk et al. [16] recently reported similar
success rates regarding arrhythmia-free follow-up in 67 (18%) patients with
AF and left ventricular systolic dysfunction compared to those with normal
LVEF. Thus, pulmonary vein isolation is a feasible therapeutic option in AF
patients with impaired LVEF, although the potential advantages and disadvantages of this technique must be carefully weighed for each patient.
Randomized studies with more patients and longer follow-up are warranted.
If HF is primarily due to the arrhythmia, especially in younger patients
(< 65 years) with paroxysmal AF usually due to focal mechanisms (focus or
microreentry), pulmonary vein ablation probably should be the first option,
particularly in patients with preserved LVEF. This is important to keep in
mind since the later the treatment is performed, the more difficult it is to
avoid electrical and histological remodeling. In contrast, HF in the older
population is frequently the result of a combined mechanism; thus, while in
selected cases pulmonary vein ablation may be considered, in the vast majority of the patients the best choice would probably involve a simpler procedure (pacemaker device with or without atrioventricular node ablation
regarding LVEF damage, see below).
Atrioventricular Node Ablation and Pacemaker Implantation

Atrioventricular node (AVN) ablation is the simplest treatment alternative in
patients with permanent AF and poorly controlled ventricular rate or in
those with complex, refractory, and highly symptomatic episodes of arrhythmia. However, the mandatory requirements for pacemaker implant have
raised concerns about the long-term performance of these devices, especially
regarding the risk of worsening HF.
The MOST substudy [17] showed that, the higher the percentage of right
ventricular pacing, the higher the number of HF-related hospitalizations and
episodes of AF. For this reason, although it is currently the most frequently
prescribed technique, doubts remain about the role of AVN ablation and the
type of device that is indicated, i.e., single (or dual in paroxysmal AF) chamber or biventricular ones. Therefore, concurrently with these options, pacemaker implantation without AVN ablation should be considered.
78
While symptomatic benefits have been described following AVN ablation,

these may be the only ones demonstrated as neither a reduction in the burden or number of AF episodes nor a consistent long-term hemodynamic
benefit have been definitively proven. In the PA3 study [18], patients with
paroxysmal, drug-refractory AF were randomized after AVN ablation to VVI
or DDDR pacing; no significant differences in terms of episodes and time to
first recurrence between the groups was found. Furthermore, Anguera et al.
[19] described a detrimental hemodynamic effect in patients who underwent
AVN ablation, mainly in those with left ventricular systolic dysfunction. By
the time of that work, detrimental consequences on LV fuction were not suspected. So, the authors attributed the impairment to an increase in the severity of mitral regurgitation.
Direct, solid evidence about the long-term results of RV pacing plus AVN
ablation is lacking, but at least theoretically the effect of subsequent dyssynchrony must be considered in this setting. The PAVE study [20] mildly supported this hypothesis in that cardiac resynchronization therapy (CRT) in
AF patients after AVN ablation yielded modest results in terms of morbidity
improvement (6-min walk test) at 6-month follow-up, although improvement
was greater in patients with low LVEF. Until further trials have been conducted, it seems prudent to use the information derived from the MOST trial
in daily practice, avoiding RV pacing in patients with HF or left ventricular
systolic dysfunction, in whom a cumulated percentage of ventricular pacing
> 40% is associated with a very high risk of worsening HF and increasing
HF-related hospitalizations [21]. Ongoing trials such as APAF (Ablate and
Pace in Atrial Fibrillation) will provide additional and explanatory information on this subject.
While taking into account the results of atrial pacing in AF prevention, in
some patients it is nonetheless worthwhile to wait longer than usual (our
practice is to perform AVN ablation 1 month after pacemaker insertion) in
order to determine whether the new setting allows better control of the
arrhythmia. Atrial pacing minimizing ventricular stimulation can decrease
the number of AF episodes, making it less likely that the patient will develop
permanent AF, especially if there is coexisting bradycardia. This was demonstrated by Andersen et al. in the Danish study [22] comparing AAI/R pacemakers with VVI/R, although obviously the results were partially linked to
the detrimental effects of ventricular pacing, In the MOST study [17], there
were significantly fewer AF episodes in bicameral than with ventricular
stimulation. Similar results were recorded in the CTOPP trial [23].
In the Danish trial, the NYHA classification was also higher (and worsened) in the ventricular group vs the atrial group at long-term follow-up.
79
The mean dose of diuretics increased in the ventricular group vs the atrial
group, while death due to cardiovascular causes was reduced [22]. Nielsen et
al. [24] compared AAIR and DDDR with different programmed AV intervals
and found impaired LVEF in DDDR mode and increased left atrial diameter.
The shorter AV interval was the most harmful setting, as it resulted in
decreased LVEF and an increased number of AF episodes (7.4, 17.5, 23.3% in
AAIR, DDDR with larger and shorter AV interval, respectively).
Further investigations (MVP, PreFER) will reveal whether the avoidance
of ventricle stimulation lessens the incidence of AF arrhythmic and HF
events.
In addition, the exact value of the available, dedicated, AF-prevention
algorithms remains to be determined. The efficacy of these algorithms has
been shown in the setting of bradycardia pacing indication [2528], except
in the AFTherapy trial [29]. These studies evaluating prevention algorithms
have reported a significant reduction in supraventricular ectopic beats and
AF burden and no increase in the incidence of new episodes of AF. Whether
these effects can work synergistically with ventricular pacing reduction algorithms is so far unknown.
Dual Implantable Cardioverter Defibrillator for Atrial Fibrillation

Delivery of synchronous shocks between the high right atrial wall and coronary sinus effectively terminated episodes of AF in a sheep model [30].
Based on these findings, the efficacy of an implantable atrial defibrillator
was evaluated as an alternative in patients with AF [31]. Although initially
atrial stand-alone implantable cardioverter defibrillators (ICDs) were used,
these are no longer available and have been replaced by dual ICDs (Fig. 1).
Anti-tachycardia therapies and atrial and ventricle shocks were shown to
improve quality of life and decrease hospitalizations in patients with drugrefractory AF in the Jewel AF-only study [32]. However, in a small but significant number of patients a large number of atrial discharges is required.
Unfortunately, the energy needed to restore normal sinus rhythm (over 10 J)
is uncomfortable without sedation, making such devices difficult to recommend for wide clinical use.
Recently, the DATAS trial [33, 34] studied 354 patients with class I indication for ICD who were randomized to either dual-chamber or single-chamber defibrillator. The devices were programmed to avoid ventricular pacing.
The composite endpoint (all-cause mortality, invasive intervention, hospitalization due to cardiovascular causes, inappropriate shocks, and sustained
80
Fig. 1. Left anterior oblique projection. Use of a dual defibrillator for the treatment of
drug-refractory atrial fibrillation (AF), with an additional lead in the coronary sinus.
The lead has a coil allowing shock delivery affecting both atria
symptomatic atrial tachyarrhythmias) was significantly reduced in the dualICD group (RR 0.42, 95% CI = 0.180.97) compared to those with singlechamber ICDs. While further investigation is needed in this field, the DATAS
trial nonetheless showed that in patients with class I indication for ICD, i.e.,
a population with a high incidence of atrial tachyarrhythmias and HF, the
tolerance and efficacy of dual-chamber ICD can be maintained when careful
technique and programming that minimizes complications are employed.
Thus, dual-chamber ICDs have an important role in patients without permanent AF and who have ICD indications. In patients with AF only, further
investigations are required to better delineate the most appropriate subgroup of candidates.
Cardiac Resynchronization Therapy

Up to 40% of unselected patients with HF and left ventricular systolic dysfunction who fulfill CRT inclusion criteria have AF [34]. As already stated,
81
AF has an important deleterious influence in the prognosis of HF [35].

However, albeit as yet unconfirmed, it is possible that if CRT reduces NYHA
class, the prevalence of AF and the consequences of this condition will
decrease accordingly. It is important to keep in mind that, although patients
with AF were excluded from large trials that support current CRT guidelines,
relevant work delineating both the efficacy of CRT in AF patients and the
ability of this technique to reduce AF episodes is available.
Several studies pointed out that the results of CRT in AF patients are very
similar to those obtained in sinus rhythm patients. Kies et al. [36] showed
that 6 months of CRT resulted in significant clinical benefits with significant
left atrial and left ventricular reverse remodeling. Despite these beneficial
effects, 93% of patients did not revert to sinus rhythm.
Perhaps, one of the main challenges imposed by AF in CRT is the difficulty to adequately deliver therapy, as shown in Fig. 2. Regardless of this limitation, in one large Spanish registry, the SPARE registry, which enrolled more
than 200 CRT recipients with permanent AF and compared them with sinus
rhythm patients, there were no differences in terms of clinical status or
Fig. 2. Effect of AF on CRT evaluated by the Cardiac Compass storaged data

(Medtronic). Coincident with persistent AF episodes (upper panel) spontaneously
conducted at a high rate to the ventricle (lower panel) there is a significant loss of
biventricular pacing (middle panel). Thus, therapy is not or incompletely delivered.
Even many of the beats marked virtually as paced will be fusion beats with no resynchronization capability
82
anatomical remodeling between the two groups. Interestingly, mortality in

AF patients remained higher than in the control group [37].
Few studies are available on the influence of CRT on the efficacy of atrial
therapies. Complexes devices, such as Concerto (Medtronic) and Renewal 4
AVT (Boston Guidant), offer CRT, atrial anti-tachycardia therapy, and atrial
shocks. Preliminary results have supported the idea that this combined
approach is effective. Fung et al. [38] found that CRT reduced the incidence
of AF in patients with poor left ventricular systolic function, although this
was not the case in CARE-HF patients, probably due to the type of analysis
[39]. Our group [40] described a lower rate of AF (hours of AF and AF
episodes > than 12 h) was associated with CRT vs ICD (7.7 vs 31%, p = 0.03,
95% CI). Based on the lack of significant changes in atrial dimension
observed in this study, our data support a beneficial effect on atrial electrical
remodeling in patients with CRT compared to those with ICD.
Several studies are currently evaluating CRT and AF. The aim of the MASCOT study (Management of Atrial fibrillation Suppression in AF-HF
Comorbidity Therapy) is to evaluate whether resynchronization therapy and
AF prevention algorithms improve the prognosis of these patients [41].
RENEWAL 4 AVT has completed enrolment and is now analyzing the system
performance of LV-Offset and LV-Only CRT modes in HF patients and the
complication-free rate in patients with a history of atrial tachyarrhythmias.
What Is the Best Approach to Drug-Refractory Atrial Fibrillation in HF

Patients?
The best approach is to define. In daily practice, age and left ventricular
function used to be the two most important factors in deciding upon a therapeutic strategy. In the young population (< 65 years old) with HF, the first
option might be pulmonary vein ablation. Unsuccessful results would then
recommend AVN ablation subsequent to a pacing device as the next step. In
patients with preserved ejection fraction without prior ischemic heart disease, a single pacemaker should suffice, with subsequent control of LVEF in
the follow-up. In case of impairment (or if LVEF is already reduced at
implant time), biventricular pacing should be considered. In older patients,
in whom pulmonary vein ablation is riskier and less successful, this
approach to treatment must be considered on a restricted, individual basis.
In the majority of cases, other options are preferable: if LVEF is preserved
and AF is probably permanent, our first option would be CRT pacemaker
with AVN ablation. In patients with systolic dysfunction (< 40%) we recommend implantation of a biventricular ICD, but electrical cardioversion with
83
ACEi or ARB plus amiodarone (if tolerated or not previously used) should be
attempted beforehand. If sinus rhythm is maintained during the following
12 months, we suggest placing an atrial lead and a device with atrial antitachycardia properties. If sinus rhythm is not restored, a biventricular ICD
should be implanted. Finally, all patients should complete treatment with
drugs aimed at establishing optimal ventricular rate control, but on some
occasions AVN ablation will also be needed.
Conclusions
Atrial fibrillation is an increasingly frequent comorbidity in patients with
severe HF, especially in the presence of left ventricular dysfunction. In several settings, the pharmacological approach is ineffective such that non-pharmacological alternatives must be considered. Pulmonary vein ablation is the
option in patients with paroxysmal, focal AF without structural heart disease. If there is associated sinus node dysfunction, atrial-based pacing with
dedicated preventive algorithms can improve outcome. CRT-ICD or dual ICD
is the preferred strategy in patients with poor LVEF, whether or not asynchrony is present. In patients with permanent AF, AVN ablation with resynchronization therapy is the method of choice. Nonetheless, the majority of
patients will need a hybrid approach with different combinations of ablation,
pacing, resynchronization, atrial antitachycardia pacing, and shock. These
approaches may have beneficial and synergistic effects with CRT.
References
1.
2.
3.
4.
5.
6.
Johnstone D, Limancher M, Rousseau M et al (1992) Clinical characteristics of

patients in studies of left ventricular dysfunction. Am J Cardiol 70:894900
CONSENSUS Investigators (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril
Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med
316:14291435
Al-Khatib SM, Stebbins AL, Califf RM et al (2003) Sustained ventricular arrhythmias and mortality among patients with acute myocardial infarction: results from
the GUSTO-III trial. Am Heart J 145:515521
Deneke T, Lawo T, Gerritse B et al (2004) The European GEM DR Trade. Mortality
of patients with implanted cardioverter/defibrillators in relation to episodes of
atrial fibrillation. Europace 6:151158
Savelieva I, Camm J (2004) Atrial Fibrillation and heart failure: natural history and
pharmacological treatment. Europace 5:S5-S19
Packer DL, Asirvathan S, Munger TM (2003) Progress in nonpharmacological therapy of atrial fibrillation. J Cardiovasc Electrophysiol 14:S96-S309
84
7.
Haissaguerre M, Jais P, Dipen C et al (2000) Electrophysiological end point for

catheter ablation of atrial fibrillation initiated from multiple pulmonary venous
foci. Circulation 101:14091417
Pappone C, Augello G, Santinelli V (2005) Atrial Fibrillation ablation. Ital Heart J
6:190199
Huang H, Wang X, Chun J et al (2006) A single pulmonary vein as electrophysiological substrate of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol
17:11931201
Pappone C, Rosanio S, Angello G et al (2003) Mortality, morbidity and quality of
life alter circumferential pulmonary vein ablation for atrial fibrillation: outcomes
from a controlled nonrandomized long term study. J Am Coll Cardiol 42:185197
ONeill MD, Jais P, Takahashi Y et al (2006) The stepwise ablation approach for
chronic atrial fibrillation. Evidence for a cumulative effect. J Interv Card
Calo L, Lamberti F, Loricchio ML et al (2006) Left atrial ablation versus biatrial
ablation for persistent and permanent atrial fibrillation; a prospective and randomized study. J Am Coll Cardiol 47:25042512
Tondo C, Mantica M, Russo G et al (2006) Pulmonary vein vestibule ablation for the
control of atrial fibrillation; a prospective and randomized study. Pacing Clin
Hsu LF, Jais P, Senders P et al (2004) Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 351:23732383
Chen MS, Marrouche NF, Khaykin Y et al (2004) Pulmonary vein isolation for the
treatment of atrial fibrillation in patients with impaired systolic function. J Am
Gentlesk PJ, Saner WH, Gerstenfeld EP et al (2007) Reversal of left ventricular
dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol
18:1517
Sweeny MO, Hellkamp AS, Ellenbogen KA et al (2003) Adverse effect of ventricular
pacing on heart failure and atrial fibrillation among patients with normal baseline
QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
Gillis AM, Connolly SJ, Lacombe P et al (2000) Randomized crossover comparison
of DDDR versus VDD pacing after atriventricular junction ablation for prevention
of atrial fibrillator. The atrial pacing peri-ablation for paroxysmal atrial fibrillation
(PA3 Study Investigators). Circulation 102:736741
Anguera I, Brugada J, Brugada P et al (1998) Deterioro hemodinmico en pacientes
sometidos a ablacin del nodo auriculoventricular. Rev Esp Cardiol 51:307313
Doshi RN, Daoud EG, Fellows C et al; PAVE Study Group (2005) Left ventricularbased cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J
Sweeney MO, Hellkamp AS (2006) Heart failure during cardiac pacing. Circulation
113:20822088
Andersen HR, Nielsen JC, Thomsen PEB et al (1997) Long-term follow up of
patients from randomised trial of atrial versus ventricular pacing for sick sinus
syndrome. Lancet 350:12101216
Connolly SJ, Kerr CR, Gent M et al (2000) Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes.
Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 342:13851391
Nielsen JC, Kristensen L, Andersen HR et al (2003) A randomized comparison of
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
33.
34.
35.
36.
37.
38.
39.
85
atrial and dual chamber in 177 consecutive patients with sick sinus syndrome:
echocardiographic and clinical outcome. J Am Coll Cardiol 42:614623
Ricci R, Santini M, Puglisi A et al (2001) Impact of consistent atrial pacing algorithm on premature atrial complexe number and paroxysmal atrial fibrillation
recurrences in brady-tachy syndrome: a randomized prospective cross over study. J
Interv Card Electrophysiol 5:3344
Carlson MD, Ip J, Messenger J et al, for the Atrial Dynamic Overdrive Pacing Trial
(ADOPT) investigators (2003) A new pacemaker algorithm for the treatment of
atrial fibrillation. Results of the Atrial Dynamic Overdrive Trial (ADOPT). J Am
coll Cardiol 42:627633
Funck RC, Adamec R, Lurje L et al (2000) Atrial overdriving is beneficial in patients
w ith atrial arry thmias: first results of the PROVE Study. Pacing Colin
Gold M, Hoffman E (2006) The impact of atrial prevention pacing on AF burden:
primary results of the Study for Atrial Fibrillation Reduction (SAFARI). Cardiostim
2006, Nice, France. Europace 8 (Suppl 1):222/3 (abs)
Camm J (2002) AF therapy study: preventive pacing for paroxysmal atrial fibrillation. Abstract presented at the 23rd Scientific Sessions NASPE, San Diego, May
2002. Pacing Clin Electrophysiol 24:554 (abs)
Ayers M, Alferness CA, Ilina M et al (1994) Ventricular proarrhythmic effects of
ventricular cycle length and shock strength in a sheep model of transvenous atrial
defibrillation. Circulation 89:413422
Levy S, Ricard P, Lau CP et al (1997) Multicenter low energy transvenous atrial defibrillation (XAD) trial results in different subsets of Atrial fibrillation. J Am Coll
Cardiol 29:750755
Ricci R, Quesada A, Pignalberi C et al (2004) Dual defibrillator improves quality of
life and decreases hospitalizations in patients with drug refractory atrial fibrillation. J Interv Card Electrophysiol 10:8592
Quesada A, Almendral J, Arribas F et al (2004) The DATAS rationale and design: a
controlled, randomized trial to assess the clinical benefit of dual chamber (DDED)
defibrillator. Europace 6:142150
Almendral J, Arribas F, Quesada A et al (2006) Are dual chamber ICD beneficial?
The DATAS trial: a randomised trial focused on clinically significant adverse
events. Cardiostim 2006, LBCT Session, Nice, France
Farwell D, Patel NR, Hall A et al (2000) How many people with heart failure are
appropriate for biventricular resynchronization? Eur Heart J 21:12461250
Khaun AG, Cleland JG, Deedwania PC (2002) Prevention of medical therapy of
atrial arrhythmias in heart failure. Heart Fail Rev 7:267283
Kies P, Leclercq C, Bleeker GB et al (2006) Cardiac resynchronisation therapy in
chronic atrial fibrillation: impact on left atrial size and reversal to sinus rhythm.
Heart 92:490494
Tolosana JM, Garcia Bolao I, Fernadez Lozano I et al (2007) Atrial fibrillation, an
independent predictor of cardiovascular mortality in patients submitted to CRT.
Europace 2007, Lisbon, Portugal, June 2427. Abstract in press
Fung JW, Yu CM, Chan JY et al (2006) Effects of cardiac resynchronization therapy
on incidence of atrial fibrillation in patients with poor left ventricular systolic
function. Am J Cardiol 96:728731
Hoppe UC, Casares JM, Eiskjaer H et al (2006) Effect of cardiac resynchronization
on the incidence of atrial fibrillation in patients with severe heart failure.
86
40.
Valle A, Quesada A, Albero V et al (2007) Incidence of atrial fibrillation in patients

with cardiac resynchronization therapy, a case control study. Europace 2007
Lisbon, Portugal, June 2427. Abstract in press
Padeletti L, Musilli N, Porciani MC et al (2004) Atrial fibrillation and cardiac resynchronization therapy: the MASCOT study. Europace(5 Suppl 1):S49-S54
41.
Conversion of Persistent Atrial Fibrillation to Sinus Rhythm by

DC Shock: Is It Still in Use Two Years After AFFIRM?
VALERIA CALVI, SALVATORE TIMINERI
The AFFIRM trial compared a rhythm-control option, which included cardioversion and maintenance of sinus rhythm (SR), to a rate-control option,
without cardioversion and with control of ventricular rate, in patients with
atrial fibrillation (AF). The 4,060 patients with AF and risk factors for stroke
or death who were enrolled in the study were randomized to one of the two
therapeutic options. At the conclusion of the study, no differences were
found between the two groups with respect to death or composite morbidity;
an increase in the number of hospitalizations was found in the rhythm control group (80.1 vs 73%) and, surprisingly, the strategy of maintaining sinus
rhythm did not lead to a lower rate of ischemic stroke. It was concluded that,
along with anticoagulation, controlling ventricular rate is as effective in preventing morbidity and mortality in patients with AF as traditional antiarrhythmic strategies [13].
However, upon closer analysis, these conclusions are questionable.
Firstly, cross-overs between strategies and subsequent return to the original strategy were common during the trial [3]. For this reason, it is necessary
to analyze the data not only on the basis of an intention to treat principle,
as done in the primary analysis of the AFFIRM study, but also and especially
on the basis of an on-treatment principle, using different types of timedependent covariates that permit the evaluation of patients according to
their actual treatment and status [4]. In this way it is possible to distinguish
the true differences between the two treatment groups and to dissociate the
use of anti-arrhythmic drugs (AADs) from the presence of SR, for a more
careful analysis. Indeed, it is interesting to notice that in this analysis SR was
Cardiology Clinic, University of Catania, Ferrarotto Hospital, Catania, Italy
88
associated with a superior life expectancy and use of AADs was related to a
higher death rate and to a greater number of hospitalizations. This reflects
the fact that currently used AADs are not completely safe and effective.
From the results, it can be concluded that the high mortality in the
rhythm-control arm of the study was due to both the secondary and proarrhythmic effects of AADs [4]. More importantly, it is clear that the results
of the study could be altered by another intrinsic defect: the very small difference between the percentages of patients in SR in the two arms of the
study [5] could have falsified and reduced the awareness of the benefits
obtained by the goal of establishing SR. Moreover, after an accurate data
analysis, the higher mortality in the rhythm-control group was found to be
due mainly to non-cardiac deaths [6], and subjects with heart failure (HF)
and those with a reduced ejection fraction (EF) were not adequately represented. However, both groups would have most likely reaped particular benefit in terms of reduced mortality from the maintenance of SR [1, 2].
These considerations help us to understand how far the AFFIRM data are
from proving a real equivalence in terms of survival between rhythm and
rate control. Moreover, a fundamental purpose of AF therapy is to guarantee,
in addition to a longer life, a better quality of life. It is well-known that AF
can cause a vast stream of symptoms, and different studies have shown that
the quality of life for patients with AF is similar to that for patients with HF
[7].
In this sense, the AFFIRM study revealed a substantial equivalence of the
two strategies, i.e., rate and rhythm control [8]. This was probably due to the
fact that 40% of patients in the rhythm-control group had AF at the end of
the study [9], to the negative effects of AADs [4], and to the exclusion from
the study of patients who could have benefited most from the restoration of
SR, i.e., young patients with lone AF and strongly symptomatic patients
[13]. Other studies have shown an increase in the quality of life and physical performance of patients whose AF was converted to SR [7, 1012]. Finally
AFFIRM did not include young patients or symptomatic patients with little
underlying heart disease, in whom restoration of SR must be considered a
useful therapeutic option.
Nonetheless, how can we use the findings and observations of AFFIRM in
clinical practice? And did the outcomes and implications of the AFFIRM
study change our views on the role of DC shock in the conversion of persistent AF to SR? The conclusions we can draw from AFFIRM are the lack of a
widely effective method for maintaining SR, one that has few side effects.
Also, the management of arrhythmia should be tailored to the patients characteristics, with the most appropriate therapeutic strategy chosen according
Conversion of PAF to Sinus Rhythm by DC Shock: Is It Still in Use Two Years After AFFIRM?
89
to patient history. Rate-control should be reserved for elderly patients with

minimal symptoms related to AF. The physician should assess the symptoms
associated with AF, the presence of HF or other cardiovascular disease, and
the patients age, preference, and compliance with therapy.
Although AFFIRM compared two mid-/long-term pharmacological therapeutic strategies for AF, it did not change current indications for DC shock,
which is the most effective method for restoring SR in patients with persistent AF and is not a mid-/long-term form of treatment. DC shock has several
advantages, including a high success rate and immediate restoration of SR, as
opposed to the unpredictable time required with pharmacologic cardioversion, and the avoidance of potential adverse drug reactions. It is also an elective therapy in patients with AF during acute myocardial infarction, in the
presence of hemodynamic impairment, in patients with Wolff-ParkinsonWhite (WPW) syndrome, and in those with chronic AF resistant to pharmacologic cardioversion. Thus, DC shock remains the most effective procedure
to treat AF, with a success rate close to 100% [1315].
DC shock consists of the delivery of an electrical shock that is synchronized with the intrinsic cardiac activity by R-wave sensing on an ECG lead.
Successful treatment depends on the patients characteristics and underlying
disease and on the current density delivered to the myocardium. The latter is
related to defibrillator voltage, output waveform, size and position of the
electrode paddles, and thoracic impedance. Regarding underlying disease, it
is very important to detect clinical and echocardiographic predictors for
successful electrical cardioversion and maintenance of SR.
The most important negative predictive factors for short-term success of
DC shock seem to be a body mass index (BMI) > 30 and hypertension [16],
whereas factors determining AF recurrence after electrical cardioversion are
older age [1618], long AF duration [18, 19], and left atrial enlargement [17,
19]. Pre-treatment with beta-blockers prior to cardioversion, if possible, has
been suggested [16].
Thoracic electrical impedance is higher in women, increases with
increasing BMI and hemoglobin concentration, and is lower in patients with
HF [20]. It is an essential factor in defining the relation between delivered
energy and transmyocardial current, which is one of the most important
determinants of effectiveness [21]. Thus, the energy delivered should be
adjusted according to clinical variables affecting thoracic electrical impedance in order to obtain sufficient transmyocardial current for successful cardioversion, with minimal myocardial injury.
The output waveform influences the energy delivered during DC shock.
Sinusoidal monophasic shock and biphasic shock can be applied; in the for-
90
mer, current transits in only one direction, while in the latter current transits
between the two electrodes, first in one direction and then in the other. A
rectilinear biphasic waveform is safer because it requires fewer shocks and
lower delivered energy. The effectiveness of this approach, which is nearly
100%, with minor energy delivery and less dermal and myocardial injury,
has been shown in several studies [1315, 22, 23]. Finally, electrode configuration is important for successful cardioversion, as an anterior-posterior
position was shown to be better than an anterior-anterior one [24, 25].
In conclusion, since the AFFIRM study did not address DC shock as a
therapeutic option, the indications for its use have not changed. At the same
time, the results of the AFFIRM study calls attention to the need for new
treatment strategies to maintain SR in patients with cardioverted AF, i.e.,
new atrial-specific AADs [26] or non-pharmacologic therapies, to avoid the
negative effects of the currently used anti-arrhythmics.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
The planning and steering committees of the AFFIRM study for the NHLBI
AFFIRM Investigators (1997) Atrial fibrillation follow-up investigation of rhythm
management: the AFFIRM study design. Am J Cardiol 79:11981202
The AFFIRM Investigators (2002) Baseline characteristics of patients with atrial
fibrillation: the AFFIRM study. Am Heart J 143:9911001
The Atrial Fibrillation follow-up investigation management (AFFIRM)
Investigators (2002) A comparison of rate control and rhythm control in patients
with atrial fibrillation. N Eng J Med 347:18251833
The AFFIRM Investigators (2004) Relationships between sinus rhythm, treatment,
and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm
Management (AFFIRM) Study. Circulation 109:15091513
Chung MK, Shemans KIL, Sherman DG et al, for the AFFIRM investigators (2005)
Functional status in rate-versus rhythm-control strategies for atrial fibrillation:
result of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management
(AFFIRM) Functional Status Sub-study. J Am Coll Cardiol 46:18911899
Steinberg JS, Sadaniantz A, Kron J et al (2004) Analysis of cause-specific mortality
in the atrial fibrillation follow-up investigation of rhythm management study.
Dorian P, Jung W, Newman D et al (2000) The impairment of health related quality
of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 336:13031309
The AFFIRM investigators (2005) Quality of life in Atrial Fibrillation Follow-Up
Investigations of The Rhy thm Management (AFFIRM) study. Am Heart J
149:112120
Singh SN, Tang XC (2006) Quality of life and exercises performance in patients in
sinus rhythm versus persistent atrial fibrillation. A Veterans Affairs cooperative
studies program sub-study. J Am Coll Cardiol 48:721730
Singh BN, Singh SN, Reda DJ et al; Sotalol Amiodarone Atrial Fibrillation Efficacy
Conversion of PAF to Sinus Rhythm by DC Shock: Is It Still in Use Two Years After AFFIRM?
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
91
Trial (SAFE-T) Investigators (2005) Amiodarone versus sotalol for atrial fibrillation. Veterans Affairs cooperative study. N Engl J Med 352:18611872
Dorian P, Paquette M, Newman D et al; CTAF Investigators (2002) Quality of life
improves w ith treatment in the Canadian Trial Fibrillation. Am Heart J
143:984990
Hagens VE, Ranchor AV, Sonderen EV et al; RACE Study Group (2004) Effect of rate
or rhythm control on quality of life in persistent AF. J Am Coll Cardiol 43:241247
Mittal S, Ayati S, Stein KM et al (2000) Transthoracic cardioversion of atrial fibrillation: comparison of rectilinear biphasic versus damped sine wave monophasic
shocks. Circulation 101:12821287
Santomauro M, Borrelli A, Ottaviano L et al (2004) Transthoracic cardioverson in
patients with atrial fibrillation: comparison of three different waveforms. Ital Heart
J Suppl 5:3643
Lindell P, Svenarud P, Albage A et al (2001) Electrical conversion of atrial fibrillation. Superior effects of biphasic transthoracic method when compared with the
conventional monophasic method. Lakartidningen 25:33193321
Miry B, Yeouda E (2006) Electrical cardioversion for persistent or chronic atrial
fibrillation: outcome and clinical factors predicting short and long term success
rate. Int J Cardiol 107:389394
Alt E, Ammer R, Lehmann G et al (1997) Patient characteristics and underlying
heart disease as predictors of recurrent atrial fibrillation after internal and external cardioversion in patients treated with sotalol. Am Heart J 134:419425
Duytschaever M, Haerynck F, Tavernier R et al (1998) Factors influencing long
term persistence of sinus rhytm after a first electrical cardioversion for atrial
fibrillation. Pacing Clin Electrophysiol 21:284287
Frick M, Frykman V, Jensen Urstad M et al (2001) Factors predicting success rate
and recurrence of atrial fibrillation after first electrical cardioversion in patients
with persistent atrial fibrillation. Clin Cardiol 24:238244
Fumagalli S, Boni N, Padeletti M et al (2006) Determinants of thoracic electrical
impedance in external electrical cardioversion of atrial fibrillation. Am J Cardiol
98:8287
American Heart Association (2000) Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care; Part 6: advanced cardiovascular life
support; Section 2: defibrillation. The American Heart Association in collaboration
with the international Liaison Committee on resuscitation. Circulation 102:I90-I94
Block M, Hammel D, Bocker D et al (1994) A prospective randomized cross-over
comparison on mono- and biphasic defibrillation using non thoracotomy lead
configurations in humans. J Cardiovasc Electrophysiol 5:581590
Krasteva V, Trendafilova E, Cansell A, Dasalov I (2001) Assessment of balanced
biphasic defibrillation waveforms in transthoracic atrial cadioversion. J Med Eng
Technol 25:6873
Page RL, Kerber RE, Russell JK et al (2002) Biphasic versus monophasic shock
waveform for conversion of atrial fibrillation: the results of an international randomized, double-blind multicenter trial. J Am Coll Cardiol 39:19561963
Botto GL, Politi A, Bonini W et al (1999) External cardioversion of atrial fibrillation: role of paddle position on technical efficacy and energy requirements. Heart
82:726 730
Roy D, Rowe BH, Stiell IG et al (2004) A randomized, controlled trial of RSD1235, a
novel antiarrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am
Lone Atrial Fibrillation and Sports Activities

F RANCESCO F URLANELLO 1,2, G IUSEPPE I NAMA 3, C LAUDIO P EDRINAZZI 3, LUIGI D E
AMBROGGI1, RICCARDO CAPPATO1
Introduction
Atrial fibrillation (AF) and atrial flutter (AFl) are two of the most frequent
causes of prolonged palpitations [18] in young competitive athletes, even
including those performing sport activities at an elite level. Specifically, these
arrhythmias can occur frequently during training and competitions or in the
post-exercise recovery period, but rarely at rest.
Recurrences of paroxysmal AF in young competitive athletes may interfere with competitive professional activity, mainly if they are characterized
by a high ventricular rate and if their occurrence is exercise-related. In such
cases, AF and AFl may be a cause of non-eligibility for competitive sport
activity [9]. From the pathophysiological point of view, AF in competitive
athletes (with intact heart) seems to be due to adrenergic or vagal mechanisms in susceptible subjects, with neurohormonal imbalance related to
prolonged athletic training [17, 10]. An interesting animal model of AF can
be found in racehorses, in which there is a combination of a large heart
(including the atria), high vagal tone, and episodes of strenuous exercise
leading to atrial stimulation through sudden and strong epinephrine release
[11, 12]. The role of a long-term vigorous and regular sport practice in favoring AF occurrence is supported by the higher prevalence of AF/AFl in master than in younger (< 35 years) athletes and in the general population
[1317].
From 1974 until March 2007, we studied and monitored a population of
3,222 arrhythmic competitive athletes, with a mean age of 22.3 years [5]. In
this population, 285 subjects performed sports activities at an elite level
1IRCCS
Policlinico San Donato, University of Milan; 2Casa di cura Villa Bianca, Trento;
Department of Cardiology, Ospedale Maggiore, 3Crema (CR), Italy
94
Francesco Furlanello, Giuseppe Inama, Claudio Pedrinazzi, Luigi De Ambroggi, Riccardo Cappato
(mean age 24.2 years). Through standardized noninvasive and invasive workups during a long-term follow-up, we found a prevalence of AF/AFl of about
5% among arrhythmic symptomatic competitive athletes and of 5.2% in
those performing sport at an elite level [6].
Even though the lone form of AF/AFl is the most frequent clinical presentation [15, 16, 18], AF/AFl can be the first sign of an underlying heart disease, i.e., myocarditis, hypertrophic cardiac myopathy (HCM), dilated cardiomyopathy (DCM), Brugada syndrome, arrhythmogenic right ventricular
disease (ARVD), ischemic heart disease, and short QT syndrome [17, 19]. A
well-identified initiation mechanism, such as atrioventricular nodal reentrant tachycardia (AVNRT), a concealed form of Wolff-Parkinson-White
(WPW) syndrome, or focal atrial tachycardia, besides left atrial ectopic beats
may sometimes be found.
The present management of athletes with AF is complicated by the problem of illicit drug consumption. The majority of illicit drugs included in the
IOC WADA 2007 list that are taken to improve athletic performance or as
masking agents (in particular alcohol, stimulants, cocaine, cannabinoids,
anabolic androgenic steroids, or a combination of different forbidden substances, or certain dietary supplements) may induce AF through a direct or
indirect arrhythmogenic effect, in healthy subjects and in those with a latent
underlying arrhythmogenic heart disease, including some forms related to
the consumption of illicit drugs [17, 2024].
Discussion
The prevalence of AF/AFl among young competitive athletes actively practicing sport activities and who complain of palpitations is about 5%. This condition predominantly affects males and it is frequently associated with a
sinus bradyarrhythmia mimicking sick sinus syndrome. Moreover, in these
patients AFl is almost always present. If the prescribed medication is taken
correctly by patients, in some cases detraining may be useful in order to
avoid arrhy thmia recurrences without the need for catheter ablation.
However, the interventional approach is the most effective way to treat this
type of arrhythmias.
Furthermore, it is very important to point out that among athletes > 35
years of age who continue to perform sports activities there is a relative risk
of developing AF/AFl of about 3 when compared to young competitive athletes. However, in some cases the arrhythmia may be resolved by a period of
detraining. In consideration of the high prevalence of AFl, interventional
Atrial Fibrillation in Athletes
95
treatment of this arrhythmia is very important in patients undergoing

radiofrequency catheter ablation for lone AF. In fact, AFl rarely occurs in the
isolated typical or atypical form (originating from the left atrium); instead,
during the clinical course of patients with AF who are on anti-arrhythmic
therapy, episodes of IIIIC, drug-induced AFl are relatively frequent. These
are easily prevented through radiofrequency ablation. Moreover, AFl should
be considered as an additional risk factor for the development of AF over
time in endurance athletes who continue to practice their sport [25].
Radiofrequency catheter ablation is also effective in treating some cases
of sinus bradyarrhythmia resembling sick sinus syndrome in competitive
athletes affected by AF/AFl. In such cases, successful ablation of the AF substrate can effectively resolve this associated condition. This approach avoids
the necessity of cardiac pacing, which has been frequently proposed as a
treatment option in middle-aged athletes with particularly evident bradyarrhythmic episodes, especially during the recovery period [26, 27].
There is a growing interest in studying the pathophysiological mechanisms of AF not only in populations of young athletes performing sports
activities at a highly competitive level [1, 3, 4, 6, 7, 28] but even more so in
subjects who continue intense-endurance sports activities after age 35 [15,
18, 29, 30]. Both types of subjects are more highly predisposed than sedentary people to develop AF [31]. It would be very interesting to determine
whether there is a link between excessively strenuous sports activities and
the development of AF with respect to the pathophysiological mechanisms of
the overtraining syndrome. The latter may be the cause of inflammatory
processes and immunological modifications, including the presence of
increased levels of C-reactive protein. It may be that the morphofunctional
modifications occurring beyond the paraphysiological adaptations to sports
activities can be adequately addressed by the prescription of glucocorticoids,
statins, ACE inhibitors, and angiotensin-receptor blockers, in addition to
detraining.
Aknowledgements
The authors thank secretary Anna Stenghel for her help in preparing the manuscript.
References
1.
2.
Furlanello F, Bertoldi A, Dallago M et al (1998) Atrial fibrillation in elite athletes. J

Cardiovasc Electrophysiol 9(Suppl):S63-S68
Zehender M, Meinertz T, Keul J et al (1990) ECG variants and cardiac arrhythmias
in athletes: clinical relevance and prognostic importance. Am Heart J
119:13781394
96
Francesco Furlanello, Giuseppe Inama, Claudio Pedrinazzi, Luigi De Ambroggi, Riccardo Cappato
3.
Biffi A, Piovano G, Verdile L et al (1997) Prognostic evaluation on supraventricular

arrhythmias in athletes. In: Pelliccia A, Caselli G, Bellotti P (eds) Advances in sport
cardiology. Springer, Berlin-New York-Milan, pp 4044
Delise P, Bonso A, Cor L et al (1992) Electrophysiologic substrates of idiopathic
atrial fibrillation in the general population and in athletes. New Trends Arrhyth
8:719724
Furlanello F, Bertoldi A, Fernando F, Biffi A (2000) Competitive athletes with
arrhythmias. Classification, evaluation and treatment. In: Bayes de Luna A,
Furlanello F, Maron BJ, Zipes DP (eds) Arrhythmias and sudden death in athletes.
Kluwer Academic, Dordrecht, pp 89105
Naccarella F, Furlanello F, Bertoldi A et al (2003) Lone atrial fibrillation in athletes: a consequence of long-term intensive sport practice. In: Raviele A (ed) Cardiac
Arrhythmias 2003, Proceedings of the 8th International Workshop on Cardiac
Arrhythmias. Springer Verlag Italia, Milan, pp 1121
Furlanello F, Bertoldi A, Dallago M et al (1994) Atrial fibrillation in top-level athletes. In: Olsson SB, Allessie MA, Campbell RWF (eds) Atrial fibrillation: mechanisms
therapeutic strategies. Futura, Armonk, NY, pp 203204
Durin O (2005) La fibrillazione atriale nello sportivo: quale significato e quali
provvedimenti. In: Inama G (ed) Corso di Aggiornamento ANMCO. Problemi aperti in Cardiologia dello Sport. Crema, Aprile 2005, pp 1526
Heidbuchel H, Panhuyzen-Goedkoop N, Corrado D et al (2006) Recommendations
for participation in leisure-time physical activity and competitive sports in
patients with arrhythmias and potentially arrhythmogenic conditions. Part I:
Supraventricular arrhythmias and pacemakers. Eur J Cardiovasc Prev Rehab
13:475484
Link MS, Hamud MK, Wang PJ et al (2001) Cardiac arrhythmias in the athlete.
Cardiol Rev 9:2130
Williams RB, Harkins LS, Hammond CJ, Wood JL (2001) Racehorse injuries, clinical problems and fatalities recorder on British race courses from flat racing and
National Hunt racing during 1996, 1997 and 1998. Equine Vet J 33:478486
Bove AA (2004) Arrhythmias in professional athletes: focus and atrial fibrillation.
ACC Curr J Rev 2004:4748
Hood S, Northcoic BJ (1999) Cardiac assessment of veteran endurance athletes: a
12-year follow up study. Br J Sports Med 33:239243
Karjalaine U, Kujala U, Kaprio J et al (1998) Lone atrial fibrillation in vigorously
exercising middle aged men: case-control. BMJ 316:17841785
Elosua R, Arquer A, Mont L et al (2006) Lone atrial fibrillation and sport practice.
The no gain without pain history revisited again? Int J Cardiol (epub ahead of
print)
Elosua R, Arquer A, Mont L et al (2006) Sport practice and the risk of lone atrial
fibrillation: a case-control study. Int J Cardiol 108:332337
Saoudi N, Yaici K, Zarkane N et al (2005) Arythmies du sportif. Arch Mal Coeur
98:4853
Turhan H, Aksoy Y, Yetkin E et al (2006) An undesirable cardiac impact of vigorous
sport practice: Lone atrial fibrillation. Int J Cardiol (epub ahead of print)
Liuk MS, Hamoud MK, Wang PJ (2002) Cardiac arrhythmias in the athlete: the
evolving role of electrophysiology. Curr Sci Sports Med Report 1:7585
Furlanello F, Bentivegna S, Cappato R, De Ambroggi L (2003) Arrhythmogenic
effect of illicit drugs in athletes. Ital Heart J 4:829837
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Atrial Fibrillation in Athletes

21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
97
Kloner AR (1998) Illicit drug use in the athlete as a contributor to cardiac events.
In: Estes NA, Salem DN, Wang Pj (eds) Sudden cardiac death in the athlete. Futura,
Armonk, NY, pp 441451
Rich EC, Siebold C, Campion B (1985) Alcohol-related acute atrial fibrillation. A
case-control study and review of 40 patients. Arch Intern Med 145:830833
Bove AA (2002) Dietary supplements in athletes. ACC Curr J Rev 11:1820
Sullivan ML, Martinez CM, Gallagher EJ (1999) Atrial fibrillation and anabolic steroids. J Emerg Med 17:851857
Heidbuchel H, Anne W, Willems R et al (2006) Endurance sports is a risk factor for
atrial fibrillation after ablation for atrial flutter. Int J Cardiol 107:6772
Khaykin Y, Marrouche N, Martin D et al (2004) Pulmonary vein isolation for atrial
fibrillation in patients with symptomatic sinus bradycardia or pauses. J Cardiovasc
Furlanello F, Esposito C, Lupo P et al (2005) Fibrillazione atriale parossistica nel
bradicardico. In: Prati PL (ed) Conoscere e curare il cuore 2005. Essebiemme
Editore, Firenze, pp 261270
Pelliccia A, Maron BJ, Di Paolo FM et al (2005) Prevalence and clinical significance
of left atrial remodeling in competitive athletes. J Am Coll Card 46:690696
Karjalainen J, Kujala UM, Kaprio J et al (1998) Lone atrial fibrillation in vigorously
exercising middle aged men: case-control study. BMJ 316:17841785
Mont L, Sambola A, Brugada J et al (2002) Long-lasting sport practice and lone
atrial fibrillation. Eur Heart J 23:477482
Swanson DR (2006) Atrial fibrillation in athletes: implicit literature-based connections suggest that overtraining and subsequent inflammation may be a contributory mechanism. Med Hypotheses 6:10851092
HEART FAILURE
Determination of Left Ventricular Contractile Reserve

by Dobutamine Stress Echocardiography To Predict the
Response to CRT
CARMINE MUTO, BERNARDINO TUCCILLO
Introduction
Cardiac resynchronization therapy (CRT) has been shown to be a useful
therapeutic option to improve the symptoms, functional capacity, and prognosis of patients with severe heart failure (HF). However, 2030% of patients
do not respond to this form of therapy, underscoring the need for additional
selection criteria to identify potential responders. The aim of this study was
to investigate the value of low-dose dobutamine stress echocardiography
(DSE) to predict reverse remodeling after CRT.
Methods
Forty-two patients with HF (33 males, 10 females; age 65 9 years) with left
ventricular ejection fraction (EF) < 35%, NYHA class IIIIV, and with QRS
duration > 120 ms participated in the study. All patients underwent echocardiographic evaluation, including left ventricular volumes and EF before CRT
and 6 months after implantation.
A 15% reduction of end-systolic volume after 6 months of CRT defined
reverse remodeling. Prior to CRT, intra-left-ventricular asynchrony (LLD)
was defined as a delay between the septum and posterior wall 130 ms, as
determined by M-mode echocardiography. A left contractile reserve shown
by DSE to be 20g/kg min was defined as an increase in EF 10%.
Division of Cardiology, S. Maria di Loreto Hospital, Naples, Italy
118
Carmine Muto, Bernardino Tuccillo
Results
After CRT, reverse remodeling was observed in 25 (59.5%) patients (R group)
whereas 17 (40.5%) (NR group) did not respond to therapy. At baseline, there
were no significant differences between the two groups regarding in end-systolic volume (160 64 ml vs 168 56 ml, n.s.), end-diastolic volume (213
75 ml vs 230 65 ml, n.s.), and EF (26 6% vs 27 7%). Contractile reserve,
evaluated by DSE was present in 100% (25/25) of patients in the R group
while LLD was present in 92% (23/25).
Among the 17 patients in the NR group, contractile reserve was present in
47.2% (8/17) while a LLD was found in 29.4% (5/17). The percent contractile
reserve and the percent LLD were significantly higher in R patients than in
NR ones (p < 0.0001). Reverse remodeling was significantly related to contractile reserve (r = 0.63; p < 0.00001) and to LLD (r = 0.65; p < 0.00001).
Multivariate logistic regression including QRS duration showed that contractile reserve (OR: 11.2; CI: 6.219.8; p < 0.001) and LLD (OR: 18.1; CI:
4.416.8; p < 0.00005) were independent predictors of reverse remodeling.
Conclusions
Our results show that contractile reserve, as evaluated by DSE, is a useful tool
to predict reverse remodeling after CRT. Echocardiographic selection of
patients for CRT should thus include the determination of LLD and contractile reserve.
Evaluation of the Clinical State of Cardiac Resynchronization

Therapy Patients by Continuous Heart-Failure Monitoring
HENRI BENKEMOUN, BERTRAND COLOMBO, JEAN SACREZ, PHILIPPE LAGRANGE,
PHILIPPE CABROL, GABRIEL ROBERT, MARC MOULICHON
Introduction
Heart failure is a major and growing public health problem, affecting more
than 22 million people worldwide. Despite effective drug therapies, the morbidity and mortality associated with heart failure remain unacceptably high.
Increasing numbers of heart-failure patients are receiving device-based therapy, either cardiac resynchronization therapy (CRT) alone or cardiac resynchronization therapy with an implantable cardioverter-defibrillator (CRTICD). Over 60,000 patients around the world were supplied with a CRT system in 2006 alone.
In the USA, heart failure is the most common cause for hospitalization
among patients over 65 years of age [13]. In many developed countries
besides the USA, heart failure is one of the most costly diseases in health
care budgets, with 70% of the expenses going to the treatment of decompensation due to acute heart failure [4]. The factors contributing to hospital
readmission as a result of heart failure include noncompliance (33%), inadequate follow-up (20%), and the patients failure to seek medical attention
when experiencing worsening symptoms (20%) [5].
Although regular monitoring of heart-failure patients is recommended in
management programs [6], none of these measures has shown conclusive
impact on morbidity associated with this condition [7, 8].The ability to better monitor the clinical status of heart-failure patients may provide an early
warning of decompensation, help to reduce hospitalization rates, and
improve patient quality-of-life. The latest generation CRT devices offer tools
to detect changes in clinical status (symptoms or clinical parameters) and to
Cardiologie, Clinique Saint Pierre, Perpignan, France
126
Henri Benkemoun et al.
provide this information to medical staff. Both sides of this new approach of
diagnosis and evaluation of CRT patients by continuous monitoring of heart
failure are aimed at detecting changes in clinical status and providing the
tools with which to communicate them.
Tools To Detect Changes in Clinical Status (Symptoms or Clinical

Parameters)
Automated Monitoring of Intrathoracic Impedance by an Implantable Device
Patients with heart failure are frequently hospitalized for fluid overload.
Measuring intrathoracic impedance in patient with a special CRT-ICD device
implanted in the left pectoral region is a reliable method to identify fluid
overload [9]. Intrathoracic impedance decreases before each decompensation by an average of 12.3% over an average of 18 days. Impedance reduction
begins 15.3 days before the onset of worsening symptoms. There is an
inverse correlation between intrathoracic impedance and pulmonary wedge
pressure, and between intrathoracic impedance and net fluid loss during
hospitalization.
Regular monitoring of intrathoracic impedance may provide an early
warning of impending decompensation. The algorithm proposed for the
detection of intrathoracic impedance reduction produces 1.5 false-positive
detections per patient-year of monitoring.
Heart-Rate Variability Measured by an Implanted CRT Device

Long-term, continuous heart-rate variability (HRV) can be measured from
an implantable CRT device [10]. Continuous HRV is measured as the standard deviation of 5-min median atrial-atrial intervals (SDAAM) sensed by
the device. SDAAM < 50 ms when averaged over 4 weeks is associated with
an increased mortality risk. Moreover, SDAAM was found to be persistently
lower in patients who required hospitalization. SDAAM decreases a median
of 16 days before hospitalization for decompensation due to acute heart failure and returns to baseline after treatment. Automated detection of decreases in SDAAM has a sensitivity of 70% in detecting cardiovascular hospitalization, with 2.4 false-positives per patient-year of follow-up.
These reports indicate that continuous long-term SDAMM is a useful tool
in the clinical management of pat ients w ith chronic hear t failure.
Neurohormonal activation, as suggested by a decrease in SDAAM, occurs
several days to weeks before patients decompensate enough to require hospi-
Evaluation of the Clinical State of CRT Patients by Continuous Heart-Failure Monitoring
127
talization. This finding provides insight into the autonomic mechanisms of

heart-failure physiopathology. In addition, autonomic markers, when continuously measured by implanted CRT devices, offer meaningful information
that may be useful in the day-to-day management of heart failure patients.
Other Parameters Measured by CRT Devices

Body-weight scale, reflecting fluid status and blood pressure, can be measured by the patients and integrated into the data transmitted to the clinical
center. Patient activity, as measured by the activity sensor of the CRT device,
as well as quality of life issues, atrial fibrillation burden, percentage of CRT
delivered, and premature ventricular complex are other relevant parameters
that can be evaluated.
Tools To Communicate
Different systems and approaches are used to transmit information to the
general practitioner and/or the heart-failure specialist. Data from the device
collected are communicated automatically or not and continuously or not,
depending on the extent of patient compliance. Some systems use a call center to answer patients questions. In the future, remote access for pro-active
care will be technically possible.
Conclusions
The new CRT devices are expected to improve patient care with respect to
preventing decompensation induced by acute heart failure. Additional benefits include reduced hospitalizations and heart-failure cost burden and
improvements in the patients quality-of-life. The optimal sensor to detect
changes in clinical status and the best way to transmit the collected data are
still being debated. Ultimately, the best tool to detect heart failure using a
CRT device may be an association of different sensors that monitor each
other. The energy spent to collect and send the data is a key point and poses
a challenge to medical engineering. Evaluation of the clinical state of CRT
patients by continuous heart failure monitoring will eventually become the
responsibility of the physician. These considerations imply that, on the one
hand, clinicians must change their perception of treating heart-failure
patients and, on the other, industry has to not only supply clinicians with
more specific and sensitive tools but also educate them regarding their use.
Henri Benkemoun et al.
128
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Wang L, Lahtinen S, Lentz L et al (2005) Feasibility of using an implantable system

to measure thoracic congestion in an ambulatory chronic heart failure canine
model. Pacing Clin Electrophysiol 28:404411
Mc Alister FA, Ezekowitz JA, Wiebe N et al (2004) Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med
141:381390
Bristow MR, Saxon LA, Boehmer J et al (2004) Cardiac resynchronization therapy
with or without an implantable defibrillator in advanced chronic heart failure. N
Engl J Med 350:21402150
Stewart S, Jenkins A, Buchan S et al (2002) The current cost of heart failure to the
National Health Service in the UK.
Eur J Heart Fail 4:361371
Vinson JM, Rich MW, Sperry JC et al (1990) Early readmission of elderly patients
with heart failure. J Am Geriatr Soc 38:12901295
Hunt SA, Baker DW, Chin MH et al (2001) ACC/AHA Guidelines for the evaluation
and management of chronic heart failure in the adult: executive summary.
Goldberg LR, Piette JD, Walsh MN et al (2003) Randomized trial of a daily electronic home monitoring system in patients with advanced heart failure: the Weight
Monitoring in Heart Failure (WHARF) trial. Am Heart J 146:705712
Louis AA, Turner T, Gretton M et al (2003) A systematic review of telemonitoring
for the management of heart failure. Eur J Heart Fail 5:583590
Yu C, Wang L, Chau E et al (2005) Intrathoracic impedance monitoring in patient
with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 112:841848
Adamson PB, Smith AL, Abraham WT et al (2004) Continuous autonomic assessment in patients with symptomatic heart failure: prognostic value of heart rate
variability measured by implanted cardiac resynchronization device. Circulation
110:23892394
Focus on Optimization of Cardiac Resynchronization

Therapy Techniques
MAURIZIO LUNATI1, YANN POEZEVARA2, ANDREA BONCOMPAGNI3
Introduction
Although cardiac resynchronization therapy (CRT) is now a first-line therapy in moderate to severe congestive heart failure patients with broad QRS, a
number of treatment modalities remain open issues. Patient selection criteria need to be further specified, as a broader population can probably benefit
from CRT. For instance, several clinical trials are currently addressing the
role of CRT in patients with narrow QRS, with mild heart failure (HF) symptoms, or with complete AV block to prevent HF development. But even in
those patients who meet current selection criteria, we need to further understand some aspects of the treatment modalities to offer maximum benefit
from the therapy: Which location for the right ventricular (RV) and left ventricular (LV) pacing leads offers the best resynchronization? How should
CRT parameters (AV and VV delays) be programmed to provide maximum
hemodynamic benefit? Answers to these questions are crucial to reduce the
number of non-responders to CRT, and to maximize the response to CRT by
the majority of patients. In this review we will focus on techniques to optimize CRT programming.
Rationale for Optimization of CRT Parameters

It is commonly admitted that roughly one-third to one-fourth of CRT-indicated patients do not respond to the therapy, showing neither improved
quality of life nor increased exercise capacity. These were the results from
1Cardiology Department, Electrophysiology Unit, Niguarda Ca' Granda Hospital, Milan,

Italy; 2SORIN Group; Les Plessis Robinson Cedex, France; 3SORIN Group, Milan, Italy
120
landmark CRT trials (MUSTIC, MIRACLE, CONTAK CD, PATH CHF), which
demonstrated the efficacy of CRT on functional capacity, and is generally
confirmed by clinical experience. As none of those trials included atrioventricular delay (AVD) optimization, and because right to left ventricle pacing
delay (VV delay) was introduced only in later devices, one can conclude that
CRT optimization will turn out to be a promising way to improve therapeutic
efficacy. However, since those landmark studies, a number of smaller clinical
trials have been carried out. Several studies included invasive contractility
measurements during different pacing configurations. Auricchio et al. found
that AVD was a significant determinant of all LV systolic parameters; also,
optimal AVD was found to be highly patient-dependent [1]. Compared to
conventional simultaneous biventricular pacing, sequential pacing using
VVD was observed to yield incremental benefit from 25 to 35% in terms of
contractility [2, 3]. Some authors found that, during CRT delivery, cardiac
performance is dependent mainly on an optimized AVD, whereas interventricular delay (VVD) accounts for only about 25% of hemodynamic performance [4]. Considering that programmed VVD affects the time to achieve a
global depolarization [5, 6], optimizing CRT should take into account simultaneous AVD and VVD optimization to determine the optimal AVD/VVD
combination.
Although data from these later trials need to be confirmed by long-term
follow-up studies, there is clinical evidence in favor of optimizing CRT parameters. The difficulty lies, of course, in assessing the combination of parameters tailored to each patients needs. Moreover, due to HF evolution over
time, patients usually need constant monitoring with continuous adjustments of AVD and VVD to obtain the best clinical benefit [7, 8]. In the earliest era of resynchronization, optimizing CRT corresponded to selecting the
configuration with the narrowest QRS, but further definitive data demonstrated no relationships between QRS duration and dyssynchrony in HF
patients [9]. For this reason, over time, many echocardiographic techniques
became the gold standard to optimize timing in CRT (optimal AVD and VVD
intervals).
Echocardiography
Leaving out the key role of patient selection in therapeutic success, echocardiography techniques represent the most reliable approach used today to
optimize CRT devices.
As a rule, echocardiographic Doppler is used to measure mitral inflow or
aortic outflow velocities [10] to evaluate different pacing conditions, from
Focus on Optimization of Cardiac Resynchronization Therapy Techniques
121
sinus rhythm to biventricular pacing at different AVD and VVD values. This
method takes into account the present hemodynamic performance of the
cardiac pump, providing, in turn, a direct evaluation of the benefit related to
the chosen optimal configuration. Extensive experience in echocardiography
has led to the widespread use of this method. However, performance is,
unfortunately, very operator-dependent.
Optimal conditions necessarily combine AVD and VVD to obtain the best
hemodynamic systolic and diastolic echocardiographic pattern. Several echo
measurements should then be evaluated, at each AVD interval for each VVD,
resulting (on average) in the need for 30 measurements. Moreover, AVD optimization should be repeated at different pacing rates to obtain an optimal
value also during exercise [11, 12]. Last but not least, an optimal AVD-VVD
combination is a dynamic concept, implying the need for repeated optimization procedures.
Nonetheless, echocardiographic techniques are time-consuming and burdensome procedures; they require skilled staff and are virtually impossible
to perform while the patient exercises [13]. Due to this lack of convenience,
it is very common in clinical practice that echocardiography-based CRT is
optimized only in non-responders to CRT, as a second chance.
Alternative methods have therefore been developed. These are based on
different technologies, with the aim to shorten optimization procedures and
to provide the possibility of easy long-term monitoring.
Hemodynamic Sensors
Many hemodynamic sensors, including pressure sensors and chemical sensors (pH, temperature) were tested in the past, particularly at the time of
rate-response development in pacemakers. Most of them did not overcome
the technological challenge posed by the need for an implantable sensor with
adequate resistance to fibrosis and limited signal drift (de-calibration) over
time. Presently, the only such technology available in the field of CRT is the
peak endocardial acceleration (PEA) sensor.
During isovolumetric contraction and relaxation phases, the myocardium
generates mechanical vibrations; those vibrations are transmitted through
the entire cardiac muscle, independent of ischemia and wall thickness, and
can be measured as endocardial acceleration (EA) by an accelerometer sensor placed in contact with the cardiac walls. The peak-to-peak amplitude
measured during isovolumetric contraction (PEA-I) corresponds to the first
heart sound (FHS) and is highly correlated with heart contractility [14]. In
fact, PEA-I is the principal component of PEA signals and, exactly like the
122
FHS, represents mitral valve closure. Thus, it is very well-correlated with the
LV dP/dt max, in healthy as well as in failing hearts [15] and even during
atrial fibrillation [16]. The capability of a sensor embedded in the tip of a
right ventricular permanent pacing lead to detect PEA signal is well known
[17], but only in the past few years has it been used in the context of a CRT
device. This sensor offers the possibility of long-term monitoring of cardiac
contractility and can be used to optimize AVD and VVD.
According to the concept of FHS detection over different AV activation
sequences, a novel CRT device equipped with PEA sensor implements a proprietary AVD scanning algorithm able to compute optimal AVD based upon
the evaluation of PEA-I [18]. In this CRT device, the procedure to optimize
the AVD is automatically launched every week, without the need of external
intervention. Moreover, the system is able to discriminate between the resting and exercise phases of the patient (by means of a standard gravimetric
accelerometer): every measured optimal AVD is then referred to the corresponding heart rate. This allows the system to build up an optimal AVD
curve with respect to heart rate, enabling AVD optimization for all heart
rates.
PEA can also be used to automatically compute the optimal ventricular
pacing configuration (chamber/s and VVD), leading to a global CRT optimal
assessment. Evaluation of system performance in this regard (VVD optimization) is currently ongoing.
IEGM-Based Method
A new method to determine an optimal CRT configuration has been recently
proposed [19] based on the observation that sequential ventricular pacing
with an appropriate VVD can further increase the mechanical efficiency of
the heart. This method is based on intracardiac electrograms (IEGM) and
consists of estimating optimal VVD. During the latter, the total LV activation
time is reduced, leading to synchronization of the activation pattern and of
mechanical contraction. The system measures the conduction delays
between all the following IEGMs: atrium to sensed IEGM from the LV lead,
atrium to sensed IEGM from the RV lead, pacing from the RV to the sensed
IEGM from the LV, pacing from the LV to the sensed IEGM from the RV
(interventricular conduction delay: pacing from one ventricle to sensing
from the other = correction factor). The optimal VVD is defined by adding
the correction factor to the difference between the atrial and RV IEGM (with
final multiplication by 0.5). This method has been tested in acute conditions
only and remains to be evaluated in chronic conditions.
Focus on Optimization of Cardiac Resynchronization Therapy Techniques
123
Similar to the way described for optimal VVD calculation, the IEGM
method can also be applied for optimal AVD setting, by considering the
intra-atrial delay, and measured in the same way as previously described for
VVD [20].
The main limitation of this approach is that optimization of CRT parameters is based only on conduction times. For the same reason that the QRS
width does not well-reflect the mechanical dyssynchrony of the heart, analysis of conduction times does not indicate the improvements in contractility
that can be expected from CRT.
Conclusions
Echocardiography is currently considered to be the gold standard for CRT
optimization, as it is the most accurate and widespread technique. A proper
analysis should include both AVD and VVD optimization and tissue Doppler
imaging to evaluate the reduction in intra-ventricular dyssynchrony.
However, there is no consensus on the best method to use, and echocardiography can only provides isolated assessment with the patient at rest. For those
reasons, it has a limited role in the day-to-day management of CRT patients,
which would ideally require CRT optimization during patient daily activities
and repeated on a regular basis. To meet these important expectations [21],
researchers will need to focus on the development of implantable sensors
such as the PEA, which is capable of continuously monitoring patient status
and of providing a quick and reliable method for CRT optimization.
References
1.
2.
3.
4.
5.
Auricchio A, Stellbrink C, Block M et al (1999) Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart
failure. Circulation 9:29933001
Perego G, Chianca R, Facchini M et al (2003) Simultaneous vs sequential biventricular pacing in dilated cardiomyopathy: an acute hemodynamic study. Eur J Heart
Fail 5:305313
Van Gelder B, Bracke FA, Meijer A et al (2004) Effect of optimizing the VV interval
on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol
93:15001503
Riedlbauchova L, Kautzner J, Fridl P (2005) Influence of different atrioventricular
and interventricular delays on cardiac output during cardiac resynchronization
therapy. Pacing Clin Electrophysiol 28(Suppl 1):S19-S23
Auricchio A, Fantoni C, Regoli F et al (2004) Characterization of left ventricular
activation in patients with heart failure and left bundle-branch block. Circulation
109:11331139
124
6.
Sogaard P, Egeblad H, Pedersen AK et al (2002) Sequential versus simultaneous

biventricular resynchronization for severe heart failure. Circulation 106:20782084
Porciani MC, Dondina C, Macioce R et al (2006) Temporal variation in optimal
atrioventricular and interventricular delay during cardiac resynchronization therapy. J Card Fai 12:715719
ODonnel D, Nadurata V, Hamer A et al (2005) Long-term variation of cardiac
resynchronization therapy devices. Pacing Clin Electrophysiol 28(Suppl 1):S24-S26
Bleeker GB, Schalij MJ, Molhoek SG et al (2004) Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J
Burri H, Sunthorn H, Shah D, Lerch R (2006) Optimization of device programming
for cardiac resynchronization therapy. Pacing Clin Electrophysiol 29:14161425
Scharf C, Li P, Muntwyler J et al (2005) Rate-dependent AV delay optimization in
cardiac resynchronization therapy. Pacing Clin Electrophysiol 28:279284
Verbeek XA, Vernooy K, Peschar M et al (2003) Intra-ventricular resynchronization
for optimal left ventricular function during pacing in experimental left bundle
branch block. J Am Coll Cardiol 42:558567
Porciani MC, Dondina C, Macioce R et al (2005) Echocardiographic examination of
atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 95:11081110
Plicchi G, Marcelli E, Parlapiano M, Bombardini T (2002) PEA I and PEA II based
implantable haemodynamic monitor: pre clinical studies in sheep. Europace
4:4954
Plicchi G, Marcelli E, Bombardini T, Gaggini G (2002) PEA I and PEA II based
implantable system for monitoring acute ventricular failure. Pacing Clin
Electrophysiol 28(4 Part II):691
Bombardini T, Gaggini G, Marcelli E et al (2000) Peak endocardial acceleration
reflects heart contractility also in atrial fibrillation. Pacing Clin Electrophysiol
23:13811385
Rickards AF, Bombardini T, Corbucci G, Plicchi G (1996) An implantable intracardiac accelerometer for monitoring myocardial contractility. The Multicenter PEA
Study Group. Pacing Clin Electrophysiol 19(12 Pt 1):20662071
Ritter P, Padeletti L, Gillio-Meina L, Gaggini G (1999) Determination of the optimal
atrioventricular delay in DDD pacing. Comparison between echo and peak endocardial acceleration measurements. Europace 1:126130
Min X, Meine M, Baker JH 2nd et al (2007) Estimation of the optimal VV delay by
an IEGM-based method in cardiac resynchronization therapy. Pacing Clin
Electrophysiol 30 (Suppl 1): S19-S22
Gold MR, Niazi I, Giudici M et al (2007) A prospective comparison of AV delay programming methods for hemodynamic optimization during cardiac resynchronization therapy. J Cardiovasc Electrophysiol 18:17
Braunschweig F, Kjellstrom B, Gadler F, Linde C (2004) Optimization of cardiac
resynchronization therapy by continuous hemodynamic monitoring. J Cardiovasc
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Predicting Heart Failure Events in CRT Patients:

Future Challenges
ROBERTO MANTOVAN1, DANILO CONTARDI2, VITTORIO CALZOLARI1, MARTINO CROSATO1,
ZORAN OLIVARI1
Background
Advanced heart failure (HF) and related acute decompensations have
become the single most costly medical syndrome in cardiology. HF leads to
frequent re-hospitalizations: in the US alone, yearly HF hospitalizations
number more than 1 million [1]. A recent analysis carried out in all
European countries led to the conclusion that 75% of all HF-related costs
have to be attributed to HF hospitalizations [2].
Although HF is a syndrome that trends to become chronic, it does not
evolve gradually. In HF patients, phases of relative stability alternate with
acute exacerbations that frequently lead to HF hospitalizations [3]. Thus, the
ability to predict acute events implies an ability to improve patients quality
of life (QoL) and prognosis.
Many clinical and instrumental variables are limited (or of limited usefulness) in predicting HF evolution, as they are often influenced by psychological and subjective factors (dyspnea, QoL, NYHA class) or only able to
describe the clinical status at follow-up (echocardiographic exam, effort test,
6 WT, etc.). There are indeed useful variables to define a worsening profile
(edema, body weight) but the predictive delay is often very short (23
days).
Thus predicting HF events remain a challenge to HF specialists. In this
brief report, we focus our attention on HF patients with indications for cardiac resynchronization therapy (CRT). In addition, we provide an overview
of the potential/real application of several sensors on-board CRT devices
that allow the early identification of acute HF events.
1Cardiovascular Department, S. Maria dei Battuti Hospital, Treviso, Italy; 2SORIN

Group, Clinical Department, Milan, Italy
130
Roberto Mantovan, Danilo Contardi, Vittorio Calzolari, Martino Crosato, Zoran Olivari
The prediction of acute HF events in the population of patients indicated

for CRT has been facilitated by the availability of common sensors technologies in CRT devices. Among them, we discuss the few sensors used in pilot
experiences or which have given interesting preliminary results.
Heart Rate Variability

Several reports have been recently published about the usefulness of heart
rate variability (HRV) in determining the prognosis of HF patients. A first
significant positive experience was reported by Adamson [4] in a 1-year follow-up of 370 CRT patients of NYHA class III/IV. The prognostic value of
HRV in terms of RR variability measured by the CRT device was demonstrated through SDAAM, defined as the average value of the standard deviation of
5-min RR interval clusters. A markedly depressed HRV was significantly
associated with major HF events (HF hospitalizations or death due to HF).
More recently, the HF-HRV Registry [5] reported a significant association
between HRV and clinical outcome in a population of 1,421 CRT patients.
Whether the reverse relationship (reduced HRV and worse clinical profile)
also holds remains to be demonstrated. An Italian observational report on a
large CRT-ICD population (INSYNC ICD Registry) [6] found the same trend
of HRV over time (as measured by implanted CRT-ICDs) in patients of different NYHA classes, but at significantly higher levels in NYHA class II
patients (Fig. 1).
Fig. 1. Trend of SDAAN (specific

measure of HRV defined as the
average value of the standard deviation of 5-min RR interval clusters)
in 509 CRT patients over a 1-year
follow-up. The same profiles were
obtained over time, but at different
levels of variability according to the
different NYHA class (significantly
higher for class II than for class
III/IV)
Predicting Heart Failure Events in CRT Patients: Future Challenges
131
Implantable Hemodynamic Sensor

Several years ago, an implantable hemodynamic monitoring system, the
Chronicle (Medtronic), was realized and implanted in small cohorts of HF
patients. The subcutaneously implanted device (similar to a cardiac pacemaker) was connected to an implantable lead placed in the right ventricular
outflow tract and was equipped with a hemodynamic sensor able to estimate
left ventricular pre-load by measuring pulmonary artery pressures. The
technical feasibility of this approach was successfully tested [7]. Furthermore
in deep safety and efficacy aspects were also tested. The Compass HF randomized efficacy trial [8] showed that this implantable system, together with
a home monitoring network that directly alerts the physician when an
event is foreseen, was able to reduce HF events by 22% vs controls on a 6month follow-up basis (Fig. 2).
Chronicle systems have been confirmed to provide objective hemodynamic and associated clinical data, both in real-time via a programmer and
by telephone hook-up to a central computer site where data can be viewed
via the Internet. With the use of monitoring parameters, appropriate and
timely interventions can be initiated to ensure optimal patient outcome. The
impact of this technology, however, on the mortality and morbidity of
patients with HF has not yet been established. Further testing in larger clinical trials specifically designed to evaluate patient outcome and QoL is therefore needed. Nevertheless, preliminary results are encouraging, such that
implantable monitoring may be a step in the management of patients with
HF that moves beyond traditional care-delivery systems.
Fig. 2. Efficacy objective of the Compass heart HF randomized trial: reduction of heart
failure (HF) events by prediction. A hemodynamic, implantable monitoring system
(Chronicle) vs controls: event rate at short-term follow-up. *Hypothesized event rate=1.2
132
Fluid Overload Sensor

Significant results were obtained with the Optivol (Medtronic) diagnostic
system, which is currently indicated in patients in whom CRT-D is indicated.
Optivol performs daily measurements of intrathoracic impedance in order to
estimate fluid overload in that region, as that finding is often one of the earliest signs of worsening HF. The concept behind the Optivol sensor is very
simple, but powerful: the lower the intrathoracic impedance, the higher the
fluid overload.
To date, the most interesting data were reported by Yu [9] in a study of 33
HF patients, NYHA class III/IV, who were observed for 20 months. The sensitivity of the Optivol sensor (correct detection of true HF events) was 76.9%,
with a predictive delay of 15.3 10.6 days. However, the specificity (rejection
of false HF events) of the system was not satisfactory, since an average of 1.5
inappropriate visits/patient per year of observation was determined.
Transvalvular Impedance Sensor

Only limited animal studies have been carried out for bio-impedance sensors. An abstract was recently published that described the implantation of a
pacemaker (Sophos, Medico) in sheep. The system was equipped with special
algorithms to derive intracardiac impedance values. The authors claimed
[10] that the sensor was able to accurately detect changes in right ventricular
volumes and to directly compute the contractility-derived rate during
inotropic (isoproterenol) stimulation. So far, however, no convincing human
test results have been published.
Workload and Ventilatory Dynamics

Taking advantage of already available sensors technologies in cardiac
implantable devices, some researchers have attempted to use the close relationship between physical activity and ventilatory dynamics [11], which is
thought to be very relevant in the context of progressively failing hearts.
A recent retrospective evaluation concerned patients implanted with a
CRT-pacemaker who were included in the DESIRE clinical trial (n = 49 HF
patients in NYHA class III/IV, with narrow QRS < 150 ms). In this trial,
information regarding capacitive accelerometer and minute ventilation was
obtained from two commonly used sensors and fed to an expert system. A
day by day functional status flag was thus obtained in which -1 = worsening, 0 = stable, and +1 = improving. Accordingly, the system, called Diag-
133
Phy (physiological diagnosis), was able to store an alert in PM memory. All

stored alerts were retrospectively compared to real HF events reported in the
clinical files of the respective patients. This permitted evaluation of: (1) the
performance of Diag-Phy in terms of sensitivity, specificity, negative/positive
predictive values (NPV/PPV); and (2) the predictive delay of Diag-Phy,
defined as the time-distance (days) between the alert and the real event.
The impressive results, still retrospective, were recently published [12]: 25
real HF events (documented by clinical files) were reported in 16 of 49
patients. The sensitivity/specificity of the expert system was, respectively, 88
and 95%, whereas the PPV/NPV was, respectively, 71 and 98%. The predictive
delay, measured by true events, was 14 10 days (min = 3, max = 30 days).
The authors of the study concluded that an analysis of the daily variations in
minute ventilation and physical activity offers a simple and reliable method
to predict acute HF events, and thus to reduce HF-related hospitalizations
(see example in Fig. 3).
Fig. 3. Trend over time (day by day) of ventilatory dynamics (MVR, minute ventilation
at rest; MVA maximum minute ventilation) and physical activity (W, patients workload measured by accelerometer sensor). The patient in this example was hospitalized (HFH) due to progressive dyspnea and signs of heart failure (HF). This event
could have been predicted by the expert system with a 30-days predictive delay
(Alert)
134
Future Perspectives
Several hemodynamic sensors, with very different approaches, limitations,
and efficacies, have been tested to date. Of those technologies potentially
applicable to CRT devices, BEST (SORIN Group) is a very well-known acceleration sensor able to measure mechanical heart vibrations when placed in
contact with the heart walls. The signal generated by the sensor is referred to
as the PEA (peak endocardial acceleration), and it is based on a technology
developed by the manufacturer more than 15 years ago. The sensor mimics
phonocardiography in that it measures the amplitude and timing of heart
vibrations induced by the opening and closing of the cardiac valves (Fig. 4).
The different components of the PEA signal have been investigated during
the last 10 years, leading to the conclusion that PEA-I (principal component,
expression of the mitral valve closure) is very well correlated with left ventricular dP/dt in both healthy and failing hearts [13]. This is the reason why
PEA-I is considered to be a reliable monitor of cardiac inotropic status
(intrinsic contractility), one of the major variables that describe the mechanics of the heart.
Fig. 4. Correspondence between peak endocardial acceleration (PEA) signal components and left ventricular pressure. The sensor tracks the vibrations induced by the
isovolumetric phases of cardiac contraction. The PEA-I component is significantly
correlated with the left ventricular pressure gradient (LV dP/dt)
135
Researchers today are directing their efforts towards the integration of

predictive technologies with hemodynamic sensors in order to develop
approaches that can be used in routine clinical practice.
Future ICD platforms will be aimed at predicting HF events by means of
expert systems able to process several signals on a daily basis: respiratory
variables (Optivol, Diag-Phy, transthoracic impedance), autonomic variables
(HRV, others), cardiac contractility (PEA signal, intracardiac impedance),
and left ventricular pre-load estimation (e.g., the Chronicle experience). The
real issue is to fine-tune the expert system in order to correctly classify and
prioritize the information coming from multiple sensors, mainly to avoid
false-positives (which lead to a high rate of inappropriate visits to the
respective implant centers). For this reason, one of the required features of
such systems is auto-learning (i.e., the system tunes itself automatically). In
this context, fuzzy logic and neural networks may act as optimal partners in
future monitoring systems.
Conclusions
Several implantable sensors are able today to accurately track the evolution
over time of cardiac, metabolic, and ventilatory variables, which provide the
basis for identifying (possibly at a very early stage) trends toward the occurrence of an acute HF event.
Considering the sudden instability of HF patients, instead of obtaining a
clinical image when they present for follow-up, current CRT-Ds can take
advantage of the enormous diagnostic value of the sensor-generated information to continuously describe the clinical profile of HF patients from follow-up to follow-up.
True hemodynamic implantable sensors together with auto-learning software (and, of course, remote monitoring networks) are the last barriers to
making monitoring systems totally autonomous regarding their ability to
predict HF events at early stages, with the aim of reducing HF-related hospitalizations and their tremendous impact on health-care costs, patient QoL,
and prognosis.
Clinical trials to evaluate this technology are on-going, and the preliminary observations have been very promising.
References
1.
Levy D, Kenchaiah S, Larson MG et al (2002) Long-term trends in the incidence of

and survival with heart failure. N Engl J Med 347:13971402
136
2.
Swedberg K, Cleland J, Dargie H et al (2005) Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J
26:11151140
Jain P, Massie BM, Gattis WA et al (2003) Current medical treatment for the exacerbation of chronic heart failure resulting in hospitalization. Am Heart J 145(2
Suppl):S3-S17
Adamson PB, Smith AL, Abraham WT et al (2004) Continuous autonomic assessment in patients with symptomatic heart failure: prognostic value of heart rate
variability measured by an implanted cardiac resynchronization device.
Circulation 110(16):23892394
Gilliam FR III, Kaplan AJ, Black J et al (2007) Changes in heart rate variability, quality of life, and activity in cardiac resynchronization therapy patients: results of the
HF-HRV registry. Pacing Clin Electrophysiol 30(1):5664
Gasparini M, Lunati M, Santini M et al (2006) Long-term survival in patients treated with cardiac resynchronization therapy: a 3-year follow-up study from the
InSync/InSync ICD Italian Registry. Pacing Clin Electrophysiol 29(Suppl 2):S2-S10
Steinhaus D, Reynolds DW, Gadler F et al; Chronicle Investigators (2005) Implant
experience with an implantable hemodynamic monitor for the management of
symptomatic heart failure. Pacing Clin Electrophysiol 28(8):747753
Anonymous (2005) Compass-HF Trial finds continuous monitoring of intracardiac
pressure associated with significant reduction in heart failure hospitalization.
Available at: http://www.medscape.com/viewarticle/501568 (last access July 29,
2005)
Yu CM, Wang L, Chau E et al (2006) Intrathoracic impedance monitoring in
patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 112(6):841848
Chirife R, Di Gregorio F, Gonzales JL et al (2006) Hemodynamic assessment using a
transvalvular impedance sensor. Initial animal experience with implanted Sophos
TM pacemaker. Europace Suppl 1, abs 216/2
Bonnet JL, Geroux L, Cazeau S (1998) Evaluation of a dual sensor rate responsive
pacing system based on a new concept. French Talent DR Pacemaker Investigators.
Pacing Clin Electrophysiol 21(11 Pt 2):21982203
Landolina M, Page E, Galley D et al (2006) Minute Ventilation and patients activity
may predict acute heart failure events in CRT patients. Heart Rhythm Suppl 3(5),
abs P4/95
Plicchi G, Marcelli E, Bombardini T, Gaggini G (2002) PEA I and PEA II based
implantable system for monitoring acute ventricular failure. Pacing Clin
Electrophysiol 24(Part II):691
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Use of Fluid Accumulation Monitoring in HF Patients

SAVERIO IACOPINO1, ROSSELLA ALEMANNI1, ANTONELLA TALERICO1, GENNARO FABIANO1,
SERGIO CANONACO2, FRANCESCO BORRELLO1
Introduction
Decompensated heart failure (HF) is the leading cause of hospital admissions for US Medicare patients. Early detection of intrathoracic fluid accumulation may reduce the morbidity and mortality associated with cardiac
decompensation. Much of the medical costs incurred by decompensated HF
patients are related to hospitalization and rehospitalization [1]. Therefore,
monitoring pulmonary fluid status may be valuable in detecting early
decompensation, and the following adjustment of medical therapy may prevent hospitalization. The new generation of cardiac resynchronization therapy devices, biventricular implantable cardioverter-defibrillators (ICDs;
Medtronic, Minneapolis, MN, USA), permit intrathoracic impedance measurements and thus the detection of changes in pulmonary fluid status. The
feasibility of the InSync Sentry device was recently reported by Yu et al. [2],
who demonstrated an inverse correlation of intrathoracic impedance and
pulmonary capillary wedge pressure with fluid balance. Furthermore, in
these devices, an audible alarm (the OptiVol alert) can be triggered when a
decrease in intrathoracic impedance indicates pulmonary fluid accumulation
secondary to left-sided HF. Accordingly, these new devices may detect HF in
the preclinical phase, which may allow the adjustment of therapy and thereby obviate the need for HF-related hospitalization. Therefore, the aim of this
study was to evaluate the clinical value of this alarm for patients with
decompensated HF.
1Cardiovascular
2Medtronic
Department, Electrophysiology Unit, SantAnna Hospital, Catanzaro;

Italia, Sesto San Giovanni (MI), Italy
138
Saverio Iacopino et al.
Methods
The series consisted of 106 consecutive patients with severe HF who received
InSync Sentry or Concerto biventricular ICDs. Patients were selected according to the traditional criteria for cardiac resynchronization therapy :
advanced HF (New York Heart Association class III or IV), depressed left
ventricular (LV) ejection fraction (< 35%), and prolonged QR duration (>
120 ms). Patients with atrial fibrillation or previously implanted pacemakers
were included. The study protocol was as follows: before device implantation, the patients clinical status was assessed and echocardiography was performed to measure LV ejection fraction. During follow-up, standard outpatient clinic visits and biventricular ICD printouts were scheduled every 3
months. Patients were instructed to visit the hospital in case of OptiVol
alerts.
Device Implantation
A coronary sinus venogram was obtained, after which the LV pacing lead was
inserted. A 9-Fr guiding catheter was used to position the LV lead (Attain
OTW 4193-88, Attain Bipolar OTW 4194-88, Attain Starfix 4195, Medtronic)
in the coronary sinus. The preferred position was a lateral or posterolateral
vein [3]. The right atrial and ventricular leads were positioned conventionally. All leads were connected to the InSync Sentry or Concerto biventricular
ICD.
Intrathoracic Impedance Monitoring

In OptiVol fluid-status monitoring, intrathoracic impedance is measured
every 20 min from 12 a.m. to 5 p.m. using an electrical-impulse vector that
travels between a lead in the right ventricle of the heart and the pulse generator. As a result, the electrical impulse passes through lung tissue.
Comparison of the daily average impedance values with a reference impedance line allows the assessment of a trend line in the OptiVol fluid index
chart. OptiVol fluid-status monitoring is initiated 30 days after device
implantation to allow wound healing. As fluid accumulates in a patients
lungs, the OptiVol fluid index increases. If the condition is not resolved, and
the OptiVol index crosses a predefined threshold, an observation will be triggered. If enabled, an OptiVol alert will also be audible from the implanted
device at a programmed time. If the fluid build-up has resolved and the
trend of the daily impedance value is at or greater than the reference imped-
139
ance values, the OptiVol fluid index returns to zero. The OptiVol threshold
can be programmed at device implantation or at follow-up device checks. In
our analysis, the threshold was programmed at the default value of 60 per
day, on the basis of clinical data for optimal sensitivity and low false-positive
rates [4].
Clinical and Biventricular ICD Monitoring

During follow-up, clinical status and biventricular ICD check-up were performed every 3 months in the outpatient clinic. Based on the biventricular
ICD printouts, the OptiVol index trend and thoracic impedance were determined. Additional visits were planned in case of OptiVol alerts. In patients
who presented with an OptiVol alert, current hemodynamic status was evaluated with respect to patient history, drug use, physical examination, laboratory tests, and chest radiography. An alert was considered as true-positive
and follow-up visits were planned if significant HF needing medical adjustment was confirmed.
Statistical Analysis
Continuous data are presented as mean SD; dichotomous data are presented as numbers and percentages. The data were compared using the unpaired
Students t test for continuous variables and Fishers exact test for proportions. For all tests, p < 0.05 was considered statistically significant.
Results
The baseline characteristics of the 106 patients included in this study (76
men; mean age 66 12 years) are listed in Table 1. Device and lead implantation were successful in all patients and without major complications. All
OptiVol thresholds were set at 60 per day, and an audible alarm was
enabled in all patients. During follow-up (mean 15 5 months), 21 patients
presented with 32 OptiVol alerts. One patient presented with an alert 1 year
after implantation due to subclavian vein thrombosis. The mean time
between implantation and OptiVol alert was 269 117 days. The mean maximal OptiVol fluid index was 109 32 per day. In only 13 alerts, clinical
signs and symptoms of HF requiring medication adjustment were present,
whereas in the remaining alerts these clinical signs and symptoms were
absent (p < 0.05). Only one patient with true-positive alerts had to be admit-
140
Saverio Iacopino et al.
ted for intravenous therapy. It is important to note that no patients were

admitted for acute decompensation after OptiVol alerts. The maximum
OptiVol index was significantly greater in patients with symptoms of HF
than in those without such symptoms (136 39 vs 108 41 per day, p <
0.05). Evaluation of the biventricular ICD printouts did not result in the
detection of inappropriate elevation of the OptiVol fluid index.
Table 1. Patient characteristics (n = 106)

Variable
Age (years)
Men/women
New York Heart Association functional class
Value
66 12
76/30
2.6 0.6
Etiology
Ischemic
Nonischemic
QRS duration (ms)
Sinus rhythm
Atrial fibrillation
Paced
Left ventricular ejection fraction (%)
Left ventricular end-diastolic volume (ml)
Left ventricular end-systolic volume (ml)
75 (70%)
31 (30%)
153 37
96 (90.6%)
8 (7.5%)
2 (1.9%)
24 6
214 75
161 77
Medication
Diuretics
Angiotensin-converting-enzyme inhibitors
-Blockers
Spironolactone
Digoxin
102 (96%)
99 (93%)
83 (78%)
56 (52%)
36 (33%)
Discussion
Decompensated HF is associated with high morbidity, mortality, and treatment costs [1]. The ability to monitor pulmonary fluid status may permit the
early identification of decompensated HF, which in turn may reduce the
number of hospitalizat ions and improve pat ients qualit y of life.
Intrathoracic fluid-status monitoring was first tested in the Medtronic
Impedance Diagnostics in Heart Failure Trial (MID-HeFT) [2]. A considerable delay between the onset of symptoms and the initiation of therapy was
found. Evangelista et al.. [5] reported a mean delay from the onset of worsening symptoms to hospital admission of 3 days, and almost 30% of the
patients had delays > 5 days.
141
The present findings demonstrate that OptiVol intrathoracic impedance

measurement may be a useful tool to prevent worsening HF symptoms. The
proposed threshold for the OptiVol fluid alert of 60 per day is very sensitive, but at the cost of low specificity, because more than half of the alerts
were false-positives. The maximum OptiVol index was significantly greater
in patients with symptoms of HF than in patients without these symptoms.
Consequently, increasing the threshold for the OptiVol alert provided a better balance between sensitivity and specificity to predict decompensated HF.
In conclusion, with a cut-off value for the OptiVol threshold of 60 per
day, a reasonable balance between sensitivity and specificity is obtained. Our
results confirm the clinical value of the Optivol alert for patients with
decompensated HF. These findings are relevant to the increasing number of
patients with HF who are being considered for device therapy.
References
1.
2.
3.
4.
5.
Thom T, Haase N, Rosamond W et al (2006) Heart disease and stroke statistics

2006 update: a report from the American Heart Association Statistics Committee
and Stroke Statistics Subcommittee. Circulation 113:e85-e151
Yu CM, Wang L, Chau E et al (2005) Intrathoracic impedance monitoring in
patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 112:841848
Alonso C, Leclercq C, Victor F et al (1999) Electrocardiographic predictive factors
of long-term clinical improvement with multisite biventricular pacing in advanced
heart failure. Am J Cardiol 84:14171421
Stadler RW, Wang L, Yu CM et al (2003) Automated detection of decreases in
intrathoracic impedance to predict CHF hospitalization. Pacing Clin Electrophysiol
26:16
Evangelista LS, Dracup K, Doering LV (2000) Treatment-seeking delays in heart failure patients. J Heart Lung Transplant 19:932938
Heart-Failure Management: Focus on Heart-Failure

Practice Guidelines
EUGENE CRYSTAL, RAJNEESH CALTON
Introduction
Heart failure (HF) is associated with a high burden of mortality and morbidity, reduced quality of life, and increasing healthcare costs [1, 2]. HF is largely
a disease of old age, and it is becoming increasingly prevalent with the gradual aging of the global population [3]. HF is a complex syndrome in which
abnormal heart function results in, or increases the subsequent risk of clinical symptoms and signs of low cardiac output and/or pulmonary and systemic congestion [4].
Because most evidence-based recommendations for HF management
derive from clinical trials involving patients with significant left ventricular
systolic dysfunction, the term heart failure in various guideline documents
has been used to refer to predominant left ventricular systolic dysfunction,
unless otherwise reported [57]. The increasing recognition of the existence
of clinical HF in patients with normal ejection fraction (EF) has led to
heightened awareness of the limitations of evidence-based therapy for this
important group of patients. A better understanding of the underlying
pathophysiological mechanism, combined with the many new treatments
developed over the last 20 years, has greatly improved the prognosis of
patients with HF, and many patients can now hope for long periods of stable
improved symptoms and improved heart function. Nonetheless, an inexorable course of HF can also occur, while many new approaches to treatment
continue to develop. Advances in multidisciplinary care, heart failure clinics,
polypharmacy, device therapy, and surgical approaches have greatly helped
in improving the care of patients with HF [6].
Department of Cardiology, Schulich Heart Centre, Sunnybrook Health Sciences Centre,

University of Toronto, Toronto (ON), Canada
102
Heart failure is major and growing public health problem. In the USA,
approximately 5 million patients have HF, and more than 550,000 patients
are diagnosed with first-time HF each year. HF is the primary reason for
1215 million office visits and 6.5 million hospital days each year [6]. Over
one million patients are hospitalized annually for HF as the primary diagnosis [6]. HF treatment also causes a major economic burden on healthcare
expenditures. In the USA, in 2005, the estimated total direct and indirect cost
of HF was approximately $27.9 billion [6].
The European society of Cardiology (ESC) represents European countries
with a population of over 900 million and these countries have at least 10
million patients with HF [7]. There are also patients with myocardial systolic
dysfunction without symptoms of HF who also constitute approximately a
similar prevalence [8]. The prognosis of HF is uniformly poor if the underlying problem cannot be rectified. Half of patients carrying a diagnosis of HF
die within 4 years; in patients with severe heart failure, more than 50% die
within 1 year [9].
Management of Heart Failure

Management of HF begins with an accurate diagnosis and requires a rational
combination-drug therapy; individualization of care for each patient based
on their symptoms, clinical presentation, and disease severity; appropriate
mechanical interventions, including revascularization and devices; collaborative efforts among healthcare professionals; and education and cooperation of the patient and their immediate caregivers. Managing patients with
HF can be challenging, and practice guidelines provide a great help in caring
for such patients. These published guidelines and consensus recommendations provide an evidence-based roadmap to translate knowledge into practice and allow healthcare practitioners to reach the best clinical judgment
and decisions for their individual patients.
Presently, three main guidelines for the diagnosis and management of
chronic HF in adults are followed internationally. These are: (1) ACC/AHA
2005 guideline update for the diagnosis and management of chronic heart
failure in adults: a report of the American College of Cardiology /American
Heart Association task force on practice guidelines: Developed in collaboration with the American College of Chest Physicians and the International
Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm
Society [6]; (2) ESC Guidelines: guidelines for the diagnosis and treatment of
chronic heart failure (Update 2005). The task force for the diagnosis and
treatment of chronic heart failure of the European Society of Cardiology [7];
Heart-Failure Management: Focus on Heart-Failure Practice Guidelines
103
and (3) Canadian Cardiovascular Societ y Consensus Conference

Recommendations on heart failure 2006: diagnosis and management [5].
All three guidelines are in agreement in defining the class of recommendation and the grade of evidence for any diagnostic procedure or treatment.
Class I: Evidence or general agreement that a given procedure or treatment is beneficial, useful, and effective.
Class II: Conflicting evidence or a divergence of opinion about the usefulness or efficacy of the procedure or treatment.
Class IIa: Weight of evidence is in favor of usefulness or efficacy.
Class IIb: Usefulness or efficacy is less well-established by evidence or
opinion.
Class III: Evidence or general agreement that the procedure or treatment
is not useful or effective and in some cases may be harmful.
Level of evidence A: Data derived from multiple randomized clinical trials or meta-analysis.
Level of evidence B: Data derive from a single randomized clinical trial or
nonrandomized studies.
Level of evidence C: Consensus of opinion of experts and/or small studies.
Management of HF in general constitutes nonpharmacological methods,
pharmacotherapy, device therapy, and surgical procedures. This article compares the recommendations made by different practice guidelines for the
management of patients with chronic HF.
Nonpharmacological Interventions
In patients with HF in the presence of systolic left ventricular (LV) dysfunction
(LVEF 40%), all symptomatic patients should be advised about exercise training, salt and fluid restriction, and weight management. Aggressive risk factor
reduction should be attempted and lifestyle modification should be advised.
All the guidelines recommend dietary salt restriction (class I, level C).
The CCS and ESC guidelines recommend exercise training in HF patients
(class I, level C). The ACC/AHA guidelines recommend exercise training in
patients with HF as class I, level B indication. The CCS guidelines stress daily
weight measurements (class I, level C) while ACC/AHA guidelines advise
that the healthcare provider should record the body weight of the patient at
each visit. Avoidance of smoking, excessive use of alcohol, and use of illicit
drugs is stressed in ACC/AHA and ESC guidelines. Recommendations made
in different practice guidelines for nonpharmacological interventions in HF
are shown in Table 1.
104
Table 1. Non-pharmacological management of heart failure (HF): comparison of different practice guidelines
Indication
ACC/AHA
ESC
CCS consensus
guideline (2005) guideline (2005) conference on HF
recommendations
(2006)
Exercise training
Class I, level B
Class I, level C
Class II a, level B
Dietary salt restriction
Class I, level C
Class I, level C
Class I, level C
Daily morning weight

monitoring
Class I, level C
Daily fluid restriction

Avoid: smoking,
excessive alcohol use,
and illicit drug use
Class I, level C
Class I, level C
Class I, level C
Class I, level C
Pharmacotherapy
There have been many landmark clinical trials and meta-analysis of the use
of angiotensin-converting enzyme inhibitors (ACEI) [10] and beta-blockers
(BB) [11] in HF, such that these types of drugs have become standard therapy and should be considered in all patients diagnosed with HF. The timing of
introduction should be individualized to maximize tolerability and longterm persistence with therapy. In general, acute symptoms should be
relieved, but an ACEI or a BB should be introduced as early as the patients
condition allows. All of the practice guidelines are in agreement for strongly
recommending (class I, level A) the use of ACEI and BB in patients with HF
unless contraindications exist. Tables 2 and 3 list the practice guideline recommendations for the use of ACEIs and BBs in HF patients.
In patients who are already on a combination of ACEI and BB but continue to have heart failure symptoms or hospitalizations, an angiotensin-IIreceptor blockers (ARB) should be added [12]. Aldosterone antagonists
(spironolactone, eplerenone) are effective in patients with severe postmyocardial-infarction HF or in long-term follow-up, especially in those
patients recently hospitalized for HF [13]. Recommendations of practice
guidelines is shown in Table 2.
105
Table 2. Pharmacotherapy of heart failure: comparison of different practice guidelines

Drugs
ACC/AHA
guideline (2005)
ESC
guideline (2005)
CCS consensus
conference on HF
recommendations
(2006)
ACE inhibitors
HT and LVH,
no symptom of HF
Class IIa, level B
Class IIa, level B
Asymptomatic patients,
LVEF 35%
Class I, level A
Class I, level A
Class I, level A
HF symptoms,
LVEF 40%
Class I, level A
Class I, level A
Class I, level A
Post-AMI, LVEF 40%,

AHF post AMI
Class I, level A
Class I, level A
Class I, level A
ARBs
Patients who cannot
tolerate ACEI; low EF,
no symptom of HF
Class I, level A
Class I, level A
ARBs instead of ACEI

in AHF with AMI or HF
symptoms with LVEF 40%
Class IIa, level A
Class I, level B
Class I, level B
ARBs added to ACEI for

persistent HF symptoms
Class IIb, level B
Class IIa, level B
Class I, level A
ARBs with ACEI when

beta-blockers are
contraindicated
or not tolerated
Class IIa, level B
Aldosterone antagonists
Severe HF symptoms,
LVEF 30%, and optimized
drug therapy
AHF with LVEF 30%
following AMI
Class I, level B
Class I, level B
Class I, level B
Class I, level B
Class IIa, level B
ACEI, Angiotensin-converting-enzyme inhibitors; ARBs, angiotensin II receptor blockers; HF, heart failure; LVEF, left ventricular ejection fraction; AHF, acute heart failure;
AMI, acute myocardial infarction; LVH, left ventricular hypertrophy
106
Angiotensin-Converting-Enzyme Inhibitors
ACEI should be used in all patients as soon as safely possible after acute
myocardial infarction, and should be continued indefinitely if LVEF is <
40% or if acute HF complicated the myocardial infarction (class I, level A).
ACEI should be used in all asymptomatic patients with an LVEF < 35%
(class I, level A).
ACEI should be used in all patients with symptoms of HF and an LVEF <
40% (class I, level A).
Angiotensin-Receptor Blockers
ARBs should be used in patients who cannot tolerate ACEIs, although

renal dysfunction and hyperkalemia may recur (class I, level A).
ARBs should be added to an ACEI for patients with persistent HF symptoms who are assessed to be at increased risk of HF hospitalization, despite
optimal treatment with other recommended drugs (class I, level A).
ARBs may be considered instead of an ACEI for patients with acute MI
with acute HF or LVEF < 40% (class I, level B).
ARBs may also be considered as adjunctive therapy to ACEI when BB are
either contraindicated or not tolerated after careful attempt at initiation
(class IIa, level B).
Beta-blockers
All HF patients with an LVEF 40% should receive a BB proven to be

beneficial in large-scale clinical trials (carvedilol, bisoprolol, metoprolol
CR/XL) (class I, level A).
Patients with NYHA class IV symptoms should be stabilized before initiation of a BB (class I, level C).
Therapy should be initiated at a low dose and titrated to the target dose
used in large-scale clinical trials or the maximum tolerated dose if less
than the target dose (class I, level B).
Beta-blockers should not normally be introduced in patients with symptomatic hypotension despite adjustment of other therapies, severe reactive airway disease, symptomatic bradycardia, or significant AV block
without a permanent pacemaker. Stable chronic obstructive pulmonary
disease is not a contraindication (class I, level B).
107
Aldosterone Antagonists
Aldosterone antagonism with spironolactone or eplerenone should be

considered for patients with an LVEF < 30% and severe symptomatic
chronic HF despite optimization of other recommended treatments (class
I, level B), or acute HF with an LVEF < 30% following myocardial infarction (class IIa, level B), if serum creatinine is < 200 mol/l and potassium
is < 5.2 mmol/l.
Vasodilators
The combination of isosorbide dinitrate and hydralazine should be considered in addition to standard therapy for African-Americans with systolic dysfunction (class IIa, level B), and may be considered for other HF
patients unable to tolerate other recommended standard therapy (class
IIb, level B). Practice guideline recommendations for the use of vasodilators are given in Table 3.
Diuretics
A loop diuretic, such as furosemide, is recommended for most patients

with HF and congestive symptoms. Once acute congestion is cleared, the
lowest minimal dose should be used that is comparable with stable signs
and symptoms (class I, level C).
For patients with persistent volume overload despite optimal, other medical therapy and an increase in loop diuretics, cautious addition of a second diuretic (for example, a thiazide or low-dose metolazone) may be
considered as long as it is possible to closely monitor morning daily
weight, renal function, and serum potassium (class IIb, level B).
Digoxin
In patients in sinus rhythm who continue to have moderate to severe persistent symptoms despite optimized HF medical therapy, digoxin is recommended to relieve symptoms and reduce hospitalizations (class I, level A).
In patients with chronic atrial fibrillation and poor control of ventricular
rate despite BB therapy, or when BBs cannot be used, digoxin should be
considered (class IIa, level B).
108
Table 3. Pharmacotherapy of heart failure: comparison of different practice guidelines

Drugs
ACC/AHA
guideline (2005)
ESC
guideline (2005)
All recent or remote

MI, regardless of
LVEF or HF
Class I, level A
Class I, level A
Reduced LVEF,
no HF Sx
Class I, level C
HF with LVEF 4 0%
Class I, level A
CCS consensus
conference on HF
recommendations
(2006)
Beta-blockers
Class I, level A
Digoxin
Current or prior Sx of
HF, reduced LVEF,
optimized medical
therapy
Class IIa, level B
Any degree of HF with

AF
Class IIa, level B
Class I, level A
Class I, level B
Class IIa, level B
Vasodilators (nitrates,
hydralazine)
Reduced LVEF,
persistent HF Sx on
ACEI and BB
Class IIa, level A
Reduced LVEF, HF
Sx, intolerant to ACEI
or ARBs
Class IIb, level C
Class IIb, level B

Afro-Americans:
Class IIa, level A
Class IIa, level B
ACEI, Angiotensin-converting-enzyme inhibitors; ARBs, angiotensin II receptor blockers; BB, beta-blockers; HF, heart failure; LVEF, left ventricular ejection fraction; MI,
myocardial infarction; Sx, symptom
CCS guidelines [5] recommend the use of digoxin as a class I indication

to reduce hospitalization in patients with sinus rhythm and moderate to
severe HF symptoms despite optimized HF medical therapy, while ESC
guidelines [7] recommend the use of digoxin as a class I indication for
patients with atrial fibrillation (AF) and HF.
109
Drugs To Be Avoided in Heart-Failure Patients

It is also important to recognize that certain classes of drugs can exacerbate
the syndrome of HF and thus should be avoided in most patients [6]. These
are:
Anti-arrhythmic agents: Only amiodarone and dofetilide have been
shown not to adversely affect survival.
Calcium-channel blockers (CCB): only vasoselective CCBs have been
shown not to adversely effect survival.
Nonsteroidal anti-inflammatory drugs.
Focus on Specialized Heart-Failure Clinics

Despite the clear survival benefits supporting the use of pharmacological
therapies in the management of HF patients, prognosis associated with
recurrent and prolonged hospitalization remains poor. Strategies incorporating post-discharge follow-up by a multidisciplinary team of specially trained
staff and/or access to specialized HF clinics reduce mortality and all-cause
hospitalizations. A recent review found a significant reduction in all-cause
mortality when such multidisciplinary teams were used [14].
Multidisciplinary outpatient management of HF and disease management programs staffed by physicians, nurses, pharmacists, and other healthcare professionals with expertise in HF management should be developed
and used for assessment and management of high -risk patients with HF.
Multidisciplinary care should include close clinical follow-up, patient and
caregiver education, telemanagement or telemonitoring, and home visits by
specialized HF healthcare professionals, where resources are available. CCS
consensus conference recommendations have stressed the role of multidisciplinary outpatient HF management and disease management programs [5].
Implantation of an ICD To Prevent Sudden Cardiac Death in Patients with

Heart Failure
In patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), the implantable cardioverter defibrillator (ICD) is
highly effective in treating recurrences of these arrhythmias, either by antitachycardia pacing or cardioversion/defibrillation. Implantation of an ICD
has been shown to reduce mortality in cardiac-arrest survivors. An ICD is
indicated for secondary prevention of sudden cardiac death (SCD) due to
ventricular tachyarrhythmia in patients with otherwise good clinical func-
110
tion and prognosis, for which the prolongation of survival is the goal. All the
three guidelines are in agreement about ICD implantation in such patients
(Table 4). ACC/AHA and ESC guidelines have considered this as a class I,
level A recommendation. The CCS guidelines have mentioned that ICDs are
the therapy of choice for prevention of SCD and all-cause mortality in
patients with a history of sustained VT or VF, cardiac arrest, or unexplained
syncope in the presence of left ventricular dysfunction.
Table 4. Implantable cardioverter defibrillator implantation: comparison of different
heart-failure practice guidelines
Indication
ACC/AHA
guideline (2005)
ESC
guideline (2005)
CCS consensus
conference on HF
recommendations
(2006)
CAD, LVEF 30%, 1 month

post-MI, 3 months
post-coronary
revascularization
procedure
Class I, level A
Class I, level A
Class I, level A
(LVEF < 3035%)
NIDCM present for at

least 9 months, NYHA
class IIIII, LVEF 30%
Class I, level B
Class II a, level B
NIDCM present for at least

9 months, NYHA class
IIIII, LVEF 3135%
Class IIa, level B
Class II b, level C
Implantable cardioverter
defibrillator (ICD)
CAD, prior MI, 3 months

post-revascularization,
LVEF 3135%, inducible
VT/VF on EPS
Class IIa, level B
CAD, prior MI, 3 months

post-revascularization,
LVEF 3135% without EPS
Class IIb, level C
HF, reduced LVEF, with

history of cardiac arrest,
VF or hemodynamically
destabilizing VT
Class I, level A
CAD, Coronary artery disease; MI, myocardial infarction; LVEF, left ventricular ejection
fraction; NIDCM, nonischemic dilated cardiomyopathy; NYHA, New York Heart
Association; EPS, electrophysiological study; VT, ventricular tachycardia; VF, ventricular fibrillation
111
All of the multicenter trials aimed at the primary prevention of SCD that
assessed the usefulness of ICD implantation to reduce all-cause mortality
selected patients with low LVEF. The most common LVEF cutoff was 35%,
although the MADIT II study had a cutoff of 30% [15]. Most studies did not
specifically select patients with symptomatic congestive heart failure (CHF),
although the largest study, Sudden Cardiac Death and Heart Failure Trial
(SCD-HeF Trial), did select patients with current HF symptoms, NYHA class
II or III, and a history of HF for more than 3 months [16]. In the SCD-HeF
Trial, 2,521 patients with HF and LVEF 35% were randomized to placebo,
amiodarone, or single-lead ICD implantation. After a median follow-up of
45.5 months, there was a significant reduction in mortality in patients with
ICD therapy. There was no difference between placebo and amiodarone on
survival [16].
All three practice guidelines for HF management are in agreement and
have recommended ICD implantation for primary prevention to reduce total
mortality by a reduction of SCD in patients with LV dysfunction due to prior
myocardial infarction (MI) who are at least 40 days post-MI, have an LVEF
3040%, are NYHA functional class II or III, are receiving chronic optimal
medical therapy, and who have reasonable expectation of survival with a
good functional status for more than 1 year. A class I, level of evidence A recommendation has been given to this patient subset (Table 4). The ACC/AHA
and CCS consensus conference HF guidelines also give separate recommendations for patients with nonischemic dilated cardiomyopathy (Table 4). The
ECS HF guidelines do not mention nonischemic cardiomyopathy recommendations separately.
While ICDs are highly effective in preventing death due to ventricular
tachyarrhythmia, frequent shocks from the ICD can lead to a reduced quality
of life. For symptoms from recurrent discharges triggered by ventricular
arrhythmias or AF, anti-arrhythmic therapy, most often amiodarone, may be
added [6]. For recurrent ICD discharges from VT despite anti-arrhythmic
therapy, catheter ablation may be effective (ACC/AHA guidelines). It is
important to note that ICDs have the potential to aggravate HF and have
been associated with an increase in HF hospitalizations (ACC/AHA guidelines).
Cardiac Resynchronization Therapy

Patients with HF and LV dysfunction commonly have intra- and interventricular conduction delays that are associated with cardiac mechanical dyssynchrony. These compromise ventricular function and are frequently asso-
112
ciated with severe symptoms and poor prognosis. CRT uses biventricular
pacing to attempt to synchronize the activation of the septum and the LV
free wall, and to improve overall LV function [17].
CRT, when added to optimal medical therapy in persistently symptomatic
patients, has resulted in significant improvements in quality of life, functional class, exercise capacity, exercise tolerance, EF, and survival in patients randomized to such therapy [17]. Two major trials (COMPANION and CAREHF) assessed the role of CRT in patients with NYHA class IIIIV symptoms
on optimal medical therapy, QRS duration 120 ms, and an LVEF 35% [18,
19].The CRT group, compared with the medical therapy group, had significantly fewer deaths from any cause and fewer unplanned hospitalization for
a major cardiovascular event. As well, the CRT group had better improvement in EF, overall symptoms, and quality of life scores than the medicaltherapy-only group [18, 19].
All three guidelines are in agreement with recommending CRT for
patients with symptomatic (NYHA III or IV) HF despite optimal medical
therapy, who are in normal sinus rhythm and a QRS duration 120 ms, and
a LVEF 35% (class I, level A) (Table 5).
Table 5. Cardiac resynchronization therapy: comparison of different heart-failure practice guidelines

Indication
ACC/AHA
ESC
CCS consensus
guideline (2005) guideline (2005) conference on HF
recommendations
(2006)
Cardiac
resynchronization
therapy (CRT)
HF, NYHA class III-IV
despite optimal medical
therapy, NSR, QRS 120
ms, LVEF 35%
ICD + CRT for patients
meeting requirement
criteria for ICD
Class I, level A
Class I, level A
Class I, level A
Class IIa, level B
Class IIa, level B
HF, Heart failure; NYHA, New York Heart Association; NSR, normal sinus rhythm;
ICD, implantable cardioverter defibrillator
113
ICD therapy combined with biventricular pacing can be effective for primary prevention to reduce total mortality by a reduction in SCD in patients
with NYHA functional class III or IV, who are receiving optimal medical
therapy, in sinus rhythm with a QRS complex of 120 ms, and who have reasonable expectation of survival with a good functional status for more than
1 year. According to the ESC and CCS guidelines, this is a class II A, level B
recommendation (Table 5).
Future Directions
The understanding of HF has grown exponentially over the past 20 years and
has fuelled many landmark clinical trials that have given definitive answers.
The recommendations made in the present guidelines are based on clinical
trials that have already been published. There are many trials that are in
progress and planning, and these will no doubt provide new information and
evidence to guide future recommendations and guidelines [20].
Some of these new and ongoing HF trials are:
HF-ACTION: Heart Failure - A controlled trial investigating outcomes of
exercise training
AF-CHF: Atrial fibrillation in congestive heart failure
WARCEF: Warfarin versus aspirin in reduced cardiac ejection fraction
RED-HF: Reduction of events with darbepoetin alpha in heart failure
I-PRESERVE: Irbesartanin heart failure with preserved systolic function
UNLOAD: Use of nitroprusside in left ventricular dysfunction and
obstructive aortic valve disease
STICH: Surgical treatment for ischemic heart failure
RAFT: Resynchronization /defibrillation for advanced heart failure trial
REVERSE: Resynchronization reverses remodeling in systolic left ventricular dysfunction
MADIT-CRT: Multicentre automatic defibrillator implantation cardiac
resynchronization therapy trial
Conclusions
The provision of optimal care to patients with HF presents many challenges
to the patient, their family or caregivers, the physician, other healthcare
providers, and healthcare systems. Practicing guidelines provide support for
physicians and other healthcare professionals concerned with the management of HF patients. They also provide advice on how to manage these
114
patients. Documented and published evidence on diagnosis, efficacy, and

safety is the main basis of these guidelines. An organized system of specialist
HF care improves symptoms and reduces hospitalization and mortality.
Multidisciplinary disease-management programs for patients at high risk for
hospital admission or clinical deterioration are recommended to facilitate
the implementation of practice guidelines [7].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Dargie HJ, McMurray JJ (1994) Diagnosis and management of heart failure. BMJ
308:321328
Stewart S, MacIntyre K, Hole DJ et al (2001) More malignant than cancer? Fiveyear survival following a first admission for heart failure. Eur J Heart Fail
3:315322
American Heart Association (2005) Heart disease and stroke statistics: 2005 update. American Heart Association, Dallas
Johansen H, Strauss B, Arnold JM et al (2003) On the rise: the current and projected future burden of congestive heart failure hospitalization in Canada. Can J
Cardiol 19:430435
Arnold JM, Liu P, Demers C et al (2006) Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol 22:2345
Hunt SA, Abraham WT, Chin MH et al (2005) ACC/AHA 2005 guideline update for
the diagnosis and management of chronic heart failure in adult summary article:
a report of the American College of Cardiology/American Heart Association Task
Force on practice guidelines (writing committee to update the 2001 guidelines for
the evaluation and management of heart failure). Developed in collaboration with
the American College of Chest Physicians and the International Society for Heart
and Lung Transplantation. Endorsed by the Heart Rhythm Society. Circulation
112:18251852
Swedberg K, Cleland J, Dargie H et al (2005) ESC guidelines: guidelines for the diagnosis and treatment of chronic heart failure executive summary (update 2005).
The Task Force for the diagnosis and treatment of chronic heart failure of
European Society of Cardiology. Eur Heart J 26:11151140
Cleland JG, Khand A, Cklark A (2001) The heart failure epidemic: exactly how big
is it? Eur Heart J 22:623626
Cleland JG, Gemmell I, Khand A et al (1999) Is prognosis of heart failure improving? Eur J Heart Fail 1:229241
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators (1993) Effect of
ramipril on mortality and morbidity of survivors of acute myocardial infarction
and clinical evidence of heart failure. Lancet 342:669677
Merit HF Study Group (1999) Effect of metoprolol CR/XL in chronic heart failure:
Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
(MERIT-HF). Lancet 353:20012007
Granger CB, McMurray JJ,Yusuf S et al; CHARM Investigators and Committee
(2003) Effect of candesartan in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensin converting enzyme inhibitors: the CHARM alternative trial. Lancet 362:772776

13.
14.
15.
16.
17.
18.
19.
20.
115
Pitt B, Zannand F, Remme WJ et al; Randomized Aldactone Evaluation Study

Investigators (1999) The effect of spironolactone on morbidity and mortality in
patients with severe heart failure. N Engl J Med 341:709717
McAlister FA, Stewart S, Ferrua S, McMurray JJ (2004) Multidisciplinary strategies
for the management of heart failure patients at high risk for admissions: a systematic review of randomized trials. J Am Coll Cardiol 44:810819
Moss AJ, Zareba W, Hall WJ et al; Multicentre Automatic Defibrillator Implantation
Trial II Investigators (2002) Prophylactic implantation of a defibrillator in patients
with myocardial infarction and reduced ejection fraction. N Engl J Med
346:877883
Bardy GH, Lee KL, Mark DB et al; Sudden Cardiac Death in Heart Failure Trial
(SCD-HeFT) Investigators (2005) Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med352:225237
McAlister FA, EzeKowitz JA, Wiebe N et al (2004) Systematic review: cardiac resynchronization in patients with sy mptomatic heart failure. Ann Inter Med
141:381390
Bristow MR, Saxon LA, Boehmer J et al; Comparison of Medical therapy, Pacing
And Defibrillation in Heart Failure (COMPANION) Investigators (2004) Cardiac
resynchronization therapy with and without an implantable defibrillator in advance chronic heart failure. N Engl J Med 350:21402150
Cleland JG, Daubert JC, Erdmann E et al; Cardiac Resynchronization Heart Failure
(CARE-HF) Study Investigators (2005) The effect of cardiac resynchronization on
morbidity and mortality in heart failure. N Engl J Med 352:15391549
Arnold JM, Howlett JG, Dorian P et al (2007) Canadian Cardiovascular Society
Consensus Conference recommendations on heart failure update 2007: prevention,
management during intercurrent illness or acute decompensation,and use of biomarkers. Can J Cardiol 23:2145
SYNCOPE
Performing Carotid Sinus Massage

ROBERTO MAGGI, MICHELE BRIGNOLE
Introduction
Carotid sinus syndrome is a frequent cause of syncope, especially in the
elderly. The initial evaluation for this condition consists of a patient history,
physical examination, standard electrocardiogram (ECG) and systemic
blood pressure measurement in the supine and upright positions. If the origin of syncope remains uncertain, carotid sinus massage (CSM) together
with the tilt test becomes the method of choice to unmask neuromediated
syncopes.

Continuous ECG monitoring must be carried out during the test. Continuous
beat-to-beat noninvasive blood pressure monitoring is also important, as the
vasodepressor response is rapid and cannot be adequately detected with
devices that do not measure continuous blood pressure. After baseline measurements, the right carotid artery is firmly massaged for 510 s at the anterior margin of the sternocleidomastoid muscle at the level of the cricoid cartilage. After 12 min, if the massage on one side fails to yield a positive
response, a second massage is performed on the opposite side. If an asystolic
response is evoked, then the contribution of the vasodepressor component
(which may otherwise be hidden) is assessed by repeating the massage after
intravenous administration of atropine (1 mg or 0.02 mg/kg body weight).
The response to CSM is generally classified as cardioinhibitory (i.e., asys-
Arrhythmologic Centre, Department of Cardiology, Ospedali del Tigullio, Lavagna

(GE), Italy
146
tole), vasodepressive (fall in systolic blood pressure), or mixed. The mixed

response is diagnosed by the association of an asystole of 3 s and a decline
in systolic blood pressure of 50 mmHg on rhythm resumption from the
baseline value (Table 1).
In general, CSM is performed by one of two different methods:
In the first, the massage is performed for a short time (usually 5 s) during
which the patient is in the supine position, and the result is defined as
positive if an asystole 3 s and/or a fall in systolic blood pressure 50
mmHg are induced [15]. Pooled data from four studies performed in
elderly patients with syncope showed a positive response rate of 35%
(235 of 663 patients) [14]. However, previous studies found that the
diagnosis may be missed in about one-third of patients if only supine
massage is performed [5, 6].
In the second method, the method of symptoms, CSM is performed for
10 s with the patient in the supine position and then again for another 10
s with the patient in the upright position. The test is defined as positive if
during the massage the spontaneous symptoms are reproduced in association with cardioinhibition and/or vasodepression [711]. In an intrapatient comparison study [9], a higher positivity rate (49 vs 41%) in
patients with syncope and a lower positivity rate (5 vs 15%) in patients
without syncope were obtained with the method of symptoms than
with the first method. In a large population of 1,719 consecutive patients
Table 1. Carotid sinus massage: classification of the positive responses
Carotid sinus massage, baseline: asystole 3 s with reproduction of spontaneous

symptoms
Carotid sinus massage after atropine: no further symptomsa
Mixed form
Carotid sinus massage, baseline: asystole 3 s and fall in systolic blood pressure 50
mmHg with reproduction of spontaneous symptoms.
Carotid sinus massage after atropine: milder symptoms due to systolic blood pressure fall 50 mmHg
Dominant vasodepressor form
Carotid sinus massage, baseline: reproduction of the spontaneous symptoms due to

systolic blood pressure fall 50 mmHg without asystole
Carotid sinus massage after atropine: unchanged
aIn
this case, the vasodepressor reflex is absent or, if present, the patient is asymptomatic
147
with syncope unexplained after the initial evaluation (mean age 66 17

years), carotid sinus hypersensitivity was found in 56% and syncope was
reproduced in 26% [12]. The positivity rate increased with age, ranging
from 4% in patients < 40 years to 41% in patients > 80 years. The test was
positive only in the upright position in 49% of patients.
Whatever method is used, the importance of administering the massage
with the patient in the upright position, usually using a tilt table, has been
recognized [5, 6, 12, 13]. In addition to yielding a higher positivity rate compared with supine massage only, upright massage allows for better evaluation of the magnitude of the vasodepressor component and for better reproduction of symptoms. The vasodepressor component of the reflex was
underestimated in the past, but is actually present in most patients who
exhibit an asystolic response [13]. Correct determination of the vasodepressor component of the reflex is of practical importance for the choice of therapy. Indeed, pacemaker therapy has been shown to be less effective in mixed
forms with an important vasodepressor component rather than in dominant
cardioinhibitory forms [1, 14]. The syndrome is misdiagnosed in half of the
patients if CSM is not performed in the upright position.
The main complications of CSM are neurological [15]. In three studies,
neurological complications were reported in seven of 1,600 patients (5,000
massages), with an incidence of 0.45% [12]; in 11 of 4,000 patients (16,000
massages), with an incidence of 0.28% [16]; and in three of 1,719 patients,
with an incidence of 0.17% [12]. Even if neurological complications are rare,
carotid massage should be avoided in patients with previous transient
ischemic attacks or strokes within the past 3 months (except if carotid
Doppler studies have excluded significant stenosis) or in patients with
carotid bruits [15]. Rarely, CSM may elicit self-limited atrial fibrillation of
little clinical significance [17, 1]. Since asystole induced by the massage is
self-terminating shortly after the end of the massage, resuscitative measures
are not usually needed.
Recommendations According to the Guidelines on Syncope of the

European Society of Cardiology
Indications and Methodology
Carotid sinus massage is recommended in patients > 40 years of age with
syncope of unknown etiology after the initial evaluation. If there is a risk of
stroke due to carotid artery disease, massage should be avoided. Electrocardiographic monitoring and continuous blood pressure measurement during
148
carotid massage are mandatory. Duration of massage for a minimum of 5

and a maximum of 10 s is recommended. Carotid massage should be performed with the patient both supine and erect.
Diagnosis
The procedure is considered positive if syncope is reproduced during or
immediately after massage in the presence of asystole > 3 s and/or a fall in
systolic blood pressure 50 mmHg. A positive response is diagnostic of the
cause of syncope in the absence of any other competing diagnosis.
Diagnostic Value of Carotid Sinus Massage

There is considerable disagreement regarding the diagnosis of carotid sinus
syndrome (CSS); its reported prevalence ranges from 1 to 60% [14, 810,
1921]. This discrepancy, which creates confusion and may lead to underestimation of the real importance of CSS, is probably due to different interpretations of the results of CSM and the different indications for the test in the
clinical setting. This controversy may partly be resolved by considering
spontaneous and induced CSS separately. Thus, spontaneous CSS can be
defined as syncope that, by its history, seems to occur in close relationship
with accidental mechanical manipulation of the carotid sinuses and which
can often be reproduced by CSM. Spontaneous CSS is rare and accounts for
only about 1% of all causes of syncope [1921]. By contrast, induced CSS is
more broadly defined and can be assumed to be present even though a close
relationship between manipulation of the carotid sinus and the occurrence
of syncope is not demonstrated. Thus, induced CSS is diagnosed in patients
who are found to have an abnormal response to CSM. Regarded in this way,
CSS is much more frequent, with 2660% of patients affected by unexplained
syncope [14, 911]. Moreover, CSS may be responsible for many cases of
syncope or unexplained falls in older persons. Objections could be raised
that the latter definition lacks specificity and that several false-positive cases
could be misinterpreted as CSS, when the real cause of syncope is different.
However, this does not seem to be true; indeed, some observational and controlled studies have shown that pacing therapy is able to reduce syncopal
relapses in patients with induced CSS [8, 20, 2224]. In other words, the
results of therapy indirectly validate the utility and efficacy of extending the
indications for performing CSM according to the method of symptoms.
Unlike vaso-vagal syncope, which is present in young people, the prevalence of positive CSM progressively increases with age, suggesting a phys-
149
iopathological role of age-related degenerative processes in the genesis of

the abnormal reflex. Since CSS is rare in persons under the age of 40, CSM
could be limited to people older than 40 years.
The association with orthostatic blood pressure drop is more common
than might otherwise be considered and suggests that an impairment of the
mechanism of adaptation to the upright position is frequently involved. CSM
is able to unmask this type of abnormality, which would not otherwise be
revealed by the standard orthostatic hypotension testing performed during
initial evaluation of syncope [6].
In conclusions, the systematic administration of method of symptoms
CSM testing reveals that CSS is a frequent cause of syncope, especially in the
elderly. Its rate is probably underestimated when the massage is not systematically performed in patients with syncope of uncertain origin after initial
evaluation.
CSS is misdiagnosed in half of the cases if the massage is not performed
with the patient in the upright position. The method of sy mptoms
approach is safe, with a complication rate similar to that of CSM performed
according to the short time method.
Correlation between Carotid Sinus Massage and Spontaneous Syncope

Recently, our group prospectively evaluated whether a cardioinhibitory
carotid sinus hypersensitivity (CSH) was correlated (and therefore could
predict) the clinical outcome and the mechanism of implantable loop
recorder (ILR)-documented spontaneous syncope [25]. The correlation of
spontaneous syncopal episodes with an abnormal ILR finding can be regarded as a reference standard when an arrhythmia is suspected to have a role in
the genesis of syncope.
The study included 18 consecutive patients with suspected recurrent neurally mediated syncope and a positive cardioinhibitory response during CSM
(maximum pause 5.5 1.6 s) who had subsequent documentation of a spontaneous syncope by means of an ILR. The patients were compared with a 2:1
age- and sex-matched group of 36 patients with a clinical diagnosis of recurrent neurally mediated syncope and negative response to CSM, tilt testing,
and ATP test. Asystole > 3 s was observed at the time of the spontaneous syncope in 16 (89%) of the CSH patients and in 18 (50%) of the control group (p
= 0.007). Sinus arrest was the most frequent finding among CSH patients but
not among controls (72 vs 28%, p = 0.003). After ILR documentation, 14 CSH
patients with asystole received dual-chamber pacemaker implantation; during 35 22 months of follow-up, two syncopal episodes recurred in two
150
patients (14%) and presyncope occurred in another two patients (14%).

Syncope burden decreased from 1.68 (95%, confidence interval 1.661.70)
episodes per patient per year before to 0.04 (0.0380.042) after pacemaker
implant (98% relative risk reduction).
In this study we found that a long asystole, mainly due to sinus arrest,
was the most frequent finding at the time of spontaneous syncope in patients
with cardioinhibitory CSH. In patients with a clinical diagnosis of suspected
neurally mediated syncope, the finding of a cardionihibitory response during
carotid sinus massage predicted, with a probability of 89%, that a long asystolic reflex was also present at the time of the spontaneous syncope. The
finding of progressive sinus bradycardia followed by ventricular asystole
(types 1A and 1B of the ISSUE classification [26] was consistent with the etiology of neurally mediated syncope. In the absence of a cardioinhibitory
CSH, the electrocardiographic findings at the time of spontaneous neurally
mediated syncope were heterogeneous, with bradycardia or asystole accounting for only approximately one-half of the syncope events [26].
The finding of asystolic syncope during spontaneous episodes forms the
background for the potential benefit of cardiac pacing in CSH patients.
Indeed, according to our study, cardiac pacing resulted in a 98% reduction of
the syncope burden during 3 years of follow-up.
References
1.
2.
3.
4.
5.
6.
7.
8.
Mc Intosh SJ, Lawson J, Kenny RA (1993) Clinical characteristics of vasodepressor,

cardioinhibitory and mixed carotid sinus syndrome in the elderly. Am J Med
95:203208
Graux P, Mekerke W, Lemaire N et al (1989) Le syndrome du sinus carotidien.
Apport de la monitorisation de la pression arterielle a lexploration electrophysiologique endocavitaire. Arch Mal Coeur 82:193199
Huang SKS, Ezri MD, Honser RG, Denes P (1988) Carotid sinus hypersensitivity in
patients with unexplained syncope: clinical, electrophysiologic, and long-term follow-up observation. Am Heart J 116:989996
Volkmann H, Schnerch B, Kuhnert H (1990) Diagnostic value of carotid sinus
hypersensitivity. Pacing Clin Electrophysiol 13:20652070
Parry SW, Richardson D, OShea D et al (2000) Diagnosis of carotid sinus hypersensitivity in older adults: carotid sinus massage in the upright position is essential. Heart 83:2223
Brignole M, Sartore B, Prato R (1983) Role of body position during carotid sinus
stimulation test in the diagnosis of cardioinhibitory carotid sinus syndrome. G Ital
Cardiol 14:6972
Thomas JE (1969) Hyperactive carotid sinus reflex and carotid sinus syncope.
Mayo Clin Proc 44:127139
Brignole M, Menozzi C, Lolli G et al (1992) Long-term outcome of paced and non
paced patients with severe carotid sinus syndrome. Am J Cardiol 69:10391043

9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
151
Brignole M, Menozzi C (1992) Carotid sinus syndrome: diagnosis, natural history

and treatment. Eur J Cardiac Pacing Electrophysiol 4:247254
Brignole M, Menozzi C, Gianfranchi L et al (1991) Carotid sinus massage, eyeball
compression and head-up tilt test in patients with syncope of uncertain origin and
in healthy control subjects. Am Heart J 122:16441651
Brignole M, Menozzi C, Gianfranchi L et al (1991) Neurally mediated syncope
detected by carotid sinus massage and head-up tilt test in sick sinus syndrome. Am
J Cardiol 68:10321036
Puggioni E, Guiducci V, Brignole M et al (2002) Results and complications of the
carotid sinus massage performed according to the Methods of Symptoms. Am J
Cardiol 89:599601
Gaggioli G, Brignole M, Menozzi C et al (1995) Reappraisal of the vasodepressor
reflex in carotid sinus syndrome. Am J Cardiol 75:518521
Brignole M, Menozzi C, Lolli G et al (1991) Validation of a method for choice of
pacing mode in carotid sinus syndrome with or without sinus bradycardia. Pacing
Clin Electrophysiol 14:196203
Munro N, McIntosh S, Lawson J et al (1994) The incidence of complications after
carotid sinus massage in older patients with syncope. J Am Geriatr Soc
42:12481251
Davies AG, Kenny RA (1998) Neurological complications following carotid sinus
massage. Am J Cardiol 81:12561257
Franke H (1963) Uber das karotissinus-syndrome und den sogennanten hyperactiven karotissinus reflex. Fridrich-Kave Schattaueur, Stuttgart
Brignole M, Alboni P, Benditt DG et al (2004) Guidelines on management (diagnosis and treatment) of syncope Update 2004. Europace 6:467537
Kapoor W, Snustad D, Peterson J et al (1986) Syncope in the elderly. Am J Med
80:419427
Mathias CJ, Deguchi K, Schatz I (2001) Observation on recurrent syncope and presyncope in 641 patients. Lancet 357:348353
Ammirati F, Colivicchi F, Santini M (2000) Diagnosing syncope in clinical practice.
Eur Heart J 21:935940
Morley CA, Perrins EJ, Chan SL, Sutton R (1983) Long-term comparison of DVI
and VVI pacing in carotid sinus syndrome. In: Steinbach K (ed) Proceedings of the
VII World Symposium on Cardiac Pacing. Steinkopff Verlag, Darmstadt, pp
929935
Stryjer D, Friedensohn A, Schlesinger Z (1986) Ventricular pacing as the preferable
mode for lomg-term pacing in patients with carotid sinus syncope of the cardioinhibitory type. Pacing Clin Electrophysiol 9:705709
Blanc JJ, Boshat J, Penther Ph (1984) Hypersensibilit sino-carotidienne. Evolution
moyen terme en fonction du traitement et de ses symptomes. Arch Mal Coeur
77:330336
Maggi R, Menozzi C, Brignole M et al (2007) Cardioinhibitory carotid sinus hypersensitivity predicts an asystolic mechanism of spontaneous neurally-mediated
syncope. Europace (in press)
Brignole M, Moya A, Menozzi C et al (2005) Proposed electrocardiographic classification of spontaneous syncope documented by an implantable loop recorder.
Europace 7:1418
Performing Tilt Testing and Physical Countermaneuvers

Training
GIUSEPPINA M. FRANCESE, MICHELE M. GULIZIA
Introduction
Vasovagal syncope is a common clinical condition and has an estimated lifetime prevalence of 35% [13]. Although the disorder is episodic in nature, it
can be considered a chronic disorder since symptoms often occur over many
years due to recurrent episodes of (pre)syncope [1, 2], with deleterious
effects on patients quality of life [4]. A correct initial evaluation (history,
physical examination, supine and upright systolic blood pressure measurement, ECG) in accordance with European Society of Cardiology Syncope
Guidelines [5] facilitates a diagnosis of suspected or certain neurally mediated syncope. In this case, additional, specific diagnostic tests should be performed. Different diagnostic examinations are used in actual clinical practice to identify the syncope mechanism. These include carotid sinus massage
(CSM), tilt-table testing, and implantable loop recorder. In patients > 40
years of age, CSM can identify an abnormal response. This so-called carotid
sinus hypersensitivity is characterized by a ventricular pause lasting 3 s
and a fall in systolic blood pressure of 50 mmHg. However, carotid sinus
hypersensitivity is not diagnostic of carotid sinus syndrome (CSS); rather,
reproducibility is a crucial diagnostic element. If the latter is to be obtained,
the patient should undergo tilt-table testing under secure conditions in
order to prevent his or her injury from a fall.
Cardiology Department, Garibaldi-Nesima Hospital, Catania, Italy
154
Tilt-Table Testing
The gold standard diagnostic examination for neurally mediated syncope
has always been the tilt-table test. From 1986 to 1995, different test execution
protocols were proposed [610]. In 1994, Raviele et al. [11] proposed the use
of intravenous nitroglycerin infusion. With this protocol, 21 of 40 (53%)
patients with syncope of unknown origin had positive responses, with a
specificity of 92%. Ten of 40 patients (25%) had progressive hypotension
without bradycardia. The latter was classified as an exaggerated response
consisting of an excessive hypotensive effect of the drug. More recently,
Raviele et al. [12] used sublingual nitroglycerin instead of an intravenous
infusion. After 45 min of baseline tilting, 0.3 mg of sublingual nitroglycerin
was administered. With this protocol the overall rate of positive responses in
patients with syncope of unknown origin was 51%, with a specificity of 94%.
The main advantage of sublingual nitroglycerin is that venous cannulation is
not needed for patient testing. Recently, many clinicians have used a shortened protocol consisting of 400 g of nitroglycerin spray administered sublingually after a 20-min baseline phase. This method is known as the Italian
Protocol. Other drugs used as provocative agents during tilt testing include
isosorbide dinitrate [13], edrophonium [14], clomipramine [15], and adenosine. In 1992, Sutton et al. [16] assessed the different hemodynamic responses evoked by tilt-table testing and developed a classification that has been
successively modified (Table 1) [17]. In order to use the tilt test effectively in
Table 1. New Vasovagal Syncope International Study (VASIS) classification. Adapted from
[17]
Type 1
Mixed. Heart rate falls at the time of syncope but the ventricular rate does
not fall to < 40 bpm or falls to < 40 bpm for < 10 s. Blood pressure falls
before the heart rate falls
Type 2A
Cardioinhibition without asystole. Heart rate falls to a ventricular rate

< 40 bpm for > 10 s but asystole of > 3 s does not occur. Blood pressure
falls before the heart rate falls
Type 2B
Cardioinhibition with asystole. Asystole occurs for > 3 s. Blood pressure

fall coincides with or occurs before the heart rate fall
Type 3
Vasodepressor. Heart rate does not fall > 10% from its peak at the time of
syncope
Exception 1 Chronotropic incompetence. No heart rate rise during tilt testing

(i.e., < 10% from the pre-tilt rate)
Exception 2 Excessive heart rate rise. An excessive rise in heart rate both at the onset
of the upright position and throughout its duration before syncope
(i.e., > 130 bpm)
Performing Tilt Testing and Physical Countermaneuvers Training
155
the evaluation of therapeutic options, two conditions are needed: (1) a high
reproducibility of the test and (2) responses to the test that are predictive of
outcome at follow-up. The overall reproducibility of an initial negative
response (8594%) is higher than the reproducibility of an initial positive
response (3192%). In addition, data from controlled trials showed that
approximately 50% of patients with a baseline positive tilt test became negative when the test was repeated with treatment or with placebo [18].
Moreover, acute studies were not predictive of the long-term outcome of
pacing therapy [19]. These data showed that tilt testing aimed at assessing
the effectiveness of different treatments has important limitations (level A).
While the head-up tilt test is a safe procedure and the rate of complications is very low, in some patients the tilt-table test is negative even when
neurally mediated syncope is strongly suspected. In these circumstances and
when the interval between recurrences is measured in months or years, consideration should be given to implantable ECG loop recorder (ILR). This
device is placed subcutaneously under local anesthesia, and has a battery life
of 1824 months. It has a solid-state loop memory, and the current version
can store up to 42 min of continuous ECG. Retrospective ECG allows activation of the device after consciousness has been restored. The ILR may ultimately become the reference standard, to be adopted when an arrhythmic
cause of syncope is suspected but not sufficiently proven to allow an etiological treatment. Recently, ISSUE 2 study results have been published [20]. That
study examined the effectiveness of a new strategy for managing patients
with suspected neurally mediated syncope, apart from those with carotid
sinus syndrome. The strategy requires early implantation of an ILR, irrespective of tilt-testing results, and delay of therapy until after ILR documentation
of recurrent syncope and establishment of a mechanism for the spontaneous
syncope. ISSUE2 also demonstrated that the mechanism of spontaneous syncope as documented by ILR is poorly correlated with the results of tilt-table
testing and not predicted by the results of an ATP test. Therefore, these tests
are of poor or no value in guiding specific therapy [21]. In another study
[22], Brignole et al. reported that older patients with unexplained syncope
are more likely than younger ones to have an indication for an ILR. In these
older patients, ILR has a higher diagnostic value and arrhythmia are more
likely detected and successfully treated. In asystolic neurally mediated syncope documented by ILR, ISSUE-2 demonstrated that the pacemaker was
effective in reducing the 1-year first syncope recurrence rate from 33%
before implantation (ILR phase 1) to 5% after implantation (phase 2).
Moreover, the control non-asystolic group continued to have a 41% recurrence rate after the first recurrence of syncope, thus supporting that the
156
pacemaker-mediated reduction was due to the beneficial effect of the pacemaker itself and not to other factors. However, a formal controlled trial is
needed to confirm these findings.
Physical Counterpressure Maneuvers

Vasovagal syncope is preceded by prodromal symptoms in about two-thirds
of patients. During the prodromal phase, blood pressure falls markedly. This
fall usually precedes the decrease in heart rate, which may be absent at least
at the beginning of this phase. Hypotension is caused by vasodilatation in
the skeletal muscles due to inhibition of sympathetic vasoconstrictive activity. In normal and hypertensive subjects, isometric handgrip exercises are
able to induce a significant blood pressure increase, which is mediated largely by endogenous catecholamine release. Muscle sympathetic nerve discharge and vascular resistance increase during handgrip exercises by healthy
subjects. Physical counterpressure maneuvers have previously been shown to
be effective in stabilizing blood pressure in patients with autonomic failure.
Recently, Krediet et al. [23, 24] published reports on controlling or aborting
impending vasovagal syncope by leg crossing and muscle tensing. Brignole
et al. [25] found a comparable effect of isometric arm counterpressure
maneuvers. Several physical countermaneuvers have been proposed in the
management of orthostatic hypotension [26], such as the handgrip (maximal
voluntary contraction of a rubber ball taken in the dominant hand for the
maximum tolerated time or till complete disappearance of symptoms), armtensing (maximum tolerated isometric contraction of the two arms achieved
by gripping one hand with the other and contemporarily abducting the arms
for the maximum tolerated time), and leg crossing (combined with maximum tensing of leg, abdominal, and buttock muscles for the maximum tolerated time). A randomized, controlled trial of physical countermaneuvers [27]
showed that education and physical counterpressure maneuvers performed
at the time of appearance of symptoms of impending syncope are effective in
reducing syncopal recurrences in young patients affected by vasovagal syncope. This implies that isometric arm contraction is able to abort syncope in
most cases, even when the patient remains in the standing position. The
practical consequence is that when symptoms of impending syncope occur
the patient will have enough time to apply counterpressure treatment before
losing consciousness. In some cases, treatment will definitely abort the vasovagal reaction, or at least delay syncope for the duration of the maneuver,
thus allowing enough time to initiate other maneuvers to abort syncope
(e.g., supine posture). The physical counterpressure trial also found that
Performing Tilt Testing and Physical Countermaneuvers Training
157
patients were able to enact a counterpressure maneuver in 98% of cases and

to relieve symptoms in 99% of these.
Counterpressure maneuvers can be regarded as a first-line treatment in
association with other conventional measures recommended by the international guidelines for treating vasovagal syncope, namely, reassurance regarding the benign nature of the condition, training in the recognition of premonitory symptoms, avoidance of triggering events, the adoption of maneuvers to abort the episode (e.g., supine posture), and avoidance of volume
depletion and prolonged upright posture. ISSUE 3 is a new, multi-center,
prospective, randomized, controlled double-blind study aimed at assessing
the effectiveness of pacemaker therapy for prevention of asystolic neurally
mediated syncope. This study, in which physical counterpressure maneuvers
will be evaluated in older patients, will last until December 2010 [22].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Colman N, Nahm K, Ganzeboom KS et al (2004) Epidemiology of reflex syncope.

Clin Auton Res 14(Suppl 1):i9-i17
Ganzeboom KS, Colman N, Reitsma JB et al (2003) Prevalence and triggers of syncope in medical students. Am J Cardiol 91:10061008
Sheldon RS, Sheldon AG, Connolly SJ et al (2006) Age of first faint in patients with
vasovagal syncope. J Cardiovasc Electrophysiol 17:16
Rose MS, Koshman ML, Spreng S, Sheldon R (2000) The relationship between
health-related quality of life and frequency of spells in patients with syncope. J Clin
Epidemiol 53:12091216
Brignole M, Alboni P, Benditt D et al (2004) Guidelines on management (diagnosis
and treatment) of syncope - Update. Europace 6:467537
Kenny RA, Ingram A, Bayliss J, Sutton R (1986) Head-up tilt: a useful test for investigating unexplained syncope. Lancet 1:13521355
Almquist A, Goldenberg IF, Milstein S et al (1989) Provocation of bradycardia and
hypotension by isoproterenol and upright posture in patients with unexplained
syncope. N Engl J Med 320:346351
Kapoor WN, Brant N (1992) Evaluation of syncope by upright tilt testing with isoproterenol. A nonspecific test. Ann Intern Med 116:358363
Morillo CA, Klein GJ, Zandri S, Yee R (1995) Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J May 129:901906
Natale A,Aktar M, Jazayeri M et al (1995) Provocation of hypotension during head-up
tilt testing in subjects with no history of syncope or presyncope. Circulation 92:5458
Raviele A, Gasparini G, Di Pede F et al (1994) Nitroglycerin infusion during upright
tilt: a new test for the diagnosis of vasovagal syncope. Am Heart J 127:103111
Raviele SA, Menozzi C, Brignole M et al (1995) Value of head-up tilt testing potentiated with sublingual nitroglycerin to assess the origin of unexplained syncope.
Am J Cardiol 76:267272
Ammirati F, Colivicchi F, Biffi A et al (1998) Head-up tilt testing potentiated with
low-dose sublingual isosorbide dinitratte: a simplified time-saving approach for
the evaluation of unexplained syncope. Am Heart J 135:671676
158
14.
Voice RA, Lurie KG, Sakaguchi S et al (1998) Comparison of tilt angles and provocative agents (edrophonium and isoproterenol) to improve head-upright tilt-table
testing. Am J Cardiol 81:346351
Theodorakis G, Markianos M, Zarvalis E et al (2000) Provocation of neurocardiogenic syncope by clomipramine administration during the head-up tilt test in
vasovagal syncope. J Am Coll Cardiol 36:174178
Sutton R, Petersen M, Brignole M et al (1992) Proposed classification for tilt induced vasovagal syncope. Eur J Cardiac Pacing Electrophysiol 3:180188
Brignole M, Menozzi C, Del Rosso A et al (2000) New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of the presyncopal phase of the tilt test without and with nitroglycerin challenge. Europace
2:6676
Moya A, Permanyer-Miralda G, Sagrista-Sauleda J et al (1995) Limitations of headup tilt test for evaluating the efficacy of therapeutic interventions in patients with
vasovagal syncope: results of a controlled study of etilefrine versus placebo. J Am
Raviele A, Brignole M, Sutton R et al (1999) Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized,
placebo-controlled trial. The Vasovagal Syncope International Study. Circulation
99:14521457
Brignole M, Sutton R, Menozzi C et al (2006) Early application of an implantable
loop recorder allows a mechanism-based effective therapy in patients with recurrent suspected neurally-mediated syncope. Eur Heart J 27:10851092
Brignole M, Sutton R, Menozzi C et al (2006) Lack of correlation between the
responses to tilt testing and adenosine triphosphate test and the mechanism of
spontaneous neurally mediated syncope. Eur Heart J 27:22322239
Brignole M, Menozzi C, Maggi R et al (2006) The usage and diagnostic yield of the
implantable loop-recorder in detection of the mechanism of syncope and in guiding effective antiarrhythmic therapy in older people. Europace 7:273279
Krediet CT, van Dijk N, Linzer M et al (2002) Management of vasovagal syncope:
controlling or aborting faints by leg crossing and muscle tensing. Circulation
106:16841689
Krediet CT, de Bruin IG, Ganzeboom KS et al (2005) Leg crossing, muscle tensing,
squatting, and the crash position are effective against vasovagal reactions solely
through increases in cardiac output. J Appl Physiol 99:16971703
Brignole M, Croci F, Menozzi C et al (2002) Isometric arm counterpressure maneuvers to abort impending vasovagal syncope. J Am Coll Cardiol 40:20532059
Bouvette CM, McPhee BR, Opfer-Gehrking TL, Low PA (1996) Role of physical
countermaneuvers in the management of orthostatic hypotension: efficacy and
biofeedback augmentation. Mayo Clin Proc 71:847853
van Dijk N, Blanc JJ, Quartieri F et al (2006) Randomized trial of optimal conventional therapy versus optimal conventional therapy plus counterpressure manoeuvres in patients with neurally-mediated syncope. J Am Coll Cardiol 48:16521657
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Implanting a Loop Recorder

MICHELE BRIGNOLE
Holter Monitoring in Syncope

Episodes of syncope over the course of a 24-h Holter monitoring are rare.
The vast majority of patients have a syncope-free interval, which can be
measured in weeks, months, or years, but not days; therefore, symptom-ECG
correlation is seldom achieved with Holter monitoring. In an overview [1] of
the results of eight studies of ambulatory monitoring in syncope, only 4% of
patients (range between 1 and 20%) had a correlation of symptoms with
arrhythmia. The true yield of conventional ECG monitoring in syncope may
be as low as 12% in an unselected population.
An asymptomatic arrhythmia detected by Holter monitoring is often
used to make a diagnosis by inference. However, in the absence of symptomECG correlation, ECG findings may be inappropriately maximized, leading to
unnecessary therapy, e.g., pacemaker implantation in a patient with vasomotor syncope. Alternatively, symptoms may be inappropriately minimized by
physicians if Holter monitoring fails to yield any evidence of an arrhythmia.
Holter monitoring in syncope may be of greater value if symptoms are
very frequent (> 1 per week). Daily single or multiple episodes of loss-ofconsciousness might increase the likelihood of symptom-ECG correlation.
Nonetheless, experience in these patients suggests that many have psychogenic blackouts. Undoubtedly, in such patients, true negative findings of
Holter monitoring may be useful in confirming the underlying cause.
Arrhythmologic Centre, Department of Cardiology, Ospedali del Tigullio, Lavagna

(GE), Italy
160
Michele Brignole
External Loop Recorder in Syncope

Conventional event recorders are external devices equipped with fixed electrodes, through which an ECG can be recorded by direct application to the
chest wall. Provided the patient is able to comply at the time of symptom
occurrence, a high-fidelity recording can be made.
Recordings can be prospective, retrospective (loop recorders), or both.
Prospective external event recorders are of limited value in syncope because
the patient must be able to apply the recorder to the chest during the period
of unconsciousness and activate recording. Retrospective ECG allows activation of the device after consciousness has been restored.
External retrospective loop recorders, by contrast, show a higher diagnostic yield in syncope. In one study [2], in 25% of enrolled patients syncope or
pre-syncope was recorded during the monitoring period, which lasted up to
1 month. However, since patients usually do not comply with external retrospective loop recorders for more than a few weeks, symptom-ECG correlation cannot be achieved when the syncopal recurrence rate is less frequent.
In a recent study [3], the external loop recorder was not useful for diagnosis
of syncope in patients with 3 4 episodes (more than 2) of syncope during
the previous 6 months, no overt heart disease, and a negative tilt test.
External loop recorders in syncope may be valuable if symptoms are frequent (> 1 per month).
Implantable Loop Recorder in Syncope

The implantable loop recorder is placed subcutaneously under local anesthesia, and has a battery life of 1824 months. With this device, high-fidelity
ECG recordings can be made. Retrospective ECG allows activation of the
recorder after consciousness has been restored. Automatic activation is also
available if predefined arrhythmias should happen to occur.
In a preliminary clinical experience, implantable loop recorders were
used diagnostically in patients whose syncope still could not be explained at
the end of full conventional work-ups. Symptom-ECG correlation was
achieved in 88% of a small series of highly selected patients, within a mean
of 5 months of implantation [4]. In a larger series [5], correlation between
symptoms (syncope or pre-syncope) and ECG was achieved in 59% of 85
patients within a mean of 10 months of implantation. Syncope-ECG correlation was achieved in 27% of patients and presyncope-ECG correlation in
32%; presyncope was much less likely to be associated with an arrhythmia
161
than syncope and did not prove to be an accurate surrogate for syncope in
establishing a diagnosis. Pooled data from four studies [47] for a total of
247 patients with unexplained syncope at the end of a complete conventional
investigation showed a correlation between syncope and ECG in 84 patients
(34%); of these, 52% had bradycardia or asystole at the time of the recorded
event, 11% had tachycardia, and 37% had no rhythm variation.
In another study [8] 60 patients with unexplained syncope were randomized to conventional testing with external loop recorders and tilt and electrophysiological testing or to prolonged monitoring with the implantable
loop recorder. The results showed that implantation of the loop recorder
during an initial phase of the work-up was more likely than conventional
testing to provide a diagnosis (52 vs 20%). However, patients at high risk of
life-threatening arrhythmias as well as those with an ejection fraction < 35%
were excluded.
Based on the preliminary experience involving patients with unexplained
syncope, monitoring with the implantable loop recorder may become the reference standard. This approach could be implemented when an arrhythmic
cause of syncope is suspected but not sufficiently proven to allow etiologically directed treatment. There are several areas of interest that merit further
clarification:
Patients in whom epilepsy was suspected but in whom treatment has
proven ineffective [9].
Patients with recurrent and unexplained syncope and without structural
heart disease, when an understanding of the exact mechanism of spontaneous syncope may alter the therapeutic approach [6].
Patients who have a diagnosis of neurally mediated syncope, when an
understanding of the exact mechanism of spontaneous syncope may alter
the therapeutic approach [6].
Patients with bundle branch block in whom a paroxysmal AV block is
likely, despite a complete negative electrophysiological evaluation [10].
Patients with definite structural heart disease and/or non-sustained ventricular tachyarrhythmias in whom a ventricular tachyarrhythmia is likely despite a completed negative electrophysiological study [11].
Patients with unexplained falls [12].
The implantable loop recorder carries a high up-front cost of approximately 1,500. However, if symptom-ECG correlation can be achieved in a
substantial number of patients, then analysis of the cost per symptom-ECG
yield might demonstrate that the implanted device is more cost-effective
than a conventional investigation [8].
162
Michele Brignole
Diagnosis
Whatever the type of ECG monitoring used (Holter, external or implantable
loop recorder) the diagnostic criteria are similar: ECG monitoring is diagnostic when a correlation between syncope and an electrocardiographic
abnormality (brady- or tachyarrhythmia) is detected. Conversely, ECG monitoring excludes an arrhythmic cause when there is a correlation between
syncope and no rhythm variation. In the absence of such correlations, additional testing is recommended, with the possible exception of ventricular
pauses longer than 3 s when the patient is awake, or periods of Mobitz II or
3rd degree atrioventricular block in the awake patient, or rapid paroxysmal
ventricular tachycardia [13].
Presyncope may not be an accurate surrogate for syncope in establishing
a diagnosis; therefore, therapy should not be guided by presyncopal findings.
ECG Monitoring in Syncope: Where in the Work-up?

The role of ECG monitoring in syncope cannot be defined in isolation.
Physicians may be guided by the results of the patients clinical history and
physical examination as well as objective testing, for example, by tilt testing.
Knowledge of what transpires during a spontaneous syncopal episode is the
gold standard for syncope evaluation. For this reason, it is likely that
implantable monitors will become increasingly important in the evaluating
syncope and that their use will be incorporated into the diagnostic flow
instead of or before many other conventional investigations are carried out.
References
1.
2.
3.
4.
5.
6.
Kapoor WN (1992) Evaluation and management of the patient with syncope. JAMA
268:25532560
Linzer M, Pritchett ELC, Pontinen M et al (1990) Incremental diagnostic yield of
loop electrocardiographic recorders in unexplained syncope. Am J Cardiol
66:214219
Schuchert A, Maas C, Kretzschmar C et al (2003) Diagnostic yield of external loop
recorders in patients with recurrent syncope and negative tilt table test. Pacing
Krahn A, Klein G, Norris C, Yee R (1995) The etiology of syncope in patients with
negative tilt table and electrophysiologic testing. Circulation 92:18191826
Krahn AD, Klein GJ, Yee R et al (1999) Use of an extended monitoring strategy in
patients with problematic syncope. Reveal Investigators. Circulation 99:406410
Moya A, Brignole M, Menozzi C et al (2001) Mechanism of syncope in patients with
isolated sy ncope and in patients w ith tilt-positive sy ncope. Circulation
104:12611267

7.
8.
9.
10.
11.
12.
13.
163
Nierop P, Vam Mechelen R, Elsacker A et al (2000) Heart rhythm during syncope

and presyncope. Pacing Clin Electrophysiol 23:15321538
Krahn A, Klein GJ, Yee R et al (2001) Randomized Assessment of Syncope Trial.
Conventional diagnostic testing versus a prolonged monitoring strategy.
Zaidi A, Clough P, Cooper P et al (2000) Misdiagnosis of epilepsy: many seizurelike attacks have a cardiovascular cause. J Am Coll Cardiol 36:181184
Brignole M, Menozzi C, Moya A et al (2001) The mechanism of syncope in patients
with bundle branch block and negative electrophysiologic test. Circulation
104:20452050
Menozzi C, Brignole M, Garcia-Civera R et al (2002) Mechanism of syncope in
patients with heart disease and negative electrophysiologic test. Circulation
105:27412745
Kenny RA, Richardson DA, Steen N et al (2001) Carotid sinus syndrome: a modifiable risk factor for nonaccidental falls in older adults (SAFE PACE). J Am Coll
Cardiol 1:14911496
Brignole M, Alboni P, Benditt D et al (2004) Guidelines on management (diagnosis
and treatment) of syncope Update 2004. Europace 6:467 14. Brignole M, Alboni
P, Benditt D et al (2004) Guidelines on management (diagnosis and treatment) of
syncope Update 2004 - Executive summary and recommendations. Eur Heart J
25:2054
SUDDEN DEATH
Managing Hypertrophic Cardiomyopathy:

Screening in Young Subjects
MAURIZIO SANTOMAURO1 ON BEHALF OF THE AIAC TASK FORCE OF RISK MANAGEMENT,
GIANLUCA BOTTO2, CORRADO DIACO2, MICHELE M. GULIZIA3, GIUSEPPE MARCECA4,
FRANCESCO MELANDRI5, FRANCO NACCARELLA6, CARLA RIGANTI7, MASSIMO SANTINI8
Introduction
Myocardial diseases (MDs) include an infrequently occurring heterogeneous
group of potentially lethal abnormalities in children and young adults.
Recent epidemiological studies have shown that dilated and hypertrophic
cardiomyopathies are the most frequent morphological substrata of cardiomyopathy in children [1, 2]. Furthermore, MDs have been associated with
unexpected sudden death (SD) in apparently healthy people < 35 years old
[39]. Acute myocarditis and hypertrophic cardiomyopathy are the leading
causes of SD in this age group. In addition, arrhythmogenic right ventricular
cardiomyopathy/dysplasia has been recognized as a relatively frequent cause
of SD in southern European countries [4, 9, 10]. In some cases, SD is the first
manifestation of disease, although sometimes the child or young adult has
had some symptom during their lifetime [11, 12]. The actual incidence and
distribution of cardiac SD by sex and age group in well-defined populations
are poorly characterized, and only a few observational studies have assessed
this problem in children and young adults. Most studies have been done in
selected samples or in reference centers, with the consequent bias making it
impossible to provide epidemiological data. A population-based observational retrospective study was carried out in children and young adults < 35
years old in the Italian province of Campania between 1998 and 2005 with
the aims of assessing the epidemiological and clinical data on MD mortality
and determining the causes of SD and non-sudden death (NSD).
1 Department
of Cardiovascular and Internal Medicine, Faculty of Medicine and

Surgery, Federico II University, Naples; 2Department of Cardiology, S. Anna Hospital,
Como; 3Division of Cardiology, GaribaldiNesima Hospital, Catania; 4Scuola di
Specializzazione Medicina del Lavoro, La Sapienza University, Rome; 5Cardiology Unit,
Nuovo Ospedale Civile, Sassuolo (MO); 6Cardiovascular Epidemiology Unit, Cardiology
Department AUSL, Bologna; 7 Direzione Sanitaria, AOU Federico II, Naples;
8Cardiovascular Department, San Filippo Neri Hospital, Rome, Italy
198
Maurizio Santomauro et al.
Patients and Methods

The study was done in Campania (approximate population 5,100,000), which
has a homogeneous population. Foreig ners for m 1.7% of the total.
Individuals between the ages of 1 and 35 years who died due to an MD during the period from January 1998 to December 2005 were included in this
study. The cases were classified as SD or NSD as follows: SD was defined as
death occurring naturally (non-violently), unexpectedly, and instantaneously, or less than 1 h from the onset of premonitory symptoms or collapse, in a
person in an apparently good state of health, not admitted to the hospital,
and while carrying out habitual activities at the time of the fatal event [6,
13]. In line with Italian legislation, a forensic autopsy is required for deaths
due to violence or when crime is suspected. The latter include sudden unexpected natural deaths in non-hospitalized children and young people. In
NSD, legislation requires a medical death certificate signed by the physician
who was treating the patient for a previously known disease. In Italy, in the
case of the death of a child or young adult outside the hospital, a preliminary
investigation is done and, assuming that there are signs of violent death or
an unexpected SD (for forensic purposes unexpected SD involves a potentially criminal activity), a forensic autopsy is requested and the medical
death certificate is annulled. Consequently, all medical death certificates and
forensic autopsy reports are coded according to the underlying cause of
death in the Mortality Registry of the Campania Region, following the
International Classification of Diseases (ICD-9).
To achieve the aim of this work, Mortality Registry data were analyzed
and the files in Campania were checked for the period 1998 to 2005, inclusive. All SDs occurring in people age 1 to 35 years old were examined. In all
cases, a complete autopsy and toxicological and histopathological studies
had been carried out. The cardiac conduction system was studied via a simplified method previously described [14]. Clinical data and the circumstances surrounding the death were also reviewed. This information was
obtained from the reports of physicians and forensic doctors. It was not possible to review physicians reports on NSD patients.
Statistical Analysis
The total incidence rates and those for each sex and age group were calculated according to the population census data for Campania province for the
years 1998 and 2005. For non-census years, year interpolations were calculated for the population for each sex and age group, assuming a linear yearly
increase or decrease in the population.
Managing Hypertrophic Cardiomyopathy: Screening in Young Subjects
199
The relative risk (RR) (and its 95% confidence interval [CI] of SD due to
MD compared to NSD was calculated for the total series and for the different
age and sex groups. Similarly, the RR (and its 95% CI) of SDs and NSDs were
compared between sex and between age groups (114 and 1535 years old).
The Fisher exact test was used to calculate the difference in distribution of
the absolute frequency of SD regarding the activity carried out at the time of
death (physical vs another activity) between the SD due to MD groups and
SD due to other causes. The significance level was set at p < 0.05.
Results
According to Mortality Registry data, there were 25,320 deaths in people
between the ages of 1 and 35 years (16,880 males and 8,440 women) in
Campania from 1998 to 2005. The cause of death was MD in 39 cases. In 30
cases, a forensic autopsy for SD was carried out. In the other nine cases, the
appropriate medical death certificate was issued as no evidence indicative of
SD due to suspected crime was found by the Forensic Pathology Service;
these were therefore included in the NSD group. Of the 39 cases of death due
to MD, 29 were male and 10 female; the average age was 27.40 7.17 years.
All were Caucasian. The mortality rate due to MD was 0.55/100,000 inhabitants/year. This was higher for males than for females, and for subjects 1524
and 2535 years of age than for children 114 years old. The RR of SDs was
significantly higher than that of NSDs, especially between adolescents and
young males.
Analysis of the Registry data showed 270 cases of SD in people between
the ages of 1 and 35 years; 39 of these were due to the following MDs:
myocarditis, dilated cardiomyopathy, arrhythmogenic cardiomyopathy,
hypertrophic cardiomyopathy, and idiopathic concentric left ventricular
hypertrophy (CLVH). Myocarditis was the most frequent cause of SD (35.5%)
followed by arrhythmogenic cardiomyopathy (25.5%). Dilated cardiomyopathy was the most frequent cause of NSD (70%).
Only in three cases of SD had the MD been diagnosed during the patients
lifetime. Each of them had hypertrophic cardiomyopathy and was under cardiological treatment, and two of them were under pharmacological treatment (1 with verapamil and the other with amiodarone). Some cardiovascular symptoms and/or electrocardiographic abnormalities were recorded in
ten people during their lifetime, but without the disease being diagnosed
before death; the main diagnoses were arrhythmogenic cardiomyopathy (n =
5) and myocarditis (n = 3). In the other 17 cases, SD was the first manifestation of disease. Comorbid conditions were reported in six patients: two with
200
myocarditis who had received medical care for viral gastroenteritis and four
who presented with morbid obesity. Six patients (20%) had prodromic
symptoms, mainly syncope and chest pain.
In 25 patients cardiopulmonary resuscitation (CPR) maneuvers were carried out. In nine, the ECG obtained during CPR showed ventricular fibrillation; in eight, asystole; and in one, ventricular tachycardia that degenerated
into ventricular fibrillation.
Arrhythmia-triggering factors were reported in 11 patients. In three
young people, toxicological analysis detected the presence of ethanol. In
seven, death occurred during the practicing of a sports activity (five during
football, one while cycling, and one during basketball). In one patient, information was obtained regarding acute psychological stress in the instant
prior to death. Of the arrhythmogenic cardiomyopathy cases, 71% of the
patients died during a sports activity. SD related to a sports activity occurred
in 23.3% of the cases of MD (7 out of 30) compared to 9.3% (13 out of 140) of
the remaining causes of SD (p = 0.05).
In seven people, the death was not witnessed and occurred in the bed,
probably while sleeping. Death occurred within 15 min (almost instantly) in
21 patients and within 15 and 60 min in two others. In 47% of cases death
occurred outside a hospital, whereas 53% of the patients were admitted to
the emergency ward in a state of cardiorespiratory arrest.
Discussion
The incidence of mortality due to MD in people between the ages of 1 and 35
years is low, and the risk of SD is significantly higher than that associated
with NSD. Thus, it is important to include forensic case studies to avoid
underestimation of the incidence of MD. In the present study, 75% of all the
deaths due to MD were sudden.
Unlike in other MDs, in which death is mainly sudden and caused by an
arrhythmic mechanism, in dilated myocardiopathy NSD predominates. This
indicates that death occurs at a more advanced phase of the disease, due to
congestive heart failure [37, 15].
Arrhythmogenic cardiomyopathy, hypertrophic cardiomyopathy, and
idiopathic CLVH [8, 1618] are well-known causes of SD during sports activities, with geographical variations among them: the second is especially frequent in North America [8], and the first in southern Europe [911, 18, 19].
Arrhythmogenic cardiomyopathy is a disease of unknown origin, although
genetic and inflammatory causes have been proposed [12, 20]. In some
patients, it could represent a form of myocarditis with scarring.
201
Idiopathic CLVH is a clinical condition in which the heart is morphologically very similar to an athletes heart. Distinguishing between the two is
fundamental in professional athletes but is not easy [8], as shown in the present series. A non-familial variant of hypertrophic cardiomyopathy or a form
of hypertrophic cardiomyopathy without typical morphological expression
has been suggested [17].
Preventing deaths due to MD in children and young adults is a difficult
task, as a high percentage of these occur suddenly and without the subject
having experienced previous cardiovascular symptoms [11]. One of the main
findings in this study was the relatively high percentage of people with cardiovascular symptoms or electrocardiographic abnormalities before death,
and in whom the disease had not been diagnosed during life, although all the
patients had been examined by a physician. It may have been possible to prevent death in some of these cases, especially those involving arrhythmogenic
cardiomyopathy and myocarditis. However, both diseases can be difficult to
diagnose while the patient is alive. In contrast, half of the cases of hypertrophic cardiomyopathy had been diagnosed, which shows that SD risk stratification is not easy due to the clinical heterogeneity of the contributing diseases. Both arrhythmogenic and hypertrophic myocardiopathy are becoming
an emerging indication for an implantable cardioverter defibrillator [20].
This could have been effective in two of our cases. Our results agree with the
well-known greater risk of SD in people with morbid obesity [21]. The prevention and treatment of obesity could therefore be of interest regarding
reducing mortality due to MD.
Certain triggering factors can precipitate lethal arrhythmias in a vulnerable myocardium; among these, vigorous physical activity is the most important in the context of MD, especially in arrhythmogenic cardiomyopathy [9,
10, 18]. Thus, in young men diagnosed with this disease, vigorous sports
activities [12] should be strongly discouraged. In line with the protocol of
the American Heart Association [22], at least three of our patients should
have received this advice until a detailed cardiological examination had been
done. One of the patients with myocarditis died during a cycling event,
which supports the contraindication of sports activities during the acute
phase of the disease [8]. Although hypertrophic cardiomyopathy has been
pointed out as the leading cause of SD in young adult athletes [8], none of
the subjects in the present series who were diagnosed with this disease died
while engaged in sports activities.
Alcohol intake can induce malignant ventricular arrhythmias in susceptible myocardium [23]. Ventricular fibrillation is the rhythm most frequently
leading to SD [12], which we also observed. Thus, efforts should be made to
202
achieve early defibrillation in cases of out-of-hospital cardiac arrest, especially in sports centers.
We should mention some limitations of the present study. Although the
clinical histories of the cases for which medical death certificates had been
issued were not available, we assumed that they did not fulfill the criteria for
SD, since they involved in-hospital or out-of-hospital deaths but the patients
had undergone forensic examination. As pointed out in other SD studies in
Europe [7, 13, 24, 25], it is highly unlikely that a medical-forensic investigation would not be carried out in the case of an out-of-hospital SD in a child
or young adult. However, the different distributions of MD in the SD and
NSD groups provide additional support for the reliability of the present
results. In all cases of SD in children and young adults, a forensic autopsy
should be carried out for two fundamental reasons: (1) it offers useful and
reliable information for epidemiological and preventive studies, and (2)
since some MDs are hereditary, a precise diagnosis may prevent death in
family members. Thus, it is desirable that genetic studies eventually be
included in the autopsy protocol. Nevertheless, death may have been prevented in some cases through early diagnosis of the disease, and by identifying and modifying the risk factors of the disease as well as factors triggering
SD. Finally, it would be useful to implement effective resuscitation programs
(basic life-support defibrillator) for victims of cardiac arrest.
Acknowledgments
We express our gratitude to Dr. Gennaro Galasso and to Gianluigi Galizia for their
editorial support.
References
1.
2.
3.
4.
5.
6.
Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC et al

(2003) The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med
348:16391646
Lipshultz SE, Sleeper LA, Towbin JA et al (2003) The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 348:16471653
Neuspiel DR, Kuller LH (1985) Sudden and unexpected natural death in childhood
and adolescence. JAMA 254:13211325
Corrado D, Basso C, Poletti A et al (1994) Sudden death in the young. Is acute coronary thrombosis the major precipitating factor? Circulation 90:23152323
Shen W, Edwards WD, Hammill SC et al (1995) Sudden unexpected nontraumatic
death in 54 young adults: a 30-year population-based study. Am J Cardiol 76:
148152
Morentin B, Surez-Mier MP, Audicana C et al (2001) Incidencia y causas de muerte sbita en menores de 36 aos. Med Clin (Barc) 116:281285

7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
203
Wisten A, Forsberg H, Krantz P, Messner T (2002) Sudden cardiac death in 15-35year olds in Sweden during 199299. J Intern Med 252:529536
Maron BJ (2003) Sudden death in young athletes. N Engl J Med 349:10641075
Corrado D, Basso C, Rizzoli G et al (2003) Does sports activity enhance the risk of
sudden death in adolescents and young adults? J Am Coll Cardiol 42:19591963
Aguilera B, Surez-Mier MP, Morentin B (1999) Miocardiopata arritmognica
como causa de muerte sbita en Espaa. Presentacin de 21 casos. Res Esp Cardiol
52:656662
Liberthson RR (1996) Sudden death from cardiac causes in children and young
adults. N Engl J Med 334:10391044
Huikuri HV, Castellanos A, Myerburg RJ (2001) Sudden death due to cardiac
arrhythmias. N Engl J Med 345:14731482
Morentin B, Aguilera B, Garamendi PM, Surez-Mier MP (2000) Sudden unexpected non-violent death between 1 and 19 years in north Spain. Arch Dis Child
82:456461
Surez-Mier MP, Gamallo C (1998) AV node fetal dispersion and His bundle fragmentation of the cardiac conduction system in sudden cardiac death. J Am Coll
Cardiol 32:18851890
Dec GW, Fuster V (1994) Idiopathic dilated cardiomyopathy. N Engl J Med
331:15641575
Virmani R, Burke AP, Farb A, Kark JA (1997) Causes of sudden death in young and
middle-aged competitive athletes. Cardiol Clin 15:439466
Virmani R, Burke A, Farb A, Atkinson JB (2001) Sudden cardiac death. In: Virmani
R, Burke A, Farb A, Atkinson JB (eds) Cardiovascular pathology, 2nd edn.
Saunders, Philadelphia, pp 340385
Surez-Mier MP, Aguilera B (2002) Causes of sudden death during sports activities
in Spain. Rev Esp Cardiol 55:347358
Kishimoto C, Ochiai H, Sasayama S (1992) Intracardiac thrombus in murine
Coxsackievirus B3 myocarditis. Heart Vessels 7:76781
Tom MT, Garca-Pinilla JM, McKenna WJ (2004) Actualizacin en miocardiopata
arritmognica del ventrculo derecho: gentica, diagnstico, manifestaciones clnicas y estratificacin de riesgo. Rev Esp Cardiol 57:757767
Duflou J, Virmani R, Rabin I et al (1995) Sudden death as a result of heart disease
in morbid obesity. Am Heart J 130:306313
Maron BJ, Thompson PD, Puffer JC et al (1996) Cardiovascular preparticipation
screening of competitive athletes. A statement for health professionals from the
Sudden Death Committee (clinical cardiology) and Congenital Cardiac Defects
Committee (cardiovascular disease in the young) American Heart Association.
Panos RJ, Sutton FJ, Young-Hyman P, Peters R (1998) Sudden death associated with
alcohol consumption. Pacing Clin Electrophysiol 11:423424
Bowker TJ, Wood DA, Davies MJ et al (2003) Sudden, unexpected cardiac or unexplained death in England: a national survey. Q J Med 96:269279
Felicani C, Moccia E, Naccarella F et al (2007) La morte improvvisa da sport. Due
database prospettici: 19902004 e 20052016: aspetti epidemiologici, preventivi,
assistenziali. Giornale Italiano di Aritmologia e Cardiostimolazione (in press)
Noninvasive Risk Stratification of Sudden Death:

T-Wave Alternans
ROBERTO F.E. PEDRETTI, SIMONA SARZI BRAGA, RAFFAELLA VANINETTI,ANTONIO LAPORTA,
SERGIO MASNAGHETTI, ROSSELLA RAIMONDO, MARIO SALERNO, FRANCESCO SANTORO
Introduction and Background

Sudden cardiac death (SCD) accounts for approximately 400,000 deaths each
year in the USA and remains a health problem of epidemic proportions.
Most SCDs are caused by fatal ventricular arrhythmias, i.e., ventricular
tachycardia (VT) and ventricular fibrillation (VF), in patients with and without known structural heart diseases [1, 2]. Identifying patients at risk for
these arrhythmias remains a major challenge since < 2% of patients who
have sudden cardiac arrest are resuscitated and survive hospital discharge.
Given the large number of patients potentially at risk for developing ventricular arrhythmias, any strategy for treating them prophylactically requires
efficient and effective risk stratification. A number of recently completed
randomized clinical trials showed that an implantable cardioverter defibrillator (ICD) can prevent SCD in selected high-risk patients. These trials have
used different methods for identify ing patients at risk for SCD. The
Multicenter Automatic Defibrillator Implantation Trial (MADIT) and the
Multicenter Nonsustained Tachycardia Trial (MUSTT) identified patients
with left ventricular (LV) dysfunction and nonsustained VT who had VT
induced by programmed ventricular stimulation [3, 4]. These two studies
demonstrated that implantation of an ICD can reduce the risk of death in
this group of high-risk patients. In contrast, in the Coronary Artery By-pass
Graft (CABG) Patch Trial, which identified a group of high-risk patients with
LV dysfunction and an abnormal signal-averaged electrocardiogram who
were undergoing elective CABG surgery, implantation of an ICD did not
reduce all-cause mortality [5]. Also, the Defibrillator in Acute Myocardial
Division of Cardiology, IRCCS Fondazione Salvatore Maugeri, Scientific Institute of

Tradate, Tradate (VA), Italy
180
Roberto F.E. Pedretti et al.
Infarction Trial (DINAMIT) did not show a survival benefit from an ICD in
patients who had a reduced left ventricular ejection fraction (LVEF) and
impaired cardiac autonomic function, 640 days after a myocardial infarction (MI) [6]. When viewed together, the CABG Patch Trial, DINAMIT,
MADIT, and MUSTT raise important issues about our understanding of
high-risk patients, and that not all high-risk patients benefit from ICD therapy. Based on these trials, the only patients in whom the prophylactic implantation of an ICD proved beneficial were those identified by documented
spontaneous nonsustained or inducible sustained ventricular arrhythmias.
The publication of MADIT II radically changed our ability to identify
those patients who may derive benefit from the implantation of a prophylactic ICD [7]. MADIT II aimed to evaluate the effects of an ICD on survival in
patients with prior MI ( 1 month before enrollment) and severe impairment
of LVEF (< 30%). The study population comprised 1,232 patients from 76
centers mainly in the USA. Patients were randomized with a 3:2 ratio to ICD
(742 patients) or conventional medical therapy (490 patients); the end-point
of the study was all-cause mortality. The main clinical and demographic
characteristics as well as medical therapy were not significantly different in
the two groups of patients. At a mean follow up of 20 months, mortality was
19.8% in the medically treated group and 14.2% in the ICD group. Hazard
ratio for the risk of death from all-causes was 0.69 (95% IC, 0.510.93; p =
0.016), with a risk reduction of 31% in patients implanted with an ICD compared with those treated with medical therapy. Kaplan-Meier survival curves
diverged at 9 months from the enrollment, showing a mortality reduction of
12 and 28% at 1 and 2 years, respectively. Based on these results, the prophylactic implant of an ICD improved survival in patients with prior MI and
severely impaired LV function.
More recently, three studies further supported the clinical relevance for
ICD implantation in different groups of patients, who in all cases were
selected by clinical data and LVEF, without additional noninvasive/invasive
risk markers.
The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation
(DEFINITE) Trial included 458 patients with nonischemic dilated cardiomyopathy, LVEF < 36%, and premature ventricular complexes or nonsustained
VT [8]; the mean LVEF was 21%. Two hundred and twenty nine patients were
randomly assigned to receive standard medical therapy and another 229
standard medical therapy plus ICD. At a mean follow-up of 29 months, there
were 68 deaths: 28 in the ICD group and 40 in the standard-therapy group
(hazard ratio 0.65; 95% CI 0.401.06; p = 0.08). The mortality rate at 2 years
Noninvasive Risk Stratification of Sudden Death: T-Wave Alternans
181
was 14.1% in the standard-therapy group and 7.9% in the ICD group. There
were 17 sudden deaths from arrhythmia: three in the ICD group as compared
with 14 in the standard-therapy group (hazard ratio 0.20; 95% CI 0.060.71;
p = 0.006). The study investigators concluded that in patients with severe,
nonischemic dilated cardiomyopathy ICD implantation significantly reduced
the risk of sudden death from arrhythmia and was associated with a non significant reduction in the risk of death from any cause.
The Comparison of Medical Therapy, Pacing, and Defibrillation (COMPANION) in Heart Failure Trial tested the hypothesis that prophylactic cardiac-resynchronization therapy (CRT) with or without a defibrillator backup
would reduce the risk of death and hospitalization among patients with
advanced congestive heart failure (CHF) and intraventricular conduction
delay [9]. A total of 1,520 patients with advanced CHF (New York Heart
Association class III or IV) of either ischemic or nonischemic etiology, QRS
interval 120 ms, PR interval > 150 ms, and end-diastolic LV diameter > 60
mm were randomly assigned in a 1:2:2 ratio to receive optimal pharmacological therapy alone or CRT or CRT plus ICD therapy. The primary end-point
was the time to death from or hospitalization for any cause. Compared with
optimal pharmacological therapy alone, both CRT and CRT plus ICD significantly reduced the primary end-point (hazard ratio 0.81 and 0.80; p = 0.014
and 0.01 respectively). CRT reduced the risk of the secondary end-point of
death from any cause by 24% (p = 0.059), CRT plus defibrillator-backup
reduced the risk by 36% (p = 0.003). In conclusion, in patients with advanced
CHF and prolonged QRS interval, combined electrical therapy (CRT+ICD)
significantly reduced all-cause mortality.
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [10] compared the impact on all-cause mortality of three different treatments in
patients affected by mild to moderate CHF (NYHA class II, III) of either
ischemic or nonischemic etiology, with LVEF 35%: placebo, amiodarone
(200400 mgr per day), ICD. The primary end-point of the study was allcause mortality. At 60 months of follow-up, no significant difference was
observed between the amiodarone and placebo groups; conversely, a clear
reduction in all-cause mortality was observed in patients treated with an
ICD compared with placebo group patients (hazard ratio 0.77, p = 0.007).
These preliminary data strongly supported the use of ICD in this group of
CHF patients. Moreover, further evidence about the inefficacy of amiodarone in reducing deaths from any causes was provided, confirming previous clinical trials (EMIAT and CAMIAT) that tested this drug in patients
after MI [11, 12].
182
Guidelines and Recommendations

On the basis of the recent recommendations of the American Heart
Associat ion/Amer ican College of Cardiolog y/European Societ y of
Cardiology regarding SCD [13], an ICD should be implanted (class I) in
MADIT-MUSTT like patients and in patients with ischemic or nonischemic
cardiomyopathy who have a LVEF 30 to 35%, are in NYHA functional class
IIIII and receiving optimal medical therapy, and with an expectation of survival in a good functional status > 1 year. An ICD may also be recommended
in those patients who are in NYHA functional class I because of a prior MI
(IIa) or a nonischemic dilated cardiomyopathy (IIb).
Focus on Risk Stratification

Prior to the above mentioned studies, the aim of noninvasive risk stratification was to identify patients at high enough risk to warrant treatment as
aggressive as an ICD (sensitivity was sacrificed in order to maximize positive predictive accuracy). This approach was based on the assumption that
ICDs are expensive, associated with certain risks, and thus should be
reserved for patients who are extremely likely to need them. Noninvasive
risk-stratifying tests were judged based on their positive predictive accuracy.
Nowadays, the results of these recent studies are associated with a transition
to a completely different type of thinking: a much wider group of patients
has been omitted in an attempt to maximize sensitivity. This new approach
is based on the assumption that ICDs can be implanted more easily, less
expensively, and with less risk, and should not be reserved only for the highest risk patients. The focus of noninvasive risk stratifying testing is thus on
maximizing negative predictive accuracy.
In the following T-wave alternans (TWA) analysis, a recent and promising
noninvasive risk marker is reviewed.
T-Wave Alternans
T-wave alternans is a beat-to-beat fluctuation in the amplitude or morphology of the T wave that alternates every other beat and has been closely associated with ventricular arrhythmias and SCD. More recently, using sensitive
signal-processing techniques, the detection of microvolt-level, virtually
unapparent TWA was found to be a potent predictor of life-threatening ventricular arrhythmias in several subgroups of patients.
Many studies demonstrated macroscopic TWA in different clinical condi-
183
tions that are associated with malignant ventricular arrhythmias, including

long QT syndrome, acute myocardial ischemia and infarction, Prinzmetals
angina, and electrolyte derangements [1420]. TWA is caused by primary
alternations in the repolarization phase of the action potential [21, 22].
Moreover, above a critical heart-rate threshold, repolarization potentials
from adjacent regions of the ventricle alternate with those of opposite phase,
that is discordant alternans, causing spatial gradients of repolarization and
yielding an electrophysiologic substrate for functional block, reentry, and
VF. When electrical uncoupling by a structural barrier is present, there is a
higher probability of discordant alternans at lower critical heart-rate threshold which, by inducing a maximum spatial gradient of repolarization, may
cause unidirectional block, reentry, and sustained monomorphic VT. In
either case, TWA suggests the presence of electrophysiologic properties of
the myocardium that are associated with the genesis of ventricular arrhythmias.
Clinical Studies
The original studies of TWA comprised different subgroups of very high-risk
patients. The results of the first study, published in 1994 by Rosenbaum et al.,
were obtained from a group of patients who underwent electrophysiological
(EP) studies because of nonfatal sustained ventricular tachyarrhythmias,
syncope or, in a minority of cases, supraventricular arrhythmias [23]. A
strong relationship was found between the presence of TWA evaluated during atrial pacing and the inducibility of ventricular tachyarrhythmias during
EP testing as well as 20-month arrhythmia-free-survival. Subsequent similar
studies confirmed the association between TWA measured during bicycle
exercise and both inducible and spontaneous ventricular arrhythmias in
patients who underwent EP study and also in ICD recipients [2426]. It is
also important to note that good reproducibility of TWA testing results and
TWA heart-rate threshold was demonstrated during both atrial pacing and
exercise-induced sinus tachycardia [27].
A number of small studies in patients with congestive HF (CHF) suggested that TWA is associated with an increased risk of ventricular arrhythmias
and sudden death. Klingenheben et al. evaluated 107 CHF patients without
history of sustained ventricular arrhythmias over a mean follow-up period
of 15 months [27, 28]. Patients had a mean LVEF of 28%, coronary artery disease in 67% of cases, and received angiotensin converting enzyme (ACE)
inhibitors and beta-blockers in 93 and 42% of cases, respectively. In this
study, TWA was a strong and significant predictor of arrhythmic events.
184
Remarkably, none of the patients with a negative TWA test had an arrhythmic event, indicating a very high negative predictive value. We obtained similar results in a study of 46 patients with CHF, NYHA class III in 35%, mean
LVEF 29%, and ischemic etiology 61% [29]; at a mean follow-up of 1.6 years,
a significant relationship with cardiac death was found: seven of 23 (30%)
patients with positive TWA died during follow-up. Interestingly, also in our
study, none of the 13 patients who had negative TWA died or had malignant
ventricular arrhythmias.
The prognostic value of TWA was also confirmed in patients with dilated
nonischemic cardiomyopathy. Hohnloser et al. studied 137 patients with
dilated cardiomyopathy, mean age 55 years, and LVEF 29% [30]. Their results
were similar to those found in CHF patients of both etiologies. More recently, Costantini et al. [31] reported preliminary results of a study that included
282 patients with a LVEF 40% and dilated nonischemic cardiomyopathy.
The study tested the hypothesis that a negative TWA would identify patients
at low risk of death. The primary end-point of the study was actuarial allcause mortality at 2 years. TWA testing was normal (negative) in 95 patients
(34%), and abnormal (positive or indeterminate) in 187 patients (66%).
None of the patients with a normal TWA test and 12 patients with an abnormal TWA test (8.6%) died (p 0.02), further supporting the very high negative predictive value of a negative TWA.
Results of the Marburg Cardiomyopathy Study contradicted the abovementioned promising results [32]. In that study, arrhythmia risk stratification was performed prospectively in 343 patients with idiopathic dilated cardiomyopathy, including analysis of LVEF, signal-averaged ECG, arrhythmias
on Holter ECG, QTc dispersion, heart-rate variability (HRV), baroreflex sensitivity (BRS), and TWA. During a mean follow-up of 52 months, major
arrhythmic events occurred in 46 patients (13%). On multivariate analysis,
LVEF was the only significant arrhythmia risk predictor in patients with
sinus rhythm, with a relative risk of 2.3 per 10% decrease of ejection fraction
(95% CI, 1.53.3; p = 0.0001), whereas beta-blocker therapy was associated
with a trend toward lower arrhythmia risk (RR, 0.6; 95% CI, 0.31.2; p =
0.13). Thus, in this study TWA as well as other noninvasive risk markers did
not seem to be helpful for arrhythmia risk stratification. However some criticisms should be noted: (1) Interpretation of TWA results was not based on a
negative and non-negative classification [33]; in fact, of 38 arrhythmic
events, 31 (81%) occurred in the 191 (16%) patients with a non-negative
result compared to seven of 72 (10%) patients with a negative TWA (p =
0.06). (2) More importantly, as reported by the same authors, the use of betablockers in this study was not uniform and many patients did not have this
185
type of therapy at study entry, when risk stratification was performed, but
received it during follow-up (52 vs 73%). (3) Beta-blockers were withheld for
24 h before TWA testing whenever possible because the development of TWA
is critically dependent on heart rate. This may have increased the proportion
of false-positive results, with a possible unapparent change of TWA from
positive to negative during the follow-up period. (4) The rate of events was
very low, about 3% per year, making the follow-up significantly longer (4.3
years) than the follow-up available in the other TWA studies (in general, 2
years).
On the basis of these conflicting results, further studies are needed in
order to define the prognostic value of this promising marker in patients
with nonischemic cardiomyopathy. A large multicenter prospective study, the
ALPHA Study (T-Wave Alternans in Patients with Heart Failure), is currently
ongoing in Italy. Its aim is to assess the prognostic power of TWA in a large
cohort of patients with nonischemic dilated cardiomyopathy, NYHA class
IIIII, and a LVEF 40% [34].
T-wave alternans has also been demonstrated to be an effective tool for
identifying high-risk patients after MI. Ikeda et al. evaluated the prognostic
significance of TWA between 2 and 10 weeks after an acute MI in a large
cohort of 850 consecutive unselected patients [35]. During a mean follow-up
25 months, only TWA and LVEF 40% were significant multivariate predictors for primary events, defined as SCD or resuscitated VF [relative hazard
5.9 (p = 0.007) and 4.4 (p = 0.005), respectively]. In contrast, in a study of 379
patients post-MI, Tapanainen et al. reported that TWA was not associated
with increased mortality [36]. This study was flawed, however, because the
TWA study was performed too early after MI (8.1 2.4 days), when TWA is
believed to be unstable and unreliable.
Interestingly, two recent studies strongly supported the potential role of
TWA in the risk stratification of MADIT-II like patients. In 129 post-MI
patients, all with a LVEF < 30%, TWA testing was prospectively assessed [37].
At 24 months of follow-up, no SCD or sudden cardiac arrest occurred among
patients who tested TWA-negative, compared with an event rate of 15.6%
among the remaining patients. More recently, a study evaluated the ability of
microvolt TWA to identify groups at high and low risk of dying among HF
patients who met MADIT II criteria for ICD prophylaxis [38]. Primary endpoint was 2-year all-cause mortality. Of the 177 MADIT II-like patients
included in the study, 32% had a QRS duration > 120 ms and 68% had an
abnormal (positive or indeterminate) microvolt TWA test. During an average
follow-up of 20 months, 20 patients died and patients with an abnormal TWA
test were compared to those with a normal (negative) test. The hazard ratios
186
for 2-year mortality was 4.8 (p = 0.020) and the actuarial mortality rate was
substantially lower among patients with a normal TWA test (3.8%), with a
corresponding false-negative rate of 3.5%. Notably, in this study TWA testing
was a better predictor than QRS complex duration an index recommended
in the USA for the selection of MADIT-II patients suitable for ICD therapy
in identifying groups of patients at high or low risk of death.
Recently, Chow et al. [39] noted that mortality reduction with ICD
implantation differs according to TWA status in patients with ischemic cardiomyopathy and no prior history of ventricular arrhythmia, with implications for risk stratification and health policy. This study consisted of a
prospective cohort of 768 patients with LVEF 35% and no prior sustained
ventricular arrhythmia, of which 392 (51%) received ICDs. The mean followup time was 27 12 months. A non-negative TWA test result identified 514
(67%) patients. After multivariate adjustment, ICDs were associated with
lower all-cause mortality in TWA-non-negative patients (hazard ratio 0.45, p
= 0.003) but not in TWA-negative patients (hazard ratio 0.85, p = 0.73). The
number needed to treat with an ICD for 2 years to save one life was nine
among TWA-non-negative patients and 76 among TWA-negative patients.
Another interesting aspect was evaluated by Ikeda et al. [40], who conducted a collaborative study to evaluate the predictive power of TWA in
patients with preserved LVEF after MI. This study enrolled 1,041 post-infarction patients with a LVEF 40% in whom TWA testing was performed an
average 48 days after the infarction. During a follow-up of 32 14 months,
38 patients (3.7%) died of non-arrhythmic cause and were not considered
for analysis. Of the 1,003 evaluable patients, 18 (1.8%) had sudden death or a
life-threatening arrhythmic event. TWA was positive in 169 (17%) patients,
negative in 747 (74%), and indeterminate in 87 (9%). A positive TWA test
was the most significant predictor, with a hazard ratio of 19.7 (p < 0.0001).
This marker had the highest sensitivity and negative predictive value for
events. Therefore, the investigators conclude that TWA could be used for
risk-stratification in the low-risk population of post-infarction patients with
preserved LVEF.
Conclusions
In conclusion, an abnormal TWA test is associated with a significant increase
of cardiac death and life-threatening ventricular arrhythmias in patients
with left ventricular dysfunction of both ischemic and nonischemic etiology.
Moreover, patients with a normal TWA test appear to have a very good prognosis, as shown by the high negative predictive value of the test. The results
187
suggest that TWA can be effectively used to identify a subgroup of patients

who are unlikely to benefit from ICD therapy despite heart failure and left
ventricular dysfunction.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Myerburg RJ, Interian AJ, Mitrani RM et al (1997) Frequency of sudden cardiac

death and profiles of risk. Am J Cardiol 80:10F-19F
Zipes DP, Wellens HJ (1998) Sudden cardiac death. Circulation 98:23342351
Moss AK, Hall WJ, Cannom DS et al (1996) 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 335:19931940
Buxton AE, Hafley G (1999) A randomized study of the prevention of sudden death
in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial
Investigators. N Engl J Med 341:18821890
Bigger JT (1997) Prophylactic use of implanted cardiac defibrillators in patients at
high risk for ventricular arrhythmias after coronary-artery bypass graft surgery.
Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med
337:15691575
Hohnloser SH, Kuck KH, Dorian P et al; DINAMIT Investigators (2004)
Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 351:24812488
Moss AJ, Zareba W, Hall WJ et al for the Multicenter Automatic Defibrillator
Implantation Trial II Investigators (2002) Prophylactic implantation of a defibrillator in patients with myocardial infarction and a reduced ejection fraction. N Engl J
Med 346:877883
Kadish A, Dyer A, Daubert JP et al; Defibrillators in Non-Ischemic Cardiomyopathy
Treatment Evaluation (DEFINITE) Investigators (2004) Prophylactic defibrillator
implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med
350:21512158
Bristow MR, Saxon LA, Boehmer J et al; Comparison of Medical Therapy, Pacing,
and Defibrillation in Heart Failure (COMPANION) Investigators (2004) Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350:21402150
Bardy GH, Lee KL, Mark DB et al; SCD-HeFT Investigators (2005) Amiodarone or
implantable cardioverter defibrillator for congestive heart failure. N Engl J Med
352:225237
Julian DG, Camm AJ, Frangin G et al (1997) Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial
Investigators. Lancet 349:667674
Cairns JA, Connolly SJ, Roberts R, Gent M (1997) Randomised trial of outcome
after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction
Arrhythmia Trial Investigators. Lancet. 349:675682
Anonymous (2006) ACC/AHA/ESC guidelines for management of patients with
ventricular arrhythmias and the prevention of sudden cardiac death. A report of
188
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.

the American College of Cardiology/American Heart Association Task Force and
the European Society of Cardiology Committee for practice guidelines. Circulation
114:10881132
Schwartz PJ, Malliani A (1975) Electrical alternans of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and
with the long Q-T sindrome. Am Heart J 89:4550
Puletti M, Curione M, Righetti G, Jacobellis G (1980) Alternans of the ST segment
and T wave in acute myocardial infarction. J Electrocardiol 13:297300
Hohnloser SH, Huikuri HV, Schwartz PJ et al (1999) T wave alternans in post myocardial infarction patients (ACES Pilot Study). J Am Coll Cardiol 33:144A
Kleinfeld MJ, Rozanski JJ (1977) Alternans of the ST segment in Prinzmetals angina. Circulation 55:574577
Cheng TC (1983) Electrical alternans. An association with coronary artery spasm.
Arch Intern Med 143:10521053
Reddy CV, Kiok JP, Khan RG, El-Sherif N (1984) Repolarization alternans associated with alcoholism and hypomagnesemia. Am J Cardiol 53:390391
Shimoni Z, Flatau E, Shiller D et al (1984) Electrical alternans of giant U waves with
multiple electrolyte deficits. Am J Cardiol 54:920921
Pastore JM, Girouard SD, Laurita KR et al (1999) Mechanisms linking T-wave alternans to the genesis of cardiac fibrillation. Circulation 99:13851394
Watanabe MA, Fenton FH, Evans SJ et al (2001) Mechanisms for discordant alternans. J Cardiovasc Electrophysiol 12:196206
Rosenbaum DS, Jackson LE, Smith JM et al (1994) Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 330:235241
Estes NAM III, Michaud G, Zipes DP et al (1997) Electrical alternans during rest
and exercise as predictors of vulnerability to ventricular arrhythmias. Am J
Cardiol 80:13141318
Gold MR, Bloomfield DM, Anderson KP et al (2000) A comparison of T-wave alternans signal-averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification. J Am Coll Cardiol 36:22472253
Hohnloser SH, Klingenheben T, Li YG et al (1998) T-wave alternans as a predictor
of recurrent ventricular tachyarrhythmias in ICD recipients: prospective comparison with conventional risk markers. J Cardiovasc Electrophysiol 9:12581268
Hohnloser SH, Klingenheben T, Zabel M et al (1997) T wave alternans during exercise and atrial pacing in humans. J Cardiovasc Electrophysiol 8:987993
Klingenheben T, Hohnloser SH, Cohen RJ et al (2000) Predictive value of T-wave
alternans in patients with congestive heart failure. Lancet 356:651652
Sarzi Braga S, Vaninetti R, Laporta A et al (2004) T-wave alternans is a predictor of
death in patients with congestive heart failure. Int J Cardiol 93:3138
Hohnloser SH, Klingenheben T, Bloomfield D et al (2003) Usefulness of microvolt
T-wave alternans for prediction of ventricular tachyarrhythmic events in patients
with dilated cardiomyopathy: results from a prospective observational study. J Am
Costantini O, Kaufman ES, Bloomfield DM et al (2004) Patients with a nonischemic
cardiomyopathy and a negative T-wave alternans stress test are at a low risk of
death. American Heart Association Scientific Session, New Orleans, LA, Nov 710
Grimm W, Christ M, Bach J et al (20039 Noninvasive arrhythmia risk stratification
in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy
Study. Circulation 108:28832891

33.
34.
35.
36.
37.
38.
39.
40.
189
Kaufman ES, Bloomfield DM, Steinman RC et al (2006)9 Indeterminate microvolt

T-wave tests predict high risk of death or sustained ventricular arrhythmias in
patients with left ventricular dysfunction. J Am Coll Cardiol 48:13991404
Salerno-Uriarte JA, Pedretti RF, Tritto M et al (2004) The ALPHA study (T-wave
alternans in patients with heart failure): rationale, design and endpoints. Ital Heart
J 5:587592
Ikeda T, Saito H, Tanno K et al (2002) T-wave alternans as a predictor for sudden
cardiac death after myocardial infarction. Am J Cardiol 89:7982
Tapanainen JM, Still AM, Airaksinen KE, Huikuri HV (2001) Prognostic significance of risk stratifiers of mortality, including T-wave alternans, after acute myocardial infarction. Results of a prospective follow-up study. J Cardiovasc
Hohnloser SH, Ikeda T, Bloomfield DM et al (2003) T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation. Lancet
362:125126
Bloomfield DM, Steinman RC, Namerow PB et al (2004) Microvolt T-wave alternans
distinguishes between patients likely and patients not likely to benefit from
implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic
Defibrillator Implantation Trial (MADIT) II conundrum. Circulation
110:18851889
Chow T, Kereiakes DJ, Bartone C et al (2007) Microvolt T-wave alternans identifies
patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy. J Am Coll Cardiol 49:5058
Ikeda T, Yoshino H, Sugi K et al (2006) Predictive value of microvolt T-wave alternans for sudden cardiac death in patients with preserved cardiac function after
acute myocardial infarction: results of a collaborative cohort study. J Am Coll
Cardiol 48:22682274
Noninvasive Sudden Death Risk Stratification: Heart Rate

Variability and Turbulence, and QT Dynamicity
ANTONIO VINCENTI, STEFANO PEDRETTI
Heart-Rate Variability
General Considerations
Variability in sinus-rhythm pacemaker activity over time is a major physiological characteristic of heart-rate behavior, and many cardiovascular and
metabolic conditions result in a change in heart rate variability. The numerous studies of time- and frequency-dependent variability have improved our
knowledge of the physiological and pathological patterns of heart-rate variability (HRV). The standard deviation of 24-h mean RR value (SDNN), and
measurement of the total variance (or power) in the change of RR at high
(HF) and low (LF) frequencies are commonly used to estimate HRV. Powerspectrum analysis (i.e. recording the distribution of power as a function of
the frequency at which it occurs) requires the transformation of time-series
data by means of advanced mathematical algorithms, generally the fast
Fourier transform (FFT) (Fig. 1), which is particularly useful in disclosing
the harmonic components of variability.
A high SDNN, high HF, and low LF/HF ratio are generally considered the
hallmarks of parasympathetic prevalence in autonomic balance; conversely,
low SDNN (< 100 ms), high LF, and a high LF/HF ratio (> 6) indicate sympathetic prevalence [1].
Some studies have reported that the LF band is also influenced by
parasympathetic components. This is particularly evident in advanced congestive heart failure (CHF), in which a low LF value is often observed.
Consequently, LF and the LF/HF ratio are less reliable in CHF patients [2, 3].
Arrhythmology Unit, Cardiac/Thoracic/Vascular Department, San Gerardo Hospital,

Monza, Italy
168
Fig.1. a Time domain representation of RR series, as proportion of beats in function of

RR duration. b FFT of RR time series, (short term sampling), showing two high-density
area in the HF and LF band
More recently, multidisciplinary research investigations have sought to

clarify the behavior, mechanisms, and clinical relevance of nonlinear components of HRV. Complex algorithms used elsewhere in the scientific field
to describe chaos phenomena have proven to be also relevant for HRV with
respect to the recursive, non-linear (fractal) behavior of heart beats [4].
Poincar analysis, in which each normal-to-normal RR interval is plotted
against the subsequent normal-to-normal interval, is a simple representation
of this aspect of HRV. Another approach to estimating non-linear phenomena of HRV consists of examining the proportionality of RR variance in samples of different dimensions. Computational analysis yields a log-log linear
relationship between sample size and variability. The slope of this relationship (called the fractal scaling component, 1) ranges between 0.5 (completely unpredictable variability) and 1.5 (brownian variability). An 1 value close
to 1 is the hallmark of the presence of a physiological, fractal-like signal,
which means perfect proportionality between the scale of the RR phenomena and the variance (what happens on a large scale seems to be repeated on a
small scale in a similar fashion) [5].
HRV and Survival

Evidence of the prognostic value of low SDNN in unselected patients with
previous myocardial infarction (MI) dates to results from the MPIP trial, in
Noninvasive Sudden Death Risk Stratification: HRV and Turbulence, and QT Dynamicity
169
1986 [6]. Later, the UK-Heart study [7] confirmed that in patients with CHF
who had a moderate risk profile (mean ejection fraction = 0.41), a value of
SDNN < 100 ms was associated with increased all-cause mortality, while
SDNN < 50 ms indicated a very poor prognosis.
The independent prognostic value of HRV in post-MI patients has been
confirmed in other studies, including those focusing on patients with preserved or reduced ventricular systolic function [810]. The prognostic value
of HRV, when determined long after the occurrence of MI, is less clear.
However, the Cardiac Arrhythmia Pilot Study (CAPS), the pilot study for the
Cardiac Arrhythmia Suppression Trial (CAST), reported that HRV measured
within 1 year post-MI continues to predict mortality during an approximately 2-year follow-up [11].
Recently reviewed data from the DEFINITE trial (non-ischemic dilated
cardiomyopathy, ejection fraction < 36%) [12] showed a high value of SDNN
in risk stratification, since patients in the upper tertile (SDNN >113 ms) had
a 0% mortality during follow-up compared to those in the lower levels
(SDNN 81113 ms: 7%; SDNN < 81 ms: 10%). Of note, about one in four
patients was excluded from the analysis due to atrial fibrillation or a high
incidence (> 25%) of ventricular ectopic beats (VEBs); in this cohort, mortality was the highest (17%; p = 0.03).
HRV and Arrhythmic Risk

The value of HRV in assessing the risk of sudden cardiac death (SCD) is less
well-defined. Reduced 24-h SDNN was present as a significant risk factor for
SCD in one study but not in others (including UK-Heart) [7, 14, 15]. There is
no evidence that low SDNN maintains predictive values after adjustment for
covariates [16]. With respect to frequency domain analysis, one study supported an independent value of low LF [< 3.3 ln(ms2)] in predicting SCD in
CHF, but only when derived from analysis (day-time) over a long period of
time [15]. Conversely, other studies reported that night-time low LF was an
independent predictor of SCD [17].
Nonlinear Methods
Concerning non-linear methods, univariate and multivariate analyses provided evidence that an abnormal Poincar plot distribution is indicative of a
worse prognosis in CHF and SCD [14]. In another study, a low 1 value
(< 0.9) was predictive of all-cause mortality in CHF [18].
170
Heart-Rate Turbulence
By definition, heart-rate turbulence (HRT) refers to the physiological shortterm instability of sinus rhythm that follows the occurrence of a VEB [19]. In
normal subjects, HRT evolution is biphasic, with an initial shortening and
subsequent widening of the RR cycle; the whole phenomenon generally lasts
for 1520 sinus beats. The physiological mechanism of HRT is believed to be
the baroreflex response to VEB and pause-determined hemodynamic perturbations [2022]. Classically, HRT is represented by a tachogram (Fig. 2) and
quantified by two parameters:
Turbulence onset (TO), which is given by the formula:
TO =100 [(RR+1 + RR+2)-(RR-2 + RR-1)]/(RR-2 + RR-1)
where a physiological initial acceleration in beats +1 and +2 results in a
negative TO; a positive TO is considered pathological.
Turbulence slope (TS), which describes the maximum rate of RR increase
obtained by performing a linear regression in multiples of five consecutive beat samples (from beat +1 to beat +15); the steepest regression
slope is by definition TS. The cut-off value for normal TS is > 2.5 ms/beat.
HRT is inversely correlated to initial heart rate [2325], which may
reduce the reliability of absolute TO and TS values in unselected patients. TS
is also structurally linked to the number of ectopic beats and thus indirectly
to time-series length, since HRT is determined after averaging all RR values,
leading to smoothing of HR perturbations [26]. TS is inversely correlated to
the square root of the number of VEBs [27].
The influence of the VEB coupling interval (CI) on HRT magnitude is still
a matter of debate, since published data reported an inverse correlation
between CI and HRT in some cases [28, 29]. However, for other authors this
was confirmed only in subjects with a left ventricular ejection fraction >
0.40 [30], whereas still others found no correlation [24]. A few methods to
obtain more reliable HRT values have been proposed. These include:
Re-scaling the tachogram by normalizing it either to a heart rate of 80
bpm before analysis [31] or to a combination of a cycle length of 800 ms,
duration of the time series, and number of VEBs [26].
Quantification of the heart-rate dependence of TS by linear regression, as
proposed by Schmidt et al. [32] with the term turbulence dynamicity
(TD) (Fig. 3).
Measuring HRT during ventricular programmed stimulation [33].
171
Fig. 2. Tachogram representing HRT evolution, with beats nomenclature. The steepest
5-beat regression that gives TS value is also shown
Fig. 3. Schematic representation of TS/HR relation; the most negative slope of the linear
regression obtained with variable 10 bpm windows is by definition TD.Adapted from [34]
172
Furthermore, certain clinical conditions and therapeutic regimens have

been associated with worse HRT values, including previous myocardial infarction and reduced left ventricular systolic function [35]. Statin therapy seems to
improve TS, while the effects of beta-blockers therapy are controversial. HRT
is also reduced in diabetic patients with autonomic dysfunction [3638].
HRT analysis shares with HRV some advantages: both are easily elaborated from Holter monitoring data, noninvasive, and low-cost. HRV has a
methodological limit in heart-beat series with high rates of ectopic occurrences, whereas this is not the case for HRT. Neither is valuable in patients
with atrial fibrillation. According to current opinion, once atrial fibrillation
patients are excluded, HRT can be determined in 90% of subjects [31].
Prognostic Value of HRT in Post-infarction

The overall prognostic value of HRT with respect to post-infarction mortality was described by post-hoc analysis of a few clinical trials. In the EMIAT
trial, multivariate analysis showed an independent prognostic value of TO,
TS, history of myocardial infarction, mean heart rate > 75 bpm, and ejection
fraction (EF). In the MPIP trial, only TS and EF were independent predictors.
In both trials, the combination of TO and TS was the most powerful predictor of outcome.
Data from the CAST trial [39] showed that TS was the best predictor of
total mortality, irrespective of EF; after adjustment for covariates, only TS
and HRV were independent indicators, with HRV still dependent on TS [33].
The ISAR-HRT trial [40], involving 1,455 subjects with previous MI and
age below 76 years, was the first prospective study to evaluate HRT. The
results showed that a combination of altered TO and TS was as powerful as
EF as a prognostic indicator (RR = 6). The presence of pathological TO-TS
and EF < 30% identified a cohort with the highest mortality rate (40% in 2
years). A 44% sensibility and 23% positive predictive value (PPV) were
declared for the HRT study in post-MI patients with EF < 0.30, or > 0.30 in
the presence of diabetes or age > 65 years. TO and TS showed better tradeoffs for sensibility/specificity than SDNN or EF.
Concerning SCD in post-MI patients, the role of HRT is less well-established.
In the ATRAMI trial, which enrolled also patients with EF > 0.40, abnormal TS and TS-TO combined allowed the classification of high-risk subjects
(respectively, RR = 4.1 and RR = 6.9), with additional value given to stratification according to SDNN and the baroreflex sensitivity index. Positive predictive value of abnormal TS was 12.5% with a sensibility of 40%, which was
173
better than baroreceptors sensitivity (PPV = 7.8%) [41].

The FINGER trial [42] prospectively evaluated 2,130 patients with recent
(< 2 weeks) MI for a mean follow-up of 1,012 days. Cardiovascular mortality
at the end of follow-up was 5%, of which sudden death accounted for half.
After multiparametric noninvasive evaluation, only TS and nonsustained
ventricular tachycardia (NSVT) during Holter monitoring were independent
predictors of SCD, but this effect was abolished in the low EF subgroup (<
0.35), i.e., the group in which SCD predictors are highly desirable for therapeutic purposes.
Prognostic Value of HRT in CHF

In the UK-HEART trial [7], only TS was predictive of death for patients with
acute decompensation, but not of total mortality. In a recent publication on
symptomatic CHF patients, TS was predictive of death for progressive
decompensation, but not for SCD [43], since TO and TS were significantly
higher in patients who died suddenly.
Evidence of the predictive value of HRT in non-ischemic cardiomyopathy
is limited. Zareba reported an independent value of TS and EF in predicting
mortality in a small cohort, although SDNN was a more powerful mortality
stratifier [44].
It has also been reported that in a group of CHF patients with a prevalent
non-ischemic etiology, pathological TO or TS were correlated with a worse
prognosis (cardiovascular death and hospitalization for heart failure), but
were not statistically different in subjects who experienced major ventricular
arrhythmias in the follow-up. In that group, late potentials, T-wave alternans
analysis, and QT dispersion were altered [45].
QT Dynamicity
The term QT dynamicity refers to the physiological adaptation of electrical
repolarization to variations of the cardiac cycle in time, both under steadystate and dynamic conditions. Some adaptive mechanisms are intrinsic to
the regulation of the electrophysiologic cycle in myocytes, which leads to a
linear regression between the QT and RR cycle (QT/RR relationship).
Indeed, QT/RR function does not fully describe the complex physiological
adaptation. Instead, several physiological non-steady-state phenomena, such
as autonomic drive, HRV, and physical exercise, confer additional variance to
174
the QT/RR relationship. When considered as a time delay to the QT adaptation, this variability is termed QT hysteresis.
Many pathological conditions can alter the complex relationship between
QT and cycle length, possibly leading to major rhythm disturbances, including SCD. This explains the clinical interest in this phenomenon, in addition
to its use in SCD risk stratification.
QT/RR Regression
In recent years, a linear regression of QT with respect to the RR of the preceding cycle, as obtained from 24-h ECG registrations, has been the subject
of clinical interest for use in arrhythmic risk stratification. An increased
slope indicates hypercorrection of repolarization, which eventually exposes
to excessively long QT during bradycardia and increases excitable gap during
tachycardia.
Nevertheless, the QT/RR slope is particularly prone to intra- and intersubjects variability, which limits its standardization and use in clinical trials
and practice [46]. Moreover, scientific evidence on the stratification power of
QT/RR slope is limited. An analysis of QT/RR in subjects enrolled in the
EMIAT trial showed steeper regression in patients who died due to arrhythmic causes than in controls, when evaluated in the morning hours [47].
QT Hysteresis
In normal subjects, physiologic HRV is coupled with QT variability after a
temporal delay. This phenomenon, known as hysteresis, is highly variable
between subjects and may last up to 3 min during cardiac pacing.
Chauan et al. [48] reported sex differences in the QT-interval dynamics
during exercise and recovery in healthy subjects. In women, there is greater
QT-interval shortening during accelerating heart rates and greater QT-interval prolongation during decelerating heart rates. This results in greater QTinterval hysteresis, possibly contributing to the higher prevalence of druginduced torsade de pointes in women.
Beat-to-Beat Variability of Repolarization

This process, often termed QT variability, refers to cyclic variations in
repolarization over time, either coupled or not to HRV. An automated QT
175
variability algorithm based on a time series (e.g., Holter monitoring) has

been proposed [49]. It provides time-domain values, such as QT variance
(QTV, in ms2) and QTV as the log ratio between QTV and HRV (QTV index,
QTVI). A power-spectrum analysis of QT variability discloses the grade of
overlap between QT and HR spectra (coherence).
In that same study [49], patients with dilated cardiomyopathy were
shown to have greater QT variance than control subjects (60.4 63.1 vs 25.7
24.8 ms2, p < 0.0001) and QTVI (-0.43 0.71 vs -1.29 0.51, p < 0.000100.00012), the latter being directly correlated with NYHA functional class.
When matched with a reduced heart rate variance (6.7 7.8 vs 10.5 10.4
bpm2, p = 0.01), the coherence between heart rate and QT-interval fluctuations at physiological frequencies was lower in DCM patients than in control
subjects (0.28 0.14 vs 0.39 0.18, p < 0.0001).
A more recent re-evaluation of MADIT-II trial data found that median
normalized QTV and QTVI were significantly higher in patients who experienced VT/VF in the follow-up than in patients with clinically silent disease,
and conferred a higher events risk even after adjustments for covariates [34].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
De Maria M, Marconi M (2004) Stratificazione del rischio di morte improvvisa aritmica dopo infarto miocardico: ruolo degli esami strumentali invasivi e non invasivi. Giornale Italiano di Aritmologia e Cardiostimolazione 7(3)
Lombardi F, Mortara A (1998) Heart rate variability and heart failure. Heart
80:213214
Lombardi F (2000) Chaos theory, heart rate variability, arrhythmic mortality.
Circulation 101:810
Perkiomaki JS, Makikallio TH, Huikuri HV (2005) Fractal and complexity measures of heart rate variability. Clin Exp Hypertens 27:149158
Goldberger AL, Amaral LA, Hausdorff JM et al (2002) Fractal dynamics in physiology: alterations with disease and aging. Procl Natl Acad S USA 99:24662472
Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ (1987) Decreased heart rate variability
and its association with increased mortality after acute myocardial infarction. Am
J Cardiol 59:256262
Nolan J, Batin PD, Andrews R et al (1998) Prospective study of heart rate variability
and mortality in chronic heart failure: results of the United Kingdom Heart Failure
Evaluation and Assessment of Risk Trial (UK-Heart). Circulation 98:15101516
Zuanetti G, Neilson JM, Latini R et al (1996) Prognostic significance of heart rate
variability in post-myocardial infarction patients in the fibrinolytic era. The GISSI2 results. Circulation 94: 432436
Malik M, Camm AJ, Jansse MJ et al (2000) Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with
amiodarone: a substudy of EMIAT (The European Myocardial Infarct Amiodarone
Trial). J Am Coll Cardiol 35:12631275
176
10.
Camm AJ, Pratt CM, Schwartz PJ et al (2004) Mortality in patients after a recent
myocardial infarction: a randomized, placebo-controlled trial of azimilide using
heart rate variability for risk stratification. Circulation 109:990996
Bigger JT, Fleiss JL, Rolnitzky LM, Steinman RC (1993) Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am
Rashba EJ, Estes NAM, Wang P et al (2006) Preserved heart rate variability identifies low-risk patients with nonischemic dilated cardiomyopathy: results from the
DEFINITE trial. Heart rhythm 3:281286
Bilchick KC, Fetics B, Djoukeng R et al (2002) Prognostic value of heart rate variability in chronic congestive heart failure (Veterans Affairs Survival Trial of
Antiarrhythmic Therapy in Congestive Heart Failure). Am J Cardiol 90:2428
Brouwer J, van Veldhuisen DJ, Man in t Veld AJ et al (1996) Prognostic value of
heart rate variability during long-term follow-up in patients with mild to moderate
heart failure. The Dutch Ibopamine Multicenter Trial Study Group. J Am Coll
Cardiol 28:11831189
Galinier M, Pathak A, Fourcade J et al (2000) Depressed low frequency power of
heart rate variability as an independent predictor of sudden death in chronic heart
failure. Eur Heart J 21:475482
Sandercock GRH, Brodie DA (2006) The role of heart rate variability in prognosis
for different modes of death in chronic heart failure. Pacing Clin Electrophysiol
29:892904
Guzzetti S, La Rovere MT et al (2005) Different spectral components of 24 h heart
rate variability are related to different modes of death in chronic heart failure. Eur
Heart J 26:357362
Makikallio TH Huikuri H et al (2001) Fractal analysis and time- and frequencydomain measures of heart rate variability as predictors of mortality in patients
with heart failure. Am J Cardiol 87:178182
Watanabe MA, Schmidt G (2004) Heart rate turbulence: a 5-year review. Heart
Rhythm 1:732738)
Wichterle D, Melenovsky V et al (2002) Mechanism involved in heart rate turbulence. Card Electrophysiol Rev 6:262266
Mrowka R, Persson PB (2000) Blunted arterial baroreflex causes pathological
heart rate turbulence. Am J Physiol Regulatory Integrative Comp Physiol
279:R1171-R1175
Dejan D et al (2006) Effects of atropine and pirenzepine on heart rate turbulence.
Ann Noninv Electrophysiol 11:3437
Bauer A, Schneider R et al (2001) Heart rate turbulence dynamicity. Eur Heart J
22(Suppl):436
Schwab JO, Coch M, Veit G et al (2001) Post-extrasystolic heart rate turbulence in
healthy subjects: influence of gender and basic heart rate. Circulation 104:II-490,
2324
Watanabe MA, Marine JE et al (2002) Effects of ventricular premature stimulus
coupling interval on blood pressure and heart rate turbulence. Circulation
106:325330
Hallstrom AP, Stein PK et al (2004) Structural relationships between measures
based on heart beat intervals: potential for improved risk assessment. IEEE
Transactions on Biomedical Engineering 51:14141420
Francis J, Watanabe MA (2005) Heart rate turbulence: a new predictor for risk of
sudden cardiac death. Ann Noninv Electrophysiol 10:102109
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
177
Bauer A, Barthel P et al (2001) Impact of coupling interval on heart rate turbulence. Eur Heart J 22(Suppl):438
Indik JH, Ott P et al (2002) Heart rate turbulence and fractal scaling coefficient in
response to premature atrial and ventricular complexes and relationship to the
degree of prematurity. J Am Coll Cardiol 39(Suppl A)
Savelieva I, Wichterle D et al (2002) Different effects of atrial and ventricular prematurity on heart rate turbulence: relation to left ventricular function. Pacing Clin
Electrophysiol 25:II-608
Watanabe MA (2003) Heart rate turbulence: a review. Indian Pacing Electrophys J
3:10
Bauer A, Barthel P (2002) Dynamics of heart rate turbulence as independent risk
predictor after dynamic myocardial infarction. Pacing Clin Electrophysiol 25:II-608
Hallstroma AP Steinb PK et al (2005) Characteristics of heart beat intervals and
prediction of death. Int J Cardiol 100:3745
Haigney MC, Moss AJ et al (2004) QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Defibrillator
Implantation Trial (MADIT) II patients. J Am Coll Cardiol 44:14811487
Cygankiewicz I, Wranicz JK et al (2003) Clinical covariates of abnormal heart rate
turbulence in coronary patients. Ann Noninv Electrophysiol 8:289295
Schmidt G Malik M et al (2000) Heart rate turbulence in post-MI patients on and
off beta-blockers. Pacing Clin Electrophysiol 23:II-619
Jeron A, Holmer S et al (2003) Association of the heart rate turbulence with classic
risk stratification parameters in postmyocardial infarction patients. Ann Noninv
Lin LY, Hwang JJ et al (2004) Restoration of heart rate turbulence by titrated betablocker therapy in patients with advanced congestive heart failure: positive correlation with enhanced vagal modulation of heart rate. J Cardiovasc Electrophysiol
15:752756
Echt DS, Liebson PR et al (1991) Mortality and morbidity in patients receiving
encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. N Engl
J Med 324:781788
Barthel P et al (2003) Risk stratification after acute myocardial infarction by heart
rate turbulence. Circulation 108:12211226
Malik M, Schmidt G et al (1999) Heart rate turbulence is a post-infarction mortality predictor which is independent of and additive to other recognised risk factors. Pacing Clin Electrophysiol 22:II-741
Makikallio TH, Barthel P et al (2005) Prediction of sudden cardiac death after
acute myocardial infarction: role of Holter monitoring in the modern treatment
era. Eur Heart J 26:762769
Moore RK et al (2006) Heart rate turbulence and death due to cardiac decompensation in patients with chronic heart failure. Eur J Heart Fail 8:585590
Zareba W, Karcz M et al (2002) Heart rate turbulence, variability, and dynamics in
nonischemic dilated cardiomyopathy. Circulation 106(Suppl):2977
Koyama J, Watanabe J et al (2002) Evaluation of heart-rate turbulence as a new prognostic marker in patients with chronic heart failure. Circ J 66:902907
Sredniawa B et al (2005) Methods of assessment and clinical relevance of QT dynamics. Indian Pacing Electrophysiol J 5:221232
Milliez P, Coumel P et al (2005) Usefulness of ventricular repolarization dynamicity
in predicting arrhythmic deaths in patients with ischemic cardiomyopathy (from the
European Myocardial Infarct Amiodarone Trial). Am J Cardiol 95:821826
178
48.
Chauan VS, Krahn AD et al (2002) Sex differences in QTc interval and QT dispersion: dynamics during exercise and recovery in healthy subjects. Am Heart J
144(5):858864
Berger RD, Kasper EK et al (1997) Beat-to-beat QT interval variability novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 96:15571565
49.
Risk Stratification for Sudden Death in Hypertrophic

Cardiomyopathy
DOMENICO CATANZARITI, MASSIMILIANO MAINES, GIUSEPPE VERGARA
Early studies suggested that hypertrophic cardiomyopathy (HCM), an inherited and primary disease of cardiac muscle characterized by a thickening of
the left ventricular (LV) walls, was a relatively uncommon but malignant disorder. The annual mortality rates were reported to be 24% in adults and 6%
in adolescents and children, the majority of deaths being sudden. Recently it
has been found that HCM is, in fact, more common than originally assumed,
with a prevalence estimated from echocardiographic population screening of
0.2%. It is also now clear that HCM is much more benign, with an annual
mortality rate in large unselected non-referred series of approximately 1.5%.
More than half of these deaths are sudden while the remainder are largely
caused by heart failure and stroke [13]. This relatively low incidence creates
a challenge for risk stratification. Furthermore, most individuals with HCM
are asymptomatic and the first manifestation may be sudden cardiac death
(SCD), related to ventricular arrhythmia with potential triggers including
ischemia, outflow obstruction, and atrial fibrillation.
In recent years, the identification of various noninvasive indicators associated with SCD has allowed patients to be stratified according to their risk
of developing this complication. A consensus document of the ACC and ESC
has categorized the known risk factors for SCD as major and possible in
individual patients [4]. Major risk factors for SCD in HCM are: (1) Cardiac
arrest (ventricular fibrillation, VF); (2) spontaneous sustained ventricular
tachycardias (VT); (3) family history of premature SCD; (4) unexplained
syncope; (5) LV thickness 30 mm; (6) abnormal exercise blood pressure;
and (7) non-sustained spontaneous VT. Possible risk factors in individual
patients are: atrial fibrillation [5]; myocardial ischemia; LV outflow obstruc-
Cardiology Division, S. Maria del Carmine Hospital, Rovereto (TN), Italy
192
tion [6]; high-risk mutation; and intense competitive physical exertion. By

contrast, the absence of risk factors identifies a low-risk group. In this
respect, the low positive predictive accuracy of the previously recognized
major risk factor of SCD is a major limitation.
Hospital-based HCM patients with a combination of two or more sudden
death risk factors have been recently identified as higher risk group,
although an extreme single factor may identify young patients exposed to a
relevant risk in very long term follow-up. Such patients represent an additional subgroup at high risk. However, intermediate risk has been related to
the presence of only one of the major risk factors. A more precise assessment
of SCD risk stratification should be undertaken in relation to communitybased HCM patients. Prospective registries could be helpful in this type of
assessment although individuals who have undergone implantable cardioverter defibrillator (ICD) implantation will modify risk assessment stratification and follow-up clinical end-points (e.g., ICD-based VTs as clinical
surrogates of SCD).
Recently, the guidelines of the AIAC (acronym of the Italian Association
of Cardiac Pacing and Arrhythmia Specialists) regarding ICD implantation
were published [7]. Indications for ICD implantation in HCM were determined according to stratification based on incorporation of either single
strong risk factors or multiple risk factors, with the aim of improving the
positive predictive accuracy of the algorithm. Such efforts to obtain an effective risk stratification algorithm are motivated by the consideration that ICD
represents a very efficacious tool for preventing SCD in HCM [8].
In the case of HCM, the available data are less consistent; the patient
series are small; and the length of follow-up is short. In clinical studies for
ICD in HCM patients, the main reason for device implantation is secondary
prevention following aborted SCD or sustained VT. Nevertheless, the results
of a retrospective multicenter study containing a large number of patients, in
which the benefit of ICD implantation was shown in both primary and secondary prevention of SCD, suggested that the indications for ICD implantation should be expanded in HCM.
Various authors have recommended ICD implantation for primary prevention in patients with HCM and two or more risk factors for SCD, and
even in some patients with only a strong single risk factor. However, also
assuming a slightly less restrictive position regarding the more widespread
use of ICDs, the economic costs and risks in this young population of either
repeated device substitutions or lead-related malfunctions should be considered. Thus, it is important to correctly identify candidates, since this mode of
treatment is not without complications.
Risk Stratification for Sudden Death in Hypertrophic Cardiomyopathy
193
Risk factors
Secondary Prevention of Cardiac Arrest
A history of cardiac arrest or episodes of sustained VT are predictors of high
risk representing an absolute indication for ICD implantation and secondary
prevention of SCD.
Family History of Sudden Death

A multiple family history with two or more premature (< 45 years) SCDs is
considered a strong single risk factor justifying ICD implantation. However,
this is infrequent (5% of patients), and a history of a single premature SCD is
a more common situation (25% of patients). In these patients, risk assessment and the subsequent decision for ICD implantation are more uncertain.
Such a decision is based on the identification of additional risk factors, such
as syncope. Regardless, all patients with a single family history of SCD
should be informed of device-related problems, as well as the limitation of
each risk stratification in HCM.
Extreme LV Hypertrophy
Extreme hypertrophy of the LV wall (> 30 mm) is a strong predictor of SCD
in young patients with HCM and is associated with an estimated long term
risk of SCD of about 20% at 10 years and of > 40% at 20 years. Serious consideration should be given to implantation of an ICD in those young patients
with extreme hypertrophy, independently of the presence of other risk factors, due to the clinically significant impact on SCD prevention of ICD
implantation during long-term (over many decades) risk exposure [9].
Syncope
Syncope challenges the accurate clinical and prognostic evaluation of
patients, due to the multiple potential mechanisms responsible for syncopal
episodes in HCM (supraventricular or ventricular tachyarrhythmias as well
as bradyarrhythmias, dynamic obstruction, diastolic dysfunction, myocardial ischemia, and vasovagal mechanisms). In clinical series involving multiparametric assessment of SCD risk in hospital-based HCM patients, unexplained syncope has been combined with a multiple familiar history of SCD
as a high risk factor for SCD [10].
194
Accurate evaluation of the clinical profile of each patient is important in

order to precisely identify the role of each single syncopal episode, although
clinical perceptions and experience are also essential in this assessment.
Recent (< 1 year), recurrent syncope, either during effort or a non-neurally
mediated episode at rest, is generally considered a marker of increased risk
in young patients and a possible indication for ICD implantation.
Non-sustained Ventricular Tachycardia

In young patients (< 35 years), brief runs of non-sustained VT (three or
more beats) on Holter monitoring are associated with a significant increase
in the risk for SCD. In very young patients (children and adolescents), nonsustained VT is rare and indicative of high risk. In other patients, multiple
(e.g., more than two episodes in 6 months) or prolonged runs of non-sustained VT may be of particular concern and raise the issue of ICD implantation, even in the absence of other risk factors. If not recurrent, then brief
episodes of non-sustained VT are not considered significant risk factors in
community-based patients, in the absence of additional risk factors [11].
Abnormal Blood Pressure Response to Exercise

Hypotensive blood pressure response during upright exercise suggests an
increased risk for SCD and may be included in the overall risk profile, particularly in patients < 50 years of age. In adults, the absence of a hypotensive
response to exercise is reassuring, although in young patients the absence of
additional risk factors is also needed.
Electrophysiologic Study
Electrophysiologic study seems to be not clinically relevant for risk assessment, as unspecific responses are also induced in patients with very low risk.
This examination does not have any role in the stratification of SCD risk in
the vast majority of cases.
Low Clinical Risk Profile

Patients with mild LV hypertrophy (wall thickness < 20 mm) and without
any additional risk factors (included in the list of major risk factors) can
Risk Stratification for Sudden Death in Hypertrophic Cardiomyopathy
195
be considered at low risk and have a mean life expectancy similar to that of
the general population [12].
Clinical Reassessment
Patients are annually re-evaluated periodically during follow-up or as considered necessary by the patients doctor on the basis of either clinical suspicion or change of risk-factor burden.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Spirito P, Seidman CE, McKenna WJ, Maron BJ (1997) The management of hypertrophic cardiomyopathy. N Engl J Med 336:775785
Maron BJ 2002)Hypertrophic cardiomyopathy. A systematic review. JAMA
287:13081320
Elliott P, McKenna WJ (2004) Hypertrophic cardiomyopathy. Lancet 363:18811891
Maron BJ, McKenna WJ, Danielson GK et al (2003) 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 Documents and the
European Society of Cardiology Committee for Practice Guidelines. J Am Coll
Cardiol 42:16871713
Olivotto I, Cecchi F, Casey SA et al (2001) Impact of atrial fibrillation on the clinical
course of hypertrophic cardiomyopathy. Circulation 104:25172524
Maron MS, Olivotto I, Betocchi S et al (2003) Effect of left ventricular outflow tract
obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med
348:295303
AIAC (2005) Linee guida allimpianto di PM e ICD. Giornale Italiando di
Aritmologia e Cardiostimolazione 8(4):5466; available at: www.aiac.it
Maron BJ, Shen WK, Link MS et al (2000) Efficacy of implantable cardioverter defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 342:365373
Spirito P, Bellone P, Harris KM et al (2000) Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med
342:17781785
Elliott PM, Poloniecki J, Dickie S et al (2000) Sudden death in hypertrophic cardiomopathy: identification of high risk patients. J Am Coll Cardiol 36:22122218
Monserrat L, Elliott PM, Gimeno JR et al (2003) Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death
risk in young patients. J Am Coll Cardiol 42:873879
Spirito P, Autore C (2006) Management of hypertrophic cardiomyopathy. BMJ
332:12511255
The Prevention of Sudden Death: New Perspectives

SAVINA NODARI, MARCO METRA, ALESSANDRA MANERBA, SILVIA FRATTINI, GIUSEPPE
SERESINI, LIVIO DEI CAS
Epidemiology and Etiology

Sudden cardiac death (SCD) is unexpected natural death due to cardiac causes, and includes the abrupt loss of consciousness within 1 h from the onset of
acute symptoms, with or without preexisting heart disease. It is very difficult
to evaluate the exact incidence of SCD because the concept of sudden
events has not been precisely defined [1].
Estimates for the US show a mean incidence of 300,000 SCDs per year,
0.10.2% of the entire population [1]. In Italy, the number of events per year
is around 50,000 (about 1/1,000 subjects/year) [2]. These estimates are related to the whole population, thus including SCDs as a primary cardiac event
in healthy subjects and those occurring in high-risk patients. Despite the
high number of events per year in the population, the percentage remains
very low although it has increased progressively in high-risk subgroups. For
example, in post-myocardial infarction (MI) patients and in subjects with
prior malignant ventricular tachyarrhythmias the incidence of SCD is 35%
[1]. In a Framingham Study re-analysis, risk factors for coronary artery disease were shown to be statistically related to SCD. The incidence in patients
with several risk factors is 60 times higher than in those with only one [3].
Therefore, considering that the 80% of SCD is due to ischemic events, primary and secondary coronary artery disease prevention is of major importance.
According to international guidelines and evidence-based medicine, the control of risk factors and of pharmacological treatment is very important.
Department of Cardiology, Spedali Civili, University of Brescia, Brescia, Italy
206
Savina Nodari et al.
In the last 30 years, pharmacological and nonpharmacological approaches have improved the prognosis of post-acute-MI patients. The use of blockers and cardiac defibrillation in intensive care units has significantly
reduced early mortality, from 3035% to 1518%. In acute MI (AMI)
patients, thrombolysis and primary percutaneous transluminal coronary
angioplasty (PTCA) have additionally reduced the mortality to 68%.
Ventricular fibrillation, the most frequent of early complications, is now
almost totally controlled in protected areas, even if 4050% of patients with
AMI still die from arrhythmias occurring before hospitalization. Malignant
arrhythmias remain the most important cause of late mortality, thus underlining the importance of secondary prevention, too.
New interventional strategies and pharmacological approaches have
reduced early mortality but increased the incidence of late complications,
such as ischemic cardiomyopathies and heart failure. Chronic ischemia and
post-AMI heart failure are associated with ventricular hyperkinetic arrhythmias such as ventricular sustained tachycardia, ventricular flutter, torsades
de pointes, all of which often degenerate into ventricular fibrillation (VF)
and cardiac arrest. It is well-understood that ~80% of SCDs in adults are
caused by recognized or unrecognized coronary artery disease and that the
percentage of mortality in patients with AMI is about 50% in the so-called
door to needle time. In 25% of patients, SCD is the first event of acute
ischemia. More often, it is a late complication of AMI or post-infarction cardiomyopathy, which account for 75% of deaths in patients with a previous
MI. Fibrosis and hypoperfusion in perinecrotic areas induce electrophysiological changes, promoting reentrant arrhythmias and increasing automaticity [1].
Sudden death is the final event in 50% of patients with heart failure.
Mortality is positively related to clinical severity (12% in NYHA class II, 24%
in class III, and 36% in class IV), while SCD is the most frequent cause of
mortality in NYHA class II (64%) and class III (59%) patients [4].
Arrhythmogenic mechanisms depend on the underlying pathologies
(scar-tissue infarction, acute ischemia, ventricular hypertrophy, ventricular
enlargement). Transient modulating factors, such as acute myocardial
ischemia, adrenergic stimulation, and hypokalemia, play an important role
as well, particularly in patients with severe left ventricular dysfunction.
Additional important causes of arrhythmia are plaque rupture, intracoronary thrombosis, platelet emboli, coronary spasm induced by flow reduction,
post-ischemic reperfusion damage, changes in membrane ionic currents, and
adrenergic hyperstimulation [1].
207
Adrenergic hyperactivation increases automatism and reentrant arrhythmias. Acute myocardial ischemia alters the biochemical and biophysical features of myocytes, thus interfering with transmembrane ionic currents and
electrophysiological status. As a consequence, the likelihood of automatism
and reentrant-triggered arrhythmias may increase, such that prolonged
acute ischemia may be associated with sustained ventricular tachycardia and
VF.
Prevention of Sudden Death

The administration of -blockers prevents SCD by reducing myocardial oxygen consumption and counteracting ventricular remodeling and neuroendocrine activation. Thus, -blocker- and amiodarone-based therapies are
fundamental components of the guidelines for SCD prevention [5].
Angiotensin-converting-enzyme inhibitors and aldosterone-receptor blockers are important in preventing ventricular remodeling, interstitial myocardial fibrosis, and arrhythmias [6].
A new pharmacological option in the prevention of SCD is the n-3
polyunsaturated fatty acids (n-3 PUFAs). These compounds act by opposing
cellular remodeling and counteracting membrane structural changes as well
as cellular electric instability. They also influence sympathovagal balance
and have anti-ischemic properties [79].
A possible explanation for the anti-arrhythmogenic effects of n-3 PUFAs
is their modulation of sympathovagal balance. n-3 PUFAs increase heart rate
variability in healthy subjects and in patients at high risk for arrhythmia
(post-AMI patients with left ventricular dysfunction, patients with chronic
renal failure who undergo dialysis, and those with diabetes mellitus). The
effect has been shown to be due to a higher membrane concentration of
these compounds [10, 11].
Many studies have shown a decrease in HRV after AMI, as an expression
of increased sympathetic influence on cardiac activity that is related to
increased arrhythmic risk and mortality. The anti-arrhythmogenic effect of
n-3 PUFAs has been demonstrated in isolated myocytes and in experimental
studies, and is caused by a change in the concentration of cell-membrane
phospholipids. Higher concentrations of n-3 PUFAs (eicosapentaenoic and
docosahexaenoic acids) induce the production of thromboxane (TX)A3 and
leukotriene (LT)B5 during ischemia. In addition, they have fewer vasoconstrictive and inflammatory effects than TXA2 and LTB4, which are derived
208
from n-6 PUFAs. The release of TXA3 and LTB5 leads to a reduction in both
infarct size and the production of superoxide radicals, which reduce electric
instability in peri-infarction areas [79].
By modulating the fluidity of lipid bilayers, n-3 PUFAs influence the conductance of membrane ion channels and increase the opening threshold in
Na+ ion channels [12]. Besides cell membrane hyperpolarization, n-3 PUFAs
induce a lengthening of the cardiac cycle refractory period. In Ca2+ ion
channels, n-3 PUFAs inhibit L-type voltage-dependent currents, thus reducing the high Ca2+ cytosolic concentration responsible for partial membrane
depolarization, arrhythmogenic post-potentials, and arrhythmias [13]. In
ischemic or dysfunctional myocardium there is cytosolic-calcium overload
because of sarco/endoplasmic reticulum Ca2+ (SERCA) dysfunction and
diminished ryanodine receptor sensibility towards cytosolic calcium storage.
Consequently, there is a reduction in calcium uptake in the sarcoplasmic
reticulum and a nonmodulated outward current of this ion from the reticulum itself. Additionally, the NA+ inward current in exchange with Ca2+ ions
increases, which also enhances arrhythmogenic triggers. Experimental studies on isolated ventricular myocytes showed the inhibitory effect of n-3
PUFAs on type L Ca2+ channels currents and SERCA activity. Microsomal
Ca2+/Mg2+-ATPase stimulation, with a reduction in cytosolic Ca2+ concentration and fluctuations, was also observed and may contribute to the antiarrhythmogenic effects of n-3 PUFAs. The possibility that these drugs reduce
the risk for SCD is actually based on evidence from a prospective cohort
study, a case-control study, and prospective dietary intervention trials.
Results from Secondary-Prevention Clinical Trials

Following several observational prospective studies that confirmed an
inverse correlation between n-3 PUFA intake from fish and cardiovascular
mortality, randomized clinical trials for secondary prevention of CHD were
established. DART was the first such trial to evaluate the effects of n-3 PUFAs
on post-infarction survival [14]. After a 2-year follow-up, the results showed
that intake of n-3 PUFAs (by diet or pharmacological therapy) induced a significant reduction in total mortality (-29%) and in fatal ischemic events (32%); this benefit was observed as early as after 3 months. This result and
the significant reduction in coronary death but not in non-fatal ischemic
events indicated that n-3 PUFAs have a protective effect on arrhythmia-related death during ischemia.
209
The anti-arrhythmogenic effect of n-3 PUFAs was also confirmed by the

GISSI Prevenzione trial [15], which showed a significant reduction in the primary end-point (15% in total mortality, non-fatal AMI, non-fatal stroke; 20%
in cardiovascular mortality, non-fatal AMI and non-fatal stroke) only in the
n-3 PUFAs group; in particular, a significant reduction in total mortality
(20%), cardiovascular mortality (30%), and sudden death (45%) was documented (Fig.1). The early favorable effect on prognosis shown by the study
supports a direct protective anti-arrhythmogenic effect of n-3 PUFAs on
myocardium, independent from their anti-thrombotic and anti-atherogenic
effects. A meta-analysis of n-3 PUFA secondary prevention trials, including
about 15,700 patients, validated the GISSI Prevenzione trial results [16].
Primary Prevention
A recent re-analysis of the results of the US Physicians Health Study confirmed the potential role of n-3 PUFAs in the primary prevention of sudden
death [17]. In that study, a blood sample was taken at baseline in 22,071
Fig. 1. The GISSI prevention study showed that treatment with n-3PUFAs significantly
reduces cardiovascular events; in particular, sudden death decreased by 45%. AMI,
Acute myocardial infarction
210
healthy American physicians. In a 17-year follow-up, 94 subjects died from

SCD. Analysis of red-cell membrane fatty acids in these patients and in a
control group of 184 patients with a similar cardiovascular risk profile
demonstrated that only long-chain n-3 PUFA plasma concentrations were
significantly lower in the group of patients who died suddenly. No statistically significant difference was found in the two groups with respect to saturated, mono-unsaturated, or n-6 PUFAs, or short-chain n-3 PUFAs (-linolenic
acid). In the same study, multivariate analysis confirmed the prognostic
value of low-level n-3 PUFAs in sudden death, proving a strong inverse relationship between plasma concentrations of long-chain n-3 PUFAs and the
risk of sudden death. The authors also found an 81% risk reduction in the
quartile with higher n-3 PUFAs. These results were confirmed after statistical correction for age and smoking habit (Fig. 2).
Considering the high prevalence (50%) of sudden death in subjects without previous cardiovascular events, the usefulness of supplementary PUFA
n-3 intake in primary prevention was emphasized.
Fig. 2. Correlation between n-3 polyunsaturated fatty acid (n-3 PUFA) levels and the relative risk of sudden death. Patients with a higher blood concentration of long-chain n-3
PUFAs are at lower risk, even when the values are adjusted to take into account other
risk factors. Adapted from [17]
211
Conclusions
The epidemiological observations, experimental study results, but most of all
the secondary prevention clinical trial evidence together justify the use of n3 PUFAs in the prevention of post-AMI sudden death. Moreover, while further confirmation is required, it appears that n-3 PUFAs also benefit patients
at high risk for sudden death. The new AHA guidelines recommend the alimentary/pharmacological intake of n-3 PUFAs not only in CHD secondary
prevention, but also in primary prevention and in patients with hypertriglyceridemia [18] (Table 1).
The recent report of the ESC Task Force for risk stratification and sudden
death prevention [19] recommends n-3 PUFA treatment for primary prevention of SCD, with a type B evidence level (a single randomized trial).
Table 1. Recommendations of the AHA/ACC for n-3 PUFA intake in primary and secondary prevention. Adapted from [18]
Population
Recommendations
Patients without demonstrated CHD
Oily fish intake tw ice a week. Include

oils and foods with -linoleic acid (linseed
oil, soybean oil, peanut oil, etc.)
Patients with demonstrated CHD
Intake ~1 g of EPA + DHA per die from oily

fish. Possible EPA +DHA supplements
Patients with hypertriglyceridemia
24 g of EPA + DHA per die, capsules prescribed by the doctor
CHD, Chronic heart disease; EPA, Eicosapentaenoic acid; DHA, docosahexaenoic acid
References
1.
Zipes DP, Camm AJ, Borggrefe M et al; European Heart Rhythm Association; Heart
Rhythm Society; American College of Cardiology; American Heart Association
Task Force; European Society of Cardiology Committee for Practice Guidelines
(2006) ACC/AHA/ESC 2006 Guidelines for Management of Patients with
Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. A Report of
the American College of Cardiology/American Heart Association Task Force and
the European Society of Cardiology Committee for Practice Guidelines (Writing
Committee to Develop Guidelines for Management of Patients With Ventricular
Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol
48:e247-e346
212
2.
Tunstall-Pedoe H, Vanuzzo D, Hobbs M et al (2000) Estimation of contribution of

changes in coronary care to improving survival, event rates, and coronary heart
disease mortality across the WHO MONICA project populations. Lancet
355:688700
Kannel WB, Schatzkin A (1985) Sudden death: lessons from subsets in population
studies. J Am Coll Cardiol 5(6 Suppl):141B-149B
Anonymous (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol
CR/X1L Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
Lancet 353:20012007
Anonymous (1997) Effect of prophylactic amiodarone on mortality after acute
myocardial infarction and in congestive heart failure: meta-analysis of individual
data from 6500 patients in randomized trials. Amiodarone Trials Meta-Analysis
Domanski MJ, Exner DV, Borkowf CB et al (1999) Effect of angiotensin converting
enzyme inhibition on sudden cardiac death in patients following acute myocardial
infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol
33:598604
Kim D, Duff RA (1990) Regulation of K+ channels in cardiac myocytes by free fatty
acids. Circ Res 67:10401046
Leaf A (2001) Electrophysiologic basis for the antiarrhythmic and anticonvulsant
effects of omega 3 polyunsatured fatty acids. World Rev Nutr Diet 88:7278
Lundmark K, Abelnoor M, Urdal P et al (1998) Use of fish oils appears to reduce
infarct size as estimated from peak creatinine kinase and locate dehydrogenase
activities. Cardiology 89:94102
Christensen JH, Kroup E, Aaroe J et al (1997) Fish consumption, n-3 fatty acids in
cell membranes, and heart rate variability in survivors of myocardial infarction
with left ventricular dysfunction. Am J Cardiol 79:16701673
Christensen HJ, Skou HA, Fog L et al (2001) Marine n-3 fatty acids, wine intake,
and heart rate variability in patients referred for coronary angiography.
Xiao YF, Wright SN, Wang JK et al (2000) Coexpression with beta(1) subunit modifies the kinetics and fatty acid block of hH1(alpha) Na+ channels. Am J Physiol
Heart Circ Physiol 279:H 35-H46
Pepe S, Bogdanov K, Hallaq H et al (1994) Omega 3 polyunsatured fatty acids
modulates dihydropiridine effects on L-type Ca2+ channels, cytosolic Ca2+ and
contraction in adult rat cardiac myocytes. Proc Natl Acad Sci USA 91:88328836
Burt ML, Fehily AM, Gilbert JF et al (1989) Effects of changes in fat, fish and fibre
intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
Lancet 2:757761
Marchioli R, Barzi F, Bomba E et al (2002) Early protection against sudden death by
n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of
the results of the Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto
Miocardico (GISSI)-Prevenzione. Circulation 105:18971903
Bucher HC, Hengstler P, Schindler C, Mayer G (2002) N-3 polyunsaturated fatty
acids in coronary heart disease: a meta-analysis of randomized controlled trials.
Am J Med 112:298308
Albert CM, Campos H, Stampfer MJ et al (2002) Blood levels of long-chain n-3 fatty
acids and the risk of sudden death. N Engl J Med 346:11131118
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.

18.
19.
213
Penny M, Kris-Eherton, William S et al (2002) Appeal for Nutrition Committee.

Fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106:27472757
Priori SG, Aliot E, Blomstrom-Lundqvist C et al (2002) Task Force on Sudden
Cardiac Death, European Society of Cardiology. Europace 4:318
Cost-Effectiveness of ICD Therapy in the Prevention of Sudden

Death in CAD and/or HF Patients
ANDREA POZZOLINI
Introduction
Sudden cardiac death (SCD) is one of the most common causes of death in
Western countries [1, 2], and its prevention poses a major challenge to both
policymakers and health-care providers. The fundamental principle of evidence-based medicine is that clinical practice should rest on a sound scientific foundation established by clinical studies involving human subjects. The
strategies of primary and secondary prevention of SCD with the implantable
cardioverter defibrillator (ICD) have received increased attention in the last
few years, mainly because multiple prospective randomized clinical trials
(RCT) [3, 4] have yielded concordant and consistent results showing that
ICD therapy is highly effective in reducing SCD and all-cause mortality in
selected patients with impaired left ventricular function on optimized medical treatment (OMT), including post-MI patients as well as patients with
nonischemic cardiomyopathy. It is now known that in such patients ICDs
reduce mortality by approximately one-third over and above OMT [38].
Faced with this evidence, recently updated practice guidelines [911] have
suggested a broadening of the indications for prophylactic ICD use; but
opinions diverge on the desirability for expansion of this expensive therapeutic strategy, whose widespread implementation threatens to impact heavily on public health-care spending. Thus nowadays, due to the high cost of
ICDs and the large population of patients potentially eligible to receive
them, the debate on ICDs has moved from issues of feasibility and effectiveness to questions about costs and cost-effectiveness. The persisting controversy reflects the evolution from evidence-based to value-based medicine
Cardiology Operative Unit, Santa Croce Hospital, Fano (PU), Italy
264
Andrea Pozzolini
[12]. Since health-care resources are limited, when therapies are both effective and expensive, it is both reasonable and necessary for health-care
providers and purchasers to quantify the expected benefits for the money
they spend, particularly when in the face of the many competing programs
in an atmosphere of cost containment. The basic assumption is that clinical
efficacy does not necessarily imply public priority. The challenge to healthpolicymakers is to conjugate equity in distribution with efficiency in allocation of health-care resources. Newer therapies are typically more expensive
than older ones; thus, an important question is whether patient outcomes are
improved sufficiently to justify the added expense [13]. The academic discipline of formal cost-effectiveness analysis is the best available approach to
the question, which it seeks to answer by comparing alternative therapeutic
strategies, calculating the ratio of incremental cost to incremental effectiveness (incremental cost-effectiveness ratio, ICER) and expressing clinical outcomes in terms of years of added life or quality-adjusted life years
(QALY) gained [1418]. Comparisons to other therapies are then possible.
The lower the ICER, the better the use of resources and the more cost-effective the therapy. The typical upper-limit benchmark conventionally used to
identify therapies that provide good value is US$ 50,000 per life-year saved
(per QALY gained), which is the cost of dialysis treatment for end-stage renal
disease [19]. An ICER of US$ 100,000 or more is typically considered a poor
value for the money. Nowadays, in a context of cost-overburdened healthcare systems, health economics is considered an integral part of clinical science, and includes an assessment of whether an intervention is worthwhile
given the resources and alternative options available. The subsequent decisions drive and support societal decision-making for resource allocation in
those cases in which not everything that is potentially possible can be done.
ICD Cost-Effectiveness: the Evidence from Randomized Clinical Trials

We will now consider the clinical and economic evidence from the major
individual ICD trials, always bearing in mind that cost-effectiveness depends
on the population being studied, and that comparing the results from costeffectiveness analyses of trials enrolling appreciably different patients
requires caution and careful consideration of design features [20, 21].
Early clinical studies showed that the implantation of ICDs reduced mortality in the small population of patients who had survived a spontaneous
episode of ventricular fibrillation (VF) or sustained ventricular tachycardia
(VT) [22].
Cost-Effectiveness of ICD Therapy in the Prevention of Sudden Death in CAD and/or HF Patients
265
The AVID Trial [6] concluded that ICD therapy reduces mortality compared with anti-arrhythmic drugs (AADs) in survivors of serious ventricular
tachyarrhythmias. However, by confining its length of follow-up to only 1.5
years, rather than patient life-expectancy or device longevity, the base-case
ICER was found to be moderately expensive: at 3 years of follow-up, the
expected survival for patients treated with the ICD was 0.21 years longer
than for AAD at an incremental cost of US$ 14,101, yielding an ICER of US$
66,677 per life-year saved (LYS) by the ICD over AADs [23].
The Canadian Implantable Defibrillator Study (CIDS) demonstrated a
trend toward a lower risk of death with ICD therapy vs amiodarone (20% relative reduction, p = 0.14) over an average follow-up of 36 months in survivors of life-threatening ventricular arrhythmias [24]. The 4.3% absolute
reduction in mortality rates translated in a number needed to treat (NNT) to
save one life of 23 patients, significantly higher than the NNT of 9 at 3 years
of follow-up of AVID, while the smaller survival benefit (0.23-year, not
achieving statistical significance) and an increased cost difference (US$
31,925) between ICD- and amiodarone-treated patients resulted in a CIDS
base-case ICER over 6.3 years of follow-up of US$ 138,803, roughly twice as
high as the AVID trial and economically unattractive [25]. This notwithstanding, the long-term follow-up study of a subset of 120 CIDS patients by
Bokhari et al. [26] showed how long-term efficacy at up to 11 years (mean 5.9
years) may be higher than at mid-term, with a reduction in the relative risk
of mortality of 43%, compared with 20% at 3 years in the original CIDS
study [24]. Boriani et al. [27] calculate that such an increase in long term
efficacy would reduce the NNT to save one life to just five patients (at the
long-term follow-up of Bokharis sub-study).
After the clinical evaluation of ICD therapy for the secondary prevention
of SCD, eventually other trials evaluated the therapy as a means of primary
prevention of SCD in high-risk patients with ischemic and non-ischemic
heart disease and reduced left ventricular ejection fraction (EF); the results
of these primary prevention trials provide unequivocal proof of the survival
benefits of ICD therapy. Economic analyses were conducted to evaluate the
incremental cost-effectiveness ratio of ICD for primary prevention of SCD
compared to optimal medical treatment.
Economic analysis of the MADIT population (patients at high risk of
sudden arrhy thmic death, with EF 35% and spontaneous as well as
inducible ventricular arrhythmias) resulted in an ICER of US$ 27,000/LYS
[28]. The ICER (corrected to 1997 dollars) in MADIT was less than half that
found in AVID, US$ 30,337/LYS vs US$ 66,677/LYS, mainly because the survival difference was 3.6 times greater in MADIT.
266
Andrea Pozzolini
The MADIT II study highlighted the possibility of effective primary prevention of sudden death in those patients with coronary artery disease who
were selected by straightforward clinical data and without expensive screening, such as electrophysiological study. For patients with healed myocardial
infarction and EF < 30%, ICD therapy was shown to reduce mortality risk by
approximately 31% in the following 2 years compared with drug therapy [5].
The study raised concern about its impact on health-care systems, because
32,00066,000 people in the US annually fit its eligibility requirements [29,
30].
As reported by Al-Khatib et al. [30] in a study based on data from published literature, databases owned by Duke University Medical Center and
Medicare data, without use of cost information from the trial, ICDs were
projected to improve survival in MADIT II-like patients by 1.80 discounted
years, w ith a marg inally att ract ive ICER of US$ 50,500/LYS (US$
57,000/QALY). Sensitivity analysis suggested that the ratio could vary greatly
depending on the assumptions made, with the cost of replacing ICD batteries
and leads exerting the greatest effect on cost-effectiveness.
A cost-effectiveness analysis combining patient outcome and economic
data from the MADIT II trial [31] included 1,095 US patients with complete
data relating to clinical costs, including number of office visits, diagnostic
tests and procedures, hospitalizations, emergency department visits, medications, and other health-care services. During the 3.5-year period of the study,
the average survival gain for the ICD arm was 0.167 years (2 months), clearly
smaller than that seen in MADIT, which randomized only those patients who
had inducible ventricular arrhythmias in response to invasive electrophysiology (EP) studies; the additional costs were US$ 39,200, and the ICER of ICD
therapy was in the very expensive range (US$ 235,000/LYS). However, three
alternate projections extrapolated to 12 years of follow-up revealed incremental cost-effect iveness rat ios rang ing from US$ 78,600 to US$
114,000/LYS. The authors concluded that the estimated cost per year of life
saved by ICD therapy in the MADIT-II study was high, at 3.5 years, but it was
considerably lower based on projections for longer intervals.
The COMPANION trial [7] was the first trial that was sufficiently powered to evaluate the effects of cardiac resynchronization therapy (CRT) on
the incidence of death and hospitalization, and demonstrated that CRT
either without (CRT-P) or with the addition of an ICD function (CRT-D)
reduced the combined risk of all-cause mortality or first hospitalization
among patients with advanced heart failure and intraventricular conduction
delays [7]. Investigators from the COMPANION trial modeled the trial data
on an intention-to-treat basis to estimate the incremental cost-effectiveness
267
of CRT-P and CRT-D plus OMT relative to OMT alone over a base-case 7year treatment episode [32]. Over 2 years, follow-up hospitalization costs
were reduced by 29% for CRT-D. With extension of the cost-effectiveness
analysis to a 7-year base-case time period, the ICER for CRT-D was US$
46,700/LYS and US$ 43,000/QALY gained relative to OMT [32], below the
benchmark of US$ 50,000, generally accepted to identify therapies that provide good value. This suggests that the clinical benefits of CRT-D can be
achieved at a reasonable cost. In a recent work, Yao et al. [33] assessed the
long-term cost-effectiveness of CRT-P compared OMT alone, and the costeffectiveness of CRT-D plus OMT compared with CRT-P plus OMT, on incremental cost per QALY and life-year using data from the CARE-HF [34] and
the COMPANION [7] studies. Using a decision-analytic model based on a
Markov model and a Monte Carlo simulation, and taking into account the
estimated additional benefit of an ICD on survival, as determined by COMPANION, the authors concluded that long-term treatment with CRT-P for
patients with heart failure and cardiac dyssynchrony is much more costeffective than medical therapy (ICERs of US$ 9528/QALY gained and US$
7011/LYS). Meanwhile, the ICERs of CRT-D compared with CRT-P were US$
62,067/QALY gained and US$ 46,456/LYS, suggesting that from a lifetime perspective, the addition of an ICD function, assuming the patient has a reasonable life expectancy if he or she receives effective treatment for heart failure,
may further reduce the risk of sudden death, and may also be more costeffective than CRT-P plus OMT [33].
Considered a landmark study, the Sudden Cardiac Death in Heart Failure
Trial (SCD-HeFT) [8] enrolled patients with NYHA class II/III HF of ischemic
or nonischemic origin and a left ventricular EF 35% who were on OMT.
Patients were randomized to receive ICD therapy (single-chamber, shockonly ICDs implanted in an outpatient setting), amiodarone anti-arrhythmic
drug treatment, or placebo. Over a 5-year follow-up, the study demonstrated a
significant, 7% absolute reduction in all-cause mortality and a 23% decline in
relative risk in the ICD arm vs the placebo arm, whereas those who received
amiodarone showed no mortality benefit over placebo. Analyses of the subgroups showed that the majority of the ICD mortality benefit was obtained by
patients with less severe, NYHA class II disease; these patients showed a 46%
reduction in relative risk. NYHA class III patients demonstrated no significant mortality benefit from ICD therapy [8]. An economic analysis was
designed and conducted to determine the long-term cost-effectiveness of ICD
for prevention of SCD in patients with heart failure who were enrolled in the
study [35]. Cost-effectiveness was calculated from cost and survival data
gathered in the trial. Lifetime cost-effectiveness was estimated using projec-
268
Andrea Pozzolini
tions of cost and life-expectancy beyond the mean study follow-up of 46

months. The results indicated that: (a) the projected life expectancy from
time of randomization was 10.9 years in the ICD arm and 8.4 years in the
placebo arm; (b) amiodarone did not prolong survival compared to placebo;
(c) there was no evidence that ICD patients had significantly more hospitalizations, major cardiac procedures, or outpatients visits over the first 5 years
of follow-up than patients in the placebo arm; (d) ICD cost-effectiveness,
expressed as the incremental lifetime cost to save a life-year relative to placebo, was US$ 38,389/LYS. This cost varied depending on survival time: US$
127,503/LYS at 5 years, US$ 88,657/LYS at 8 years, and US$ 58,510/LYS at 12
years. When NYHA class II patients were analyzed separately, the analysis
yielded an even better discounted ICD ICER of US$ 29,872/LYS, due to the
greater survival benefit in this group. The cost-analysis concluded that prophylactic use of conservatively programmed, single-lead ICDSs for primary
prevention of SCD in HF patients with an ejection fraction 35% is an economically efficient way to improve patient outcomes based on the currently
established benchmarks, provided that the devices are implanted in stable,
moderately symptomatic patients (particularly NYHA class II) and that
patients survive at least 8 years following implantation [35].
The cost-effectiveness of the ICD in the population of patients represented in eight primary-prevention ICD trials was assessed by Sanders et al. [36].
Based on a Markov model, the cost, quality of life, survival, and ICER of the
ICD for primary prevention of sudden death were compared with medical
therapy among patients with survival and mortality rates similar to those in
each of the clinical trials. The efficacy of the ICD was modeled as a reduction
in the relative risk of death on the basis of the hazard ratios reported in the
individual clinical trials. The results showed that use of the ICD increased
lifetime costs in every trial. In two trials in which no survival benefit was
associated with ICD therapy, DINAMIT [37] and the CABG Patch trial [38],
the authors concluded that the prophylactic implantation of an ICD did not
reduce the risk of death and thus was both more expensive and less effective
than control therapy. For the other six trials showing clinical benefit
(MADIT I, MADIT II, MUSTT, DEFINITE, COMPANION, and SCD-HeFT),
use of an ICD was projected to add between 1.01 and 2.99 QALY and between
US$ 68,300 and US$ 101,500 in cost. With these base-case assumptions, the
authors found that the ICER of the ICD as compared with control therapy in
these six populations ranged from US$ 34,000 to US$ 70,200 per QALY
gained [36]. Further sensitivity analyses showed that this ICER would
remain below US$ 100,000 per QALY as long as the ICD reduced mortality
rates for 7 or more years. On the basis of their analysis, it was concluded that
prophylactic implantation of an ICD has an ICER below US$ 100,000 per
269
QALY gained in populations in which a significant device-related reduction

in mortality is demonstrated [36].
ICDs and the Real World: the SEARCH-MI Registry

The generalizability of randomized clinical trials, that is, whether the results
of the economic analyses from landmark trials such as MADIT II and SCDHeFT apply to the real-world population of patients, has been raised as a
concern [39]. The objections are based on the fact that selection bias is very
difficult to eliminate from any clinical trial, and real-world patients are older
and generally sicker than patients included in trials [40]. Generalizability is
best assessed through the evaluation of outcomes in clinical practice.
A comparison of the data from 556 patients enrolled from July 2002 to
April 2005 in the Italian sub-study of the prospective Multicenter Survey to
Evaluate Arrhythmia Rate in so-Called High-risk Myocardial Infarction
Patients (Search-MI) Registry with data from the ICD arm of MADIT II
showed comparable results, both in terms of appropriate shocks and overall
mortality, thus confirming in real-world practice the benefits of primary
prevention in MADIT II-like patients [41]. Describing an economic analysis based on real expenditure data from 2002 to 2005, as recorded in the
Search-MI Registry, Boriani et al. [42] estimated the daily costs associated
with the device and leads. Over a 57 year time horizon, the average daily
cost was estimated to be 4.60 6.70. Translation of these figures into US
market conditions results in a daily cost of around US$ 7.9011.40. It is
important to bear in mind that these estimates only refer to hardware costs
and do not take into account hospitalization and physicians fees at the time
of implant, nor were costs secondary to complications and device replacement included in the calculations; therefore, the cited values somewhat
underestimate the entire cost of treatment [42]. Nevertheless, the dilution in
terms of daily costs over a predefined time horizon of the high initial expenditure of ICD purchase and implant makes it somewhat easier to compare
such costs with those generated by the continuous use of chronic pharmacological treatment, and thereby to evaluate the affordability of ICD.
The Influence of Risk Stratification among Patients on the

Cost-Effectiveness of ICDs
Although expensive, in appropriate patients ICDs provide value. Ideally, ICDs
would be placed only in patients who are likely to develop life-threatening
270
Andrea Pozzolini
ventricular arrhythmias and would not be placed in those who are not destined to have such arrhythmias. However, given the number of patients now
eligible for ICD implantation, based on the EF alone, there is a need to identify the clinical characteristics or diagnostic tests that will enable clinicians
to select patients who are at increased risk for sudden death but whose low
competing risks of death would allow them to benefit the most from receipt
of an ICD.
Conversely, from a societal perspective, identification of the MADIT IIlike patients least likely to benefit from ICD implantation might allow for
substantial cost savings with a small or even negligible sacrifice in population life expectancy [43]. Furthermore, as cost-effectiveness needs to be
adjusted for the tolerability of the therapy by the patients, i.e., qualityadjusted, better selection might decrease the percentage of patients in whom
an ICD will only lower quality-of-life, producing inappropriate discharges
and other undesirable effects, thus affecting cost-utility analyses [44].
Although multiple clinical, electrocardiographic, and electrophysiologic
parameters have been assessed as potential markers to stratify risk for
VT/VF and SCD, scarce progress has been made over the last years in this
field by researchers.
Promising results have been recently obtained with microvolt T wave
alternans (MTWA) testing, which potentially could be employed to improve
cost-effectiveness [45]. The MTWA test noninvasively measures beat-to-beat
microvolt variations in the shape, amplitude, or timing of the ECG T wave
that are linked with the development of clinical ventricular arrhythmias. The
test has a high negative predictive value, that is, a negative test result identifies a patient at very low risk of fatal SCD.
In the absence of direct studies examining whether there is any benefit to
be derived from implanting ICDs among the patients testing negative for
microvolt T wave alternans, Chan et al. [45] used a mathematical model based
on recent studies to compare the lifetime costs and benefits of a medical therapy strategy to prevent death by implanting ICDs in all currently eligible
MADIT II-like patients, or implanting defibrillators in only those patients
considered to be at higher risk according to the MTWA test and using drugs
to treat the rest. Overall, they calculated that, on average, patients who
received an ICD would live almost one-and-a-half quality-adjusted years
longer than patients on drug therapy (7.3 vs 5.9 years) and the additional cost
per QALY would be about US$ 56,000. However, when the screening test was
factored, the authors found that almost all the benefits went to high-risk
patients, and that the patients testing negative and who received defibrillators
would live only slightly longer than if they were treated with medical therapy.
271
The ICER for implanting an ICD in the lower risk group testing negative for
microvolt T wave alternans was closer to US$ 90,000/QALY, which would not
be considered cost-effective by commonly accepted thresholds. In contrast,
implanting an ICD in an eligible MADIT II-like population that tests nonnegative would be less than US$ 50,000/QALY. Thus, a strategy of making
ICDs available to all eligible patients according to MADIT II criteria would be
less cost-effective than a more discriminating strategy of implanting ICDs
only among those testing MTWA non-negative [45].
Conclusions
Although there is consistency among the majority of primary- and secondary-prevention ICD studies regarding the effectiveness of the device, calculated figures on cost-effectiveness in different trials vary significantly [31,
35, 36], as cost-effectiveness depends on the population being studied. As we
have already stressed, comparing the results from cost-effectiveness analyses
of trials enrolling appreciably different patients requires caution and careful
consideration of design features [20, 21]. Furthermore, most ICD clinical trials underestimate the cost-effectiveness of ICD therapy because the followup periods are short. In fact, failure to consider therapy duration can incorrectly alter cost-effectiveness findings. Compared with medical treatment,
ICD therapy has a high up-front cost but very few costs thereafter. Many trials, such as MADIT II, have follow-up periods of only 18 months. Given a
current battery life of 7 years, only 20% of the life of the device will be used
by the end of a typical follow-up period, yet the full cost of the device is used
in cost-effectiveness calculations.
In the end, in the range of survival benefit observed in randomized clinical studies, ICD therapy appears to be acceptably cost-effective and economically attractive by conventional standards in the patients indicated by current clinical guidelines. Although the ICD is expensive, it can be justified
when considered in the context of other accepted therapies (revascularization procedures, antihypertensive treatment) [46], and, at least in certain
subsets of patients, ICD therapy falls under US$ 50,000/LYS, which is the
commonly accepted benchmark to identify therapies that provide good value
[31, 35]. Conversely, one must also consider that cost-effective does not mean
inexpensive. There is diffuse concern among policymakers that the large
number of patients eligible for ICDs under currently accepted criteria may
strain societal ability to perform and pay for these procedures.
Undoubtedly, ICD therapy would be more attractive if certain modifications in the factors affecting ICD cost-effectiveness occurred, i.e., reduced
Andrea Pozzolini
272
cost, extended longevity and improved reliability of the hardware, reduced

length of hospitalization, and better risk-stratification. The latter issue is of
paramount importance, as the use of more selective, more efficient riskstratifiers would lead to lower NNT to prevent one premature death, and
would result in fewer cases in which patients receive ICDs although they do
not stand to benefit from them as well as fewer patients exposed to unnecessary risks. Furthermore, the use of biventricular ICDs for cardiac resynchronization therapy (CRT-D) in selected patients with severe heart failure and
ventricular electromechanical dyssynchrony substantially improves qualityof-life, modifies disease progression, and favorably influences both hospitalization for heart failure and mortality [7]. This, in turn, would make the
ICER of ICDs used for cardiac resynchronization therapy more attractive
than that for ICDs implanted only to prevent SCD [32, 47].
As for the general problem of how the results of clinical trials can be
transposed in the real world, data from the prospective multicenter registries
in the USA on ICD use in primary prevention [48] and the already available
data from the multicenter European SEARCH-MI Registry [42] will allow
better clinical as well as economical evaluation of ICD use in the coming
years.
References
1.
2.
3.
4.
5.
6.
7.
8.
Zheng ZJ, Croft JB, Giles WH et al (2001) Sudden cardiac death in the United States,
1989 to 1998. Circulation 104:21582163
Josephson M, Wellens HJ (2004) Implantable defibrillators and sudden cardiac
death. Circulation 109:26852691
Nanthakumar K, Epstein A, Kay GN et al (2004) Prophylactic implantable cardioverter-defibrillator therapy in patients with left ventricular systolic dysfunction: a
pooled analysis of 10 primary prevention trials. J Am Coll Cardiol 44:21662172
Desai A, Fang J, Maisel W et al (2004) Implantable defibrillators for the prevention
of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. JAMA 292:28742879
Moss AJ, Zareba W, Hall WJ (2002) Prophylactic implantation of a defibrillator in
patients with myocardial infarction and reduced ejection fraction. N Engl J Med
346:877883
The Antiarrhythmic Versus Implantable Defibrillator (AVID) Investigators (1997)
A comparison of antiarrhythmic drug therapy with implantable defibrillators in
patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med
337:15761583
Bristow M, Saxon L, Boehmer J et al (2004) Cardiac-resynchronization therapy
with or without an implantable defibrillator in advanced chronic heart failure. N
Engl J Med 350:21402150
Bardy GH, Lee KL, Mark DB et al (2005) Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 352:225237
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
273
Hunt SA, Abraham WT, Chin MH et al (2005) ACC/AHA 2005 Guideline update for
the diagnosis and management of chronic heart failure in the adult : a report of the
American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 46:e1-e82
Zipes DP, Camm AJ, Borggrefe M et al (2006) ACC/AHA/ESC 2006 Guidelines for
management of patients with ventricular arrhythmias and the prevention of sudden cardiac death executive summary. J Am Coll Cardiol 48:10641108
Lunati M et al (2005) Linee guida AIAC allimpianto di pacemaker, dispositivi per
la resincronizzazione cardiaca (CRT) e defibrillatori automatici impiantabili (ICD).
Giornale italiano di Aritmologia e Cardiostimolazione 8:158
Brown GC, Brown MM, Sharma S (2003) Value-based medicine: evidence-based
medicine and beyond. Ocul Immunol Inflamm 11:157170
Boriani G, Biffi M, Martignani C et al (2003) Cardioverter-defibrillators after
MADIT II: the balance between weight of evidence and treatment costs. Eur J
Heart Failure 5:419425
Meltzer MI (2001) Introduction to health economics for physicians. Lancet
358:993998
Mark DB, Hlatky MA (2002) Medical economics and the assessment of value in
cardiovascular medicine. Part I. Circulation 106:516520
Mark DB, Hlatky MA (2002) Medical economics and the assessment of value in
cardiovascular medicine. Part II. Circulation 106:626630
Boriani G, Biffi M, Martignani C et al (2001) Cost-effectiveness of implantable cardioverter-defibrillators. Eur Heart J 22:990996
Boriani G, Larsen G (2006) Cost-effectiveness of implantable cardioverter-defibrillators. In: Priori S, Zipes DP (eds) Sudden cardiac death. Blackwell Publishing,
Malden, pp 263279
Stange PV, Sumner AT (1978) Predicting treatment costs and life expectancy for
end-stage renal disease. N Engl J Med 298:372378
Spath MA, OBrien BJ (2002) Cost-effectiveness of the implantable cardioverter
defibrillator therapy versus drug therapy for patients at high risk of sudden cardiac death. Pharmacoeconomics 20:727738
Weinstein MC, Siegel JE, Gold MR et al (1996) Recommendations of the Panel on
cost-effectiveness in health and medicine. JAMA 276:12531258
Ezekowitz JA, Armstrong PW, McAlister FA (2003) Implantable cardioverter defibrillators in primary and secondary prevention: a systematic review of randomized, controlled trials. Ann Intern Med 138:445452
Larsen G, Hallstrom A, McAnulty J et al (2002) Cost-effectiveness of the implantable cardioverter-defibrillator versus antiarrhythmic drugs in survivors of serious
ventricular tachyarrhythmias: results of the Antiarrhythmic Versus Implantable
Defibrillators (AVID) economic analysis substudy. Circulation 105:20492057
Connolly SJ, Gent M, Roberts RS et al (2000) Canadian Implantable Defibrillator
Study (CIDS): a randomized trial of the implantable cardioverter defibrillator
against amiodarone. Circulation 101:12971302
OBrien BJ, Connolly SJ, Goeree R et al (2001) Cost-effectiveness of the implantable
cardioverter-defibrillator: results from the Canadian Implantable Defibrillator
Study (CIDS). Circulation 103:14161421
Bokhari F, Newman D, Greene M et al (2004) Long term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS). Circulation
110:112116
274
Andrea Pozzolini
27.
Boriani G, Biffi M, Martignani C (2005) Letter regarding article by Bokhari et al

Long-term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable
Defibrillator Study (CIDS). Circulation 111:e26
Mushlin AI, Hall WJ, Zwanziger J et al (1998) The cost-effectiveness of automatic
implantable cardiac defibrillators: results from MADIT. Multicenter Automatic
Defibrillator Implantation Trial. Circulation 97:21292135
Centers for Medicare and Medicaid Services (2003) Decision memorandum: national coverage determination (NCD) on implantable defibrillators, pp 137
Al-Khatib SM, Anstrom KJ, Eisenstein EL et al (2005) Clinical and economic implications of the Multicenter Automatic Defibrillator Implantation Trial-II. Ann
Zwanziger J, Hall WJ, Dick AW et al (2006) The cost-effectiveness of implantable
cardioverter-defibrillators: results from the Multicenter Automatic Defibrillator
Implantation Trial (MADIT) II. J Am Coll Cardiol 47:23102318
Feldman AM, de Lissovoy G, Bristow MR et al (2005) Cost effectiveness of cardiac
resynchronization therapy in the Comparison of Medical Therapy, Pacing, and
Defibrillation in Heart Failure (COMPANION) trial. J Am Coll Cardiol
46:23112321
Yao G, Freemantle N, Calvert MJ et al (2007) The long-term cost-effectiveness of
cardiac resynchronization therapy with or without an implantable cardioverterdefibrillator. Eur Heart J 28:4251
Cleland JG, Daubert JC, Erdmann E et al (2005) The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:15391549
Mark DB, Nelson CL, Anstrom KJ et al (2006) Cost-effectiveness of defibrillator
therapy or amiodarone in chronic stable heart failure: results from the Sudden
Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation 114:135142
Sanders GD, Hlatky MA, Owens DK (2005) Cost-effectiveness of implantable cardioverter-defibrillators. N Engl J Med 353:14711480
Hohnloser SH, Kuck KH, Dorian P et al (2004) Prophylactic use of an implantable
cardioverter-defibrillator after acute myocardial infarction. N Engl J Med
351:24812488
Bigger JT Jr (1997) Prophylactic use of implanted cardiac defibrillators in patients
at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery.
N Engl J Med 337:15691575
Buxton AE (2003) The clinical use of implantable cardioverter defibrillators: where
are we now? Where should we go? Ann Int Med 138:512514
Tavazzi L (2000) Ventricular pacing: a promising new therapeutic strategy in heart
failure. For whom? Eur Heart J 21:12111214
Boriani G (2006) From MADIT II to Search-MI Registry for primary prevention of
sudden death in ischemic patients. Presented at the XII International Symposium
on progress in clinical pacing, Rome
Boriani G, Biffi M, Russo M et al (2006) Primary prevention of sudden cardiac
death: can we afford the cost of cardioverter-defibrillators? Data from the SearchMI Registry-Italian Sub-study. Pacing Clin Electrophysiol 29:S29-S34
Owens DK, Sanders GD, Heidenreich PA et al (2002) Effect of risk stratification on
cost-effectiveness of the implantable cardioverter-defibrillator. Am Heart J
144:440448
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
275
Gould PA, Krahn AD (2006) Complications associated with implantable cardioverter-defibrillator replacement in response to device advisories. JAMA 295:19071911
Chan PS, Stein K, Chow T et al (2006) Cost-effectiveness of a microvolt T wave
alternans screening strategy for implantable cardioverter-defibrillator placement
in the MADIT II-eligible population. J Am Coll Cardiol 48:112121
Hlatky MA (2004) Evidence based use of cardiac procedures and devices. N Engl J
Med 350:21262128
Stevenson LW (2006) Implantable cardioverter-defibrillators for primary prevention of sudden death in heart failure. Are there enough bangs for the bucks?
Sweeney MO, Schoenfeld MH, Cannom DS (2005) Rules of evidence: CMS and primary prevention of sudden cardiac death in systolic heart failure. Pacing Clin
Current Practice in Italy of VF Testing at Implant: What Do We

Know and Where Do We Go From Here?
MICHELE BRIGNOLE1, GIOVANNI RACITI2, MARIA GRAZIA BONGIORNI3, GIUSEPPE DE
M ARTINO 4, S TEFANO FAVALE 5, M AURIZIO G ASPARINI 6, R AFFAELE LUISE 7, E RALDO
OCCHETTA8, ALESSANDRO PROCLEMER9
What Do We Know?
The standardized requirements for cardioverter defibrillator (ICD) implantation, with or without cardiac resynchronization therapy (CRT), include
defibrillation testing (DT), which consists of the induction and termination
of ventricular fibrillation (VF). This procedure has been followed from the
early days of ICD therapy in order to assess the reliability of an implanted
ICD device and to measure the defibrillation threshold. Effective DT is considered mandatory in accordance with the rules of good clinical practice.
Nowadays, since the implantation procedure for ICDs has become
markedly simplified and the surgical risk is very low, DT can be considered
to be the most critical part of the implantation procedure itself. Although the
risk associated with DT is usually low, serious complications may nonetheless occur as a consequence of this practice. Complications include transient
ischemic attack or stroke, cardiopulmonary arrest due to refractory VF or
pulseless electrical activity, cardiogenic shock, embolic events, and death.
This knowledge comes from small single-center retrospective surveys [1]
and from anecdotal experience. However, in the absence of data from large
populations enrolled in multi-center registries, the real magnitude of intraoperative complications related to DT is still largely unknown.
Although the standardized approach to ICD implantation still includes a
VF induction test, data coming from real-world experience suggest that an
increasing number of first-implantation procedures are performed without
1Department
of Cardiology, Ospedali del Tigullio, Lavagna (GE); 2Boston Scientific Italy,

Milan; 3Ospedale Cisanello, Pisa; 4Casa di Cura Santa Maria, Bari; 5Ospedale Consorziale
Policlinico, Bari; 6Istituto Clinico Humanitas, Rozzano(MI); 7Casa di Cura Villa Pini
dAbruzzo, Chieti; 8Ospedale Maggiore della Carit, Novara; 9Azienda OspedalieroUniversitaria, Fondazione IRCAB, Udine, Italy
232
Michele Brignole et al.
any induction test. It seems that some physicians are concerned about practicing DT in patients considered to be at very high clinical risk. For example,
in two single-center populations, Russo et al. [2] reported a lack of induction
testing in 4.7% and Pires et al. [3] in 24% of patients. The reasons for omitting induction testing included intraoperative hypotension or hemodynamic
instability, known cavity thrombus or previous inadequate anticoagulation
therapy, recent cardiovascular accident, severe comorbidities, and the
absence of anesthesia support.
The Associazione Italiana di Aritmologia e Cardiostimolazione (AIAC)
recently conducted a systematic nation-wide retrospective survey to determine how often and for what reason intra-operative DT was or was not performed, and the complication rate related to induction testing.
An ad-hoc questionnaire was sent to 343 centers implanting ICDs (listed
in the database of the Italian ICD Registry of the AIAC), which essentially
represents all of Italys implanting centers. The ICD implantation data collected by the Italian ICD Registry of the AIAC is formatted according to the
recommendations of the European ICD Registry (EURID).
The survey was limited to patients undergoing initial ICD implantation
during the year 2005. Questionnaire and data collection were carried out
through the World Wide Web from June to October 2006. Participating centers were asked to communicate their data regarding the total number of
ICDs (including those with CRT features), number of implantations in which
DT was performed intraoperatively or before discharge, and number and
type of DT-related complications. DT was defined as at least one induction of
VF. DT-related complications were considered those life-threatening events
occurring immediately after VF induction.
Of the 8,820 first ICD/CRTs implanted in Italy during 2005, data on 7,857
(89%) implantations (38% of whom CRT) performed in the 229 centers that
participated in the survey were analyzed. Of these, 2,356 (30%) implantations did not include an induction test (Table 1). In 35 (15%) centers, an
induction test was administered in < 25% of the patients, while in 136 (59%)
centers it was done in > 75% of the patients. In a multivariable analysis of a
subset of 1,206 patients from 107 centers, CRT device (OR 1.82) and primary
prevention (OR 1.47) were independent predictors of the decision to not
administer DT. However, all together, clinical variables accounted only for
35% of the total variance, and the remaining 65% was probably unrelated to
clinical factors (Table 2). Life-threatening complications as a consequence of
the induction test were reported in 22 (0.4%) patients: four deaths (0.07%),
eight cardiopulmonary arrests requiring resuscitation maneuvers (0.15%),
six cases of cardiogenic shock (0.11%), three strokes (0.05%), and one pul-
Current Practice in Italy of VF Testing at Implant
233
Table 1. Principal findings

Centers invited to participate
343 (%)
Centers that participated
229 (67)
Total number of first-implant procedures
7,857
With intraoperative defibrillation test
5,501 (70)
Without intraoperative defibrillation test
2,356 (30)
Total number of complications related to defibrillation test
22 (0.4)
Death
4 (0.07)
Cardiopulmonary arrest requiring resuscitation
8 (0.15)
Cardiogenic shock
6 (0.11)
Stroke
3 (0.05)
Pulmonary embolism
1 (0.02)
Table 2. Univariable and multivariable predictors of the decision to not perform the
induction test in a subset of 1,206 patients
Factors
Percent
Age (70
43
Univariable
Odds ratio
(95% CI)
Multivariable
Odds ratio
(95% CI)
1. 31(1.030.67)
0.03
1.29 (0.991.67)
0.06
< 0.001
Male gender
87
1.22 (0.861.72)
0.25
CRT device
19
2.01 (1.502.68)
< 0.001
1.81 (1.302.53)
Primary prevention
45
1.65 (1.302.09)
< 0.001
1.50 (1.141.97)
0.003
Ejection fraction (30% 51
1.68 (1.302.16)
< 0.001
1.30 (0.971.72)
0.07
Dilated vs ischemic
47
1.42 (1.121.80)
0.004
NYHA class > 2
23
1. 96 (1.462.63)
< 0.001
aMale gender was not analyzed in the multivariate model because it was not significant in
the univariable analysis

bDilated vs ischemic and NYHA class were not inserted in the multivariable model as these
resulted were covered by the parameter CRT device

CRT, Cardiac resynchronization therapy; NYHA, New York Heart Association
monary embolism (0.02%). Failure of an ICD defibrillation test, and thus the
need for a backup external defibrillator, was 2.7%, which determined a system revision (i.e., additional lead insertion, etc.) in 2.3% of patients.
This nation-wide survey was the largest ever performed and covered 89%
of the overall first-implantations in Italy during 2005. The main finding was
that, in real-world clinical practice, DT was not administered in 30% of
234
patients, and in most of these cases there was no legitimate reason for the
omission. Nonetheless, DT is still considered part of the standard procedure
of ICD implantation. There was wide heterogeneity between centers and
more than a quarter of Italian centers did not administer DT in 50% of
their patients. These figures, which were much higher than those expected
from the literature [2, 4], not only reflect the spontaneous non-conformist
opinions of several physicians they also go beyond the current recommendations of ICD manufacturers. Given the large number of physicians who do
not include DT during ICD implantation, the decision requires explanation
and merits specific actions in response.
One explanation for the limited use of DT is the increasing role of primary prevention strategies [5, 6], which address patients with very low ejection
fraction and advanced NYHA class [7]. The selection of sick patients due to
expanded ICD indications was recently confirmed in a comparison of USA
and Italian practices [8]. However, all together, the clinical variables accounted only for 35% of the total variance whereas the remaining 65% was probably unrelated to clinical factors. Therefore, the main reasons for the violation
of current standards in so many patients seem to be, on the one hand, the
concern for severe complications related to intraoperative DT and, on the
other, the conviction of a small risk of death due to failure of the ICD to
interrupt VF during long-term follow-up.
In the Italian survey study, the DT-related life-threatening complication
rate was not negligible, accounting for 0.40% of cases, considering that DT in
the analyzed cohort of patients was preferably administered to less sick
patients (Table 2). The complication rate might have been even higher if the
patients with severe heart failure and very low ejection fraction were not
preventively excluded from undergoing DT. In the literature, there are a few
reports based on small studies concerning intraoperative complications. A
report [1] on 440 consecutive single-center ICD implantations showed 0.2%
perioperative deaths, 0.5% difficulty in defibrillation with requirements for
more than three external shocks, and 0.7% perioperative ischemic attack. In
another single-center study [2], consisting of 835 ICD implantations, there
were three (0.35%) perioperative deaths (within 30 days of implant). It has
been reported that shocks during DT may cause hemodynamic compromise
[9], especially in patients with severe heart failure, as are candidates for CRT.
Moreover, anesthesia has a cardiac-depressive effect in the presence of VF
induction [10]. The clinical conditions of patients undergoing implantation
may be worse but might improve later with CRT, thus decreasing the risk of
complications related to DT. For example, a DT delayed up to 2 months after
235
CRT device implant, when the patients clinical condition has improved due
to CRT, showed effectiveness without compromising safety [11].
Few data are available on the risk of death due to the failure of the ICD to
interrupt a VF during long-term follow-up. Sudden death in patients with
ICD is reported to range from 1.8 to 2.6% during 13 years of follow-up
[1214]. Analysis of the mechanisms of sudden death, with data retrieved
from ICD diagnostic memory, showed that only a quarter of the above-mentioned cases could be attributed to shock failure during VF [13]. Therefore, it
can be assumed that the sudden death rate potentially attributable to shock
failure ranged from 0.45 to 0.65% during 13 years of follow up. This percentage is very similar to the percentage of intra-operative deaths following
VF induction during implantation. There are no data that specifically
demonstrate increased mortality among patients with high DT thresholds at
implant. In a recent study [3], both the success of ICD therapy and suddendeath-free survival were similar in patients who had defibrillation threshold
measurement, safety margin testing, or no testing.
Where Do We Go from Here?

Is it time to change the current standard of performing DT at the time of
ICD implantation? The question has been previously raised by several experienced clinicians [24, 14, 15]. However, there is no evidence-based answer
yet. The reasons for and against DT are summarized in Table 3. The clinical
impact of DT vs. no DT will remain unclear until the not-negligible intraoperative complication rate is weighted against the long-term potential benefit
of DT. Long-term follow-up data regarding the safety and efficacy of ICD
implantation in large groups of patients in whom DT is not performed are
needed. Until this information becomes available, DT should be considered
as a standard practice. Data from the literature and from the present study
support the need to carry out large multicenter studies and emphasize the
urgent need for precise recommendations from the relevant clinical specialties.
Acknowledgements
The study was officially approved by the National Board (M. Brignole, N. Bottoni, A.
Campana, A. Curnis, M. Di Biase, E. Feraco, M. Gulizia, R. Pedretti, M. Santini, M.
Tritto, R. Verlato), endorsed by the AIAC (Associazione Italiana di Aritmologia e
Cardiostimolazione), and supported by a grant from Guidant-Boston Scientific
Corporation.
236
Table 3. Advantages and disadvantages of performing DT at the time of implant

Reasons in favor of induction
Standard practice for ICD implant
Most device safety studies required DT
at implant
DT allows the choice of corrective measures at implant in case of high threshold
DT ensures that the system provides
appropriate sensing of VF
DT may include the defibrillation
threshold evaluation for better ICD
programming
Reasons in favor of noninduction

No data specifically demonstrate
increased mortality among patients
with high DT thresholds
A quite small probability of a high
threshold and a failed implant with current technology
The nature of the defibrillation threshold is probabilistic and repeated shocks
below threshold can be effective
The shocks may cause hemodynamic
compromise
The cardiac depressive effect of anesthesia in addition to VF induction
In the great majority of patients receiving an ICD, the initial spontaneous lifethreatening arrhythmia is VT and not
VF; thus, a DT at implant imposes an
additional risk that most patients
would not otherwise have in their lives
Patients at implant may have worse
clinical conditions that could improve
later with CRT, thus decreasing the risk
of complications related to DT
In one retrospective analysis, success of
ICD therapies and sudden-death-free
survival were similar in patients who
had defibrillation threshold testing,
safety margin testing, and no testing
ICD, Cardioverter defibrillator; DT, defibrillation testing; VT, ventricular tachycardia;

VF, ventricular fibrillation; CRT, cardiac resynchronization therapy
References
1.
2.
3.
4.
Alter P, Waldhans S, Plachta E et al (2005) Complications of implantable cardioverter defibrillator therapy in 440 consecutive patients. Pacing Clin Electrophysiol
28:926932
Russo AM, Sauer W, Gerstenfeld EP et al (2005) Defibrillation threshold testing: is
it really necessary at the time of implantable cardioverter-defibrillator insertion?
Heart Rhythm 2:456461
Pires LA, Johnson KM (2006) Intraoperative testing of the implantable cardioverter-defibrillator: how much is enough? J Cardiovasc Electrophysiol 17:140145
Strickberger SA, Klein GJ (2004) Is defibrillation testing required for defibrillator
implantation? J Am Coll Cardiol 44:8891

5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
237
Ezekowitz JA, Armstrong PW, McAlister FA (2003) Implantable cardioverter defibrillators in primary and secondary prevention: a systematic review of randomized, controlled trials. Ann Intern Med 138:445452
Sweeney MO, Schoenfeld MH, Cannom DS (2005) Rules of evidence: CMS and primary prevention of sudden cardiac death in systolic heart failure. Pacing Clin
Proclemer A, Ghidina M, Cicuttini G et al (2006) Impact of the main implantable
cardioverter-defibrillator trials for primary and secondary prevention in Italy. A
sur vey of the national activity during the years 20012004. Pacing Clin
Electrophysiol 29(Suppl 2):S20-S28
Greenberg SM, Epstein AE, Deering T et al (2007) Differences in international ICD
implantation rates: comparison of US and Italian practice. Pacing Clin
Electrophysiol (in press)
Tokano T, Bach D, Chang J et al (1998) Effect of ventricular shock strength on cardiac hemodynamics. J Cardiovasc Electrophysiol 9:791797
Gilbert TB, Gold MR, Shorofsky SR et al (2002) Cardiovascular responses to repetitive defibrillation during implantable cardioverter-defibrillator testing. J
Cardiothorac Vasc Anesth 16:180185
Gasparini M, Galimberti P, Regoli F et al (2005) Delayed defibrillation testing in
patients implanted with biventricular ICD (CRT-D): a reliable and safe approach. J
Fiek M, Zieg B, Matis T et al (2006) Analysis of the cause of death of ICD patients
during long-term follow-up. Herzschrittmacherther Elektrophysiol 17:612
Mitchell LB, Pineda EA, Titus JL et al (2002) Sudden death in patients with implantable cardioverter defibrillators: the importance of post-shock electromechanical
dissociation. J Am Coll Cardiol 39:13231328
Neuzner (2005) Is DFT testing still mandatory? Herz 30:601606
Favale S (2005) Test di defibrillazione durante limpianto di defibrillatore automatico: ancora necessario? G Ital Aritmol Cardiostim 2:7377
How To Choose Between Single-Chamber and Dual-Chamber

ICD
MAURIZIO DEL GRECO, LORENA GRAMEGNA, MASSIMILIANO MARINI,
MARCELLO DISERTORI
Introduction
Patients in whom an implantable cardioverter defibrillator (ICD) is indicated
and who have concomitant significant sinus-node disease or atrioventricular
block may be candidates for a dual-chamber device. However, it is still a matter of debate whether the dual-chamber ICD is also advantageous for
patients with preserved sinus and atrioventricular nodal function, as data
from prospective randomized trials are limited. Overall, the number of
implanted dual-chamber devices has been increasing and, according to the
2003 AIAC Registry data, accounted for one-third of all the defibrillators
implanted in Italy, while single chamber devices made up 39%. The theoretical advantages of dual-chamber ICDs are: better supraventricular tachycardia (SVT) discrimination, optimal treatment of bradyarrhythmias (pre-existing or drug induced), and major hemodynamic benefits.
SVT Discrimination
The performance of the SVT discrimination algorithm performance in dualchamber devices is still under debate. So-called third-generation algorithms,
such as Sudden Onset, Stability, and QRS morphology, have increased the
performance of single chamber ICDs [1, 2]. However, the weakness of these
advanced algorithms is the risk of less sensitivity in detecting actual ventricular tachycardia when they are programmed to obtain a higher specificity [3].
Electrophysiology Laboratory, Cardiology Department, S. Chiara Hospital, Trento, Italy
240
Maurizio Del Greco, Lorena Gramegna, Massimiliano Marini, Marcello Disertori
The distinctive feature of dual-chamber devices is their capability of

sensing and analyzing atrial rhythm and comparing it with ventricular
rhythm during hearth high rates. Clinical trials demonstrated that dualchamber devices had a specificity of 8090% while maintaining 100% sensibility [46]. However dual-chamber algorithms can lead to inappropriate
detections and therapies due to the fact that some arrhythmias are difficult
to interpret. Overall, the most difficult rhythms to detect are the 1:1 atrial
flutter and junctional arrhythmia. Since dual-chamber discrimination algorithms rely on information from the atrial lead, final placement of this lead
is crucial. Clinical studies [7, 8] have not demonstrated significant differences between single- and dual-chamber devices when the number of inappropriate therapies was compared. A more detailed data analysis revealed
that in patients with dual-chamber devices, 75% of the inappropriate therapies were due to atrial oversensing or undersensing. This again stresses the
primary role of the atrial lead and the need to carefully position it in order
to get both good atrial sensing and accurate ventricular far-field discrimination. The importance of the atrial lead position is greater in ICDs than in
pacemakers since the filters used in defibrillators allow continuous and accurate monitoring only if blanking periods are short or even absent. This might
lead to inappropriate detection, in particular when the amplitude of a sensed
P-wave is very low, e.g., during atrial fibrillation (AF) or when ventricular
far-field could not be correctly detected.
Recently, the rate of inappropriate detection of SVT was evaluated in the
multicenter Detect Supraventricular Tachycardia Study [9], which enrolled
patients with clinical indications for ICD. The study subjects were randomly
assigned to receive either a single-chamber ICD or dual-chamber ICD (last
generation). In this study, the odds of inappropriate detection decreased by
almost half with use of dual-chamber detection enhancement. It is worth
nothing that this result was also obtained when the device was programmed
in order to minimize unnecessary ventricular pacing.
Hemodynamic Benefits
An emerging issue when choosing the best device to implant is often the latters
impact on the patients hemodynamics parameters. It was shown that, in sinusnode-disease patients or in patients with AV conduction disease, sequential AV
pacing with optimized AV delays could yield hemodynamic benefits and
improve clinical outcome, especially in heart-failure patients [10, 11].
It was also demonstrated that asynchronous ventricular activation
provoked by right ventricular apical pacing, may lead to a deterioration of
How To Choose Between Single-Chamber and Dual-Chamber ICD
241
ventricular performance [12]. The DAVID [13] (Dual Chamber and VVI
Implantable Defibrillator) study compared the efficacy of dual-chamber pacing with backup VVI pacing in patients indicated for ICD therapy, with no
pacing indication and left ventricle ejection fraction < 40%. The study endpoint was a combined endpoint of death or first hospitalization due to heart
failure. The study was prematurely discontinued because there were fewer
events in the VVI arm (survival rate 83.9% vs 73.3% at 1 year, p 0.03).
The deleterious effects of apical right ventricular pacing were conclusively shown in a recent long term follow-up study (53 months) in which 100
ICD patients were enrolled [14]. The results demonstrated that in ICD recipients without conventional indications for dual-chamber pacing, dual chamber had no advantage over single-chamber ICD with respect to mortality and
arrhythmogenic morbidity in a long-term follow-up. However, a subgroup
analysis in which 35% of ventricular-paced beats served as the cutoff value
in the dual-chamber ICD group revealed a 42% mortality rate for patients
with frequent ventricular pacing compared to 10% of patients with a low rate
of ventricular pacing (p = 0.05, relative risk 4.21).
Furthermore, left ventricular ejection fraction was impaired to a greater
extent in patients with dual-chamber ICD than in patients with single-chamber ICD [15].
In conclusion, prolonged right ventricular pacing, as a consequence of
DDD stimulation, with subsequent impairment of left ventricular function
highlights the positive effects of AV synchronization and negatively affects
prognosis in the ICD patient population. Implementation of an algorithm
that reduced unnecessary ventricular pacing (in patients with preserved AV
conduction) could minimize these negative effects of DDD stimulation [16].
Atrial Fibrillation in ICD Patients

Dual-chamber defibrillators might provide a clinical benefit to patients with
AF, when atrial prevention algorithms and early treatment of AF are considered. Patients who are indicated for ICDs have a higher incidence of AF,
ranging from 5% to slightly less than 50% depending on the NYHA class
[17]. AF could lead to inappropriate shocks [17], induce ventricular arrhythmias [18], worsen hemodynamic status, and be associated with a higher risk
of embolism. AF in ICD patients is associated with a worse clinical outcome
[1921].
Anti-tachycardia features, such as overdrive pacing or atrial anti-tachycardia pacing therapies (ATPs), available in some of dual-chamber devices,
were demonstrated to be effective in preventing and terminating atrial
Maurizio Del Greco, Lorena Gramegna, Massimiliano Marini, Marcello Disertori
242
arrhythmias and reduced the clinical impact of such arrhythmias [22, 23].
Atrial shock, either automatic or manually delivered (with an external activator), could be used in selected patients in whom the onset of atrial fibrillation causes rapid clinical worsening.
Conclusions
A dual-chamber ICD is indicated in patients with significant sinus-node disease or atrioventricular block. In patients with preserved sinus and atrioventricular nodal function, this approach should be considered only when a previous history of AF or a high risk of AF is present. However, accurate implantation of the atrial lead and programming of the device are necessary to
reduce the inappropriate-therapy rate.
Finally, in patients with left ventricular dysfunction, the use of dualchamber ICD should be associated with alternative pacing sites or biventricular pacing.
References
1.
2.
3.
4.
5.
6.
7.
8.
Barold HS, Newby KH, Tomassoni G et al (1998) Prospective evaluation of new and
old criteria to discriminate between supraventricular and ventricular tachycardia
in implantable defibrillators. Pacing Clin Electrophysiol 21:13471355
Swerdlow CD, Chen PS, Kass RM et al (1994) Discrimination of ventricular tachycardia from sinus tachycardia and atrial fibrillation in a tiered-therapy cardioverter defibrillator. J Am Coll Cardiol 23:13421355
Neuzner J, Pitschner HF, Schlepper (1995) Programmable VT detection enhancements in implantable cardioverter defibrillator therapy. Pacing Clin Electrophysiol
18:539547
Sadoul N, Jung W, Jordaens L et al (2002) Diagnostic performance of a dual-chamber cardioverter defibrillator programmed with nominal settings: a European prospective study. J Cardiovasc Electrophysiol 13:2532
Wilkoff BL, Kuhlkamp V, Volosin K et al (2001) Critical analysis of dual chamber
implantable cardioverter defibrillator arrhythmia detection. Results and technical
considerations. Circulation 103:381386
Korte T, Jung W, Wolpert C et al (1998) A new classification algorithm for discrimination of ventricular from supraventricular tachycardia in a dual chamber implantable cardioverter defibrillator. J Cardiovasc Electrophysiol 9:7073
Hintringer F, Schwarzacher S, Eibl G, Pachinger O (2001) Inappropriate detection
of supraventricular arrhythmias by implantable dual chamber defibrillators: a
comparison of four different algorithms. Pacing Clin Electrophysiol 24:835841
Deisenhofer I, Kolb C, Ndrepepa G et al (2001 Do current dual chamber cardioverter defibrillators have advantages over conventional single chamber cardioverter
defibrillator in reducing inappropriate therapies? A randomized, prospective study.
J Cardiovasc Electrophysiol 12:134142
How To Choose Between Single-Chamber and Dual-Chamber ICD

9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
243
Friedman PA, McClelland RL, Bamlet WR et al (2006) Dual-chamber versus singlechamber detection enhancements for implantable defibrillator rhythm diagnosis:
the detect supraventricular tachycardia study. Circulation 113:2871289
Hesselson AB, Parsonnet V, Bernstein AD, Bonavita GJ (1992) Deleterious effect of
long-term single-chamber ventricular pacing in patients with sick sinus syndrome:
the hidden benefits of dual-chamber pacing. J Am Coll Cardiol 19:15421549
Frielingsdorf J, Deseo T, Gerber AE, Bertel O (1996) A comparison of quality-of-life
in patients with dual chamber pacemakers and individually programmed atrioventricular delays. Pacing Clin Electrophysiol 19:11471154
Harper GR, Pina IL, Kutalek SP (1991) Intrinsic conduction maximizes cardiopulmonary performance in patients with dual chamber pacemakers. Pacing Clin
Wilkoff BL, Cook JR, Epstein AE et al (2002) The DAVID Trial Investigators: dual
chamber pacing or ventricular backup pacing in patients with an implantable defibrillator. The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.
JAMA 288:31153123
Kolb C, Deisenhofer I, Schmieder S et al (2006) Long-term follow-up of patients
supplied with single-chamber or dual-chamber cardioverter defibrillators. Pacing
Sukhija R, Aronow WS, Sorbera C et al (2005) Left ventricular ejection fraction and
prevalence of new left ventricular wall motion abnormality at long-term follow-up
in patients with automatic implantable cardioverter-defibrillators treated with
dual-chamber rate-responsive pacing at a rate of 70/minute versus backup ventricular pacing at a rate of 40/minute. Am J Cardiol 96:412413
Sweeney MO, Ellenbogen KA, Miller EH et al (2006) The Managed Ventricular
pacing versus VVI 40 Pacing (MVP) Trial: clinical background, rationale, design,
and implementation. J Cardiovasc Electrophysiol 17:12951298
Schmitt C, Montero M, Melichercik J (1998) Significance of supraventricular
tachyarrhythmias in patients with implanted pacing cardioverter defibrillators.
Grimm W, Flores BF, Marchlinski FE (1992) Electrocardiographically documented
unnecessary, spontaneous shocks in 241 patients with implantable cardioverter
defibrillators. Pacing Clin Electrophysiol 15:16671673
Marchlinski FE, Callans DJ, Gottlieb CD et al (1995) Benefits and lessons learned
from stored electrogram information in implantable defibrillators. J Cardiovasc
Pinski SL, Yao Q, Epstein AE et al (2000 Determinants of outcome in patients with
sustained ventricular tachyarrhythmias: the antiarrhythmic versus implantable
defibrillators (AVID) study registry. Am Heart J 139:804813
Wolf PA, Mitchell JB, Baker CS et al (1998) Impact of atrial fibrillation on mortality,
stroke and medical costs. Arch Intern Med 158:229234
Ricci R, Pignalberi C, Disertori M et al (2002) Efficacy of a dual chamber defibrillator w ith atrial antitachycardia functions in treating spontaneous atrial
tachyarrhythmias in patients with life-threatening ventricular tachyarrhythmias.
Eur Heart J 23:14711479
Friedman PA, Dijkman B, Warman EN et al for the Worldw ide Jewel AF
Investigators (2001) Atrial therapies reduce atrial arrhythmia burden in defibrillator patients. Circulation 104:10231028
Implantable Cardiac Defibrillators: Is Defibrillation Threshold

Testing Still Necessary in all Patients?
F RANCO NACCARELLA 1, FABIO I ACHETTI 1,2, A NGELA WANG 3, C RISTINA F ELICANI 4,
G IOVANNINA L EPERA 1, E LVIRA M OCCIA 5, L EILEI S UN 1,2, LUCA C ASARI 6, G IORGIO
MORSELLI1, PATRIZIA CAPOGRECO1, GERALD NACCARELLI7
Defibrillation Threshold at Implantation

The defibrillation threshold (DFT) is the minimum amount of energy
required to reliably defibrillate the heart during potentially life-threatening
ventricular arrhythmia. Knowledge of the patients DFT allows the physician
and other clinicians to be sure that the ICD is programmed to deliver sufficiently high-energy shocks to defibrillate the heart.
Unlike the pacing threshold, however, the DFT is not an absolute value
above which defibrillation will always be successful and below which it will
always fail. The goal of defibrillation testing is to ensure that the maximal
energy output of the device has an extremely high (> 99%) probability of
terminating ventricular fibrillation in a given patient. Figure 1 shows a sigmoidal-shaped curve for two different patients. The second patient requires
either revision of the lead system to reduce the DFTs or the implantation of a
high-output device with at least 37 J output.
There are many testing algorithms to assess defibrillation efficacy, but
two predominate: the single energy success and step-down protocols [13].
Other algorithms that can be used to determine DFT are the binary search
method and the Bayesian search method [46].
There is increasing interest in minimizing defibrillation testing.
Consequently, the practice of testing only one episode of VF and then programming devices, to achieve maximum output, is gaining in popularity.
This strategy probably works because of the very high efficacy of modern
lead systems and due to shock waveforms. There is even a growing practice
1Cardiology
Department, Azienda USL of Bologna; 2TELBIOS, Scienfic Park S. Raffaele

Hospital, Milan, Italy; 3University of Beijing, China; 4Internal Medicine Department
Policlinico Sant Orsola, Bologna; 5Institute of Forensic Medicine Gemelli University
Hospital Rome; 6TECHNOCHIM ROCHE Milan, Modena, Italy; 7Penn State University,
Hershey, PA, USA
222
Franco Naccarella et al.
Fig. 1. Sigmoidal-shaped
curve for two different patients. (Modified from [3])
of omitting defibrillation testing at the time of implantation, although the

prospective data to support this strategy are lacking [2, 3, 7, 8].
Alternatively, determination of the upper limit of vulnerability (ULV) has
been used to estimate the DFT, while minimizing or even eliminating the
need to induce ventricular fibrillation. The lowest energy value that does not
induce fibrillation is the ULV. The ULV is as probabilistic as the actuarial
DFT [9].
In some cases, the implanting physician may opt to forego DFT testing,
because it is painful, time-consuming, and consumes battery energy. If the
implanting physician intends to program the device to maximum output
anyway, DFT testing (which would involve programming at less than maximum output values) may not be worth the effort. Furthermore, many
patients are likely to be shocked only rarely and only for serious situations.
For such patients, programming maximum energy therapy is appropriate,
and DFT testing is not necessary [1]. This approach has been criticized by
many internationally recognized clinical investigators [2, 6, 10].
Increasingly, DFT testing is omitted at implant. However, when performed, it can help physicians optimize the output settings of the device.
Furthermore, the intracardiac electrogram should be monitored to verify
ICDs: Is Defibrillation Threshold Testing Still Necessary in all Patients?
223
that: (1) there was appropriate sensing during the episode; (2) there was
appropriate detection of the episode; (3) the arrhythmia was converted; (4)
the delivered energy is known; (5) shocking impedance values are within the
acceptable range; (6) the charge time is acceptable.
At least 2 min, but more typically 35 min, should be allowed between
defibrillation episodes to ensure full hemodynamic recovery and to minimize any cumulative effects of multiple shocks. The appropriate sensing of
each episode of induced arrhythmia should be confirmed after each induction. The sensitivity is typically decreased at implant testing (e.g., from 0.3 to
1.2 mV) for adequate sensing of spontaneous ventricular arrhythmias. The
accurate postoperative management of patient, including monitoring of vital
signs and heart rhythm during recovery from anesthesia or conscious sedation, is mandatory (Figs. 2-6) [3].
Biphasic waveforms have become the standard for all ICD pulse generators. Another factor that can affect DFTs is the polarity of the defibrillation
shock. Reverse polarity, or anodal shocks, result in significantly lower DFTs.
Shock polarity has much less effect on biphasic defibrillation thresholds
than on monophasic thresholds [3, 1118].
Capacitance is another factor that may affect defibrillation efficacy.
Decreasing the capacitance to 60 to 90 f modestly reduced DFT in some
studies, but had no effect on stored energy requirements and increased peak
voltage in others. The defibrillation safety margin is reduced with lower
capacitance, because of the higher peak voltages required. As a result, the
strategy of marked reductions of pulse generator capacitance is unlikely to
be pursued in the future.
Some investigators showed that, with active pulse generators, or hot
cans, adequate DFTs (< 20 J) could be achieved in approximately 90% of
patients, with this simple single coil lead system [2, 3].
DFT is relatively insensitive to pulse generator size, indicating that defibrillation efficacy will not be affected adversely as the pulse generator
becomes progressively smaller. The effect of combining an active pectoral
pulse generator with a dual-coil lead (the triad configuration) includes
three shocking electrodes, the active can, and two transvenous coils. In the
initial study of this lead system, it was shown that mean DFT decreased to
36% compared with a dual-coil shocking vector. In that study, 98% of the
patients had a threshold less than 15 J. Of particular clinical relevance is a
reduction of the number of patients with high DFTs, because such patients
have an inadequate safety margin and often require complicated implantation procedures to test multiple lead positions or shocking vectors [1318].
224
Fig. 2. DFT programming with Guidant VITALITY 2 EL VR
Fig. 3. Induction of ventricular tachycardia at implant
225
Fig. 4. Termination of ventricular tachycardia and identification of the defibrillation

threshold (DFT) at implant 14 J
Fig. 5. ECG of a patient with post-acute myocardial infarction severe dilated cardiomyopathy and high threshold at implant even with biphasic inverted shock. At follow-up, a
new electrode position and configuration had to be found for increasing ventricular
defibrillation and defibrillation failure episodes during hospitalization
226
Fig 6. ELA Medical Programming of implantable cardiac defibrillator therapies after

DFT documentation at implant. A DFT of 18 J, and the maximum highest values were
set up at follow-up
DFT at Follow-up
Traditionally ICD patients are evaluated with device interrogation and
threshold testing every 3 months. However, given the reliability of modern
pulse generators and leads, follow-up every 6 months among clinically stable
patients is rapidly becoming the norm. Trans-telephonic monitoring of ICD
is growing in popularity, and this approach can further reduce the frequency
of office visits, as reported by Iachetti et al. [19]. Nonetheless, the FDA does
not advocate remote monitoring of critically ill patients with and without
implanted devices and does not recommend the new implanted devices
offered by Medtronic. Many expert-panel members have encouraged the
company to continue studying the device. The problem of DFT monitoring
or reprogramming during follow-up cannot be reasonably addressed by
remote monitoring [3, 19].
Causes and Correction for High DFT at Implant or Follow-up

Despite the marked reduction of DFT with active pectoral pulse generators,
there are st ill some pat ients w ith unacceptably high thresholds.
Unfortunately, identifying these patients prospectively is difficult. Raitt [20]
227
showed that there are some clinical predictors of defibrillation efficacy. The
only independent predictors of biphasic DFT were left ventricular mass and
resting heart rate, but not the underlying heart disease, dilated cardiomyopathy, or QRS width [20, 21].
Many causes of elevated DFT have been identified, including poor lead
position, increased high-voltage impedance, pneumothorax, hypoxia,
ischemia, multiple defibrillations, anti-arrhythmic drugs or anesthetics, poor
current distributions, shunting current through guidewires or retained leads,
suboptimal waveform tilt, poor myocardial substrate.
Pacifico [2] reported all the suggested ICD implant values for a 30 J maximum output ICD. Furthermore, he found that the most commonly used and
conceptually simple algorithm is a step-down determination of DFT.
Clinically, adequate approximation of the DFT can usually be achieved with
13 inductions of ventricular fibrillation. For example, successful defibrillation with 10 J using a device with a maximum output of 30 J is generally adequate to establish an accurate safety margin [2].
Furthermore, based on his own experience and that reported in the literature, Pacifico described the factors influencing DFT [2]: (1) instrumentationdependent factors (active can, shock waveform, lead system, electrode surface
area); (2) recipient-dependent factors (LV mass, LV dilation, body size, body
position, right- vs left-sided implantation, underlying heart disease including
heart failure, ischemia, cardiomyopathy, and an associated pneumothorax);
(3) drug-dependent factors, (anti-arrhythmic drugs, anesthetic agents); and
(4) ventricular-fibrillation-dependent factors (duration, spontaneous vs
induced ventricular tachyarrhythmia). Pacifico also noted the problem of
routine late (> 1 year) DFT retesting of non-thoracotomy systems.
Tokano [22] found no significant changes in the mean DFT in the followup of a series of patients; however, the DFT increased by 10 J or more after 2
years of follow-up in 15% of the patients [22].
Since a 25% increase in DFT over time may be expected for many systems, even in the absence of anti-arrhythmic therapy or apparent change in
cardiac status, a safety margin of 10 J at implantation may not be sufficient.
Typically, the goal is a safety margin of 15 J, whenever feasible. This may be
even more important for patients who are likely to receive anti-arrhythmic
drug therapy. Other clinical implications of DFT stability have been reported. Chronic DFT testing is warranted in patients who receive anti-arrhythmic drug therapy. Most investigators would agree that follow-up testing is
indicated, also in patients with a change in cardiac status, such as those with
recent infarction or worsening left ventricular function, or the occurrence of
ineffective or unexplained defibrillator shocks, marginal DFT at implant,
228
patients who would have not received an ICD shock or when adequate testing could not be performed at the time of initial implantation [1518,
2022].
In addition, Pacifico routinely carried out follow-up DFT testing after
adding any new anti-arrhythmic drug [2]. He stressed the importance of follow-up chest X-ray to asses the position and proper function of the implanted electrodes, because migration and dislodgment can affect DFT. There
have been many advisories and recalls of defibrillators and leads. It is therefore recommended that all patients, returning for an ICD evaluation with
NIPS should be tested in the electrophysiology laboratory to confirm stability of the DFT [2].
DFT in the Pediatric Patient

In pediatric patients, the initial shock is programmed to deliver 20 J and the
second is programmed to deliver the maximum output. If 20 J is successful in
terminating the arrhythmia, the permanent settings used are set for 3035 J.
If 20 J does not successfully terminate the arrhythmia, the polarity is
reversed and DFTs are performed again. If the DFT continues to be > 20 J,
the lead is repositioned. If high DFTs persist, a second coil or subcutaneous
patch is added. The first choice of coil placement is the innominate vein in
most patients, the superior vena cava in larger patients, and the inferior vena
cava in patients with transposition of the great arteries. A subcutaneous
patch is also used if the veins are too small, stenosed, or thrombosed [7].
Conclusions
The defibrillation threshold should be always tested at implantation. We and
others [2, 6, 10] do not agree with the reasoning that, because many patients
are likely to be shocked only rarely and then for serious situations, programming maximum energy therapy is appropriate for such patients and DFT
testing is not necessary [1].
Traditionally, an implantation safety margin of at least 10 J between the
measured DFTs and the maximal output of the pulse generator is considered
adequate. Since these safety margins are associated with very low rates of
death, due to arrhythmia, in patients with first-generation devices, programming shock strengths to at least 10 J greater than the defibrillation thresholds measured at implantation has become common practice. Results from
the Low Energy Safety Study (LESS) suggested that a safety margin of
229
approximately 5 J is adequate with modern ICD systems, employing biphasic

waveforms, transvenous lead, and active pectoral pulse generators, when rigorous DFT testing (DFT++) is used.
Thus, traditionally, DFTs are measured only at implantation. This strategy is supported by studies that showed no significant long-term changes of
DFT with epicardial lead systems and transvenous lead and biphasic waveforms. However, a minority of patients may show an increase of DFT over
time [20-22].
Routine revaluation of DFT is no longer commonly performed [13,
1518, 2022]. Nonetheless, such testing is still necessary among patients
treated with anti-arrhythmic drugs, particularly amiodarone, patients with
marginal defibrillation efficacy, at implantation, and patients in whom the
initial shock failed to terminate a spontaneous episode of ventricular tachycardia or fibrillation [2, 3], or at ICD substitution [3, 19].
Most investigators would agree that follow-up testing is also indicated in
patients with a change in cardiac status, such as recent infarction or worsening LV function, the occurrence of ineffective or unexplained defibrillator
shocks, marginal DFT at implant, patients who did not receive an ICD shock
or in whom, despite adequate testing, a threshold could not be established at
the time of initial implantation [13, 1518, 2022].
Acknowledgements
We thank Leilei Sun for preparing the manuscript. We thank Elena Cuomo and Elena
Seragnoli of the Knowledge Management department of the Maggiore Hospital
library of the Azienda of USL di Bologna, Bologna, Italy.
References
1.
2.
3.
4.
5.
6.
Kenny T (2006) The nuts and bolts of ICD therapy. Blackwell Futura, Oxford, pp
2636
Pacifico A et al (2002) Implantable defibrillator therapy: a clinical guide. Kluwer,
The Netherlands, pp 113145
Ellenbogen KA, Wood MA (2005) Cardiac pacing and ICD, 4th edn. Blackwell,
Oxford, pp 387394
Singer I, Lang D (1996) The defibrillation threshold. In: Knoll MW, Lehmann MH
(eds) Implantable cardioverter defibrillator therapy. The engineering clinical interface Norwell. Kluwer Academic, The Netherlands, pp 89129
Shorofsky SR, Peters RW, Rashba EJ, Gold MR (2004) Comparison of step-down
and binary search algorithms for determination of defibrillation threshold in
humans. Pacing Clin Electrophysiol 27:218220
Malkin RA, Herre JM, McGowen L et al (1999) A four-shock Bayesian up-down
estimator of the 80% effective defibrillation dose. J Cardiovasc Electrophysiol
10:973980
230
7.
Zeigler VL et al (2001) Implantable cardioverter defibrillators. In: Zeigler VL,

Gillette PC (eds) Practical management of pediatric cardiac arrhythmias. Futura,
Armonk, NY, pp 350, 359, 409
Swerdlow CD (2001) Implantation of cardioverter defibrillators without induction
of ventricular fibrillation. Circulation 103:21592164
Feder (2007) FDA panel unimpressed by heart device. The New York Times
3/22007 (also see CorbettDooren The Wall Street Journal 3/22007)
Guo JH (2006) Critical comments on: Kenny T (2006) The nuts and bolts of ICD
therapy. Blackwell Futura, Armonk, NY, pp 2627
Shorofsky SR, Gold MR (1996) Effects of waveform and polarity on defibrillation
thresholds in humans, using a transveous lead system. Am J Cardiol 78:313316
Olsovsky MR, Shorofsky SR, Gold MR (1998) Effect of shock polarity on biphasic
defibrillation thresholds using an active pectoral lead system. J Cardiovasc
Bardy GH, Johnson G, Poole JE et al (1993) A simplified, single-lead unipolar transvenous cardioversion-defibrillation system. Circulation 88:543547
Gold MR, Foster AH, Shorofsky SR (1996) Effects of an active pectoral-pulse generator shell of defibrillation efficacy with a transvenous lead system. Am J Cardiol
78:540543
Gold MR, Olsovsky MR, Pelini MA et al (1998) Comparison of single- and dualcoil active pectoral defibrillation lead systems. J Am Coll Cardiol 31:13911394
Higgins SL, Alexander DC, Kuypers CJ, Brewster SA (1995) The subcutaneous
array: a new lead adjunct for the transvenous ICD to lower defibrillation thresholds. Pacing Clin Electrophysiol 18:15401548
Epstein AE, Ellenbogen KA, Kirk KA et al (1992) Clinical characteristics and out
come of patients with high defibrillation thresholds: a multicenter study.
Gold MR, Higgins S, Klein R et al (2002) Efficacy and temporal stability of reduced
safety margins for ventricular defibrillation. Primary results from the Low Energy
Safety Study (LESS) Circulation 105:20432048
Iachetti F, Naccarella F, Naccarelli G et al (2007) Remote monitoring systems of
implanted devices: critical evaluation in US, Europe and Italy. MESPE Journal (in
press)
Raitt MH, Johnson G, Dolack GL et al (1995) Clinical predictors of the defibrillation threshold with unipolar implantable defibrillation system. J Am Coll Cardiol
25:15761583
Hodgson DM, Olsovsky MR, Shorofsky SR et al (2002) Clinical predictors of the
defibrillation thresholds with an active pectoral pulse generator lead system.
Tokano T, Pelosi F, Flemming M et al (1998) Long-term evaluation of the ventricular defibrillation energy requirement. J Cardiovasc Electrophysiol 9:916920
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Prevention of Sudden Death in Patients with Genetic

Arrhythmias
PIETRO DELISE
Introduction
In recent years a number of genetic heart diseases have been recognized that
can be complicated by malignant arrhythmias leading to sudden death [1].
These genetic diseases can be divided into two groups: (1) channelopathies
(congenital dysfunction of cellular ion-channels without macroscopic heart
disease) and (2) genetic cardiomyopathies.
Channelopathies
Table 1 summarizes the main channelopathies. Long QT syndrome (LQTS),
short QT syndrome (SQTS), Brugada syndrome (BS), and catecholaminergic
polymorphic ventricular tachycardia (CPVT) can lead to sudden death due
to malignant ventricular arrhythmias.
Long QT Syndrome
In LQTS [29] there is either a loss of function of K channels, including IKr,
IKs, and IK1, or a gain of function of the Na+ channel. In about 70% of cases
the responsible gene can be identified, and many different genes may be
involved (KCNQ1/KvLQT1, KCNH/HERG, SCN5A, etc.). Currently, eight
forms of LQTS have been identified (LQT1LQT8), the most common being
LQT1, LQT2, and LQT3 (globally 90% of genotyped patients). The respective
prevalence of LQT1, LQT2, and LQT3 is about 60, 32, and 8%. LQTS can also
Cardiology Operative Unit, Conegliano Hospital, Conegliano (TV), Italy
AD
AD
SQTS 1
LQT6
AD
LQT8
AD
AR
RyR2
CASQ2
CACNA1c/CaV1.2
ANK2
SCN5A
SCN5A
SCN5A
SCN5A
HCN4
KCNJ2/Kir 2.1
KCNJ2/Kir2.1
KCNH2
(HERG)
KCNH2/(HERG
KCNE2/MiRP
KCNQ1/KvLQT1
KCNQ1/KvLQT1
KCNQ1
KCNQ1
KCNE1/MinK
KCNE1
Gene involved
Calcium release
Calcium storage
Gain
Loss
Gain
Loss
Loss
Loss
Loss
Gain
Loss
Gain
Loss
Loss
Loss
Gain
Loss
Gain
Loss
Loss
Channel function
CPVT
CPVT
Long QT, syndactyly, septal defect,

mental retardation
Long QT, AF
Long QT
ECG types 1,2,3
Conduction disturbances
Sinus node dysfunction
Sinus node dysfunction
Long QT, periodic paralysis,

dysmorphism
Short QT
Short QT, AF
Long QT
Long QT
Long QT, AF
Short QT, AF
Long QT, deafness
AF
Long QT
Long QT, deafness
Phenotype
AD, Autosomal dominant; AR, autosomal recessive; AF, atrial fibrillation; SSS, sick sinus syndrome. For abbreviations of LQTS, SQTS, JLN, CPVT, see
text
Intracellular Ca++ CPVT 1

Movement
CPVT 2
Ca2+ channel
-subunit
AD
AD
AD
AD
AR
?
SQTS3
LQT3
Brugada syndrome
Lenegre syndrome
SSS
SSS
AD
LQT7
Ankyrin B,
LQT4
anchoring protein
Channel If
Channel Ina
Channel IK1
AD
LQT2
Channel Ikr
AD
AD
AR
AD
AD
AR
LQT1
SQTS2
JLNS 1
Familial AF
LQT5
JLN tipo2
Channel Iks
Inheritance
Clinical syndrome
Defect
Table 1. List of main channelopathies
256
Pietro Delise
Prevention of Sudden Death in Patients with Genetic Arrhythmias
257
be associated with deafness in the Jerwell and Lang-Neelsen syndrome

(JLNS) [2], which comprises two variants, JLNS1 and JLNS2.
The incidence of major events before age 40 years (syncope, cardiac
arrest, sudden death) ranges between 30 and 46% according to genotype
(LQT1 30%, LQT2 46%, LQT3 42%).
LQT1 and LJNS are characterized by the occurrence of malignant
arrhythmias almost exclusively during effort and in general during catecholamine stimulation. In LQT2, arrhythmias can occur at rest and during
effort and are frequently initiated by additive stress. In LQT3, arrhythmias
generally occur at rest or during sleep.
Short QT Syndrome
A gain of function of the K channels IKs, IKr and IK1 is the mechanism
behind SQTS [911]. Three main forms related to different genetic mutations
have been identified: SQTS1, SQTS2, and SQTS3. It is interesting to note that
thesame gene, is involved in LQT1 and SQTS2, LQT2 and SQTS1, and LQT7
and SQT3. That is KCNQ1/KvLQT1, KCNH2/HERG and KCNJ2/Kir1-2,
respectively. This syndrome can be complicated by both atrial and ventricular fibrillation.
Brugada Syndrome
The loss of Na-channel function that occurs in BS [1217] is due to a mutation of the SCN5A gene. This mutation is found in about 1830% of cases. The
syndrome is characterized by ST-segment elevation in the V1V3 leads and
right ventricular conduction delay. BS patients may present with ventricular
tachycardia (VT)/ventricular fibrillation (VF) at rest. Fever and the use of class
IC anti-arrhythmic drugs can disclose and/or enhance the ECG signs characteristic of BS. The typical ECG pattern is type 1 (coved pattern, J > 2 mm, negative T wave). Type 2 (saddle back pattern, J > 2 mm, positive T wave) and type
3 (minor J elevation) are considered diagnostic only if they are converted into
a type 1 pattern by the administration of class 1C anti-arrhythmics.
Catecholaminergic Polymorphic Ventricular Tachycardia

In CPVT [18, 19] there are defects in intracellular calcium release or storage.
The condition is complicated by malignant arrhythmias, which are typically
induced by effort.
258
Pietro Delise
Genetic Cardiomyopathies
This group of diseases includes hypertrophic cardiomyopathies, dilated cardiomyopathies, and arrhythmogenic right ventricular cardiomyopathy. In all
of these, the arrhythmias are the consequence of the organic anomalies arising from the genetic defects. In other words, the arrhythmias are not genetically determined per se, but are secondary to the genetic mutation. For this
reason, this group of diseases is not further discussed here.
Identification of Risk Factors in Genetic Arrhythmias

In channelopathies, the risk of sudden death, beyond being due to the phenotype itself, is related to multiple factors, which probably only partially
have been identified. A familial history of sudden death is generally considered a major risk factor, although some clinicians do not consider it as an
independent factor (e.g., in BS) [16].
Gender can be a risk factor in particular conditions. For example, in
LQTS gender can influence the prognosis associated with the different genetic defects [8]. In particular, male sex is a strong risk factor in LQT3 and
female sex is a strong risk factor in LQT2.
The presence of symptoms such as syncope, pre-syncope, or dizziness is
an important risk factor that has been frequently correlated to self-limited
brief episodes of malignant arrhythmias.
Comorbidity can increase the risk under particular conditions. For example, deafness (present in JLNS) [2] and a post-partum condition increase the
risk of arrhythmia in LQTS.
The entity of ECG changes in the basal tracing are generally correlated
with a risk of arrhythmia. In LQTS, lengthening of the QT interval is strongly
correlated with risk [8], with subjects showing a QTc > 500 ms being at highest risk. In BS, the presence in the basal ECG of a clear type 1 pattern is correlated to a higher risk of arrhythmia, while type 2 and 3 patterns imply a
lower risk [1416].
Effort test may be useful in LQTS in order to document the absence of
adaptation of the QT interval during increasing heart rate. It is also useful in
CPVT as it frequently reproduces ventricular arrhythmias at a fixed threshold.
Holter monitoring is generally not informative. However, in SQTS it can
aid in the recognition of a short QT interval during phases of bradycardia.
Electrophysiological study (EPS) has no role in the diagnosis of LQTS or
CPVT. In SQTS, EPS frequently induces VT/VF in symptomatic subjects [10],
259
but the prognostic significance of this finding in asymptomatic patients is

unknown.
The prognostic significance of EPS in BS is controversial. According to
Brugada et al., EPS is useful to predict the risk of sudden death [14]. These
authors suggested that the results of EPS are closely correlated with the clinical characteristics of the patients. In fact, VT/VF is inducible in 81% of
patients with a previous history of aborted sudden death, in 61% of patients
with a previous history of syncope, and in 34% of asymptomatic individuals.
Furthermore, a significant positive predictive value of EPS that varied in different categories of patients was observed: 54% in individuals with a history
of aborted sudden cardiac death, 23% in patients with syncope, and 12% in
asymptomatic patients, during a mean follow-up of 31 41 months. It is
important to note that while a 12% predictive value in asymptomatic individuals may seem low, it refers to both otherwise healthy and asymptomatic
individuals. Our own experience [17], in a more limited number of cases, is
similar to that of Brugada et al. [14].
Nonetheless, not all clinicians are in agreement with those findings.
Instead, some have suggested that EPS reproducibility is only 70%, probably
because of the variability of Na-channel function in these patients [20].
Other authors have rejected the usefulness of EPS completely [21, 22].
However it must be emphasized that in the latter series the number of
patients was small, with a high percentage being asymptomatic.
Risk Stratification on the Basis of a Polyparametric Approach

Among the LQTS subjects at highest risk (> 50% probability of experiencing
a major event before age 40) are those with a QTc > 500 ms independent of
gender in LQT1 and LQT2, and in males with LQT3 [8]. Other factors
increase the risk: previous VT/VF, deafness (JLNS) and post-partum. At lowest risk (< 30%) are patients with a QTc < 500 ms, with LQT1, and males with
LQT2.
In SQTS, symptomatic subjects with a familial history are probably at
highest risk.
In BS, according to Priori et al. [15], three groups of patients with
decreasing risk can be identified: (1) patients with a typical ECG pattern and
a history of syncope; (2) asymptomatic patients with a typical ECG pattern;
(3) asymptomatic patients whose ECG reveals the Brugada pattern only after
anti-arrhythmic drug challenge.
Brugada et al. [23] published a study in which 547 individuals with typical ECG pattern and no previous cardiac arrest were prospectively followed.
260
Pietro Delise
The study considered three major risk factors: typical ECG pattern in the
basal ECG, syncope, and inducible VT/VF during EPS. By logistic regression
analysis of these variables, eight groups were identified, with a risk of cardiac arrest during a 2-year follow-up varying from 0.5 to 27.2%. The highestrisk group (27.2%) consisted of individuals with a typical ECG, at least one
syncopal episode, and positive EPS. In the lowest-risk group (0.5%) was one
subject with an ECG that was diagnostic only after drug administration, who
was otherwise asymptomatic, and had a negative EPS. An asymptomatic subject, with a typical ECG pattern and a positive EPS, had an intermediate risk
(14%).
In CPVT, the association of family history and syncope identifies subjects
at highest risk.
Behaviors That Can Prevent Sudden Death

In some genetic diseases, particularly LQT1 and CPVT, sports activities can
facilitate the occurrence of malignant arrhythmias.
Certain drugs can be deleterious in some diseases. For this reason, all
drugs that prolong the QT interval should be avoided by patients with LQTS.
Ajmaline and class IC anti-arrhythmic drugs should be avoided in patients
with BS.
Pharmacologic Prevention of Sudden Death

Beta-blockers are recommended by current guidelines [24] for patients with
LQTS (especially LQT1 and LQT2) and CPVT (class I, evidence B and C).
They have no effect in SQTS or BS.
Quinidine may prolong the QT interval in SQTS and modify ECG changes
in BS [25]. In the latter pathology, it may reduce the inducibility of VT/FV
[25, 26]. However, prospective randomized studies are not available to establish the efficacy of quinidine in preventing sudden death.
ICD Implantation To Prevent Sudden Death

Implantable cardioverter-defibrillators (ICDs) are the most effective method
for preventing sudden death. Current guidelines [24] recommend ICD
implantation for secondary prevention in patients with previous cardiac
arrest (class I, evidence AC in various diseases).
In patients with LQTS and syncope, an ICD can reduce sudden death also
261
in patients on beta-blockers (class IIa, evidence B). In patients with BS type 1

pattern with syncope or VT without cardiac arrest, ICD implantation is considered reasonable (class IIa, evidence C).
In primary prevention, ICD is not generally recommended in asymptomatic patients without documented malignant arrhythmias.
Some clinicians have suggested the implantation of an ICD in patients at
higher risk. The problem is that it is not always easy to precisely predict risk
in a single patient. Furthermore, in contrast to other more common pathologies, such as ischemic heart disease or heart failure, randomized primary
prevention trials for patients with genetic arrhythmias are not available.
Nonetheless, in asymptomatic LQTS, ICD may be suggested for patients
in the highest risk categories (class IIb, evidence B). In asymptomatic BS, the
role of EPS in identifying candidates for ICD implantation is still considered
to be controversial (class IIB, evidence C).
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Sarkozy A, Brugada P (2005) Sudden cardiac death and inherited arrhythmia syndromes. J Cardiovasc Electrophysiol 16:S8-S20
Jervell A, Lange-Nielsen F (1957) Congenital deaf mutism, functional heart disease
with prolongation of the QT interval and sudden death. Am Heart J 54:5968
Romano C, Gemme G, Pongiglione R (1963) Aritmie cardiache rare dellet pediatrica, II: accessi sincopali per fibrillazione ventricolare parossistica. Clin Pediatr
(Bologna) 45:656683
Schwartz PJ (1985) Idiopathic long QT syndrome: progress and questions. Am
Heart J 109:399411
Marks ML, Trippel DL, Keating MT (1995) Long QT syndrome associated with syndactyly identified in females. Am J Cardiol 76:744745
Duggal P, Vesely MR, Wattanasirichaigoon D et al (1998) Mutation of the gene for
IsK associated with both Jervell and Lang-Nielsen and Romano-Ward forms of
long QT syndromes. Circulation 97:142146
Locati EH, Zareba W, Moss AJ et al (1998) Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from
the International LQTS Registry. Circulation 97:22372244
Priori SG, Schwartz PJ, Napolitano C et al (2003) Risk stratification in the long-QT
syndrome. N Engl J Med 348:18661874
Napolitano C, Bloise R, Priori S (2006) Long QT syndrome and short QT syndrome:
how to make correct diagnosis and what about eligibility for sport activity. J
Cardiovasc Med 7:250256
Gaita F, Giustetto C, Bianchi F et al (2003) Short QT syndrome. A familial cause of
sudden death. Circulation 108:965970
Brugada R, Hong K, Dumaine R et al (2004) Sudden death associated with shortQT syndrome linked to mutations in HERG. Circulation 109:3035
Brugada P, Brugada J (1992) Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol 20:13911396
262
Pietro Delise
13.
Brugada R, Brugada J, Antzelevitch C et al (2000) Sodium channel blockers identify

risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 101:510515
Brugada P, Brugada R, Mont L et al (2003) Natural history of Brugada syndrome:
the prognostic value of programmed electrical stimulation of the heart. J
Cardiovas Electrophysiol 14:455457
Priori SG, Napolitano C, Gasparini M et al (2002) Natural history of Brugada syndrome. Insight for risk stratification and management. Circulation 105:13421347
Antzelevitch C, Brugada P, Borggrefe M et al (2006) Brugada syndrome. Report of
the second consensus conference. Circulation 111:659670
Delise P, Marras E, Bocchino M (2006) Brugada-like electrocardiogram pattern:
how to stratify the risk for sudden cardiac death. Is sport activity contraindicated?
J Cardiovasc Med 7:239245
Coumel P, Fidelle J, Lucet V et al (1978) Catecholaminergic-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: report of four cases.
Br Heart J 40:2837
Leenhardt A, Lucet V, Denjoy I et al (1995) Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation
91:15121519
Gasparini M, Priori S, Mantica M et al (2002) Programmed electrical stimulation in
Brugada syndrome: how reproducible are the results? J Cardiovasc Electrophysiol
13:880887
Kanda M, Shimizu W, Matsuo K et al (2002) Electrophysiologic characteristics and
implications of induced ventricular fibrillation in symptomatic patients with
Brugada syndrome. J Am Coll Cardiol 39:17991805
Eckardt L, Probst V, Smits JP et al (2005) Long-term prognosis of individuals with
right precordial ST-segment elevation Brugada syndrome. Circulation 111:257263
Brugada J, Brugada R, Brugada P (2003) Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous
cardiac arrest. Circulation 108:30923096
ACC/AHA/ESC (2006) 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Executive summary.
Eur Heart J 27:20992140
Belhassen B, Viskin S, Fish R et al (1999) Effects of electrophysiologic-guided therapy with Class IA antiarrhyhtmic drugs on the long term outcome of patients
with idiopathic ventricular fibrillation with or without the Brugada syndrome. J
Hermida JS, Denjoy I, Clerc J et al (2004) Hydroquinidine therapy in Brugada
Syndrome. J Am Coll Cardiol 43:1853-1860
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
Which Patient and when Should Receive an ICD?

Evolving New Indications on the Horizon
ROBERTO VERLATO, MARIA STELLA BACCILLIERI, PIETRO TURRINI
Introduction
Internal cardioverter defibrillator (ICD) therapy has come a long way since
its introduction in the 1980s as the first-line treatment for the few fortunate
survivors of recurrent sudden cardiac arrest (SCA). Secondary- and primary-prevention trials enrolling patients with either ischemic or nonischemic
cardiomyopathy with depressed left ventricular ejection fraction (LVEF) and
NYHA IIIV (AVID, CIDS, CASH, MADIT, MUSTT, MADIT II, DEFINITE)
have overwhelmingly demonstrated that ICD therapy reduces total mortality
compared with anti-arrhythmic drug therapy and/or optimal medical therapy [17]. The most recent trials (COMPANION and SCD-HeFT) [8, 9]
focused on patients with NYHA class IIIV heart-failure (HF) symptoms and
depressed LVEF: ICD alone or combined with a left ventricular lead for cardiac resynchronization significantly reduced total mortality as compared
with optimal medical therapy (ACE inhibitors/ARB blockers, beta-blockers,
canrenoate, diuretics) and amiodarone.
In recent years, based on the results of clinical studies and trials, several
guidelines have been published and revised on the optimal prevention of
SCD and the indication for ICD therapy in patients with or at risk of ventricular tachyarrhy thmias and in patients w ith HF. Guidelines from the
European Society of Cardiology, the American College of Cardiology/
American Hear t Association [10], and the Associazione Italiana di
Aritmologia e Cardiostimolazione (AIAC) [11] are available. Small differences exist between them regarding class IA indications for ICD. In particular, there is general agreement that an ICD is always indicated for secondary
Interventional Electrophysiology Unit, Department of Cardiology, Camposampiero

Hospital, Padua, Italy
216
prevention of SCA not due to reversible causes, independent of the underlying cardiac pathology and the individual patients electrophysiology. When
ICDs are used in primary prevention, most recent recommendations underline the importance of chronic optimal medical therapy as well as the
patients overall clinical status and co-morbidities: only patients who have a
reasonable expectation of survival with a good functional status for more
than 1 year are candidates to receive an ICD.
A brief summary of current recommendations for ICDs implantation in
patients with different types of heart disease, and of the differences among
the guidelines is provided in the following.
Patients with Coronary Artery Disease

Patients with left ventricular dysfunction due to prior myocardial infarction
(MI), on chronic optimal medical therapy, and not candidates to further
coronary revascularization should receive an ICD if they survived ventricular fibrillation (VF) or have hemodynamically unstable ventricular tachycardia (VT) (class I, level of evidence A). ICD is also recommended for primary
prevention to reduce total mortality by a reduction in SCA in patients who
are at least 40 days post-MI, have an LVEF 3040%, and are in NYHA functional class IIIII (class I, level of evidence A). For patients with characteristics similar to the previous ones but in NYHA class I, the implantation of an
ICD is reasonable, but this is a class IIa, level of evidence B indication. A
class IIa indication for an ICD in post-MI patients is also the treatment of
recurrent sustained VT in those subjects with normal o near normal left ventricular function.
Unlike the ESC and ACC/AHA, the AIAC committee adopted more
restrictive criteria for primary prevention of SCA in post-MI patients: ICD is
a class I indication only for patients with a LVEF 30%, whereas in patients
with LVEF between 31 and 35%, an ICD is a class II indication.
Some of the most important innovations of the most recent ACC/ESC
guidelines on the prevention of SCA are the recommendations regarding
patients with nonischemic dilated cardiomyopathy (DCM). Besides the obvious class Ia indication for patients with documented sustained ventricular
arrhythmias, the implant of an ICD is now a class I indication also in primary prevention for patients with DCM who are receiving chronic optimal
medical therapy, who have a reasonable expectation of survival in a good
functional status for more than 1 year, have a LVEF 3035%, and who are
NYHA functional class II or III (class I, level of evidence B). Moreover, in this
category of patients, ICD therapy can also be beneficial for those with unex-
Which Patient and when Should Receive an ICD? Evolving New Indications on the Horizon
217
plained syncope (class IIa, level of evidence C) and it can be effective for termination of sustained VT in patients with normal or near normal ventricular
function (class IIa, level of evidence C).
In these new guidelines, great importance is given to the NYHA functional class. For patients in NYHA I, all the class IIa indications become class
IIb, level of evidence C. In clinical practice, the placement of an ICD in a
NYHA class I DCM patient is therefore not recommended for primary prevention. As for ischemic cardimyopathy, the AIAC committee adopted more
restrictive criteria for primary prevention of SCA also for patients with nonischemic DCM: the LVEF cutoff for a class I indication for primary prevention is considered to be 30%; in patients with LVEF between 30 and 35% ICD
is a class II indication.
An expanding indication for ICD treatment is the vast assortment of
arrhythmogenic cardiomyopathies, including hypertrophic cardiomyopathy
(HCM) and the so-called channelopathies, or membrane ion-channel disease, all of which are associated with an increased risk of sudden cardiac
death (SCD). Sodium-channel disease (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, and long QT syndrome type 3), potassium
channel disease causing either different types of long QT syndromes or short
QT syndrome in case of gain of function, L-type calcium channel loss of
function also associated with short QT syndrome, and catecholaminergic
ventricular tachycardia are common causes of SCD, mainly in young people,
and sudden death may be the first symptom in such patients. For this reason,
besides the accepted class I indication for secondary prevention, in all the
above-mentioned situations ICD is gaining increasing popularity for primary prevention as well. However, the implant of an ICD for primary prevention in patients with an ion-channel disease is considered a class IIa indication, due to the lack of any prospective randomized trials in this specific
patient population. Therefore, for primary prevention, ICD is class IIa, level
of evidence C in hypertrophic cardiomyopathy patients who have one or
more major risk factors for SCA. It is class IIa, level of evidence C for
patients with arrhythmogenic right ventricular dysplasia (ARVD) without
sustained VT if they have an extensive disease, including left ventricular
involvement, have one or more affected family member with SCA, or undiagnosed syncope when VT/VF cannot be excluded as the cause of syncope. ICD
is recommended as a class IIa level of evidence B also for patients with long
QT syndrome who experience syncope and/or VT while receiving betablockers, and for Brugada syndrome patients with a spontaneous pattern of
ST segment elevation coved type and syncope. The role of ICD as primary
prevention in short QT syndromes is not well-defined. ICD implantation can
218
be also effective therapy for the termination of idiopathic sustained VT in

patients with normal or near normal ventricular function (class IIa, level of
evidence C).
The ICD as an adjunctive treatment to optimized medical therapy is the
newest treatment for HF patients, considered in the most recent guidelines
of either prevention of SCD or treatment of heart failure. SCD is the primary
cause of death in NYHA functional class IIIII congestive HF patients. Over
60% of these deaths are attributable to malignant ventricular arrhythmias.
The recommendation to implant an ICD for secondary prevention in
patients who survived a VF or hemodynamically unstable VT episode is
today a class Ia indication. After the Companion and the SCDeHFT studies, a
class I, level of evidence B indication is an ICD implant for primary prevention in HF patients who have a LVEF 3040%, who are in NYHA functional
class II or III, who are receiving chronic optimal medical therapy, who have a
reasonable expectation of survival with a good functional status for more
than one year, whose LV dysfunction is due to prior MI, and who are at least
40 days post-MI. Also assessed as class I with a level of evidence B, ICD therapy is recommended for primary prevention to reduce total mortality by a
reduction in SCD in patients with nonischemic heart disease who have an
LVEF 3035%, and are NYHA functional class II or III. A class IIa, level of
evidence B indication is ICD therapy combined with biventricular pacing in
patients with NYHA functional class III or IV, in sinus rhythm with a QRS
complex of at least 120 ms, and receiving optimal medical treatment.
Clinical guidelines certainly constitute the most important reference and
they should guide our daily clinical practice. However when and in whom to
implant an ICD is always a clinical decision that has to be carefully evaluated
for each patient. Age, associated morbidities, risk of malfunction and infections, and psychological aspect also have to be considered. Further subgroup
stratification to identify patients subgroups at particularly high risk of SCA
is necessary, but unfortunately is still lacking today, to avoid an excessive
increase in health-care costs due to both the high initial price of the device,
the increased care necessary to treat device-related morbidities (recall, system malfunction, and infections), and the expanding indications. However,
when patients are carefully selected within the criteria of the guidelines, ICD
therapy is cost-effective.
Finally, guidelines are composed on the basis of the best available medical science, but their application will likely be impacted by the financial, cultural, and societal differences among individual countries.
Which Patient and when Should Receive an ICD? Evolving New Indications on the Horizon
219
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators (1997)

A comparison of antiarrhythmic-drug therapy with implantable defibrillators in
patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med
337:15761583
Connolly SJ, Gent M, Roberts RS et al (2000) Canadian implantable defibrillator
study (CIDS): a randomized trial of the implantable cardioverter defibrillator
against amiodarone. Circulation 101:12971302
Kuck KH, Cappato R, Siebels J, Ruppel R (2000) Randomized comparison of
antiarrhythimic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation
102:748754
Moss AJ, Hall WJ, Cannom DS et al (1996) Improved survival with an implantable
defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 335:19331940
Ellison KE, Hafley GE, Hickey K et al (2002) Multicenter UnStained Tachycardia
Trial Investigators. Effect of beta-blocking therapy on outcome in the Multicenter
UnStained Tachycardia Trial (MUSTT). Circulation 106:26942699
Moss AJ, Zareba W, Hall J et al (2002) Prophylactic implantation of a defibrillator in
patients with myocardial infarction and reduced ejection fraction. N Engl J Med
346:877883
Kadish A, Dyer A, Daubert J et al; Defibrillators in Non-Ischemic Cardiomyopathy
Treatment Evaluation (DEFINITE) Investigators (2004) Prophylactic defibrillator
implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med
350:21512158
Bristow MR, Saxon LA, Boehmer J et al; Comparison of Medical Therapy, Pacing
and Defibrillation in Heart Failure (COMPANION) investigators (2004) Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350:21402150
Bardy GH, Lee KL, Mark DB et al; Sudden Death in Heart Failure Trial (SCD-HeFT)
Investigators (2005) Amiodarone or an implantable cardioverter-defibrillator for
congestive heart failure. N Engl J Med 352:225237
Zipes DP, Camm AJ, Borggrefe M et al (2006) ACC/AHA/ESC 2006 Guidelines for
Management of Patients With Ventricular Arrhythmias and the Prevention of
Sudden Cardiac Death: a report of the American College of Cardiology/American
Heart Association Task Force and the European Society of Cardiology Committee
for Practice Guidelines (writing committee to develop Guidelines for Management
of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac
Death): developed in collaboration with the European Heart Rhythm Association
and the Heart Rhythm Society. Circulation 114:10881132
Lunati M, Bongiorni MG, Boriani G et al (2005) Linee Guida AIAC 2006 allimpianto di pacemaker, dispositivi per la resincronizzazione cardiaca (CRT) e defibrillatori automatici impiantabili (ICD). Giornale Italiano di Aritmologia e
Cardiostimolazione 8(4)
Which Patients Should Receive Dual Defibrillators?

Results of DATAS
AURELIO QUESADA, MNICA GIMNEZ, VICTOR PALANCA, JAVIER JIMNEZ, ALFONSO
VALLE, JOS RODA
Introduction
The dual-chamber (DC) implantable cardioverter defibrillator (ICD) was
primarily introduced in the market to add atrial-based pacing for those
patients simultaneously affecting by bradycardia and fatal ventricular
arrhythmias. Following the successful introduction of the original VVED
ICDs, device capabilities were rapidly expanded by the addition of AV discrimination and atrial anti-tachycardia therapies (DDED ICDs). It was suggested that these sophisticated devices would overcome the limitations of the
single chamber (SC) devices and that their recommended use would be
extended.
However, some cardiologists and institutions remained concerned
whether the higher costs and complexity of DC ICD could be justified in
terms of real improvement in clinical outcome, and preferred SC ICDs as the
initial option for the majority of candidate patients. In truth, to prevent sudden cardiac death from ventricular tachyarrhythmias, which is the primary
mission of a defibrillator, a SC ICD seems sufficient, and most trials focused
on the use of ICDs have been conducted using these devices, including conservative studies that used shock-only ICDs (SCD-HeFT) [13].
However, physicians involved daily in ICD follow up are aware that a nonnegligible number of patients with these devices frequently require atrial
pacing and develop atrial tachyarrhythmias that can influence clinical outcome by inducing inappropriate shocks, requiring hospitalization due to
heart failure and stroke, and even resulting in increased mortality. Moreover,
the task of differentiating a supraventricular from ventricular origin of the
Cardiac Electrophysiology and Arrhythmias Section, Department of Cardiology,

Hospital General Universitario de Valencia, Valencia, Spain
246
Aurelio Quesada, Mnica Gimnez, Victor Palanca, Javier Jimnez, Alfonso Valle, Jos Roda
episodes in stored electrograms when only the ventricular channel is available can become very difficult if not impossible.
Nevertheless, these theoretical benefits of the widely-used DC ICDs have
been questioned for several reasons, among them the higher cost and possible complications. Moreover, the possibility of deterioration in left ventricular systolic function, with an increase in hospitalizations and mortality, has
become evident in the last several years. The DAVID study [4], which tried to
assess the superiority of DC over SC ICDs, was prematurely interrupted after
detecting a worsened outcome in the DC group. This was largely attributed
to the unintended adverse effects on left ventricular structure and function
of a high percentage of the right ventricular cumulative pacing, associated
with non-controlled AV interval programming.
The Dual Chamber & Atrial Tachyarrhythmias Adverse Events Study
(DATAS) was designed to study the ability of DC ICDs to better reduce clinically significant adverse event compared to SC ICD in a non-selected population with conventional indications for ICDs [5]. DC ICD was intended as a
device able to offer atrial-based pacing, AV discrimination, and electrical
therapies for both atrial and ventricular tachyarrhythmias (DDED in the
NASPE/BPEG Defibrillation Code) [6]. In spite of the recommendation for
atrial-based stimulation, special care was taken to prevent unnecessary ventricular pacing by prolonging AV interval programming.
How Does Dual-Chamber ICD Improve Outcome?

Obviously, atrial-based pacing for correction of bradycardias not present at
the time of implant could constitute an important benefit, especially in the
treatment of drug-induced disturbances. Except for ACE inhibitors or
angiotensin II receptor blockers (ARBs), those treatments that demonstrate a
reduction in mortality and improved symptoms and quality of life, i.e. betablockers and sotalol [7, 8], are able to deteriorate sinus and AV node functions, as can amiodarone. For example, 70% of the MADIT II patients were
under beta-blocker therapy [9]. In clinical practice, beta-blocker therapy
should be withdrawn in 15% of patients, even more in the case of those with
bradycardia.
Atrial pacing can favorably impact such patients by acting synergistically
with drugs, not only preventing pauses, but providing adequate exercise rate
response. Melzer et al. reported a prevalence of chronotropic incompetence >
38% in 123 ICD patients. Chronic anti-arrhythmic therapy with beta-blockers and amiodarone, particularly a combination of the two, was associated
with a higher occurrence of the condition [10].
Which Patients Should Receive Dual Defibrillators? Results of DATAS
247
Atrial tachyarrhythmias are very prevalent in ICD recipients, resulting in

inappropriate therapies [11]. However, if atrial tachyarrhythmias are considered only as a source of inappropriate shocks, then this is probably an oversimplification of the case. Atrial tachyarrhythmias can induce or worsen heart
failure or stroke, and AF is an independent factor of increased mortality. AF
after myocardial infarction independently predicted death in the GUSTO-III
trial [12]. Furthermore, a retrospective analysis of the Studies of Left
Ventricular Dysfunction Prevention and Treatment trials [13] showed that
patients with AF at baseline, compared to those in sinus rhythm, had greater
and significant all-cause mortality (34 vs 23%), death attributed to pump failure (16.7 vs 9.4%), and were more likely to reach the composite end-point of
death or hospitalization for heart failure (45 vs 33%); but there was no significant difference between the groups regarding arrhythmia-induced deaths.
Also, the European GEM DR evaluation study detected a higher early mortality of patients with ICDs compared to patients with episodes of AF [14].
By definition, the DC ICD is a unique device with atrial electrical therapy
capabilities, i.e., anti-tachycardia pacing, and atrial shocks. A high efficiency
in the treatment of atrial tachyarrhythmias has been shown with either of
the two components. The efficacy of atrial anti-tachycardia pacing ranges
from 55 to 66% and the adjusted success rate of atrial shock for atrial fibrillation is > 60% [15, 16]. The administration of atrial electrical therapy
decreases AF burden and the number of episodes [17, 18]. Significantly, at
least in the group of patients with drug-refractory AF, the efficacy of atrial
electrical therapy seems to have clinical repercussions, with a reduction in
the number of hospitalizations and cardioversions [19].
Although the so-called additional criteria offered by SC devices can
achieve acceptable results in certain patients, the difficulty in achieving a
balance between sensitivity and specificity remains their most important
limitation. For example, in SC ICDs the use of the sudden onset and stability
alone may yield a specificity as high as 96% for rejecting sinus tachycardia
and AF at ventricular rates < 180190 bpm [20, 21]. At higher rates, because
of regularization of ventricular activation, the specificity for AF using ventricular interval stability alone declines significantly. At higher rates, because
of normalization of ventricular activation, the specificity for AF using ventricular interval stability alone declines significantly. Further improvements
come at a high price, i.e., an unacceptable reduction in sensitivity for the
detection of true ventricular arrhythmias (to 8090%). The addition of an
atrial signal can enhance detection performance. Although some studies
have not found improved discrimination with such algorithm types [22], a
specificity of 85.8%, sensitivity of 100%, and a positive predictive value of
248
95.2% with the second version of the PR Logic (Medtronic) were recently
reported [23].
It must be stressed that recognition of dual tachycardias (a condition not
rare in ICD recipients) is not possible without atrial electrograms [24] (Fig.
1). The distinction is meaningful because it has been suggested that dual
tachycardia episodes in which ventricular therapy stops only the ventricular
arrhythmia but not the AF promote earlier recurrences than when both
tachycardias are therapeutically suppressed (AF begets VT/VF) [25]. In virtually all such episodes, information from the atrial chamber allows proper
interpretation of detection and therapy outcome, avoiding speculative diagnoses of many of them. Significant changes in patient treatment and management could be introduced from this more accurate information.
The above-described benefits are assumed to be associated with a low
rate of complications with respect to implant procedure, system performance
Fig.1.Dual tachycardia. a Ventricular tachycardia during an episode of atrial fibrillation treated with unsuccessful antitachycardia pacing. b The shock administered for the ventricular tachycardia suppresses both arrhythmias and restore synus rhythm. The data are
arranged as an atrial electrogram (A-tip to A-ring), HVA-RV coil electrogram, PP interval values, atrial and ventricle marker channel, and RR interval values (25 mm/s chart speed).
The correct diagnosis is not possible without information from the atrial channels
249
during follow-up, and avoidance of the previously unsuspected deleterious

effects of right ventricular pacing. Complications reported in the evaluation
of DC devices are few and their rates are closed to those reported for SC
ICDs; the actuarial estimates of 6-month complication-free survival and total
survival were 88 and 94%, respectively [11]. Both the avoidance of complications and the ability to achieve high-quality system performance require
adequate training and implant volume [26]. It has been suggested that the
rate of complications, mainly lead dislodgements, is related to the learning
curve, and improves with increasing team experience [27]. Current algorithms to minimize ventricular pacing or biventricular stimulation prevent
previously unsuspected deleterious effects of right ventricular pacing,
although high-quality training and volume are essential requirements for
insertion of the left ventricular leads.
Thus, the different benefit mechanisms and complication sources indicate
that DC ICD evaluation should be performed through randomized trials
seeking improvements of global outcome, and avoiding investigation on only
partial aspects. This was the subjacent rationale to the design of DATAS.
The DATAS Trial Design and Results

DATAS trial was a prospective, multicenter, randomized, open-label study
with three arms (two of them cross-over and the third paralleling the other
two) (Fig. 2) involving 36 centers in Spain, Germany, Italy, the UK, Portugal,
and Israel.
Fig. 2. DATAS trial design. SC, Single chamber ICD; DC, dual chamber ICD; sim, simulated; FU, follow-up
250
Inclusion criteria were standard class I criteria for a Sc ICD [28], with an
amendment in November 2001 to include MUSTT patients, when such indications appeared in the European Society of Cardiology guidelines [29]. The
main exclusion criteria were patients without structural heart disease, indication for biventricular pacing, previous ICD implanted, and accepted indications (symptomatic sinus node disease, all second-degree AV block, except
asymptomatic Mobitz I, and all third-degree AV block) and contraindications (permanent atrial tachyarrhythmias) for DC pacing.
The 354 patients who fulfilled the study inclusion criteria were randomly
assigned in a 1:1:1 proportion between SC ICD (SC true arm), DC ICD (DC
true arm), and a DC ICD programmed as a SC device (SC-simulated). All
patients were followed for 17 months. SC-simulated and DC true were
crossed-over at 8 months of follow-up, with a 1 month wash-out period. All
DC true devices were programmed with the PR Logic discrimination algorithm activated. For SC arms, stability criteria were used and other available
SC algorithms for discrimination of supraventricular tachyarrhythmias were
allowed (i.e., onset criteria and electrogram width).
Pacing mode was DDD 6070 bpm with strong recommendation for long
AV delays (minimum values of sensed AV interval 200 ms and paced AV
interval 230 ms) to avoid unnecessary pacing in the DC arm, and mode
switch was turned on. Pacing mode was VVI-40 or less in the true SC and
SC-simulated arms.
Atrial detection was activated in both the DC and SC-simulated (atrial
fibrillation 100150 ms, atrial tachyarrythmias 100320 ms) arms, but atrial
therapies (i.e., burst, ramp, 50 Hz burst and defibrillation therapy) were only
programmed in the DC arm.
The primary composite end-point included all-cause death, invasive
intervention, hospitalization or prolongation of hospitalization of cardiac
origin, inappropriate shocks (at least 2 episodes), and symptomatic sustained (more than 48 h) atrial tachyarrythmias. This composite endpoint was
denominated Clinically Significant Adverse Events (CSAE). It was evaluated
by defining a prespecified score corrected for the follow-up duration. Each
component of the composite end-point counted as one point, except death,
which as worst outcome was assigned the maximum number of adverse
events reached plus one.
The complete analysis, which will be the primary publication objective, is
still on-going, although preliminary results regarding the main comparison,
DC vs SC have been obtained and were presented in the last Cardiostim Late
Breaking Clinical Trial.
251
Among the 334 patients, 111 were randomly assigned to SC true ICD, 111
to SC-simulated and 112 to DC true and were followed during a mean follow
up of 15.7 3.4 months.
The patients were score-ranked according to CSAE criteria, death, and
suitability of intervention by intention to treat. In the SC arm there were 193
CSAE, with a total follow-up of 1728 months, compared with 138 CSAEs and
1833 months for the DC true arm (rate of CSAEs 0.112 vs 0.075). Relative risk
of CSAEs in patients treated with DC ICDs compared to SC true ICDs was
0.67 (CI95% 0.590.78), resulting in a clinically and statistical significant
33% reduction in the risk of suffering S-CSAE in DC ICDs recipients.
Thus, the conclusion from DATAS was that if ventricular pacing is minimized and the complications rate is low, then DC ICD can improve the outcome of non-selected patients with class I ICD indications, regardless of the
absence of pacing indications.
The mean AV intervals programmed in the DC devices were 221.8 51.2
ms (spontaneous atrial activity sensed) and 231.6 45.0 ms (atrium paced).
With these AV intervals, the median cumulative right ventricular pacing was
30.0% while median atrial pacing was 35%.
DATAS and Other Clinical Studies

So far, there has been no other study comparing DC ICDs with SC ICDs. The
few trials available were conducted with DC devices without atrial therapies
and were compared, on the one hand, with AV discrimination performance
between DC algorithms vs other criteria and, on the other hand, with the
prognosis to add or not atrial-based pacing
Although other, smaller studies did not encounter differences in AV discrimination with the use of DC ICDs, the Detect SVT study [30] did. The
trial randomized 400 patients who received DC ICDs for conventional indications to single- or dual-chamber detection. The primary end-point was the
proportion of expertly adjudicated SVT episodes that met ventricular rate
detection criteria and were inappropriately classified as VT. The corrected
inappropriate detection rates were 46.5 vs 32.3% for the single- versus dualchamber groups, respectively. Thus, DC enhancements reduced overall inappropriate detections by nearly 50% compared with SC detection.
The DAVID trial [4] compared SC programming VVI-40 vs DDDR-70
(rate-responsive atrial pacing and AV discrimination) in patients very similar to those enrolled in the DATAS trial (class I) but with a ejection fraction
40%. The study was prematurely stopped after a low conditional power for
252
the original alternative was detected (DDDR-70 being better that VVI-40).
Pacing settings, specifically with AV interval duration allowing high rates of
right ventricle pacing, may have accounted for this trend to worst status in
the VVED arm. Actually, the main comparison in the DAVID trial was
patients with a high cumulative percentage of right ventricular pacing (up to
59% in the DDDR arm) vs patients hardly paced (3% in VVI-40 arm).
Similarly, control of the AV interval in the DATAS trial seems crucial to
explaining the improved outcome in patients assigned to the DC-ICD arm.
Recently, the INTRINSIC trial, a non-inferiority trial with a design very
similar to that of the DAVID study, also reported a preserved (better) outcome in patients randomized to DC ICD (DDDR mode programmed but
with an AV extension algorithm activated; AV search hysteresis, Boston
Guidant) compared to patients programmed in VVI-40. The findings pointed
out the importance of maintaining both AV and VV synchronies in this very
sensitive group of patients [31].
Conclusions
Patients with conventional indications for ICD are predisposed to frequent
atrial-related problems, with a significant clinical impact on quality of life,
morbidity, and mortality. DC ICDs with both atrial pacing and anti-tachycardia therapies offer a rational approach to solving these problems. The DATAS
trial results are thus far concordant with the data from several recent trials
and support the role of DC ICDs in the general candidate population, in spite
of the absence of atrial-based pacing indications at the time of implant.
References
1.
2.
3.
4.
5.
The AVID investigators (1997) A comparison of antiarrhythmic-drug therapy with

implantable defibrillators in patients resuscitated from near-fatal ventricular
arrhythmias. N Engl J Med 337:15761583
Buxton AE, Lee KL, Fisher JD et al (1999) A randomized study of the prevention of
sudden death in patients w ith coronary artery disease. N Engl J Med
341:18821890
Bardy GH, Lee KL, Mark DB et al; Sudden Cardiac Death in Heart Failure Trial
(SCD-HeFT) Investigators (2005) Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 352:225237
The DAVID Investigators (2002) The dual chamber and VVI implantable defibrillator (DAVID) trial. Dual chamber pacing or ventricular backup in patients with an
implantable defibrillator. JAMA 288:31153123
Quesada A, Almendral J, Arribas F et al (2004) The DATAS rationale and design: a
controlled, randomized trial to assess the clinical benefit of dual chamber (DDED)
defibrillator. Europace 6:142150

6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
253
Bernstein AD, Camm AJ, Fletcher RD et al (1987) The NASPE/BPEG generic pacemaker code for antibradyarrhythmia and adaptive-rate pacing and antitachyarrhythmia devices. Pacing Clin Electrophysiol 10:794799
Pacfico A, Hohnloser S, Williams J et al (1999) Prevention of implantable-defibrillator shocks by treatment with sotalol. N Engl J Med 340:18551862
Joglar JA, Acusta AP, Shusterman NH et al (2001) Effect of carvedilol on survival
and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program. Am
Heart J 142:498501
Moss AJ, Zareba W, Hall WJ et al (2002) Prophylactic implantation of a defibrillator
in patients with myocardial infarction and reduced ejection fraction. N Engl J Med
346:877883
Melzer C, Ohm M, Bondke HJ et al (2005) Chronotropic incompetence in patients
with an implantable cardioverter defibrillator: prevalence and predicting factors.
Wolpert C, Jung W, Spehl S et al (2003) Incidence and rate characteristics of atrial
tachyarrhythmias in patients with a dual chamber defibrillator. Pacing Clin
Wong CK, White HD, Wilcox RG et al (2000) New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO III experience. Am
Heart J 140:878885
Dries DL, Exner DV, Gersh BJ et al (1998) Atrial fibrillation is associated with an
increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective
analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J Am Coll
Cardiol 32:695703
Denekea T, Lawoa T, Gerritseb B, Lemkea B for the European GEM DR
Investigators (2004) Mortality of patients with implanted cardioverter/defibrillators in relation to episodes of atrial fibrillation. Europace 6:151158
Schoels W, Swerdlow CD, Jung W et al (2001) Worldwide clinical experience with a
new dual-chamber implantable cardioverter defibrillator system. The Worldwide
Jewel AF Investigators. J Cardiovasc Electrophysiol 12:521528
Ricci R, Pignalberi C, Disertori M et al (2002) Efficacy of a dual chamber defibrillator w ith atrial antitachycardia functions in treating spontaneous atrial
tachyarrhythmias in patients with life-threatening ventricular tachyarrhythmias.
Eur Heart J 23:1471
Friedman PA, Dijkman B, Warman EN et al (2001) Atrial therapies reduce atrial
arrhythmia burden in defibrillator patients. Circulation 104:10231028
Schwartzman D, Gold M, Quesada A et al for the Worldwide Jewel AF-Only
Investigators (2005) Serial evaluation of atrial tachyarrhythmia burden and frequency after implantation of a dual-chamber cardioverter-defibrillator. J
Ricci R, Quesada A, Pignalberi C et al (2004) Dual defibrillator improves quality of
life and decreases re-hospitalizations in patients with drug refractory atrial fibrillation. J Interventional Card Electrophysiol 10:8592
Brugada J, Mont L, Figueiredo M et al (1998) Enhanced detection criteria in
implantable defibrillators. J Cardiovasc Electrophysiol 9:261268
Kettering K, Dornberger V, Lang R et al (2001) Enhanced detection criteria in
implantable cardioverter defibrillators: sensitivity and specificity of the stability
algorithm at different heart rates. Pacing Clin Electrophysiol 24:13251333
254
22.
Deisenhofer I, Kolb Ch, Ndrepepa G et al (2001) Do current dual chamber cardioverter defibrillators have advantages over conventional single chamber cardioverter defibrillators in reducing inappropriate therapies? A randomized, prospective
study. J Cardiovasc Electrophysiol 12:134142
Wilkoff B, Gillberg J, De Souza C (2001) The enhanced PR logic dua chamger
tachyarrhythmia detection algorithm: retrospective analysis of supraventricular
tachycardia with long PR intervals. J Am Coll Cardiol 37(Suppl 2):131A (abs)
Dijkman B, Wellens HJ (2000) Importance of the atrial channel for ventricular
arrhythmia therapy in the dual chamber implantable cardioverter defibrillator. J
Stein KM, Euler DE, Mehra R et al (2002) Do atrial tachyarrhythmias beget ventricular tachyarrhy thmias in defibrillator recipients? Jewel AF Worldw ide
Investigators. J Am Coll Cardiol 40:335340
Al-Khatib S, Lucas F, Jollis J et al (2005) The relation between patients outcomes
and the volume of cardioverter-defibrillator implantation procedures performed
by physicians treating Medicare beneficiaries. J Am Coll Cardiol 46 15361540
Eberhardt F, Bode F, Bonnemeier H et al (2005) Long term complications in single
and dual chamber pacing are influenced by surgical experience and patient morbidity. Heart 91:500506
Gregoratos G, Cheitlin MD, Conill A et al (1998) ACC/AHA Guidelines for
Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Executive
Summary a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee on Pacemaker
Implantation). Circulation 97:13251335
Priori S, Aliot E, Blomstrom-Lundqvist C et al (2001) Task Force on Sudden
Cardiac Death of the European Society of Cardiology. Eur Heart J 22:13741450
Friedman PA, McClelland RL, Bamlet WR et al (2006) Dual-chamber versus singlechamber detection enhancements for implantable defibrillator rhythm diagnosis:
the Detect Supraventricular Tachycardia Study. Circulation 113:28712879
Olshansky B, Day JD, Moore S et al (2007) Is dual-chamber programming inferior
to single-chamber programming in an implantable cardioverter-defibrillator?
Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in
ICDs) study. Circulation 115:916
23.
24.
25.
26.
27.
28.
29.
30.
31.
CARDIAC PACING
Hemodynamic Impact of Right Ventricular Pacing

RAL CHIRIFE, G. AURORA RUIZ, M. CRISTINA TENTORI
Introduction
Right ventricular apical pacing has been the standard for cardiac pacing in
view of lead mechanical stability and low pacing thresholds. Patients receiving rate-adaptive dual chamber pacemakers because of high-degree atrioventricular (AV) block and/or severe chronotropic incompetence have thus
obtained the benefits of rate control for many decades, without any appreciable hemodynamic adverse effects, for as long as the device was appropriately programmed. Dual-chamber pacing provides the AV-block patient
with normal sinus function the benefit of physiological rate response and
restoration of AV sequence. Thus, the improvement of quality-of-life of
DDDR in patients w ith clear pacing indications is beyond question.
Nonetheless, in recent years there have been numerous studies showing the
deleterious effects of right ventricular apical pacing [15]. Some of these
studies, however, are not in agreement with clinical observations, mostly
because experience shows that, in prolonged follow-up, patients with DDD
devices and permanent right ventricular apical pacing do not necessarily
end up with cardiac dilatation and heart failure, even after decades of pacing. If the patients do not have a clear indication for pacing and left ventricular (LV) function is already impaired, such as was the case in the David
study [6], it is likely that artificial pacing will cause only side effects and
offer no clinical benefit. Therefore, it is apparent to us that many questions
remain to be answered.
Cardiology Department, Fernndez Hospital, Buenos Aires, Argentina
280
What Do We Expect from DDDR Pacing?

DDDR pacemakers are primarily designed to offer the patient physiological
rate adaptation and conservation of AV sequence. The former is accomplished by tracking sinus rate in patients with normal sinus function or by
the use of a rate-adaptive sensor for patients with chronotropic incompetence. Regarding the latter, DDD pacemakers have nominal AV parameters
similar to physiological PR intervals, resulting in a surface ECG with a normal P/QRS sequence.
What Do We Really Get from DDDR Pacemakers?

Rate adaptation is physiological only for patients with preserved sinus function and various degrees of AV block. All modern pacemakers can track
sinus function either with a single VDD lead or with a two-lead system.
However, if the patient has chronotropic incompetence, a rate-adaptive sensor is required. In practice, most of these sensors are not sufficiently sensitive or specific, or they have a slow response, since they use extra-cardiac
markers of metabolic demand (body motion, respiration). False-positive
responses are common in accelerometer-based sensors, since the pacing rate
frequently increases unnecessarily with passive body motion (i.e., traveling
by car). False-negative responses occur in cases of isometric effort, which
increases metabolic demands in the absence of important body motion.
Finally, delayed responses are observed with minute ventilation and QT sensors.
Conservation of AV sequence is also not achieved entirely. Although the
nominal value of programmed AV is similar to normal PR, a normal AV
sequence is accomplished only for the right heart, where pacing leads are
placed. The left-heart AV interval, or better the mechanical left AV (the
sequence between left atrial and LV contraction), may not necessarily be
physiological with a normal right heart AV interval. This is because of the
known sensing and pacing-induced delays [710]. These delays are:
1. P-sense offset (PSO), which is the time from the true onset of the right
atrial P wave to the detection point by the atrial sensing amplifier of the
pacemaker. Most pacemakers use a default PSO of around 30 ms, which
on average is the time required by the pacemaker to detect the presence
of a P wave. By virtue of this delay, the true AV interval is longer than the
programmed one.
2. Right atrial pacing is known to lengthen the interatrial delay (IAD). This
is because the right atrial lead is placed in the right atrial appendage
281
(longer delay), lateral wall, or interatrial septum (shorter delay). For practical reasons, this delay is measured from the onset of right atrial P to the
onset or end of atrial transport (best detected by transmitral Doppler
flow). This delay causes a shorter left-heart AV interval than programmed.
3. An interventricular delay (IVD) arises from the fact that right ventricular
pacing, especially if done from the apex, causes a delay in LV depolarization. Because of this delay, the resulting left heart AV interval is longer
than programmed.
From the above, it is clear that in most instances we do not get what we
expect from DDDR pacing, unless it is meticulously programmed and a
physiological rate-adaptive sensor is used. Nevertheless, even in those cases
in which rate response is physiological and AV interval has been optimized,
are there side effects of cardiac pacing?
What Is the Hemodynamic Impact of Acute Right Ventricular Apical

Pacing?
Publications describing the effects of right ventricular pacing on LV function
are not only abundant but controversial as well. Although it is well-known
that the contraction wavefront of the left ventricle is affected whenever the
depolarization wavefront is, many patients with DDDR pacemakers followed-up for decades show no demonstrable deleterious hemodynamic or
clinical impact of right ventricular (RV) pacing on cardiac function. In fact,
patients with long periods of bradycardia preceding pacemaker implantation
may show reverse remodeling of the left ventricle after DDDR implant. It is
our intention to clarify several concepts related to pacing and cardiac function by offering specific examples of typical acute and chronic effects of RV
pacing on LV function.
Effect of Pacing Rate

Since currently used rate-adaptive sensors are non-physiological, it may be
expected that the pacing rate governed by the sensor may not always be
appropriate. If the pacing rate is too slow, metabolic demands may not be
met, and if it is too fast, such as in a false-positive sensor response, symptoms may arise and blood pressures and cardiac output may drop. In the
example of Fig. 1, a DDDR pacemaker implanted for complete AV block was
programmed to optimize the AV inter val. The DDD pacing rate was
282
Fig. 1. Effect of rate of cardiac hemodynamics. Patient with a DDD pacemaker. Rate was
increased from 50 to 100 bpm, while blood pressure was recorded with a noninvasive
blood-pressure monitor allowin beat-by-beat measurements (channel 2). Channel 1 is a
photoplethysmographic recording of the right supraorbital artery, channel 3 is a marker
of prevailing heart rate, and channel 4 is the surface ECG lead II. As rate is increased, it
can be seen that systolic blood pressure drops and diastolic blood pressure rises slightly. The peak-to-peak changes in the photodensitogram are directionally similar to
blood pressure changes and suggest a drop in stroke volume during higher pacing rates
increased from 50 to 100 bpm, while blood pressure was recorded with a
noninvasive blood-pressure monitor that allows beat-by-beat measurements
(channel 2). Channel 1 is a photoplethysmographic recording of the right
supraorbital artery, channel 3 is a marker of prevailing heart rate, and channel 4 is the surface ECG lead II. It can be seen that, as the rate is increased,
systolic blood pressure drops and diastolic blood pressure rises slightly. The
peak-to-peak changes in the photodensitogram are directionally similar to
blood-pressure changes and suggest a drop in stroke volume during higher
pacing rates. Figure 2 is a plot of the changes in the same patient. Systolic
pressure area, a surrogate of stroke volume [11], and its product with heart
rate (surrogate of cardiac output) drop during incremental pacing. From
these experiments it is inferred that faster pacing rates do not necessarily
increase cardiac output, at least in patients who do not have heart failure.
283
Fig. 2. Effect of rate of cardiac hemodynamics. Plot of hemodynamic changes in the

same patient as Fig. 1. Systolic pressure area, a surrogate of stroke volume, and its product with heart rate (surrogate of cardiac output) drop during unnecessary incremental
pacing at rest
The effect of incremental pacing on arterial blood pressure is, however, different in the experimental animal (Fig. 3). For example, in a dog instrumented for another study, the animal had high-fidelity pressure catheters inserted
in the aorta and right ventricle, and fluid-filled catheter in the right atrium.
An electromagnetic probe was inserted in the pulmonary artery for continuous monitoring of pulmonary flow. A bipolar screw-in pacemaker lead was
inser ted in the right atrial appendage and another in the RV apex.
Intracardiac impedance was used to assess instantaneous RV volume
changes [12] (transvalvular impedance, measured from the right atrial ring
to the RV ring electrodes). The tracings reveal that incremental pacing
increases blood pressure in the dog (probably due to the Bowditch effect),
but stroke volume is reduced due to the Starling effect (shorter filling time),
as indicated by the reduced flow amplitude in the pulmonary artery.
284
Fig. 3. Effect of rate of cardiac hemodynamics. Dog instrumented for another study, with
high-fidelity pressure catheters in the aorta and right ventricle, and fluid-filled catheter
in the right atrium. A flow probe was placed in the pulmonary artery. A bipolar screw-in
pacemaker lead was inserted in the right atrial appendage and another in the RV apex.
Intracardiac impedance was used to assess instantaneous RV volume changes [12];
transvalvular impedance (TVI), measured from the right atrial ring to the RV ring electrodes. It can be seen that incremental pacing at rest increases blood pressure (probably
due to the Bowditch effect), but stroke volume and ejection fraction (EF) measured
from TVI are reduced as well
Direct Effect of RV Pacing on LV Function

Figure 4 shows an example in a patient with sick sinus syndrome and normal
QRS morphology. After a 5-min stabilization period with atrial pacing at 70
bpm and normal AV conduction, RV pacing was started by shortening the AV
interval, while insuring that the left-heart AV interval remained unchanged
(see How Should the Heart Be Paced?). RV pacing was switched on and off
at the arrows by shortening or lengthening the AV interval. Although no
gross change in systolic (channel 1) or diastolic (channel 3) blood pressure is
noted outside of the natural fluctuations, closer observation of the beat-tobeat blood pressure changes following the switch to RV pacing (Fig. 5)
reveals significant morphological changes in the arterial pulse: Peak systolic
pressure drops and the pulse becomes narrower (shorter ejection time) for
the first few beats. After the fourth beat, systolic and diastolic blood pres-
285
Fig. 4. Effect of RV pacing on cardiac hemodynamics. Patient with sick sinus syndrome
and normal QRS morphology, after a 5-min stabilization period with atrial pacing at 70
bpm and normal AV conduction. RV pacing was switched on and off at the arrows by
shortening or lengthening the AV interval. Although no gross change in systolic (channel 1) or diastolic (channel 3) blood pressure is noted outside, the area under pressure
pulse (channel 2) is decreased, indicating a reduction in SV
Fig. 5. Effect of RV pacing on cardiac hemodynamics. Same patient as in Fig. 4. Closer

observation of the beat-to-beat blood pressure changes with RV pacing reveals significant morphological changes in the arterial pulse: peak systolic pressure drops and the
pulse becomes narrower (shorter ejection time) for the first few beats. After the fourth
beat, systolic and diastolic blood pressures return towards normal, probably as a consequence of the baroreflex
286
sures return towards normal, probably as a consequence of the homeostatic

mechanisms, but the beat-by-beat area under blood pressure curve (a surrogate of stroke volume), drops and remains low. Although systolic pressure
returns to normal, the area under the pulse remains low for at least 8 min of
RV pacing. In addition to blood-pressure changes, RV pacing causes a significant lengthening of the left pre-ejection interval, a marker of interventricular dyssynchrony, as seen in the example of Fig. 6. In this case, the LV preejection interval lengthened by 70 ms during RV stimulation.
To study the net effect of RV pacing on RV and LV function in the dog
experiment described above, the animal was subjected to alternate (beat by
beat) intrinsic and RV pacing in order to prevent baroreflex compensatory
mechanisms. The animal was atrial paced at 10 beats above intrinsic
throughout the experiment to maintain a constant heart rate, and the AV
interval was lengthened and shortened in alternate beats. During RV pacing,
the left heart AV interval remained unchanged compared to the atrial-paced
rhythm. The following observations can be made regarding the hemodynamic effects of RV pacing, as seen in Fig. 7: (1) there is a drop in systolic arterial
pressure; (2) RV stroke volume, as measured by intracardiac transvalvular
impedance, is reduced; (3) pulmonary-artery flow is reduced; (4) there is a
reduction in the area under pulse pressure (a surrogate of stroke volume);
(5) the LV pre-ejection interval is prolonged; (6) RV pressure is reduced; and
(7) the RV pre-ejection interval is prolonged.
In summary, from this experiment it can be concluded that RV pacing
indeed causes deterioration of both RV [13] and LV performance [16].
Effect of AV Interval on LV Function

If the left-heart mechanical AV interval is either too short or too long it may
be associated with deleterious hemodynamic effects. A normal left-heart AV
interval can be defined as that causing left atrial transport to be completed
just before LV contraction. If the AV interval is too short, atrial contraction
may overlap with LV isometric contraction; if it is too long, atrial contraction may overlap with isometric relaxation of the preceding cardiac cycle.
These two conditions impair cardiac performance by two different mechanisms. The first is related to the Starling principle; it is more evident when
the AV interval is too long and atrial contraction takes place too early in
diastole, causing inadequate LV filling (ineffective atrial kick). The other
results from overlap of left atrial and LV pressures; in this case, atrial contraction takes place while the LV pressure is too high to be overcome, such as
during isometric relaxation and contraction. When this happens, atrial
287
Fig. 6. Effect of RV pacing on cardiac hemodynamics. In addition to blood-pressure

changes, RV pacing causes a significant lengthening of the left pre-ejection interval
(PEI), a marker of interventricular dyssynchrony. In this case, PEI lengthened by 70 ms
during RV stimulation
Fig. 7. Effect of RV pacing on cardiac hemodynamics, dog experiment. The following

changes are seen during RV apical pacing: (1) drop in systolic arterial pressure; (2) drop
in RV stroke volume (as measured by TVI) is reduced; (3) reduction of pulmonaryartery flow (4) there is a reduction in the area under pulse pressure (a surrogate of
stroke volume); (5) the LV pre-ejection interval is prolonged; (6) RV pressure is reduced; and (7) the RV pre-ejection interval is prolonged. In summary, this experiment
reveals that RV pacing causes deterioration of both RV [13] and LV performance [16]
288
transport is severely limited or absent (thus affecting LV filling by the

Starling mechanism). Also, all of the left-atrial contraction pressure backs up
into the pulmonary circulation, causing an increase in pulmonary wedge
pressure. This phenomenon may explain symptoms in patients with firstdegree AV block during exercise, when P waves overlap T waves, the socalled pacemaker syndrome without a pacemaker [14].
What Is the Hemodynamic Impact of Chronic RV Apical Pacing?

From a database of 869 patients with chronically implanted pacemakers, 272
patients with measurements of LV diastolic dimension (LVDD) and left atrial
dimension (LAD) in two ECGs obtained at least 6 months apart after pacemaker implant were included in the study [15]. Changes in LV and left atrial
diameters were evaluated after long follow-up periods in two groups: (1) RVpaced group (RVP), comprising patients with > 60% RV pacing on Holter
function of the pacemaker and (2) RV sensing group (RVS), comprising
patients with < 60% RV pacing. The two groups were similar in age, clinical
diagnosis, and pacing mode (all p values were non-significant). Follow-up
time was 55 37 months in the RVP group and 4832 months in the RVS
group (p = non-significant). Since in the RVP group 51% of the subjects were
males vs. 28% in the RVS group (p = 0.0051), patients were separated by gender for analysis. At the end of follow-up it was found that male patients
receiving RVP had more left atrial and LV dilatation than those with RV
sensing. However, in the RVP group, 40% of patients had either no change
(11%) or a reduction of LV size (29%) (Fig. 8).
How Should the Heart Be Paced?

If the patient needs a DDDR device, and atrial and ventricular leads are in
the right atrial appendage and RV apex, respectively, several actions can be
taken to minimize the side effects of DDDR pacing:
Rate Response
For patients with chronotropic incompetence, the use of a physiological sensor that parallels neurohormonal changes associated with increased metabolic demands is ideal. One such sensor is under evaluation in Europe
(Sophs 151, Medico SpA, Padova, Italy). It is based on transvalvular impedance, which calculates ejection fraction (contractility marker) from relative
289
Fig. 8. Effect of chronic RV pacing on LV dimension. Long-term RV apical pacing produces mixed results regarding LV chamber size: After a mean follow-up time 55 37
months, 60% of patients had LV dilatation, while 29% of patients had reduction and
11% no change in chamber size. This indicates that there is an interaction between the
benefits of pacing and the adverse effects of ventricular pacing. RR, Reverse remodeling; R, remodeling; NC, no change
ventricular volume changes. The mode of operation is relatively simple: the

device measures end-diastolic time velocity integration (TVI) (a surrogate of
end-diastolic volume) and end-systolic TVI (a surrogate of end-systolic volume). Based on these measurements, changes in the relative ejection fraction
are calculated [12]. This sensor is expected to minimize false positive and
false negative responses leading to patients symptoms. Other contractility
markers may be valuable as well.
AV Interval Optimization
This procedure is critical to avoid pacemaker syndrome. One simple way
would be to offset the delays caused by atrial and ventricular sensing and
290
pacing (see above). A previously published equation [8, 16] could be used to
evaluate patients with complete AV block: Right AV = IATD PSO IVD. In
this equation, IATD is the interatrial transport delay, the time from the onset
of right-atrial P (or pacing pulse) to the end of left-atrial transport (approximately the peak of mitral Doppler A wave); PSO is the P-sense offset, the
time needed by the pacemaker to detect the onset of the P wave; and IVD is
the interventricular delay, measured as the extension of left pre-ejection
interval caused by RV apical pacing. With this calculation, the shortest possible AV interval is used that allows atrial transport to end just before the
onset of LV contraction. Since IATD is longer with right atrial pacing (about
50 ms) than with intrinsic P waves, the resulting right-heart AV interval during atrial pacing will necessarily be longer. By restoring the left-heart AV
interval to a normal value, some of the hemodynamic consequences of RV
pacing can be diminished.
Minimizing RV Pacing
Important side effects of RV apical pacing are the inter- and intraventricular
mechanical dyssynchronizations caused by the ectopic origin of the depolarization wavefront. This causes unequivocal hemodynamic changes, as
described above. Some of these may be compensated by the baroreflex, but in
patients with already deteriorated LV function these minor changes may be
of importance. From a hemodynamic standpoint, it seems preferable to have
a long PR with intrinsic AV conduction and narrow QRS rather than pacing
the RV with an optimal AV interval. However, how long an AV is too long?
The maximal duration of AV (or PR) depends on several factors, as previously shown. These are heart rate and interatrial and interventricular delays (the
latter will dictate the duration of electromechanical systole). Whenever right
ventricular pacing is inevitable, such as in complete AV block or severe 1st
degree AV block during exercise, it must be done with a normalized mechanical left AV interval as described above, to avoid pacemaker syndrome.
Therefore, all the available algorithms to reduce ventricular pacing must be
used with caution in order to avoid pacemaker syndrome at faster rates. In
the presence of left bundle branch block, which has similar hemodynamic
implications as RV pacing, avoidance of pacing may not be as important,
since dyssynchrony is already present. In this case, it is expected that simultaneous RV and LV stimulation with biventricular pacemakers may improve,
at least in part, inter- and intraventricular dyssynchrony.
291
Conclusions
From the above observations, it is apparent that cardiac pacing offers both
benefits and side effects that have to be carefully weighed for each individual
patient. If the right ventricle must be paced, it has to be done with a normalized AV interval and only when strictly necessary. The need for RV pacing is
determined not only by the presence of complete AV block but also in situations of first-degree AV block during exercise, to avoid pacemaker syndrome without a pacemaker [14]. In patients with left bundle branch block,
there is so far no evidence that RV pacing further deteriorates LV function.
Thus, avoidance of RV pacing in these patients does not theoretically provide
any clinical benefit except for increased device longevity.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Thambo JB, Bordachar P, Garrigue S et al (1999) Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular
apical pacing. Pacing Clin Electrophysiol 22(8):12341239
Ritter O, Koller ML, Fey B et al (2002) Progression of heart failure in right univentricular pacing compared to biventricular pacing. Europace 4(1):6165
Szili-Torok T, Kimman GP, Theuns D et al (2006) Deterioration of left ventricular
function following atrio-ventricular node ablation and right ventricular apical
pacing in patients with permanent atrial fibrillation. Indian Pacing Electrophysiol J
6(3):142152
Tantengco MV, Thomas RL, Karpawich PP (2006) Left ventricular dysfunction after
long-term right ventricular apical pacing in the young. Rev Esp Cardiol
59(6):553558
Lee MA, Dae MW, Langberg JJ et al (2003) Effects of long-term right ventricular
apical pacing on left ventricular perfusion, innervation, function and histology. J
Cardiovasc Electrophysiol 14(11):11801186
Wilkoff BL; Dual Chamber and VVI Implantable Defibrillator trial investigators
(2006) The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial: rationale, design, results, clinical implications and lessons for future trials. Kardiol Pol
64(10):10821091
Chirife R, Ortega DF, Salazar AI (1991) Nonphysiological left heart AV intervals as a
result of DDD and AAI physiological pacing. Pacing Clin Electrophysiol 14(11 Pt
2):17521756
Chirife R (1995) Proposal of a method for automatic optimization of left heart
atrioventricular interval applicable to DDD pacemakers. Pacing Clin Electrophysiol
18(1 Pt 1):4956
Chirife R (1994) Left heart function during right heart pacing. Pacing Clin
Electrophysiol 17(9):14511455 (Editorial, 2002 25:888896)
Chirife R (1998) Importance of interatrial and interventricular delays in the
performance of dual chamber pacemakers. In: Barold S, Mujica J (eds) Recent
advances in cardiac pacing. Goals for the 21st century. Vol 4. Futura, Armonk NY
292
11.
Wesseling KH, Jansen JRC, Settels JJ, Schreuder JJ (1993) Computation of aortic
flow from pressure in humans using a non-linear, three-element model. J Applied
Physiol 74:25662573
Chirife R, Ortega DF, Salazar AI (1993) Feasibility of measuring relative right ventricular volumes and ejection fraction with implantable rhythm control devices.
PACE 16:16731678
Dwivedi S, Bansal S, Puri A et al (2001) Diastolic and systolic right ventricular
dysfunction precedes left ventricular dysfunction in patients paced from right ventricular apex. J Am Coll Cardiol 37(8):20932100
Chirife R, Ortega DF, Salazar AI (1990) Pacemaker syndrome without a pacemaker. Deleterious effect of first degree AV block. R Eur Tech Biomed 12:22
Chirife R, Ruiz A, Tentori C, Sztyglic E (2006) Does chronic right ventricular pacing
cause further remodeling of left heart chambers? J Cardiac Failure 12:S65
Chirife R. US Pat #5,179,949
12.
13.
14.
15.
16.
Hemodynamics in Standard Cardiac Pacing

MILOS TABORSKY
Early Experiences with Rate-Responsive Pacing

The first rate-responsive pacing systems were introduced by Center [1] and
Lagergren [2] in 19641966. Both systems used P waves, which were detected
with an atrial electrode positioned by thoracotomy or mediastinoscopy to
trigger the ventricular pacing after a short delay. A comparison of the acute
data with VVI pacing showed that the cardiac index increased by 1030%.
Despite these promising data, atrioventricular (AV) synchronous pacemakers
were not widely used until the late 1970s.
The first extensive study of the acute hemodynamic effect of AV synchronous pacing was carried out by Karlf [3] in a study of 25 patients. With a
change from fixed-rate ventricular pacing of 70 bpm to AV synchronous pacing, cardiac output increased by 20%. The change in cardiac output was
obtained without an increase in left ventricular filling pressure.
One of the first comparisons between the acute and long-term hemodynamic effects of ventricular and AV pacing was made by Kruse [4]. No significant differences were found between acute and long-term results based on
an acute invasive study of hemodynamics at rest and during exercise in AV
synchronous pacing. The increases in cardiac output and stroke volume were
significantly lower in patients with fixed-rate ventricular pacing.
Since the 1980s, dual chamber pacing and DDD/DDDR modes have
become the standard for physiological pacing. DDD/R mode has two fundamentals advantages: (1) AV synchrony and restoration of atrial function, and
(2) adaptation of heart rate to the sensed atrial activity. However, the ques-
Cardiology Department, Na Homolce Hospital, Prague, Czech Republic
294
Milos Taborsky
tion remains: are these advantages truly physiologic, especially in patients

with depressed left ventricular function and right apical pacing?
Heart Rate and Atrioventricular Synchrony

The importance of increasing heart rate to increase cardiac output during
exercise has been clearly documented in several studies [5, 6]. Since the
improvement in exercise performance is due predominantly to an increase in
heart rate, it is expected that favorable hemodynamic results will be obtained
by rate-adaptive systems.
In the era of ventricular rate-responsive pacing (VVIR), a number of different sensors have been incorporated into pacemakers. Many investigations
have compared the exercise hemodynamics between sensor-driven VVIR
pacing and those of VVI pacing. Percentage improvements of heart rate and
exercise duration during symptoms-limited exercise in the VVIR and VVI
pacing modes was determined in several large series for currently available
rate-adaptive systems. The results showed variable but consistent increases
of 69% in rate and 32% in exercise tolerance in patients with VVIR pacing
[7, 8]. Early comparisons of patients with VVI and VVIR pacing consisted of
rather small series and mixed patient populations in terms of pacemaker
indications, symptoms of heart failure, and degree of ventricular dysfunction.
The use of an atrial sensing electrode to synchronize ventricular stimulation with intrinsic sinus node discharge (atrial synchronous ventricular pacing, VAT) resulted in a more physiologic mode of pacing [9, 10]. Addition of
a ventricular sensing capability to this pacing mode resulted in the development of the VDD mode as a combination of VAT plus VVI.
The standard approach to the management of complete symptomatic
heart block involves the use of pacemaker units that provide not only basic
ventricular pacing support but also adaptation of the pacing rate to physiologic needs. Two patterns of hemodynamic response to higher rates of ventricular pacing have been described. In the flat response, after an initial
increase in heart rate and cardiac output (rate increase from 30 to 60 bpm),
cardiac output remains relatively constant as stroke volume decreases with
further rises in heart rate [11]. This response occurs most often in individuals with normal cardiac function and indicates that cardiac output is relatively independent of heart rate. In the peaked response, cardiac output
increases progressively until the optimal pacing rate is achieved and further
increases are not possible [12]. The peaked response is more commonly
observed in patients with myocardial disease, in whom cardiac output is
295
more sensitive to changes in preload, afterload, myocardial contractility, and

distensibility. The major factors limiting the increase in resting cardiac output that can be achieved by pacing rate alone are shortened diastolic filling
time, reduced left ventricular compliance at higher rates of ventricular pacing, and increased systematic resistance [7, 8].
AV Block and Ventricular Pacing

In patients with acquired complete heart block, cardiac output is less than in
patients with a normal heart rate [13]. As a result, compensatory increases in
sympathetic tone and end-diastolic ventricular volume occur, leading to
higher atrial rates, enhanced ventricular contractility, and increased stroke
volume [14].
The importance of the duration of overload is confirmed by the observation that the frequency of congestive heart failure symptoms in patients with
complete heart block correlates with the duration of heart block. Congestive
heart failure has been described during chronic complete heart block even in
patients with normal ventricular function. In two-thirds of patients with
complete heart block and congestive heart failure, symptoms were induced
by ventricular pacing alone, and no additional medical therapy was required
[15]. Janousek described that, in pediatric patients with congenital heart
block, implantation of a pacemaker and right apical pacing resulted in
increased left ventricular dilatation and the development of heart failure
[16]. However, longer-lasting ventricular pacing in hearts with AV block may
lead to left ventricular dilatation and hypertrophy secondary to the effect of
asynchronous activation in the adult population as well [1719]. These data
strongly suggest that in the patient with AV block the short- and long-term
effects of RV pacing are different, indicating that the choice of apical or septal right ventricular pacing together with algorithms minimizing ventricular
pacing may be essential.
Role of Optimal AV Interval During Pacing

An optimally timed atrial contraction (before the isovolumetric contraction
phase) maximizes filling and thereby its output, according to the FrankStarling principle. Premature atrial contraction (as in the case of first-degree
AV block and dual-chamber pacing with long AV intervals) decreases the
pump function of the atrium. In addition, it may initiate early mitral valve
closure, thereby limiting ventricular diastolic filling time. This observation
296
Milos Taborsky
can be explained by the importance of three factors collaborating to achieve

optimal closure of the AV valves: (1) termination of transvalvular flow at the
end of the atrial contraction forces the valvular leaflets to approach one
another; (2) at the beginning of ventricular contraction, the anulus of the AV
valve contracts, as do the papillary muscles that hold the leaflets; (3) at the
start of ventricular contraction, ventricular pressure rises above atrial pressure, and the valves close. When these factors are misaligned, the opportunity for diastolic and systolic mitral regurgitation arises [20].
AV Interval in Patients with Normal Left Ventricular Function

The AV interval that maximizes resting cardiac output during dual-chamber
pacing varies widely among patients, and has been reported in most studies
to be between 125 and 200 ms [21, 22]. Optimal AV interval can be determined in most patients during dual-chamber pacing by means of several different invasive and noninvasive measurements. Most commonly, optimal AV
interval is assessed by left ventricular outflow recording with Doppler
echocardiography [23].
The optimal AV interval determined with Doppler echocardiography correlates well with the optimal AV interval determined with radionuclide ventriculography. Many factors, in addition to interpatient variability, may influence the determination of optimal AV interval in the same patient, such as
heart rate, paced or sensed atrial event, posture, and exercise [24, 25]. During
the lifetime of a patient, there may be situations in which the optimal AV
interval is different from the AV interval considered to be physiologic.
Optimal hemodynamics at AV intervals in the range of 80120 ms for complete heart block complicating an acute myocardial infarction or after cardiac surgery reflect intrinsic catecholamine levels or the administration of
inotropic drugs and reduced left ventricular compliance in these acute situations.
AV Interval in Patients with Depressed Left Ventricular Function

In patients with depressed left ventricular function, relaxation is slower than
in normal hearts. Less blood enters the ventricles during the rapid filling
phase, as can be observed from the lower E waves on Doppler echocardiograms. Therefore, failing hearts are more dependent on properly timed atrial
contraction than normal hearts.
The actual role of atrial contraction in patients with dilated ventricles
297
and low ejection fraction varies among individuals. The systolic pump function of the left atrium is described as a shoulder in the left ventricular
pressure tracing, and the left ventricle does not start contracting immediately after atrial contraction. If this plateau lasts too long, diastolic mitral regurgitation may occur, as is the case in patients in whom a decrease in left ventricular pressure occurs after atrial contraction. About 20% of patients in
heart failure studies for whom complete hemodynamic data are available
show this type of diastolic left ventricular pressure waveform.
Examination and calculation of the cardiac output with Doppler echocardiography, as is easily and frequently done in patients with dual-chamber
pacemakers, is more problematic in patients with depressed left ventricular
ejection fraction [25]. The number of repetitions required to obtain a reproducible evaluation of the optimal AV interval makes this method impractical
for patients with depressed ejection fraction [26, 27].
Hemodynamic Consequences of Ventricular Asynchrony

Abnormal asynchronous activation causes abnormal contraction patterns,
inefficient and depressed pump function, and, later, ventricular remodeling.
Wiggers recognized the importance of normal electrical activation of the
ventricle for optimal pump function in 1925 [28]. In the 1960s, Kosowsky
compared right ventricular apex pacing with His-bundle pacing, the latter
maintaining the normal activation but allowing variation of the AV interval.
It was concluded that AV synchrony and proper sequence of activation are
equally important [29].
The combination of acute adverse hemodynamic effects and long-term
ventricular remodeling may explain why abnormal electrical activation and
asynchronous electrical activation have major implications for the clinical
status of the patient. Several studies have shown that morbidity and mortality are higher in patients with long-term AV apex pacing than in those with
atrial pacing [30, 31]. In patients with sinus-node disease and good ventricular function, the risk for development of heart failure was significantly high
after more than 7 years in a comparison of atrial pacing and right ventricular pacing [32]. In a similar population, the risk of hospitalization for heart
failure within 3 years increased with the percentage of time the patients
underwent pacing at the right ventricular apex [33]. The development of
heart failure and atrial fibrillation was more sensitive to the percentage of
pacing than to the pacing mode (single- or dual-chamber pacing). In
patients who received an implantable cardioverter-defibrillator (ICD), the
298
Milos Taborsky
incidence of heart failure was higher within a year in patients paced at VVI
70 bpm rather than in backup mode [34].
Experimental proof of the negative effect of left bundle branch block
(LBBB) on hemodynamics has come from studies in an animal model of
LBBB [35, 36]. The negative effect of LBBB on left ventricular pump function
was shown in several studies [3739]. Therefore, it appears that right ventricular apex pacing and LBBB are conditions that increase the risk of heart failure and cardiac death, especially in patients with already compromised function. For this reason, efforts to either prevent right ventricular apex pacing
or correct LBBB are rapidly growing. With our knowledge of electrical
impulse conduction (electroanatomical mapping and other techniques), it
becomes obvious that the best solution may depend on whether the heart
has normal or disturbed intrinsic conduction within the ventricles.
Long-term epidemiological studies determining cardiovascular morbidity have shown that LBBB always carries a poor prognosis. In a 29-year follow-up study of 3,983 pilots, the morbidity and cardiovascular mortality rate
among those showing signs of LBBB was 17.2%, and the most common clinical event observed was sudden death without any previous symptoms (17%).
These percentages are ten times higher than those in subjects without LBBB
[40]. In the Framingham Study, cumulative cardiovascular mortality over 10
years was approximately five times higher in patients with LBBB than in
those without LBBB [41].
The Role of Modern Physiological Sensors in Pacing Hemodynamics

The role of hemodynamic sensors is to assess the inotropic status of the
heart and adapt the pacing rate to the contractility and exercise level. Most
of the hemodynamic sensors available in implantable pacemakers are sensitive to different expressions of the strength of cardiac contraction, which
depends in turn on myocardial contractility (controlled by the autonomic
nervous system) and preload (independent of the autonomic nervous system), according to Starlings law [42]. Therefore, any hemodynamic parameter affected by the cardiac contraction strength can reliably reflect the input
of the autonomic nervous system to the heart only if the preload is assessed
and accounted for.
The issue has been addressed by a new sensing system based on transvalvular impedance (TVI), which is the impedance recorded between the
right atrium and right ventricle. TVI reflects the hemodynamic changes that
occur during the cardiac cycle, the minimum TVI being associated with the
299
maximum diastolic volume and the maximum TVI with the minimum systolic volume. In addition, TVI fluctuations are observed only in the presence
of ventricular ejection [43]. The signal is missing whenever the volume does
not change, as in the case of capture loss. Assuming an inverse relationship
between TVI and ventricular volume, the signal can provide information on
relative changes in end-diastolic volume, end-systolic volume, stroke volume,
and ejection fraction.
Since changes in stroke volume and end-diastolic volume are monitored,
the inotropic index can be derived from the relationship between the two
parameters, a classic way to describe contractility while accounting for the
effect of preload on pump function. Indeed, the TVI inotropic index differs
from the one obtained from the ratio of the current stroke volume, corrected
for preload changes with respect to basal conditions, and basal stroke volume. The product of the inotropic index times the resting rate and a programmable gain factor, added to the basic rate, defines the TVI-indicated
pacing rate.
In addition to the standard pacing function, the pacemaker records TVI,
determines the minimum and maximum value in each cycle, checks the data
to confirm or deny ejection, averages the results over a programmable number of cycles, and calculates inotropic index and TVI, which after a smoothing process becomes the pacing rate applied by the device. Tests were performed under overdrive atrial pacing to exclude the possibility that the
increase in the inotropic index could be dependent on a previous increase in
cardiac rate. On the contrary, even if the sinus rate was suppressed, isoproterenol administration induced a clear-cut increase in inotropic index, TVI,
and pacing rate. Moreover, an increase in cardiac rate independent of the
adrenergic input, induced by reprogramming the pacemaker basic rate, had
no effect on the inotropic index, demonstrating that the TVI rate-responsive
system is not affected by positive feedback. Another important application of
the TVI sensor is the confirmation of systolic ejection after ventricular sensing or pacing. The algorithm compares the maximums TVI detected in a
rate-adapted systolic window with a reference value derived from the average end-diastolic TVI and end-systolic TVI recorded in eight previous
cycles. If the reference is reached or exceeded, ejection is confirmed; otherwise it is denied and the stimulator activates an alarm modality [44].
TVI could be an effective tool for pacing rate auto-regulation based upon
changes in cardiac inotropic state; it is adapted according to adrenergic
input, either in the presence or absence of int r insic rate changes.
Furthermore, a TVI rate-responsive system is free of positive feedback
effects [45]. Therefore, pacing algorithms based on TVI may offer a safe and
Milos Taborsky
300
reliable alternative of rate-responsive pacing reflecting physiological hemodynamics in patients with both normal and depressed left ventricular function.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Center S, Nathan D, Wu CY et al (1964) Two years of clinical experience with the

synchronous pacemaker. J Thorac Cardiovasc Surg 48:513526
Lagergren H, Johansson L, Karlof J et al (1966) Atrial-triggered pacemaking
without thoracotomy. Acta Chir Scand 132: 678695
Karlf I (1975) Hemodynamics effect of atrial triggered versus fixed rate pacing at
rest and during exrecise in complete heart block. Acta Med Scand 197:195210
Kruse I, Bevegrd S, Ovenfors CO et al (1982) A comparison of acute and longterm hemodynamics effects of ventricular inhibited and atrial synchronous
pacing. Circulation 65:846855
Kristensson B, Arnman K, Ryden L et al (1985) The hemodynamic importance of
atrioventricular synchrony and rate increase at rest and during exercise. Eur Heart
J 6:773778
Perhsson SK (1983) Influence of heart rate and atrioventricular synchrony on
maximal work tolerance in patients treated with artificial pacemakers. Acta Med
Scand 214:311315
Benchimol A, Li YB, Simone EG (1964) Cardiovascular dynamics in complete heart
block at various heart rates. Circulation 30:542543
Sowton E (1964) Hemodynamic studies in patients with artificial pacemakers. Br
Heart 26:737746
Videem JS, Juany SK, Bazgan ID et al (1986) Hemodynamic comparison of ventricular pacing, atrioventricular sequential pacing and atrial synchronous ventricular
pacing using radionuclide ventriculography. Am J Cardiol 57:13051308
Norlander R, Pehrsson SK, Astrom H et al (1987) Myocardial demands of atrialtriggered versus fixed-rate ventricular pacing in patients with complete heart
block. Pacing Clin Electrophysiol 10:11541159
Leclercq C, Gras D, Le Helloco A et al (1995) Hemodynamic importance of preserving the normal sequence of ventricular activation in permanent cardiac pacing.
Am Heart J 129:11331141
Rowe GG, Stenlund RR, Thomsen JH et al (1969) Coronary and systemic hemodynamic effects of cardiac pacing in man with complete heart block. Circulation
40:839845
Brockman SK (1965) Cardiodynamics of complete heart block. Am J Cardiol
16:7283
Vos MA, de Groot SH, Verduyn SC et al (1998) Enhanced susceptibility for acquired
torsade de pointes arrhythmias in the dog with chronic, complete atrio-ventricular
block is related to cardiac hypertrophy and electrical remodeling. Circulation
98:11251235
Brockman SK, Stoney WS (1969) Congestive and heart failure and cardiac output
in heart block and during pacing. Ann NY Acad Sci 167:534545
Janousek J, Tomek V, Chaloupecky V et al (2004) Dilated cardiomyopathy associated with dual-chamber pacing in infants: improvement through either left ventricular cardiac resynchronization or programming the pacemaker off allowing
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
301
intrinsic normal conduction. J Cardiovasc Electrophysiol 15:470474

Tantengco MV, Thomas RL, Karpawich PP (2001) Left ventricular dysfunction after
long-term right ventricular apical pacing in the young. J Am Coll Cardiol
37:20932100
Thambo JB, Bordachar P, Garrigue S et al (2004) Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular
apical pacing. Circulation 110:37663772
Peschar M, March AM,Verbenek X et al (2004) Site of right ventricular pacing
determines left ventricular remodeling in patients with atrio-ventricular block.
Heart Rhythm 1:245
Faerestrand S, Ohm O-J (1985) A time-related study of the hemodynamic benefit
of atrioventricular synchronous pacing evaluated by Doppler echocardiography.
Bowman AW, Kovacs SJ (2004) Left atrial conduction volume is generated by deviation from the constant volume state of the left heart: a combined MRI-echocardiographic study. Am J Physiol Heart Circ 286:H2416-H2424
Mehta D, Gilmour S, Ward DE et al (1989) Optimal atrioventricular delay at rest
and during exercise in patients with dual chamber pacemakers: a non-invasive
assessment by continuous wave Doppler. Br Heart J 61:161166
Ritter P, Dib JC, Mahaut V et al (1995) New method for determining the optimal
atrio-ventricular delay in patients paced in DDD mode for complete atrioventricular block. Pacing Clin Electrophysiol 18(Part II):237
Sutton R (1992)The atrioventricular interval: what considerations influence its programming? Eur Cardiac Pacing Electrophysiol 3:169
Dupot WD, Plummer WD Jr (1998) Power and sample size calculations for studies
involving linear regression. Control Clin Trials 19:589601
Bedotto JB, Grayburn PA, Black WH et al (1990) Alterations in left ventricular
relaxation during atrioventricular pacing in humans. J Am Coll Cardiol 15:658664
Tanabe A, Mohri T, Ohga M et al (1990) The effects of pacing-induced left bundle
branch block on left ventricular systolic and diastolic performances. Jpn Heart J
31:309317
Wiggers CJ (1925) The muscular reactions of the mammalian ventricles to artificial surface stimuli. Am J Physiol 73:346378
Kosovsky BD, Scherlag BJ, Samaro AN (1968) Re-evaluation of the atrial contribution to ventricular function. Am J Cardiol 21:518524
Nielsen JC, Andersen HR, Thomsen PEB et al (1998) Heart failure and echocardiographic changes during long-term follow-up of patients with sick-sinus syndrome
randomized to single-chamber atrial or ventricular pacing. Circulation 97:987995
Santini M, Alexidou G, Ansalone G et al (1990) Relation of prognosis in sick sinus
syndrome to age, conduction defects and modes of permanent cardiac pacing. Am
J Cardiol 65:729735
Andersen HR, Nielsen JC, Thomsen PEB et al (1997) Long-term follow-up of
patients from a randomised trial of atrial versus ventricular pacing for sick sinus
Sweeny MO, Hellkamp AS, Ellenbogen KA et al (2003) Adverse effect of ventricular
pacing on heart failure and atrial fibrillation among patients with normal baseline
QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
Wilkoff BL, Cook JR, Epstein AE et al (2002) Dual-chamber pacing or ventricular
back-up pacing in patients with an implantable defibrillator. JAMA 288:31153123
302
Milos Taborsky
35.
Verbenek X, Vernooy K, Pesar M et al (2002) Quantification of interventricular synchrony during LBBB and ventricular pacing. Am J Physiol 283:H1370-H1378
Liu L, Tockman B, Girouard S et al (2002) Left ventricular resynchronization therapy in a canine model of left bundle branch block. Am J Physiol 282:H2238-H2244
Hirzel HO, Senn M, Nuesch K et al (1984) Thalium-201 scintigraphy in complete
left bundle branch block. Am J Cardiol 53:764769
Kaas DA, Chen CH, Curry C et al (1999) Improved left ventricular mechanics from
acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99:15671573
Dekker AL, Phelps B, Dijkam A et al (2004) Epicardial left ventricular lead placement for cardiac resynchronization therapy: optimal pace site selection with pressure-volume loops. J Thorac Cardiovasc Surg 27:16421647
Rabkin SW, Mathewson FAL, Tate RB (1980) Natural history of left bundle-branch
block. Br Heart 43:164169
Schneider JF, Thomas HE Jr, Sorlie P et al (1981) Comparative features of newly
acquired left and right bundle branch block in general population. The
Framingham Study. Am J Cardiol 47:931940
Khoury D, McAlister H, Wilkoff B et al (1989) Continuous right ventricular volume
assessment by catheter measurement of impedance for antitachycardia system
control. Pacing Clin Electrophysiol 12:19181926
Chirife R, Ortega DF, Salazar A (1993) Feasibility of measuring relative right ventricular volumes and ejection fraction with implantable rhythm control device.
Gasparini M, Denis A, Mantica M et al (2001) Hemodynamic sensors: what clinical
value do they have in heart failure. In: Raviele A (ed) Cardiac arrhythmias.
Springer Verlag Italia, Milan, pp 576585
Artur W, Kaye GC (2001) Clinical use of intracardiac impedance: current applications and future perspectives. Pacing Clin Electrophysiol 24(Pt I):500506
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
Hemodynamic Assessment with an Implanted Pacing Device

MARIA GRAZIA BONGIORNI1, EZIO SOLDATI1, GIUSEPPE ARENA1, GIULIO ZUCCHELLI1,
ANDREA DI CORI1, ALBERTO BARBETTA2, FRANCO DI GREGORIO2
Introduction
Continuous hemodynamic monitoring could be highly valuable in the treatment of cardiac diseases characterized by a deterioration of pump function,
allowing detection of the early signs of heart failure and thus prompt adaptation of the pharmacological regimen to the patients changing clinical condition [1]. Therefore, specific implantable devices have been developed to record
right ventricular blood pressure and dP/dt in the outflow tract, in order to
assess diastolic pulmonary pressure [2]. Indications of the pressure sensor
were shown to be correlated with invasive hemodynamic measurements and
anticipated the clinical course of the disease, predicting and potentially reducing the need for hospitalization [24]. However, an increasing proportion of
heart-failure patients have already received implantable rhythm-control
devices (pacemakers and defibrillators), which are often designed to provide
cardiac resynchronization therapy. In such patients, the same hardware needed for cardiac stimulation could be used to also assess the hemodynamic state.
For instance, a system intended to reveal fluid accumulation in the lung based
on thoracic impedance measurements by an implanted biventricular defibrillator was recently introduced in the clinical setting. Impedance is assessed
between the defibrillation coil placed in the right ventricle and the device case
in the left pectoral region. An inverse correlation with both pulmonary capillary wedge pressure and net change in body fluids during hospital care was
reported [5]. The decrease in intrathoracic impedance started approximately 2
weeks before the manifestation of pulmonary congestion symptoms requiring
hospitalization.
1Cardiothoracic Department, University of Pisa, Pisa; 2Clinical Research Unit, Medico

Spa, Rubano (PD), Italy
304
Maria Grazia Bongiorni et al.
Cardiac Impedance as Volume Sensor

Similar to thoracic impedance, cardiac impedance can be measured with the
same electrodes used for pacing or defibrillation. Different configurations
have been proposed, including unipolar impedance (derived between the tip
ventricular electrode and the stimulator can), bipolar ventricular impedance
(derived between the tip and ring ventricular electrodes of standard bipolar
pacing leads, or between two ring electrodes of a special tripolar lead, while
the testing current is applied between the tip electrode and the stimulator
can), transvalvular impedance (derived between the atrial ring and either the
tip or the ring ventricular electrode in dual-chamber pacing systems). In all
recording configurations, impedance changes during the cardiac cycle are
assumed to reflect the mechanical activity of the ventricle [6]. However, the
unipolar impedance waveform has not been related to the specific aspects of
cardiac hemodynamics; the only claim being that any waveform change with
respect to a reference signal can be taken as an indication of increased
myocardial contractility and applied to drive rate-responsive pacing in a
closed-loop system [7, 8]. In contrast, bipolar ventricular and transvalvular
recording configurations provide impedance waveforms of predictable
shape, supporting the hypothesis of an inverse relationship with ventricular
volume [9, 10]. In particular, the transvalvular impedance (TVI) has drawn
increasing attention due to its remarkably high signal stability and resolution. It is generally lower in diastole and higher in systole, increasing after an
R wave or a ventricular pacing spike throughout the QT interval to reach the
maximum peak right at the end of the T wave, when the ventricular volume
is at a minimum. TVI then decreases back to the diastolic level in two steps,
related to passive and active ventricular filling [11]. Since the TVI signal is
not high-pass filtered, changes in absolute end-diastolic and end-systolic
values (EDTVI and ESTVI, respectively) can be detected. EDTVI decreases
when the ventricular filling time is prolonged (Fig. 1) and increases when it
is shortened (for instance, in the event of an ectopic beat). Moreover, EDTVI
increases under conditions of reduced venous return (e.g., with the patient
in the standing position) and decreases when venous return is known to be
increased (e.g., with the patient in the supine position or during skeletal
muscle activity). Therefore, EDTVI can be proposed as a marker of beat-bybeat preload modifications and, possibly, of long-term changes in ventricular
volume as well [12]. In addition, TVI excursion from diastole to systole (i.e.,
the difference between absolute ESTVI and EDTVI) can be correlated with
the stroke volume (SV). Indeed, when the SV increases or decreases, the TVI
waveform peakpeak amplitude is correspondingly increased or decreased
305
Fig. 1. From top to bottom: transvalvular impedance (TVI) recorded in atrial ringventricular ring configuration, right ventricular and atrial electrograms (VEGM and
AEGM, respectively), surface ECG, blood pressure in the femoral artery (femoral P), and
its time derivative (femoral dP/dt). The recording was obtained with an external device
during the implantation of a biventricular stimulator in a patient with dilated cardiomyopathy and left bundle branch block (LBBB). The left ventricle is paced in VDD.
TVI recorded in the right heart shows the usual features, increasing in the QT interval
and decreasing after the end of the T wave (passive filling). A clear-cut change in slope
is observed after P-wave detection and indicates active filling. After two regular cycles, a
PVC (premature ventricular contraction) (arrow) fails to produce a pressure pulse, suggesting that no ejection takes place. Consistently, TVI fluctuation is virtually abolished.
The next cycle shows a long filling time and a large stroke volume (as suggested by high
pulse pressure). The corresponding TVI fluctuation is also increased, mainly due to a
decrease in the minimum diastolic value (a preload indicator). The following cycle
shows a small pressure pulse, probably due to a weak contraction. At the same time, TVI
fluctuation is depressed and a reduction in the end-systolic value (a contractility indicator) is noticed.
(Fig. 1). If SV changes are induced by changes in preload, according to

Starlings law, peakpeak TVI modifications result from changes in EDTVI
only, while ESTVI remains constant. In contrast, when SV changes are due to
stimulation or depression of myocardial contractility, peakpeak TVI modifications are associated with changes in ESTVI (Fig. 2). The relationship
between the difference in peakpeak TVI and EDTVI with respect to reference conditions (putative SV and preload indicators, respectively) reflects
the inotropic state and has proven effective in the assessment of acute
changes in adrenergic tone [13].
306
Fig. 2. TVI recorded in atrial ringventricular tip configuration (upper tracing) and surface ECG (lower tracing) before (left panel) and during a stress test on an ergometric
bicycle (right panel); VDD pacing. Physical exercise induces an increase in end-systolic
TVI, reflecting increased myocardial contractility, and a decrease in end-diastolic TVI,
due to the increased venous return
Hemodynamic Monitoring with TVI

The feasibility of deriving complex information on ventricular volumes and
related hemodynamic parameters, such as preload, SV, and ejection fraction,
by recording absolute values of cardiac impedance in telediastole and
telesystole was originally proposed by Chirife and coworkers [9]. In their
model, which was tested in vitro, volume was proportional to a negative
power of the measured impedance. The actual quantitative relationship
between volume and impedance in the beating heart has so far only been
determined with multipolar catheters used in acute hemodynamic studies
[14]. However, a new family of pacemakers equipped with the TVI sensor is
now available in the clinical setting (Sophs models 151 and 155, Medico,
Padua, Italy) and could allow evaluation of the reliability of impedance
recording by conventional pacing leads in the assessment of acute and
chronic changes in ventricular volume. Studies have already been undertaken to compare TVI indications and echocardiographic evidence during
hemodynamic challenges based on variation in pacing mode, stimulation
rate, and AV delay. In addition, patients will be followed-up in the long term
to verify whether TVI can reveal or predict significant changes in clinical
condition and hemodynamic performance. Promising results have recently
been reported with bipolar impedance measurements in a 1-year follow-up
of heart-failure patients. Pacing impedance changes in the right ventricular
apex showed positive and negative correlation, respectively, with changes in
307
left-ventricular ejection fraction (LVEF) and NYHA functional class [15].

In conclusion, theoretical considerations and acute experimental evidence support the use of TVI for continuous hemodynamic monitoring of
pacemaker patients. The sensing system is based on the same hardware
implanted to provide cardiac stimulation, with no need of dedicated pacing
leads. Hemodynamic monitoring is important in heart-failure patients and
could suggest timely adaptations in the pharmacological treatment or in the
programming configuration of a cardiac resynchronization device. However,
this new option may also be valuable in the pacing therapy of rhythm disorders, especially if a high prevalence of ventricular pacing is expected, as
early warning could be obtained in case of hemodynamic deterioration [16,
17].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Brinker JA (2005) Implantable hemodynamic monitors: success in the pursuit of

failure? Pacing Clin Electrophysiol 28:743746
Magalsky A, Adamson P, Gadler F et al (2002) Continuous ambulatory right heart
pressure measurements with an implantable hemodynamic monitor: a multicenter
12-month follow-up study of patients with chronic heart failure. J Card Fail 8:6370
Braunschveig F, Linde C, Eriksson MJ et al (2002) Continuous haemodynamic
monitoring during withdrawal of diuretics in patients with congestive heart failure. Eur Heart J 23:5969
Adamson PB, Magalsky A, Braunschveig F et al (2003) Ongoing right ventricular
hemodynamics in heart failure: clinical value of measurements derived from an
implantable monitoring system. J Am Coll Cardiol 41:565571
Yu CM, Wang L, Chau E (2005) Intrathoracic impedance monitoring in patients
with heart failure. Circulation 112:841848
Arthur W, Kaye GC (2001) Clinical use of intracardiac impedance: Current applications and future perspectives. Pacing Clin Electrophysiol 24(Pt 1):500506
Osswald S, Cron T, Gradel C et al (2000) Closed-loop stimulation using intracardiac
impedance as a sensor principle: correlation of right ventricular dP/dt max and
intracardiac impedance during dobutamine stress test. Pacing Clin Electrophysiol
23:15021508
Griesbach L, Gestrich B, Wojciechowski D et al (2003) Clinical performance of
automatic closed-loop stimulation systems. Pacing Clin Electrophysiol 26(Pt
1):14321437
Chirife R, Ortega DF, Salazar A (1993) Feasibility of measuring relative right ventricular volumes and ejection fraction with implantable rhythm control devices.
Chirife R, Tentori MC, Mazzetti H, Dasso D (2001) Hemodynamic sensors: are they
all the same? In: Raviele A (ed) Cardiac arrhythmias 2001. Springer, Milan, pp
566575
Di Gregorio F, Morra A, Finesso M, Bongiorni MG (1996) Transvalvular impedance
(TVI) recording under electrical and pharmacological cardiac stimulation. Pacing
Clin Electrophysiol 19(Pt 2):16891693
308
12.
Bongiorni MG, Soldati E, Arena G et al (2005) Haemodynamic assessment by transvalvular impedance recording. In: Gulizia MM (ed) Emerging pathologies in cardiology. Springer, Milan, pp 323330
Gasparini G, Curnis A, Gulizia M et al (2005) Rate-responsive pacing regulated by
cardiac haemodynamics. Europace 7:234241
Applegate RJ, Cheng CP, Little WC (1990) Simultaneous conductance catheter and
dimension assessment of left ventricular volume in the intact animal. Circulation
81:638648
Stambler BS, Ellenbogen KA, Liu Z et al (2005) Serial changes in right ventricular
apical pacing lead impedance predict changes in left ventricular ejection fraction
and functional class in heart failure patients. Pacing Clin Electrophysiol 28:S50-S53
Sweeney MO, Hellkamp AS, Ellenbogen KA et al (2003) Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 107:29322937
atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 42:614623
13.
14.
15.
16.
17.
Hemodynamic Optimization of Pacing Configuration in

Bradyarrhythmias
GIANFILIPPO NERI1, ROLANDO ZAMPROGNO1, DIEGO VACCARI1, GIULIANO MASARO1,
ALBERTO BARBETTA2, FRANCO DI GREGORIO2
Introduction
The electric treatment of cardiac bradyarrhythmias by an implanted pacemaker is mandatory whenever the reduction in ventricular rate results in a
functional impairment affecting health, safety, and quality of life [1].
Nevertheless, it is well-known that electrical stimulation of the heart may
have disadvantages and drawbacks, which have been progressively identified
and brought to attention as a consequence of increasing clinical experience
and medical knowledge. Parallel improvements in pacing technology have
allowed many essential issues to be addressed and solved, such as the prevention of competitive pacing and synchronization of atrial and ventricular
stimulation to maintain physiological sequential activation. In the last
decade, the increasing use of biventricular pacing in the therapy of heart
failure has underlined the relevance of interventricular and intraventricular
synchronization for effective pump function. However, conventional singlesite pacing in the right ventricular apex (RVA) necessarily implies myocardial conduction of the evoked action potential, resulting in deep modification of the ventricular activation pattern and delayed contraction of the left
ventricle (LV), as indicated by the altered axis and increased duration of the
QRS complex and confirmed by echocardiographic observation. The shortand long-term impacts of RVA pacing on cardiac hemodynamics have therefore become major concerns in the care of patients presenting with bradycardia [2].
1Cardiology Department, Carretta Hospital, Montebelluna (TV); 2Clinical Research

Unit, Medico Spa, Rubano (PD), Italy
310
Gianfilippo Neri et al.
Hemodynamic Implications of Ventricular Pacing

Ventricular dyssynchrony induced by RVA pacing can increase myocardial
stress and mitral regurgitation and affect coronary perfusion, thus leading to
long-term cardiac remodeling, atrial enlargement, and an increased incidence of atrial fibrillation and heart failure [27]. However these deleterious
effects are often associated with pre-existing conditions of ventricular function impairment [8]. Provided that baseline hemodynamics had been preserved at the time of implantation, the clinical consequences of ventricular
pacing were found to be negligible in a cohort of pacemaker patients affected by atrioventricular (AV) block and continuously paced along a 3-year follow-up [9, 10].
To keep as low as possible the incidence of ventricular pacing in patients
provided with intrinsic AV conduction, dedicated algorithms have been
designed, including AV delay hysteresis (a mechanism by which the programmed AV delay is prolonged by a defined interval as long as intrinsic AV
conduction is detected) and mode switch from AAI to DDD and back,
depending on the absence or presence of intrinsic R waves [11, 12]. Although
these systems have been shown to be effective in implantable cardioverter
defibrillators (ICD) as well as in the pacing therapy of patients with sick
sinus syndrome, they cannot be applied to the treatment of permanent AV
block, in which ventricular stimulation is required to avoid asystole or to
speed up AV conduction in order to improve ventricular filling, especially at
high cardiac rates. In these cases, the hemodynamic contraindications to
ventricular pacing can only be addressed by replacing the RVA with another
stimulation site, where lower pacing-induced ventricular desynchronization
is expected to occur. Promising results have been obtained by stimulating the
right ventricular outflow tract (RVOT), the interventricular septum or the
bundle of His [1316], and with left-ventricular and biventricular pacing [7,
17, 18]. However, all of these techniques are, at present, more difficult than
conventional RVA pacing and the risk of adverse events is higher. They are
therefore better applied in selected patients, in whom RVA pacing might
prove particularly detrimental.
At present, assessing whether RVA pacing is well-tolerated and what the
best-suited alternative pacing site may be in each individual patient is difficult and time-consuming, as the acute hemodynamic effects of electrical
stimulation should be evaluated by echocardiography or cardiac catheterization during either the implantation procedure or a previous electrophysiological study. This is virtually impossible in the actual clinical setting, where
information on ventricular mechanics would be of practical value only if it
was inexpensive and quickly obtained. Since implantable hemodynamic sen-
Hemodynamic Optimization of Pacing Configuration in Bradyarrhythmias
311
sors can be considered for this purpose, we have tested the application of
transvalvular electric impedance (TVI) in the detection of pacing-induced
ventricular desynchronization.
Tailoring the Pacing System with TVI

TVI is recorded between right atrium and ventricle with either tip or ring
conventional pacing electrodes and is claimed to reflect changes in right
ventricular volume. Indeed, TVI increases throughout ventricular systole
and decreases during passive and active ventricular filling. In addition, enddiastolic TVI was shown to increase under conditions of decreased preload,
while end-systolic TVI increased when myocardial contractility was
enhanced by adrenergic stimulation [1921]. We compared the TVI waveform properties under intrinsic AV conduction and RVA pacing in eight
patients affected by sick sinus syndrome, with or without AV block, and
implanted with the pacemaker Sophs 151 (Medico, Padova, Italy), a dualchamber rate-responsive device equipped with the TVI sensor. Immediately
after TVI recording by pacemaker telemetry, diastolic and systolic function
was assessed by two-dimensional and Doppler echocardiography under the
same pacing conditions (i.e., intrinsic conduction in sinus rhythm vs. atrium-driven RVA pacing with 80-ms AV delay). Interventricular and intraventricular desynchronization was expressed, respectively, as the delay between
the onset of pulmonary and aortic flow and between basal septum and LV
lateral-wall contraction, as detected by tissue Doppler imaging.
The average delay of aortic vs pulmonary flow (0.9 24 ms with intrinsic
AV conduction) showed a non-significant acute increase after transition to
RVA pacing (15 21 ms). Similarly, a non-significant increase in average
intraventricular delay was observed (from 7 18 to 20 22 ms). However,
the sensitivity to RVA pacing differed among patients and evidence of ventricular desynchronization was clearly obtained in some of them (Fig. 1).
Stroke volume (assessed as velocity-time integral of LVOT flow) was significantly decreased from 127 40 to 118 38 ml (p < 0.05, paired Students t
test), but the individual reduction was not correlated with either the interventricular or intraventricular desynchronization level.
The TVI waveform recorded during intrinsic AV conduction generally
showed the expected physiological time-course, characterized by a progressive
increase in the ejection phase with the maximum peak occurring within the Twave decay (Figs. 23a). RVA pacing entailed morphological modifications in
the TVI waveform, including a faster rate of rise and the presence of more
peaks in the Q-T interval. These changes were more pronounced in patients
312
Fig. 1. Time interval from the onset of pulmonary flow (Pop) to the onset of aortic flow
(Aop), during intrinsic atrioventricular (AV) conduction (open bars) or atrium-driven
pacing in the right ventricular apex (RVA), with 80-ms AV delay (full bars). Each case is
identified by the serial number of the implanted pacemaker. The impact of pacing on
interventricular synchronization differed in different patients
Fig. 2a, b. From top to bottom: pacemaker event markers (As, atrial sensing; Vs, ventricular sensing; Vp, ventricular pacing), TVI waveform, surface electrocardiogram, recorded
during intrinsic AV conduction (a) and VDD pacing in RVA with 80 ms AV delay (b), in
the patient implanted with Sophs 151 number 157. In this case, the interventricular
desynchronization induced by RVA pacing was negligible (Fig. 1). TVI was recorded in
atrial ringventricular ring configuration, with a sampling current of 20 A. The waveform showed a physiological time-course after both ventricular sensing and pacing
313
Fig. 3a, b. Patient implanted with Sophs 151 number 159, in whom a maximum delay in
left ventricular contraction induced by RVA pacing was observed (Fig. 1). The patient
presented with trifascicular block and long PR; therefore, the pacemaker was temporarily programmed in VVI at 40 bpm to inhibit ventricular stimulation (a). TVI was
recorded in atrial ringventricular tip configuration, with a sampling current of 20 A.
The waveform showed a physiological time-course after ventricular sensing, but was
heavily modified by RVA pacing (b)
showing echocardiographic evidence of interventricular desynchronization

(Figs. 23b). The peak-peak amplitude of TVI fluctuation from diastole to systole was decreased by 14 13% (p < 0.05, paired Students t test) and the individual reduction was linearly correlated with the delay of aortic vs pulmonary
flow observed during atrium-driven RVA stimulation (r = 0.68).
Conclusions
High interpatient variability characterizes the acute effects of RVA pacing on
cardiac hemodynamics. Changes in the TVI waveform associated with the
transition from intrinsic conduction to ventricular stimulation can reflect
pacing-induced alterations in ventricular mechanics and help to quickly
identify patients who might require an alternative stimulation site or the
upgrading to biventricular pacing during the implantation procedure, when
echocardiographic analysis is not practicable. In chronic conditions, the TVI
sensor available in Sophs pacemakers may allow permanent monitoring of
the patients hemodynamic efficiency and detect early signs of a possible
deterioration, which could be timely counteracted by correcting the drug
regimen, pacemaker programming, or pacing system configuration.
314
References
1.
2.
3.
4.
5.
6.
7.
8.
10.
11.
12.
13.
14.
15.
Lunati M, Bongiorni MG, Boriani G et al (2005) Linee Guida AIAC 2006 allimpianto di pacemaker, dispositivi per la resincronizzazione cardiaca (CRT) e defibrillatori automatici impiantabili (ICD). Giornale Italiano di Aritmologia e
Cardiostimolazione 8(4)
Gillis AM, Chung MK (2005) Pacing the right ventricle: to pace or not to pace?
Heart Rhythm 2:201206
Tse HF, Lau CP (1997) Long-term effect of right ventricular pacing on myocardial
perfusion and function. J Am Coll Cardiol 29:744749
Nunez A, Alberca MT, Cosio FG et al (2002) Severe mitral regurgitation with right
ventricular pacing, successfully treated with left ventricular pacing. Pacing Clin
Sweeney MO, Hellkamp AS, Ellenbogen KA et al (2003) Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 107:29322937
atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 42:614623
Simantirakis EN, Vardakis KE, Kochiadakis GE et al (2004) Left ventricular mechanics during right ventricular apical or left ventricular-based pacing in patients
with chronic atrial fibrillation after atrioventricular junction ablation. J Am Coll
Cardiol 43:10131018
Lieberman R, Padeletti L, Eastman W et al (2005) Greater sensitivity of cardiac
function to ventricular pacing lead location in patients with vs without left ventricular dysfunction. J Am Coll Cardiol 45:100A (abs)
Moro E, Marcon C, Degan P et al (2006) Conventional dual chamber apical pacing
in patients with advanced atrio-ventricular block and preserved basal left ventricular function: a prospective long-term study. Giornale Italiano di Aritmologia e
Cardiostimolazione 9(4):40 (abs)
Moro E, Marcon C, Sciarra L et al (2006) Long term evaluation of conventional dual
chamber pacing in patients with advanced atrio-ventricular block and different
hemody namic configurations. Giornale Italiano di Aritmologia e
Cardiostimolazione 9(4):64 (abs)
Melzer C, Sowelam S, Sheldon TJ et al (2005) Reduction of right ventricular pacing
in patients with sinus node dysfunction using an enhanced search AV algorithm.
Sweeney MO, Ellenbogen KA, Casavant D et al (2005) Multicenter, prospective, randomized safety and efficacy study of a new atrial-based managed ventricular
pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 16:811847
de Cock CC, Meyer A, Kamp O, Visser CA (1998) Hemodynamic benefits of right
ventricular outflow tract pacing: comparison with right ventricular apex pacing.
Mera F, DeLurgio DB, Patterson RE et al (1999) A comparison of ventricular function during high right ventricular septal and apical pacing after His-bundle ablation for refractory atrial fibrillation. Pacing Clin Electrophysiol 22:12341239
Tse HF, Yu C, Wong KK et al (2002) Functional abnormalities in patients with permanent right ventricular pacing: the effect of sites of electrical stimulation. J Am

16.
17.
18.
19.
20.
21.
315
Deshmukh P, Casavant DA, Romanyshyn M, Anderson K (2000) Permanent, direct

His-bundle pacing: a novel approach to cardiac pacing in patients with normal
His-Purkinje activation. Circulation 101:869877
Doshi RN, Daoud EG, Fellows C et al (2005) Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc
Hay I, Melenovsky V, Fetics BJ et al (2004) Short-term effects of right-left heart
sequential cardiac resynchronization in patients with heart failure, chronic atrial
fibrillation, and atrioventricular nodal block. Circulation 110:34043410
Applications of TVI Sensing in Cardiac Stimulation

ERALDO OCCHETTA1, MIRIAM BORTNIK1, FRANCO DI GREGORIO2, ALBERTO BARBETTA2,
PAOLO MARINO1
Introduction
Permanent cardiac stimulation has become increasingly complex, and modern pacing devices are now equipped with a wide set of functions aimed at
reproducing as closely as possible the physiological control of cardiac
rhythm, including dual-chamber and three-chamber architecture, sensordriven rate-response, careful management, and rate-adaptation of the atrioventricular delay. Special algorithms have been developed to allow pacing
and sensing autoregulation, self-limitation of unnecessary ventricular stimulation, pacing-mode switch in the event of supraventricular tachyarrhythmias, overdrive pacing aimed at preventing atrial fibrillation, etc. However,
in spite of the improved effectiveness in sensing and processing cardiac
electric signals, standard pacemakers do not take into account the associated mechanical activity, which is the final expression of ventricular function.
So far, a few special models have been equipped with hemodynamic sensors,
which are used to assess changes in myocardial contractility and accordingly regulate rate-responsive pacing [14]. However, no attempt has been
made to acquire information on the hearts hemodynamic activity on a
beat-by-beat basis.
The Transvalvular Impedance Sensor

A new hemodynamic sensor has been brought to the attention of the medical
community in recent years: the transvalvular impedance (TVI). TVI is the
1 Division
of Cardiology, School of Medicine, Universit degli Studi del Piemonte

Orientale, Novara; 2Clinical Research Unit, Medico Spa, Rubano (PD), Italy
318
Eraldo Occhetta, Miriam Bortnik, Franco Di Gregorio, Alberto Barbetta, Paolo Marino
electrical impedance derived between the right atrium and right ventricle
with standard pacing electrodes. The measurement shows regular periodic
fluctuation along the cardiac cycle, increasing in the QT period (systole) and
decreasing in diastole and after a P wave [5, 6]. The signal time-course thus
suggests an inverse relationship with ventricular volume [79], which was
confirmed by TVI recording in experimental animal models. When right
ventricular systolic ejection was prevented by reversible clamping of the pulmonary artery, cyclic TVI fluctuation was virtually abolished, notwithstanding the presence of ventricular electrical activity and isometric myocardial
contraction. Recording in human patients has consistently showed that TVI
rises after a spontaneous R wave or a ventricular pacing spike only if an
effective ejection occurs, as demonstrated by the detection of a pressure
pulse signal [6]. Due to its stability and remarkably high signal-to-noise
ratio, TVI can be measured without the need of high-pass filtering, so that
absolute impedance values are recorded (DC coupling). This way, the minimum and maximum TVI detected in a cardiac cycle can reflect, respectively,
the level of diastolic ventricular filling and the residual systolic volume.
Indeed, end-diastolic TVI increases under conditions of decreased preload,
and end-systolic TVI increases if myocardial contractility is enhanced
[911].
Ejection Surveillance with TVI

Since TVI fluctuation is specifically related to systolic ejection, this sensor
has been proposed as a tool for the hemodynamic check of pacing effectiveness by a pacing device [5, 10]. As long as ventricular capture is achieved,
each pacing pulse entails a properly timed increase in TVI. By contrast, in
case of capture failure, TVI remains at baseline or even continues to decrease
as a result of prolonged ventricular filling (Fig. 1). If the TVI response to
ventricular pacing is missing, the stimulator should automatically react by
increasing the energy of the next pulse to be released. This algorithm was
initially tested by an external pacemaker provided with the TVI sensor. In
order to identify a proper discriminant of true TVI responses from background noise, the signal amplitude detected within an appropriate time-window after each pacing spike was compared with the average amplitude measured in eight previous paced cycles. The lower limit of TVI relative variat ion in the presence of an evoked response was found to be 65%.
Accordingly, a cut-off level of 50% was proposed to maximize both sensitivity and specificity in capture-loss recognition [12].
319
Fig. 1. From top to bottom: transvalvular impedance (TVI), ventricular electrogram

(VEGM), atrial electrogram (AEGM), and surface ECG, recorded with an external device
during pacemaker implantation. TVI is derived between the atrial and ventricular ring
electrodes. Progressive pulse amplitude reduction during VVI pacing at 90 bpm.
Effective stimulation resulted in P wave occurrence in the QT interval and atrial contraction with closed atrioventricular valves. The last spike (spk) failed to capture the
ventricle and did not entail an increase in TVI. By contrast, diastolic TVI continued to
decrease as the passive filling time was prolonged and showed a further steep reduction
during active filling. Thereafter, the fluctuation of TVI kept pace with the intrinsic ventricular activation (R waves)
An ejection check at every heartbeat is valuable after either ventricular

pacing or sensing. In the former case, it can be applied to restore effective
stimulation by increasing pulse energy; in the latter, it may represent the
ultimate solution to prevent false inhibition of ventricular pacing. Indeed,
any sensing event that is not followed by a TVI increase can be regarded as
putative electromagnetic interference (EMI) from the external environment
(portable phones, antitheft devices, metal detectors, etc.) or from extracardiac physiological sources (myopotentials). Alternatively, it is possible that a
true ventricular depolarization does not entail systolic ejection, as the developed contraction strength is too small to overcome aortic or pulmonary
pressure. This is more likely to occur in the presence of early premature ven-
320
tricular contractions. Therefore, an algorithm designed to protect pacemaker-dependent patients from the risk of oversensing should be triggered by a
repetitive lack of ejection in a series of cycles and not by an isolated event,
especially if ventricular sensing is not sequential to previous atrial activity.
An ejection check based upon the TVI sensor is available in the
implantable pacemakers of the Sophs family (Medico, Padova, Italy), either
as diagnostic feature (Sophs model 151) or for the actual regulation of pacing function (Sophs model 155). The algorithm can be enabled after ventricular pacing, sensing, or both. Sophs 155 reacts to the lack of TVI-indicated ejection within the expected time-window after ventricular stimulation by replacing the current pulse parameters with a safety pulse of higher
energy, to be applied from the following pacing cycle. After safety stimulation for 16 cycles, a threshold test is automatically performed in an attempt
to restore the programmed pacing pulse. In case missing ejection is noticed
after ventricular sensing in three consecutive cycles, Sophs 155 will temporarily switch to asynchronous dual-chamber pacing at 100 bpm, in order
to ensure non-competitive overdrive stimulation of the heart. The procedure
can be repeated up to three times with a 1-min maximal duration a timeframe that should allow removal of the electrical interference affecting the
pacemakers sensing function.
Both Sophs models can optionally perform ventricular threshold analysis at the follow-up under TVI control. In case of capture loss, the energy
scan is automatically broken and programmed pulse parameters are promptly resumed, while the test is closed and threshold values are stored in memory (Fig. 2). TVI effectiveness and reliability in capture-loss recognition during threshold analysis is presently assessed by a multicenter registry. Each
patient is tested four times in different body positions: supine, right and left
lateral decubitus, and sitting upright. The system sensitivity is defined by the
ratio of the procedures successfully closed by TVI over the total number of
performed procedures. Specificity is derived from the pacemaker diagnostic
data collected in 20 min, while the patient changes posture and performs
physical exercise (walking). Throughout the observation period, the ventricular pulse amplitude is programmed beyond twice the threshold; therefore,
no capture loss is expected to occur. Under this assumption, the specificity in
capture surveillance is expressed as the complement to 1 of the ratio
between the number of presumed capture-loss episodes recorded by the
device (regarded as false-alarms) and the total number of paced ventricular
cycles. Preliminary results have shown 100% sensitivity and 99.9% specificity, but the sample size at present is too small to draw any conclusions.
321
Fig. 2. ECG limb leads showing ventricular threshold analysis controlled by the TVI sensor in a patient implanted with a Sophs 151 pacemaker. A pulse amplitude scan was
performed in VVI pacing at 70 bpm. After one ineffective spike, the stimulation energy
was automatically increased so that capture was regained. The procedure was then
closed and the pacing mode switched back to DDD
Benefits and Limitations of Ejection Checking

Capture recognition based on the electrical evoked response to ventricular
pacing is often ineffective in the presence of fusion beats [13, 14]. By contrast, the TVI-driven ejection check is equally responsive to paced or sensed
ventricular activity and the risk of false-alarms is minimized. On the other
hand intrinsic AV conduction might mask a condition of capture failure,
unless it is delayed enough with respect to the spike emission to entail a TVI
increase outside the expected systolic window (Fig. 1). In addition, since the
ejection occurrence must be verified hundreds of milliseconds after the pacing spike, the pulse energy can be increased in the event of capture loss
starting with the following cardiac cycle, and no back-up pulse is delivered
beforehand (Fig. 2). The above considerations make TVI better-suited to the
surveillance of ventricular activity aimed at increasing patient safety, rather
than to continuous assessment of the minimum effective pacing energy.
The ejection check after ventricular sensing is certainly a valuable task in
itself, which can only be accomplished by an advanced hemodynamic sensor.
322
This feature can be applied to protect the patient from false ventricular inhibition, by mode-switching from inhibited to asynchronous dual-chamber
pacing or from atrial to dual-chamber pacing in case of paroxysmal AV
block. Most importantly, ascertaining the presence or absence of ventricular
ejection during a tachycardia burst might become a key factor to correctly
discriminate ventricular fibrillation, thus reducing the risk of inappropriate
discharge by implantable defibrillators.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Bennett T, Sharma A, Sutton R et al (1992) Development of a rate adaptive pacemaker based on the maximum rate-of-rise of right ventricular pressure (RV
dP/dtmax). Pacing Clin Electrophysiol 15: 219-234
Rickards AF, Bombardini T, Plicchi G et al (1996) An implantable intracardiac accelerometer for monitoring myocardial contractility. Pacing Clin Electrophysiol
19:20662071
Osswald S, Cron T, Gradel C et al (2000) Closed-loop stimulation using intracardiac
impedance as a sensor principle: correlation of right ventricular dP/dt max and
intracardiac impedance during dobutamine stress test. Pacing Clin Electrophysiol
23:15021508
Occhetta E, Magnani A, Bortnik M et al (2003) Hemodynamic sensors: their impact
in clinical practice. In: Raviele A (ed) Cardiac Arrhythmias 2003. Springer, Milan,
pp 713718
Gasparini M, Curnis A, Mantica M et al (2001) Hemodynamic sensors: what clinical value do they have in heart failure? In: Raviele A (ed) Cardiac Arrhythmias
2001. Springer, Milan, pp 576-585
Chirife R, Ortega DF, Salazar A (1993) Feasibility of measuring relative right ventricular volumes and ejection fraction with implantable rhythm control devices.
Chirife R, Tentori MC, Mazzetti H, Dasso D (2001) Hemodynamic sensors: are they
all the same? In: Raviele A (ed) Cardiac Arrhythmias 2001. Springer, Milan, pp
566575
Di Gregorio F, Curnis A, Pettini A et al (2002) Trans-valvular impedance (TVI) in the
v
hemodynamic regulation of cardiac pacing. In: Mitro P, Pella D, Rybr R, Valocik G
(eds) Cardiovascular Diseases 2002. Monduzzi Editore, Bologna, pp 5357
Bongiorni MG, Soldati E, Arena G et al (2003) Transvalvular impedance: does it
allow automatic capture detection? In: Raviele A (ed) Cardiac Arrhythmias 2003.
Springer, Milan, pp 733739
Duru F, Bauersfeld U, Schller H et al (2000) Threshold tracking pacing based on
14.
323
beat by beat evoked response detection: clinical benefits and potential problems. J
Intervent Cardiol Electrophysiol 4:511522
Candinas R, Liu B, Leal J et al (2002) Impact of fusion avoidance on performance of
the automatic threshold tracking feature in dual chamber pacemakers: a multicenter prospective randomized study. Pacing Clin Electrophysiol 25:15401545
The Ideal Pacemaker for Complete AV Block

I. ELI OVSYSHCHER
Since the initial description of the use of a transvenous endocardial lead for
pacing in humans, in 1959 [1], the right ventricular apex (RVA) has served as
the traditional site for lead positioning. However, RVA pacing produces an
abnormal pattern of ventricular depolarization and there is growing evidence that pacing from this site is associated with adverse functional and
structural changes in the left ventricle. This is manifested clinically in the
deterioration of left ventricular (LV) function and increased morbidity and
mortality. The results of numerous studies have described these observations, which were summarized in a recent review [2].
Obviously, in light of the potential harmful effects of ventricular (V) pacing, every effort should be made to avoid it, if possible. However, V-pacing is
necessary in many patients because of unreliable or absent AV conduction,
i.e., in patients with advanced or complete AV block. V-pacing from the RV
outflow tract (RVOT), RV septum (RVS), His and para-His bundle area,
biventricular (BV) or LV pacing appears to have hemodynamics benefits
compared to RVA pacing.
In a recent paper, Lieberman et al. [3] attempted to identify the optimal
V-pacing site in patients with or without LV dysfunction. The authors studied the acute hemodynamic effects of AV synchronous pacing at three different RV sites (apex, free wall, and septum), at the LV free wall, and at both the
RV septum and the LV free wall (BV) during electrophysiological studies in
patients with or without preexisting LV dysfunction. All of these patients had
normal QRS duration and no conventional indication for cardiac pacing.
During the acute pacing protocol, invasive hemodynamic assessment of the
Electrophysiology, Faculty of Health Sciences, Ben Gurion University of the Negev,

BeerSheva, Israel
326
I. Eli Ovsyshcher
LV pressure-volume loop was obtained. The results showed that acute cardiac hemodynamics and functions were better during LV and BV pacing
than during RV pacing at all three sites, especially in patients with preexisting LV dysfunction. In patients with LV dysfunction, acute RV pacing at any
site resulted in worsening cardiac performance. However, in patients without
LV dysfunction, individual optimization of RV pacing sites could preserve
cardiac performance. There were substantial individual variations in the
optimal RV pacing sites. Thus, the study suggested that V-pacing sites need
to be individually optimized. In patients with preexisting LV dysfunction, an
LV-based pacing approach can avoid RVA-pacing-induced LV dyssynchrony
and may further improve LV performance. However, the clinical implications
of this finding remain unclear. In patients with conventional indications for
CRT, an acute hemodynamic benefit did not predict the long-term response
[4]. Additionally, the pacing sites tested in this study were imprecisely
defined.
With the recent advances in the active-fixation endocardial lead systems,
alternative RV pacing sites have been explored in order to replace the RVA.
In patients without significant distal conduction abnormalities, such as
those who have undergone AV node ablation for atrial fibrillation, His or
para-His bundle pacing has been shown to preserve the LV activation
sequence and LV function [5]. A recent study [6] showed that pacing at the
RVS with a screw-in electrode can stimulate ventricles antegradely and may
result in a normal LV activation sequence (interestingly, the RV septum site
was used by S. Furman in the first human implantation of the endocardial
pacing lead [1]). However, the technique for achieving successful RVS, His or
para-His bundle pacing remains challenging. One of the major issues related
to pacing in these sites is that it is difficult to define the optimal site for lead
placement. Moreover, data regarding acute and long-term effects of pacing at
sites other than that of RVA, are conflicting [7, 8]. Therefore, future studies
are needed to define the potential role of alternative RV pacing sites for
long-term pacing [2, 7, 8].
It seems evident from the MOST and DAVID trials that conventional RV
pacing (in all the large randomized trials the position of the lead in RV was
not defined) is harmful for some patients [2]. In the MOST study, only 10%
of DDD patients with sinus-node dysfunction had heart failure (HF) during
follow-up, and they were more likely to have a lower ejection fraction, to be
post-myocardial-infarction, and have a worse New York Heart Association
(NYHA) functional class than patients who did not experience HF [9]. Thus,
a significant group of RV pacing patients tolerates this approach for many
years without experiencing deleterious effects on LV function. Therefore, it
327
would be essential and useful before pacemaker implantation to identify the

subset of patients susceptible to the adverse effects of RV pacing.
The recently published Ablate and Pace in Atrial Fibrillation (APAF)
study [10] attempted to resolve this problem. It evaluated the extent to
which pacing from the RVA affects LV electromechanical activation and
assessed whether the extent of LV asynchrony during RV pacing could be
predicted by clinical, ECG, or echo findings obtained during sinus rhythm.
The authors evaluated 56 patients with normal QRS and preserved AV conduction who received permanent backup RV pacing. Intra-LV electromechanical activation was assessed during sinus rhythm and during RV
pacing. An abnormal electromechanical LV delay was found in 27% of
patients during sinus rhythm and in only 50% of patients during RV pacing
(p < 0.001). An abnormal baseline electromechanical LV delay and QRS > 85
ms were independent predictors of an abnormal electromechanical LV delay
during RV pacing. Thus, RVA pacing induces asynchrony of LV contractions
in a substantial percentage of patients, but by no means in all of them.
Although normal baseline electromechanical LV activation cannot exclude
the development of significant asynchrony during RV pacing, the presence
of preimplant LV asynchrony predicts a worsening of this detrimental
effect.
In a subgroup analysis of the DAVID trial [11], patients with abnormal
conduction (QRS 110 ms) had worse outcomes from RVA pacing than
patients with narrow QRS. These important observations [10, 11] reaffirm
the necessity to search for additional electromechanical indices that predict
a negative response to RVA paging, as well as a positive response to cardiac
resynchronization therapy in patients with conventional pacemakers. The
data can also explain why only some patients with RV pacing develop HF. As
was demonstrated in the MOST and DAVID trials, the development of HF
strongly depends on the cumulative percentage of RV pacing beats [2]. It
may be that a combination of these two factors, that is, LV dyssynchrony,
which can be detected by echo (or other cardiac imaging) techniques or
ECG, and a high percentage of RV pacing beats, can lead to a deterioration of
LV function, resulting in HF. Conversely, the absence of one of these factors
may postpone or preserve developing HF.
Currently, only patients with preexisting LV dysfunction seem more likely
to develop progressive HF after RV pacing. In those patients, LV-based pacing should be recommended to prevent deterioration of LV function (RV
pacing can be used if solid evidence emerges that any alternative site[s] in
RV can prevent the weakening of heart function). This recommendation is in
complete agreement with the results of a recent randomized prospective
328
I. Eli Ovsyshcher
study (30 patients) showing that prophylactic BV pacing in patients with AV

block resulted in better LV function (reduced LV end-diastolic, p = 0.022,
and end-systolic volumes, p < 0.001), better quality of life and exercise
capacity, and reduced N-terminal pro-B-type natriuretic peptide level (p <
0.002) when compared with RV apical pacing [12]. The benefit of BV over RV
pacing was similar for patients with (n = 9) and without (n = 21) AF. RV
function was not affected by BV pacing. Similar results were demonstrated in
two additional controlled studies on patients with AF and spontaneous [13]
or AV node ablation bradycardia [1315].
However, except in a subset of pacemaker patients, as previously discussed, the routine use of LV-based pacing for an entire cohort of patients
with AV block is impractical due to numerous disadvantages of BV pacing,
such as the longer procedure time, shorter battery life, lead dislodgement, and
higher cost and complication rates. Moreover, BV or LV pacing induces dyssynchrony in hearts with normal ventricular conduction [3, 16] and reduces
LV pumping function in patients with no baseline dyssynchrony. Therefore,
BV or LV pacing is not the ideal and not even an optimal solution for many
patients with AV block.
Recent studies have shown that 3150% of pacemaker patients have
asymptomatic LV dysfunction [17, 18]. This is an important cohort of patients
who are potential candidates for LV-based pacing. Therefore, all patients with
AV block and RV pacing should be closely monitored for worsening of LV
function [17]. Recent studies have shown that upgrading to BV pacing can
improve functional status and cardiac function in those patients in whom HF
developed after RVA pacing [19].
Conclusions
There is no ideal pacing for patients with complete AV block. However, based
on our current knowledge we can suggest optimal pacing for these patients.
Patients with AV block who need permanent pacing should be evaluated on
the issues of LVEF and LV dyssynchrony presence. Patients with normal, or
close to normal, LV function and without dyssynchrony should be treated by
RV pacing. In patients with normal, or close to normal, LV dysfunction and
signs of LV dyssynchrony, EF should be closely monitored.
Patients with preexisting LV dysfunction (LVEF 4045%) seem more likely to develop progressive HF after RV pacing. In these patients in NYHA
class IIIIV, LV-based pacing should be considered; in NYHA class III
patients, LV-based pacing may be recommended to prevent deterioration of
LV function.
329
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Furman S, Schwedel JB (1959) An intracardiac pacemaker for Stokes-Adams

Seizures. N Engl J Med 261:943948
Sweeney MO, Prinzen FW (2006) A New Paradigm for Physiologic Ventricular
Pacing. J Am Coll Cardiol 47:282288
Lieberman R, Padeletti L, Schreuder J et al (2006) Ventricular pacing lead location
alters systemic hemodynamics and left ventricular function in patients with and
without reduced ejection fraction. J Am Coll Cardiol 48:16341641
Stellbrink C, Breithardt OA, Franke A et al (2001) Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances. J Am Coll Cardiol 38:19571965
Occhetta E, Bortnik M, Magnani A et al (2006) Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation
in chronic atrial fibrillation: a crossover, blinded, randomized study versus apical
right ventricular pacing. J Am Coll Cardiol 47:19381945
Laske TG, Skadsberg ND, Hill AJ et al (2006) Excitation of the intrinsic conduction
system through His and interventricular septal pacing. Pacing Clin Electrophysiol
29:397405
Lewicka-Nowak E, Dabrowska-Kugacka A, Tybura S et al (2006) Right ventricular
apex versus right ventricular outflow tract pacing: prospective, randomized, longterm clinical and echocardiographic evaluation. Kardiologia Polska 64:10821090
McGavigan AD, Mond HG (2006) Selective site ventricular pacing. Curr Opin
Cardiol 21:714
Sweeney MO, Hellkamp AS (2005) Baseline and post-implant risk scores for predicting heart failure hospitalization during pacemaker therapy for sinus node
dysfunction. Heart Rhythm 2 (Suppl 2):7576
Lupi G, Sassone B, Badano L et al; Ablate and Pace in Atrial Fibrillation (APAF)
Pilot Echocardiographic Trial Investigators (2006) Effects of right ventricular
pacing on intra-left ventricular electromechanical activation in patients with native narrow QRS. Am J Cardiol 98:219222
Hayes JJ, Sharma AD, Love JC et al (2006) Abnormal conduction increases risk of
adverse outcomes from right ventricular pacing. J Am Coll Cardiol 48:16281633
Kindermann M, Hennen B, Jung J et al (2006) Biventricular versus conventional
right ventricular stimulation for patients with standard pacing indication and left
ventricular dysfunction: the Homburg Biventricular Pacing Evaluation (HOBIPACE). J Am Coll Cardiol 47:19271937
Leclercq C, Walker S, Linde C et al (2002). Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial
fibrillation. Eur Heart J 23:17801787
Brignole M, Gammage M, Puggioni E et al (2005) Comparative assessment of right,
left, and biventricular pacing in patients with permanent atrial fibrillation. Eur
Heart J 26:712722
Doshi RN, Daoud EG, Fellows C et al (2005) Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc
Wyman BT, Hunter WC, Prinzen FW et al (2002) Effects of single- and biventricular pacing on temporal and spatial dynamics of ventricular contraction. Am J
Physiol 282:H372-H379
330
I. Eli Ovsyshcher
17.
OKeefe JH Jr, Abuissa H, Jones PG et al (2005) Effect of chronic right ventricular

apical pacing on left ventricular function. Am J Cardiol 95:771773
Thackray SD, Witte KK, Nikitin NP et al (2003) The prevalence of heart failure and
asymptomatic left ventricular systolic dysfunction in a typical regional pacemaker
population. Eur Heart J 24:11431152
Ovsyshcher IE, Barold SS (2007) Should cardiac resynchronization be considered
for the primary prevention of heart failure? In: Ritter P, Barold SS (eds) Devices for
cardiac resynchronization. Technologic and clinical aspects. Springer (in press)
18.
19.
The Ideal Pacemaker for Elderly Patients

GULMIRA KUDAIBERDIEVA1, BULENT GORENEK2
Introduction
The number of elderly people has been rapidly increasing for several
decades. This increase in longevity has been accompanied by issues of health
and quality-of-life. Among these, the proper treatment of cardiac diseases in
the elderly has become an important concern. Sinus node dysfunction (SND)
and atrioventricular block (AVB) due to development of conduction system
fibrosis are the most common indications for cardiac pacing in elderly population [1].
Population-based studies have demonstrated that more than two-thirds
of all pacemaker implantations are done in patients older than 6570 years,
with very elderly patients over 80 years of age receiving 30% of the implantations [1, 2]. Retrospective studies demonstrated that pacemaker implantation
resulted in a reduction of disease symptoms, an improvement in functional
state and health, and an increase in long-term survival rates in elderly and
very elderly patients [26]. During the last few decades, there has been an
increase in the number of atrial-based dual-chamber pacemakers (DDD,
atrial and ventricular pacing and sensing, dual response) implanted in older
patients, from 027% in the early 1980s to 3776% by the mid-1990s [1, 7].
It is known that single-chamber ventricular-based pacing (VVI, ventricular pacing and sensing, inhibition response) has significant drawbacks due to
a loss of atrioventricular synchrony, leading to hemodynamic deterioration
and development of pacemaker syndrome. In contrast, physiological atrialbased pacing by preserving atrioventricular synchrony improves ventricular
filling and optimizes cardiac output. Elderly patients may be more sensitive
1 National Center of Cardiology and Therapy, Bishkek, Kyrgyzstan; 2 Cardiology

Department, Eskisehir Osmangazi University, Eskisehir,Turkey
332
to hemodynamic compromise because of aging-associated changes in cardiovascular and autonomic function.
Trial and Study Results

Retrospective studies in very elderly patients suggested that the pacing mode
was not an independent predictor of survival after adjustment for clinical
variables and comorbidities, and had no prognostic influence on the longterm survival of patients undergoing pacemaker implantation [2, 3, 7].
Several randomized prospective studies have compared patient outcomes
obtained with atrial-based and ventricular-based pacing modes, and recent
meta-analysis has shown that atrial-based pacing was associated with a significant reduction in the incidence of atrial fibrillation (AF) and a borderline
reduction in the risk of stroke, as compared with ventricular pacing [814].
Though many of the patients included in those studies [9, 1214] were
elderly, only two were randomized prospective studies [10, 11] designed to
evaluate outcomes in different pacing modes in the elderly population. The
PASE study included patients over 65 years with SND and AVB, and the
UKPACE study included over 70 years with AVB. In the MOST trial [14] the
inclusion criterion was age > 21 years; however, about 75% of the patients
were > 67 years of age.
The PASE trial [10] compared clinical outcomes and quality of life during
18 months of follow-up in 407 patients > 65 years of age and with SND and
AVB. Participants were assigned to either the VVIR or DDDR pacing modes.
No significant differences were found in the rate of death from all causes,
stroke or death or hospitalization due to heart failure (HF), or AF rate
between VVIR and DDDR pacing modes groups. However, there were significant differences in the entire group with respect to overall quality-of-life
measurements and health-related quality-of-life measurements favoring
DDDR pacing mode.
In the PASE trial, the quality-of-life improved to a greater extent in the
subgroup of patients with SND and DDDR pacing mode than in those with
VVIR mode, while no such a difference was observed for AVB patients
assigned to either pacing mode. The clinical outcome rates were not dependent on type of pacing mode, either in SND patients or in patients with AVB.
In patients with SND, quality-of-life scores (physical role, social function,
and emotional function subscales) at 3 months were significantly better (p =
0.02, p = 0.03 and p = 0.002) for patients with atrial-based pacing than for
those with ventricular-based pacing. There were no differences between
VVIR and DDDR modes with respect to clinical outcomes, except for a bor-
333
derline significance in the incidence of AF (p = 0.06), which was somewhat

less in the DDDR group (19 vs 28%). Further multivariate analysis of AF predictors in the PASE trial [15] showed that, after adjustment for baseline clinical variables, randomization for VVIR pacing mode was a significant clinical
predictor of AF development along with hypertension and pre-implant
supraventricular tachycardia. The adjusted risk of AF development was 2.55
times higher (95% CI 1.23, 5.29, p = 0.01) in patients with VVIR pacing than
in those with DDDR pacing. However, the development of AF did not significantly affect the risk of death from all causes, or death or stroke or hospitalization due to HF, and AF was not associated with a worsening of quality-oflife scores or cardiovascular functional status.
In patients with AVB, there were no differences between VVIR and DDDR
pacing modes in deaths from all causes (15 vs 17%), stroke or death from any
cause, or hospitalization for HF and AF. There were also no differences in
quality-of-life scores for patients with AVB with and without AV-synchronized pacing.
The incidence of pacemaker syndrome was 26% in patients with VVIR
pacing mode. Complication rates in the PASE trial [16] were 6.1%, with the
most frequent complications being pneumothorax (2%), ventricular lead dislodgement (1.7%), cardiac perforation, atrial lead dislodgement (0.5%), and
subclavian vein thrombosis (0.5%). There were no significant clinical predictors for the development of complications, including mode of pacing, except
for pneumothorax, which was associated significantly with age > 75 years,
lower weight, higher trend of occurrence in females, and with subclavian
approach. The length of hospital stay was dependent on the perioperative
complication rates.
The MOST trial [14] was designed to compare the outcomes in 2,010
patients with SND assigned to either VVIR or DDDR pacing modes during a
median 33.1 months of follow-up. There were no differences in primary outcome, death, or nonfatal stroke between patients with respect to the two pacing modes (DDDR -21.5% and VVIR -23%, p = 0.48), death, nonfatal stroke,
or hospitalization for HF. However, there was a significantly lower incidence
of AF in the DDDR group than in the VVIR group (21.4 vs 27.1%, HR-0.79,
95% CI 0.660.94, p = 0.008). After adjustment for clinical variables, including history of myocardial infarction, diabetes, congestive HF, and supraventricular tachycardia, multivariate analysis showed that the rate of reduction
of AF incidence with DDDR pacing mode increased (HR-0.77, 95% CI
0.640.92, p = 0.004). Multivariate analysis also demonstrated an association
of dual-chamber pacing with reduction of adjusted rate of hospitalizations
for HF (HR-0.73, 95% CI 0.560.95, p = 0.02) and a reduction in the inci-
334
dence of combined clinical end-point (death, nonfatal stroke, or hospitalization for HF; HR-0.85, 95% CI 0.721.0, p = 0.05).
Dual-chamber pacing was associated with better health-related qualityof-life measurements (SF-36, Medical Outcomes Study 36-Item Short Form,
General Heart Survey): role physical (p < 0.0001), role emotional (p = 0.009),
and vitality (p = 0.002) during 4 years than obtained with ventricular pacing
[17].
Pacemaker syndrome developed in 18.3% of 996 patients with VVIR pacing mode whose pacemaker modes were further reprogrammed for dualchamber pacing mode. Predictors of the development of pacemaker syndrome were a higher percentage of paced beats, higher programmed low
rate, and slower underlying spontaneous sinus rate [18]. As determined by
multivariate analysis, only a higher percentage of paced ventricular beats
was an independent predictor of pacemaker syndrome development (p =
0.0001). After switching to dual-chamber pacing, there was a significant
improvement in quality-of-life scores, which led the investigators to suggest
that the implantation of atrial leads in all patients may prevent pacemaker
syndrome development.
The 30-day post-implantation complications rate was 4.8%, with the most
frequent complications being atrial lead dislodgement (1.8%), pneumothorax (1.5%), and problems with ventricular leads (1.1%).
The recently completed UKPACE trial [11] was devoted to the assessment
of the effects of single-chamber ventricular pacing (with and without rate
adaptation) vs dual-chamber pacing (with and without sensor rate adaptation) on mortality, AF, HF, and composite stroke rates in elderly patients (>
70 years) with high-grade AVB. Among the 2,021 patients with high-grade
AVB, 1,009 patients received single-chamber pacemakers (504 patients +VVI
and 505 VVIR) and 1,012 patients had dual-chamber pacemakers implanted. There were no differences among the two pacing-mode groups with
respect to annual mortality rate (7.2% VVI pacing group vs 7.4% DDD pacing group) and death due to cardiovascular causes (3.9 vs 4.5%, p = 0.07)
during 4.6 years of follow-up. Pacing mode did not affect the incidence of AF
(3.0 and 2.8%, p = 0.74, for VVI and DDD pacing groups), HF (3.2 vs 3.3%, p
= .80, for VVI vs DDD pacing groups), combined stroke outcome (stroke,
transient ischemic attack, thromboembolism; 2.1 vs 1.7%, p = 0.20), or event
rates for coronary artery disease and myocardial infarction.
However, in the group of patients that received VVI pacing without rate
adaptation (subgroup of 505 patients), the annual event rate of combined
stroke was significantly higher than in the DDD group (2.5 vs 1.7%, p =
0.04). In addition, the 3-year event-free survival for combined stroke was
335
1.58 (CI 1.032.42, p = 0.04) times lower for fixed-rate VVI pacing than in the
DDD group. Event rates in the VVIR pacing group were similar to that of the
DDD pacing group.
Procedural complication rates (7.8 vs 3.5%, p < 0.001), therapeutic intervention rate (8.8 vs 5.6%), and need for re-operation (4.2 vs 2.5%, p = 0.04)
were higher for DDD pacing mode than for VVI pacing mode. The pacemaker syndrome rates have not yet been reported for the UKPACE trial.
Conclusions
Selection of the pacing mode in elderly patients should be based on an individual approach that takes into consideration the patients quality of life,
potential clinical outcome, and the complication rates of the procedure.
In elderly patients with SND, the primary outcomes, i.e., mortality and
stroke rate, did not differ between patients with ventricular- and atrial-based
pacing modes. However, dual-chamber pacing may be preferred to ventricular-based pacing because of greater improvement in the quality of life and
the lower number of hospitalizations for HF and AF, although the latter does
not ultimately worsen the quality of life or other clinical outcomes.
In patients with AVB, there were no differences in the incidence of death,
stroke, HF, and AF between patients with dual-chamber pacing and those
with ventricular single-chamber pacing modes. The differences in combined
stroke, transient ischemic attack, and thromboembolism resulting from
fixed-rate VVI pacing vs DDD pacing may recommend rate-adaptive ventricular-based pacing if single-chamber ventricular pacing is decided upon.
Another important factor that may affect the choice of an appropriate
pacemaker is the high incidence (18.326%) of pacemaker syndrome due to
loss of atrioventricular synchrony in elderly patients with single-chamber
ventricular-based pacing. However, it is difficult to predict which patients
will develop pacemaker syndrome, since the only independent predictor of
this complication was the number of paced ventricular beats. This finding
may favor the implantation of dual-chamber pacemakers [18].
Patients of advanced age are also prone to increased periprocedural and
implantation complication rates (4.86.1%). In selecting the mode of pacing
in elderly patients, the clinician should keep in mind that DDD pacemaker
implantation is associated with a higher rate of complications, atrial leads
dislodgement, and problems with ventricular leads, all of which necessitate
careful monitoring during both the implant procedure and follow-up. Older
(> 75 years) and sicker patients should be observed closely for the risk of
developing pneumothorax.
336
In elderly patients, the absence of a clear benefit in primary outcome

rates for DDD pacing vs VVI pacing modes may be explained in part by the
fact that the advantage of AV synchrony provided by dual-chamber pacemakers could be masked by ventricular dyssynchrony resulted from right
ventricular apical pacing. Recent results of the MOST trial [1921] revealed
that the incidence of HF in DDD pacing was closely related to the percentage
of ventricular paced beats. The increased hospitalization rate for HF in
patients with wide-paced QRS complex reported by the MOST trial also suggests a contribution of ventricular dyssynchrony. Further studies with optimal pacing sites and advanced modes are needed to find a solution for the
undesirable consequences of right ventricular pacing and ventricular dyssynchrony in elderly patients.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Rosenheck S, Geist M, Weiss A et al (1995) Permanent cardiac pacing in octogenarians. Am J Geriatr Cardiol 4:4247
Schmidt B, Brunner M, Olschewski M et al (2003) Pacemaker therapy in very
elderly patients: long-term survival and prognostic parameters. Am Heart J
146:908913
Shen WK, Hayes DL, Hammill SC et al (1996) Survival and functional independence after implantation of a permanent pacemaker in octogenarians and nonagenarians. A population-based study. Ann Intern Med 125:476480
Lopez-Jimenez F, Goldman L, Orav EJ et al (2002) Health values before and after
pacemaker implantation. Am Heart J 144:687692
Shen WK, Hammill SC, Hayes DL et al (1994) Long-term survival after pacemaker
implantation for heart block in patients > or = 65 years. Am J Cardiol 74:560564
Lamas GA, Pashos CL, Normand SL, McNeil B (1995) Permanent pacemaker selection and subsequent survival in elderly Medicare pacemaker recipients. Circulation
91:10631069
Jahangir A, Shen WK, Neubauer SA et al (1999) Relation between mode of pacing
and long-term survival in the very elderly. J Am Coll Cardiol 33:12081016
Healey JS, Toff WD, Lamas GA et al (2006) Cardiovascular outcomes with atrialbased pacing compared with ventricular pacing: meta-analysis of randomized
trials, using individual patient data. Circulation 114:1117
Andersen HR, Nielsen JC, Thomsen PE et al (1997) Long-term follow-up of
patients from a randomised trial of atrial versus ventricular pacing for sick-sinus
Lamas GA, Orav EJ, Stambler BS et al (1998) Quality of life and clinical outcomes in
elderly patients treated with ventricular pacing as compared with dual-chamber
pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med
338:10971104
Toff WD, Camm AJ, Skehan JD; United Kingdom Pacing and Cardiovascular Events
Trial Investigators (2005) Single-chamber versus dual-chamber pacing for highgrade atrioventricular block. N Engl J Med 353:145155
337
12. Connolly SJ, Kerr CR, Gent M et al (2000) Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. N Engl
J Med 342:13851391
13. Mattioli AV, Vivoli D, Mattioli G (1998) Influence of pacing modalities on the incidence of atrial fibrillation in patients without prior atrial fibrillation. Eur Heart J
19:282286
14. Lamas GA, Lee KL, Sweeney MO et al (2002) Ventricular pacing or dual-chamber
pacing for sinus-node dysfunction. N Engl J Med 346:18541862
15. Stambler BS, Ellenbogen KA, Orav EJ et al; Pacemaker Selection in the Elderly Trial
Investigators (2003) Predictors and clinical impact of atrial fibrillation after pacemaker implantation in elderly patients treated with dual chamber versus ventricular pacing. Pacing Clin Electrophysiol 26:20002007
16. Link MS, Estes NA 3rd, Griffin JJ et al (1998) Complications of dual chamber pacemaker implantation in the elderly. Pacemaker Selection in the Elderly (PASE)
Investigators. J Interv Card Electrophysiol 2:175179
17. Fleischmann KE, Orav EJ, Lamas GA et al (2006) Pacemaker implantation and quality of life in the Mode Selection Trial (MOST). Heart Rhythm 3:653659
18. Link MS, Hellkamp AS, Estes NAM et al (2004) High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based
pacing in the Mode Selection Trial (MOST). J Am Coll Cardiol 43:20662071
19. Sweeney MO, Hellkamp AS, Ellenbogen KA et al; Mode Selection Trial Investigators
(2003) Adverse effect of ventricular pacing on heart failure and atrial fibrillation
among patients with normal baseline QRS duration in a clinical trial of pacemaker
therapy for sinus node dysfunction. Circulation 107:29322937
20. Shukla HH, Hellkamp AS, James EA et al; Mode Selection Trial (MOST)
Investigators (2005) Heart failure hospitalization is more common in pacemaker
patients with sinus node dysfunction and a prolonged paced QRS duration. Heart
Rhythm 2:245251
21. Sweeney MO, Hellkamp AS (2006) Heart failure during cardiac pacing. Circulation
113:20822088
ELECTROCARDIOGRAPHY
Update on ACC/ESC Criteria for Acute ST Elevation Myocardial

Infarction
PETER W. MACFARLANE
Introduction
In 2000, the European Society of Cardiology and the American College of
Cardiology jointly published [1] guidelines defining myocardial infarction.
The definition was based partly on the availability of new biomarkers to
assist in detecting myocardial damage. As part of their report, the criteria for
acute ST elevation myocardial infarction were established. These provided
thresholds for abnormal ST elevation in the 12-lead ECG. Table 1 summarises
these criteria.
Table 1. ESC criteria for ECG changes indicative of myocardial ischemia that may
progress to myocardial infarction
Patients with ST elevation
New or presumed new ST segment elevation at the J point in two or more contiguous leads with the cut-off points 0.2 mV
in leads V1, V2 or V3 and 0.1 mV in
other leads. Contiguity in the frontal
plane is defined by the lead sequence aVL,
I, inverted aVR, II, aVF, III.
Patients without ST segment elevation
ST segment depression
T-wave abnormalities only
Medical Sciences, University of Glasgow, Scotland, UK
342
Peter W. Macfarlane
Previous work in this laboratory had shown that the normal limits of ST
amplitude were both age- and sex-dependent [2]. In 2001, a summary of the
normal limits of ST junctional (STj) amplitude were published [3] in order to
highlight this age and sex dependency. More recently, a separate study was
undertaken in this laboratory to determine the upper limits of normal ST
elevation in additional chest leads V7V9 and V3RV6R. No previous information on the normal limits in the former was available, although limited
data [4] on right-sided chest leads V4RV6R did not allow any conclusions
to be drawn on the effect of age and gender.
The availability of all of this information has allowed us to further revise
the criteria for abnormal ST elevation. As a result, it is hoped that the various
cardiology authorities, such as the ESC/ACC/AHA, will acknowledge, in their
next revision of ECG criteria for acute myocardial infarction, the fact that
criteria should be age- and sex-dependent and that the current grouping [1]
of leads to which criteria are applied is not optimal.
This short paper summarises some of the work aimed at enhancing the
criteria for acute ST elevation myocardial infarction.
Methods
For the study of the conventional 12-lead ECG, apparently healthy volunteers
were recruited from local government as well as from a small number of
staff and students at the University of Glasgow. All were examined by a
physician and none had any illness that affected the cardiovascular system.
With respect to the study on additional chest leads, individuals were
recruited from staff and patients in Glasgow Royal Infirmary, all of whom
had a healthy cardiovascular system. The additional chest leads were recorded in the resting position, with V7V9 placed at the level of V4V6 but with
V7 at the posterior axillary line, V8 at the midscapular line and V9 at the
parasternal line [5]. Leads V3RV6R were placed on the right side of the
chest in mirror image positions to V3V6. All ECG measures were derived in
an automated fashion using the University of Glasgow ECG analysis program
[6]. The ST amplitude was defined as the amplitude at the junction of the
QRS complex and the ST segment in each individual lead.
With respect to the standard 12-lead ECG, the normal limits of ST amplitude were used to obtain equations giving the age-dependent upper limit of
the normal amplitude within individual leads for males. It was readily determined that the upper limits of normal in females were not age-dependent,
although they were generally lower than in males. Therefore, revised upper
limits of normal were separately established for females.
Update on ACC/ESC Criteria for Acute ST Elevation Myocardial Infarction
343
Results
The normal limits of ST amplitude in the 12 leads were derived from a
cohort of 1,388 individuals, 731 males and 590 females, ages 17 years and
over. Subjects were divided into four age ranges: 1829, 3039, 4049 and 50
years and over. Further details are available elsewhere [3].
A separate group of 88 males, ages 42.2 13.3 years, and 112 females,
ages 42.3 13.3 years, was recruited to the study of additional chest leads.
The upper limit of normal ST in males was found to be age-dependent
and clearly lead-dependent, particularly in the precordial leads. Figure 1
illustrates the findings for V3. By contrast, the upper limits for females were
not age-related, as exemplified in Fig. 1, but they were lead-dependent. As a
result, there are unique upper limits of normal for each age and gender. As
an example, Table 2 shows the upper limits of normal STj in leads V1V6 for
males and females ages 4049 years.
Age-related equations were therefore derived for the upper limits of normal for males but constant values were selected for females. The goal was to
obtain a high specificity based on a 96% normal range. For example, the
upper limits of normal ST amplitude in V2 are given by the following equations:
STj amplitude (mV)
0,35
0,3
0,25
0,2
Male
Female
0,15
0,1
0,05
0
<=29
30-39
40-49
>=50
Age ranges (yrs)
Fig. 1. The upper limits of normal ST amplitude for males and females in lead V3. The
dependence on age for males is evident as is the lack of age dependence in females
Peter W. Macfarlane
344
Table 2. Upper-normal limits of ST amplitude V1V6 for males and females ages 4049
years. All data are in mV. Note how V1 is more aligned with V4V6 than V2, V3, and that
particularly for V2V4 the limits for males are effectively double those for females.
Males
Females
V1
0.11
0.08
V2
0.27
0.14
V3
0.22
0.10
V4
0.13
0.07
V5
0.09
0.06
V6
0.07
0.06
Upper limit STj in V2 (male) = -5 age (years) + 450 V

Upper limit STj V2 (females) = 140 V
The study of additional chest leads showed that there was no age and
gender difference except in V3R, where the upper limit of normal was 75 V
in males and 50 V in females. Otherwise, 50 V was found to be the upper
limit of normal in all other additional chest leads for males and females.
Discussion
In short, the upper limits of normal ST amplitude are lead-dependent as well
as age- and sex-dependent. It can be seen from Table 2 that it is completely
incorrect to group V1 together with V2 and V3, as was the case with the initial ESC/ACC publication [1] containing the criteria listed in Table 1. This
author strongly recommends that V1 be grouped with other chest and limb
leads and not with V2 and V3.
With respect to age dependence and gender, leads V2 and V3 again illustrate very clearly how the upper limit of normal in males is very much greater
than in females. This author suggests that the upper limit of normal in these
leads should be 0.15 mV for females but 0.2 mV in males 40 years of age
and indeed above 0.25 mV for males < 40 years of age. To facilitate the application of these criteria, it is suggested that 0.1 mV be regarded as the upper
limit of normal in all other leads. However, for automated ECG interpretation,
much more complex criteria are employed in the authors laboratory.
While this article has concentrated on ST elevation, the lower limits of
normal ST junction can be regarded as -0.05 mV in V2 and V3 and -0.1 mV
in the other leads. These criteria should be applied in conjunction with a
horizontal or downward-sloping ST segment. There is no doubt that lesser
degrees of ST depression will give an abnormal appearance to the ECG but,
for the sake of specificity in dealing with acute ischemic changes, the foregoing thresholds are suggested.
Update on ACC/ESC Criteria for Acute ST Elevation Myocardial Infarction
345
Other work in this laboratory has shown that the revised criteria, when
applied to a group of individuals with chest pain as well as to normal controls, resulted in improved sensitivity and indeed specificity in the diagnosis
of acute ST elevation myocardial infarction [7].
The AHA is expected to issue guidelines in late 2007 on setting criteria
for the diagnosis of acute ST change, and it is hoped that the above suggestions will be incorporated. Similarly, updated guidelines from an international group supported by the ESC and ACC will be issued late this year, and
it is expected that there will be some revision to the previously reported criteria of 2000.
In conclusion, there is no question that the criteria for abnormal ST elevation should be age- and sex-dependent. Moreover, further revision of the
lead dependency of criteria is merited when these are compared to the suggested criteria published in 2000 by the ESC/ACC [1]. It is expected that the
revised guidelines to be published in the near future will make use, at least in
part, of the suggestions outlined here.
References
1.
2.
3.
4.
5.
6.
7.
The Joint European Society of Cardiology/American College of Cardiology

Committee (2000) Myocardial infarction redefined A consensus document. Eur
Heart J 21:15021513
Macfarlane PW, Lawrie TDV (1989) The normal electrocardiogram and vectorcardiogram. In: Macfarlane PW, Lawrie TDV (eds) Comprehensive electrocardiology.
Pergamon Press, Oxford, p 445
Macfarlane PW (2001) Age, sex and the ST amplitude in health and disease. J
Electrocardiol 34(Suppl):235241
Andersen HR, Nielsen D, Hansen LG (1987) The normal right chest electrocardiogram. J Electrocardiol 20:2732
Pipberger HV, Arzbaecher RC, Berson AS et al; Committee on Electrocardiography
of the AHA (1975) Recommendations for standardization of leads and of specifications for instruments in electrocardiography and vectorcardiography. Circulation
52(Aug Suppl):1131
Macfarlane PW, Devine B, Latif S et al (1990) Methodology of ECG interpretation
in the Glasgow program. Meth Inform Med 29:354361
Macfarlane PW, Browne D, Devine B et al (2004) Modification of ACC/ESC criteria
for acute myocardial infarction. J Electrocardiol 37(Suppl):98103
ECG-MRI based Localization of Myocardial Infarction

HENRIK ENGBLOM, OLLE PAHLM
Introduction
Magnetic resonance imaging (MRI) has emerged in the last decade as an
important method for characterizing various aspects of cardiac anatomy,
patho-anatomy, pathophysiology, and function. Measurements of flow parameters, left ventricular function, and grade of valvular regurgitation have
been validated and proved to serve as excellent gold standards compared to
simpler, established techniques, such as echocardiography, thermodilution
measurements, and electrocardiography [1].
Introduction of the delayed contrast-enhanced MRI (DE-MRI) technique
for visualization of myocardial necrosis and scar has made MRI the method
of choice for myocardial infarct quantification in vivo [2]. Based on patterns
of hyperenhancement, DE-MRI has proved useful for predicting functional
recovery in patient with acute myocardial infarction [3, 4] and in patients
suffering from ischemic heart disease who have undergone elective revascularization therapy [5].
In electrocardiography, the conventional 12-lead electrocardiogram
(ECG) is still the dominating mode of registration, though it has at times
been challenged by vectorcardiography and other lead systems with alternative electrode placement. Some of these systems employ fewer electrodes,
while other employ several more electrodes than the 10 that are required for
the 12-lead ECG [6].
Department of Clinical Physiology, University Hospital, Lund, Sweden
348
DE-MRI for Infarct Quantification

Pathophysiological Basis and Principles
When a coronary artery is occluded, the myocardium supplied by the
occluded vessel is subject to ischemia, in the absence of extensive collateral
circulation. What determines the reversibility of the impending injury is the
duration and severity of the ischemia. If the ischemia is severe enough and
its duration long enough to cause rupture of myocyte cell membranes, the
myocardium becomes irreversibly injured, or infarcted. The loss of cell
membrane integrity provides a useful indicator when acute myocardial
infarction is visualized by DE-MRI.
Acquisition of DE-MR images is preceded by the intravenous injection of
a gadolinium-based extracellular contrast agent. This agent distributes into
the extracellular space of the myocardium. Since a myocyte with ruptured
cell membrane is unable to prevent the extracellular contrast agent from
entering its interior, the distribution volume for the contrast agent is
increased in necrotic myocardium compared to viable myocardium [7, 8].
During the infarct-healing process, the acutely necrotic myocardium is
replaced by fibrous scar tissue, which also has a larger distribution volume
than viable myocardium. Thus, old myocardial infarction can also be visualized and quantified using DE-MRI [9]. Different wash-in/wash-out profiles
have also been proposed to explain part of the difference in the amount of
contrast agent present in infarcted vs viable myocardium [7, 10]. The difference in gadolinium concentration between areas with different distribution
volumes enables distinction between viable and non-viable myocardium.
Validation Experiments
The hyperenhanced myocardium has been shown in animal models to closely resemble regions of infarction as assessed with triphenyltetrazolium chloride (TTC) [11, 12].
In order to correctly delineate the region of infarction, it is important to
consider the so-called partial volume effects that arise in the infarct borders
[12, 13]. The spatial resolution of a typical clinically acquired short-axis
image of the heart is 1.5 x 1.5 x 8 mm. Thus, the thickness of each image slice
is 8 mm. Within each slice, the infarct pattern might vary, especially at the
infarct border; thus, a partial volume effect might cause an overestimation of
the actual infarct size [14]. In a study including computer phantom experiments, animal experiments and validation in patients with acute and chronic
ischemic heart disease, Heiberg et al. [13] showed that this problem can be
349
overcome using a computer algorithm developed to compensate for partial

volume effects. The need for a common standard in the quantification of
infarcted myocardium has recently been addressed [15].
Presence of Q Waves Indicates Large Extent Rather than Transmurality

The DE-MRI technique has also been used to explore the pathologic basis of
infarct-related QRS changes. Several studies have shown that Q wave
myocardial infarction should not be equated with transmural infarction,
using DE-MRI as reference method for infarct transmurality [1618].
Furthermore, the endocardial extent of infarction has been shown to be
more predictive of infarct-related Q waves than is infarct transmurality [19].
This is illustrated in Fig. 1a, b. Figure 1c demonstrates that myocardial
infarction limited to the lateral left ventricular wall does not generate pathological Q waves but rather prominent R waves and small S waves in lead sV1
and V2.
Recent Initiatives Regarding ECG Designation of Cardiac Walls

Recently, a group of international experts published a consensus document
proposing a new terminology for left ventricular walls and the location of
myocardial infarcts based on the 12-lead ECG (Fig. 2) [20]. This work
became possible through the study of multiple patients who had undergone
ECG and MRI studies that were performed in close temporal proximity. The
focus of the consensus groups work was to adapt the ECG nomenclature to
the established 17-segment model of the left ventricular myocardium agreed
upon in 2002 by experts on various modalities for tomographic imaging of
the heart [21].
Validation of Infarct-Size Measures Based on the 12-Lead ECG

Based on the description of the human myocardial activation published by
Durrer et al. [22], Selvester and co-workers designed a computer simulation
of the human activation sequence. Using this computer model they obtained
different patterns of QRS changes on a fictitious torso surface by simulating
infarcts of different sizes at various locations in the left ventricle. The results
from the computer simulations were used to develop the Selvester QRS scoring system. However, in order to assess its diagnostic ability, the system had
to be validated in humans. The scoring system was systematically evaluated
350
Fig. 1ac. Three cases illustrating the importance of considering not only Q waves for
myocardial infarction (MI) detection and quantification by electrocardiography (ECG).
a Small transmural, non-Q wave MI in the inferior left ventricular (LV) wall. b Nontransmural, Q wave MI in the inferior LV wall. c Transmural, non-Q wave MI in the posterolateral LV wall. This patient had prominent R waves and small S waves in V1 and V2,
suggestive of posterolateral MI. Magnetic resonance (MR) imaging was aborted before
long-axis images were acquired. Arrows indicate either MI by delayed contrastenhanced (DE)-MRI or QRS changes generating QRS points. 2ch, Two chamber longaxis view. (From [18], with permission)
in human postmortem histopathology studies of single infarcts located in

the anterior [23], inferior [24], and posterolateral [25] parts of the left ventricular wall.
More recently, the Selvester QRS scoring system was evaluated using DEMRI as the reference method for infarct size. In a study of patients suffering
from chronic ischemic heart disease accompanied by old myocardial infarc-
351
Fig. 2. The ECG patterns of Q wave MI or Q wave equivalents with the names given to MI
and related infarction area documented by cardiovascular MR imaging. (From [20],
with permission)
tion in the anterior left ventricular wall, the Selvester QRS scoring system
significantly underestimated the amount of infarction at the left ventricular
apex [26]. In patients with reperfused first-time myocardial infarction, the
scoring system was shown to correlate strongly with infarct size assessed by
DE-MRI [18].
352
Since MRI is not associated with ionizing radiation, this imaging modality is feasible for serial follow-up examination. Recently, DE-MRI was used to
explore the pathologic correlate to resorption of infarct-related QRS changes
by following patients with first-time myocardial infarction after primary
percutaneous coronary intervention [4].
MRI as the Gold Standard for Refining Diagnostic ECG Criteria

Several databases are being developed that contain 12-lead ECGs and MRI
studies carried out within minutes or hours of each other. These databases
will allow elaboration of enhanced diagnostic ECG criteria for implementation in digital interpretation programs or for manual application by physicians responsible for the care of patients with suspected heart disease.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Bellenger NG, Davies LC, Francis JM et al (2000) Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2:271278
Pennell DJ, Sechtem UP, Higgins CB et al (2004) Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. Eur Heart J
25:19401965
Choi KM, Kim RJ, Gubernikoff G et al (2001) Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Circulation
104:11011107
Engblom H, Hedstrom E, Heiberg E et al (2007) Time course and magnitude of
infarct involution, functional recovery, and electrocardiographic changes in
patients with reperfused first myocardial infarction. (submitted)
Kim RJ, Wu E, Rafael A et al (2000) The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med
343:14451453
Tragardh E, Engblom H, Pahlm O (2006) How many ECG leads do we need? Cardiol
Clin 24:317330, vii
Tong CY, Prato FS, Wisenberg G et al (1993) Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn Reson Med 30:337346
Arheden H, Saeed M, Higgins CB et al (1999) Measurement of the distribution
volume of gadopentetate dimeglumine at echo-planar MR imaging to quantify
myocardial infarction: comparison with 99mTc-DTPA autoradiography in rats.
Radiology 211:698708
Rehwald WG, Fieno DS, Chen EL et al (2002) Myocardial magnetic resonance imaging contrast agent concentrations after reversible and irreversible ischemic injury.

10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
353
Klein C, Nekolla SG, Balbach T et al (2004) The influence of myocardial blood flow
and volume of distribution on late Gd-DTPA kinetics in ischemic heart failure. J
Magn Reson Imaging 20:588593
Nishimura T, Yamada Y, Hayashi M et al (1989) Determination of infarct size of
acute myocardial infarction in dogs by magnetic resonance imaging and gadolinium-DTPA: comparison with indium-111 antimyosin imaging. Am J Physiol
Imaging 4:8388
Kim RJ, Fieno DS, Parrish TB et al (1999) Relationship of MRI delayed contrast
enhancement to irreversible injury, infarct age, and contractile function.
Heiberg E, Ugander M, Engblom H et al (2007) Accounting for partial volume
effects in the automated quantification of myocardial infarction from delayed
enhancement MRI. Radiology (in press)
Hsu LY, Natanzon A, Kellman P et al (2006) Quantitative myocardial infarction on
delayed enhancement MRI. Part I: Animal validation of an automated feature
analysis and combined thresholding infarct sizing algorithm. J Magn Reson
Imaging 23:298308
Foster JE, Arheden H, Engblom H (2007) Myocardial infarct quantification: is MR
imaging ready to serve as gold standard for ECG? J Electrocardiol (in press)
Moon JC, De Arenaza DP, Elkington AG et al (2004) The pathologic basis of Q wave
and non-Q wave myocardial infarction: a cardiovascular magnetic resonance
Kaandorp TA, Bax JJ, Lamb HJ et al (2005) Which parameters on magnetic resonance imaging determine Q waves on the electrocardiogram? Am J Cardiol
95:925929
Engblom H, Hedstrom E, Heiberg E et al (2005) Size and transmural extent of firsttime reperfused myocardial infarction assessed by cardiac magnetic resonance can
be estimated by 12-lead electrocardiogram. Am Heart J 150:920
Engblom H, Carlsson MB, Hedstrm E et al (2007) The endocardial extent of reperfused myocardial infarction is a stronger determinant of pathological Q waves than
is infarct transmurality. Clin Physiol Funct Imag 27:101108
Bayes de Luna A, Wagner G, Birnbaum Y et al (2006) A new terminology for left
ventricular walls and location of myocardial infarcts that present Q wave based on
the standard of cardiac magnetic resonance imaging: a statement for healthcare
professionals from a committee appointed by the International Society for Holter
and Noninvasive Electrocardiography. Circulation 114:17551760
Cerqueira MD, Weissman NJ, Dilsizian V et al (2002) Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement
for healthcare professionals from the Cardiac Imaging Committee of the Council
on Clinical Cardiology of the American Heart Association. Circulation 105:539542
Durrer D, van Dam RT, Freud GE et al (1970) Total excitation of the isolated human
heart. Circulation 41:899912
Ideker RE, Wagner GS, Ruth WK et al (1982) Evaluation of a QRS scoring system
for estimating myocardial infarct size. II. Correlation with quantitative anatomic
findings for anterior infarcts. Am J Cardiol 49:16041614
Roark SF, Ideker RE, Wagner GS et al (1983) Evaluation of a QRS scoring system for
estimating myocardial infarct size. III. Correlation with quantitative anatomic findings for inferior infarcts. Am J Cardiol 51:382389
354
25.
Ward RM, White RD, Ideker RE et al (1984) Evaluation of a QRS scoring system for
estimating myocardial infarct size. IV. Correlation with quantitative anatomic findings for posterolateral infarcts. Am J Cardiol 53:706714
Engblom H, Wagner GS, Setser RM et al (2003) Quantitative clinical assessment of
chronic anterior myocardial infarction with delayed enhancement magnetic resonance imaging and QRS scoring. Am Heart J 146:359366
26.
Electrocardiographic Predictors of Arrhythmias In CCU Patients

AFSHIN PARSPOUR, ALPARSLAN BIRDANE, BULENT GORENEK
Introduction
Patients hospitalized in the coronary care unit (CCU) are vulnerable to many
kinds of arrhythmias, including ventricular and supraventricular arrhythmias, especially in the setting of acute coronary syndrome. Some of these
arrhythmias can be predicted electrocardiographically. This chapter discusses the arrhythmias commonly afflicting CCU patients and their electrocardiographic predictors.
Ventricular Arrythmias
Death from a ventricular tachyarrhythmia in the setting of an acute myocardial infarction (MI) has historically been one of the most frequent causes of
sudden cardiac death [1, 2]. In a 1985 report, for example, 60% of deaths
associated with acute MI occurred within the first hour after the event and
were attributable to a ventricular arrhythmia, in particular ventricular fibrillation (VF) [3]. Subsequent improvements in arrhythmia detection and
treatment have had a major impact on the outcome of ventricular arrhythmias associated with acute MI. As a result, arrhythmic and overall in-hospital mortalities have fallen significantly [4, 5]. Ventricular arrhythmias, ranging from isolated ventricular premature beats to ventricular fibrillation, are
common in the immediate post-infarction period. Observations in the
prethrombolytic era led to the identification of several types of ventricular
arrhythmias [6, 7]:
Department of Cardiology, Eskisehir Osmangazi University Medical Faculty, Eskisehir,

Turkey
356
Ventricular premature beats (VPBs), which are typically asymptomatic,

are common after acute MI and their reported incidence is as high as
93% [6]. Early VPBs do not predict short-or long-term mortality, but frequent and/or multiform VPBs that persist more than 4872 h after an MI
may be associated with an increased long-term risk of arrhythmia [6].
Ventricular tachycardia (VT) can be further classified as nonsustained or
sustained.
Nonsustained VT (NSVT) terminates spontaneously in less than 30 s.
The incidence of NSVT is 17% [7, 8]. In the first 2448 h after an
infarction, NSVT is usually due to abnormal automaticity or to triggered activity in the region of ischemia or infarction. NSVT that
occurs later is more often due to reentry. Thus, the probable mechanism and prognostic significance of NSVT depend upon the time at
which it occurs [8].
Sustained VT is defined as three or more consecutive beats originating below the atrioventricular node, with a heart rate greater than 100
or 120 beats/min. There is some disagreement as to whether 100 or
120 beats/min represents the upper limit for an accelerated idioventricular rhythm. VT is considered sustained if it lasts more than 30 s
or if it causes instability that requires termination (e.g., cardioversion) within 30 s [9]. Sustained monomorphic VT (SMVT) in the periinfarction period (i.e., within the first 48 h after the infarct) occurs in
approximately 23% of patients with an ST-elevation MI [9, 10] and in
less than 1% of patients with a non-ST elevation MI or unstable angina [9]. SMVT is associated with larger MIs [10]. The factors responsible for SMVT differ in the very early (30 min) and later (648 h) phases of the early post-MI period.
Accelerated idioventricular rhythm occurs in up to 50% of patients with
acute MI. Some studies have suggested an association with reperfusion
following thrombolytic therapy [11].
Ventricular fibrillation is the most frequent mechanism of sudden cardiac death. It is a rapid, disorganized ventricular arrhythmia, resulting in
non-uniform ventricular contraction, no cardiac output, and no recordable blood pressure. The electrocardiogram (ECG) in VF shows rapid
(300400 beats/min), irregular, shapeless QRST undulations of variable
amplitude, morphology, and interval. Over time, these wave forms
decrease in amplitude until, ultimately, asystole occurs. VF is often further classified as primary or non-primary. Primary VF occurs early after
MI (usually < 48 h) and is not associated with recurrent ischemia or
heart failure. This category comprises patients who experience VF despite
357
a relatively uncomplicated MI (i.e., as a primary electrical event). Nonprimary VF refers to all other episodes. VF is more common in patients
with MIs that are complicated by heart failure or recurrent ischemia [12].
The incidence appears to be higher with ST elevation (Q wave) MI than
with non-ST elevation (non-Q wave) MI [9].
Several predictors of ventricular arrhythmias after MI have been identified:
The clinical usefulness of measuring changes in the duration of the QT
interval in the standard 12-lead ECG is the focus of growing interest. Day
et al. [13] proposed using the QT dispersion (QTd) as an index of inhomogeneous myocardial repolarization. This measurement may provide a
prognostic tool in the detection of future ventricular tachyarrhythmic
events that may cause death [14].
In a study by Kudaiberdieva et al. [15], reduced left ventricular ejection
fraction (LVEF) and late potentials (LPs) were used in post-MI risk stratification. The authors noted that the QT clinical variability index (QTVI)
is a predictor of sudden death in patients with structural heart disease.
They showed that patients with both LPs and increased QTVI after MI
had a high likelihood of developing sustained arrhythmias. Consequently,
a simple bedside ECG recording with further analysis of LPs and the
QTVI may be the first step in a strategy to identify patients at risk for
arrhythmia after MI [15].
Since the first report by Wolf et al. [16], in1978, on the association
between decreased heart rate variability (HRV) and increased mortality
after MI, numerous studies have used HRV, either alone or in combination with other variables, to establish post-infarction risk [1719]. The
predictive value of HRV was found to be independent of other factors,
such as depressed LVEF, increased ventricular ectopic activity, and presence of LPs [20]. For prediction of all-cause mortality, the value of HRV is
similar to that of LVEF, but in predicting arrhythmic events (sudden cardiac death and ventricular tachycardia) HRV is superior [20].
T-wave or repolarization alternans (TWA) refers to variability in the timing or morphology of repolarization occurring in alternate beats on the
surface ECG [21]. TWA is indicative of repolarization heterogeneity,
which increases susceptibility to ventricular tachyarrhythmias [22]. The
presence of TWA has high sensitivity and specificity for predicting
inducible ventricular arrhythmias on electrophysiologic study (EPS). The
value of TWA vs LPs on signal-averaged ECG (SAECG) in predicting clinical events was evaluated in a prospective study of 102 patients with a
358
recent MI; 49% had TWA and 21% had LPs [23]. After a follow-up of 15
months, the sensitivity and negative predictive value of TWA for predicting arrhythmic events were 93 and 98%, respectively, while the positive
predictive value was 28%. When TWA and LPs were combined, the positive predictive value increased to 50%. Thus, TWA is a promising ECGdetectable risk factor that indicates alternate-beat changes in the shape or
amplitude of the T wave and reflects repolarization dispersion [24]. In a
decade of contemporary clinical use [25], TWA has shown a negative predictive accuracy for sudden cardiac arrest above 90% in an accumulative
population of thousands of cardiomyopathy patients, both ischemic and
non-ischemic [26, 27]. Sanjav et al. showed that TWA is a promising ECGbased index of sudden cardiac arrest and is linked with repolarization
dispersion as well as ventricular arrhythmias.
Evidence for slowed conduction after MI, assessed indirectly by SAECG
[28], successfully predicted sudden cardiac arrest in the Multicenter
Unsustained Tachycardia Trial (MUSTT) [29]. Elevated sympathetic nervous activity increases the dispersion of repolarization and, when detected by cardiac nuclear imaging [30], reduced HRV [31], or heart rate turbulence [32], predicts events after MI. SAECG often demonstrates LPs in
patients with SMVT and ischemic heart disease [3335]. The presence of
LPs on SAECG provides only indirect data that are suggestive, but not
diagnostic of SMVT. Although the SAECG has a role in predicting the risk
of SMVT in patients with ischemic heart disease, it is of limited use in the
evaluation of patients who have already experienced SMVT [36, 37]. The
Task Force of the American College of Cardiology published recommendations for the use of SAECG [38]. Also, in a study by Haghjoo et al., the
importance of HRV, LVEF < 40%, and SAECG in predicting ventricular
arrhythmias in post-MI patients was noted [39].
Heart-rate turbulence (HRT) consists of a fluctuation in the sinus rate
due to a ventricular premature beat [40]. HRV after ventricular premature beats was recently introduced as a noninvasive tool for arrhythmic
risk stratification after MI. The absence of HRT is abnormal and has been
associated with increased cardiac mortality [41, 42] and sudden cardiac
death in patients with prior MI [41].
A short-long (S-L) cardiac cycle is another predictor of ventricular
arrhythmias in CCU patients. One or more S-L cardiac cycles, usually the
result of a ventricular bigeminal rhythm, frequently precedes the onset of
malignant ventricular tachyarrhythmias [43]. El Sharif et al. proposed
that electrophysiologic mechanisms underlie the relationship between
the S-L sequence and the onset of VT [44]. In a study by Gorenek et al.,
359
the clinical and electrophysiological features of monomorphic ventricular tachycardia (MVT) with different initiation patterns were investigated
in patients with implantable cardioverter defibrillators. Non-sudden
onset MVT was shown to be characterized by shorter cycle length, higher
rate of different first-beat morphology, and the need for higher shock
energy to achieve termination. Sudden-onset MVT was precipitated by
shortening of the sinus cycle length before tachycardia [45].
Supraventricular Arrythmias
Supraventricular arrhythmias are relatively common in the peri-infarction
period and their occurrence often heralds significant myocardial dysfunction. In addition, they may, in themselves, cause congestive heart failure and
exacerbate ongoing myocardial ischemia [46].
Atrial Tachyarrhythmias
The overall incidence of atrial tachyarrhythmias in the peri-infarction period ranges from 6 to 20% and has not been altered by the use of thrombolytics [4648]. These arrhythmias primarily occur within the first 72 h after
infarction; however, only 3% were found to occur in the very early (less than
3 h) phase [48].
Atrial Fibrillation
Atrial fibrillation is the most common atrial arrhythmia. Inhomogeneous
prolongations of sinus impulses may predict its recurrence [49]. The frequency with which atrial fibrillation occurs and its prognostic significance
in the thrombolytic era were illustrated in the GUSTO-I and GUSTO-III trials [46, 50].
Atrial arrhythmias after MI can be predicted by a variety of ECG-based
methods:
P-wave dispersion (PWD) is a new electrocardiographic marker that
reflects discontinuous and inhomogeneous propagation of sinus impulses, which in some cardiac conditions has been shown to be a useful predictor of paroxysmal atrial fibrillation (PAF) [51]. In a study by Dilaveris
et al. that drew on previous studies, individuals with a clinical history of
PAF had a P-wave of significantly increased duration in 12-lead surface
ECG and SAECG recordings. Accordingly, the authors suggested that
360
PWD is a good predictor of PAF [52]. In another study, PWD was used to
predict atrial fibrillation after percutaneous coronary intervention [53].
The spontaneous onset of atrial fibrillation can also be predicted by HRV.
This approach was used by Vikman and co-workers to evaluate the recurrence of atrial fibrillation after electrical cardioversion [54].
SAECG of the P-wave is a useful predictor of idiopathic PAF among
patients without atrial enlargement, especially the elderly [55]. It may
also play a role in identifying patients at risk of developing PAF and those
likely to undergo a change from PAF to chronic atrial fibrillation [56].
In a study by Gorenek and co-workers, atrial ectopic beats with a longshort sequence were shown to be responsible for atrial-fibrillation relapse
in about 70% of patients, and thus might predict early re-initiation of
arrhythmia after electrical external cardioversion. This finding suggests
that the ECG, recorded immediately after the external cardioversion, is a
feasible approach in establishing patterns of atrial-fibrillation relapse and
may be useful in managing the recurrence of this condition [57].
Conclusions
Arrhythmias are important problems in CCU patients, especially those with
acute coronary syndrome and acute MI. In addition to the many clinical risk
factors that are predictive of these arrhythmias, such as LVEF, there are electrocardiographic predictors, as discussed herein. Although all electrocardiographic predictors are important, we recommend using a combination of
methods for a more accurate prediction of arrhythmia.
References
1.
2.
3.
4.
5.
Lown B (1979) Sudden cardiac death: the major challenge confronting contemporary cardiology. Am J Cardiol 43:313238
Myerburg RJ, Kessler KM, Castellanos A (1992) Sudden cardiac death: structure,
function and time-dependence of risk. Circulation 85(1 Suppl):I2-I10
Pell S, Fayerweather WE (1985) Trends in the incidence of myocardial infarction
and in associated mortality and morbidity in a large employed population,
19571983. N Engl J Med 312:10051011
Guidry UC, Evans JC, Larson MG et al (1999) Temporal trends in event rates after
Q-wave myocardial infarction: The Framingham Heart Study. Circulation
100:20542059
Furman MI, Dauerman HL, Goldberg RJ et al (2001) Twenty-two year (1975 to
1997) trends in the incidence, in-hospital and long-term case fatality rates from
initial Q-wave and non-Q-wave myocardial infarction: a multi-hospital, community-wide perspective. J Am Coll Cardiol 37:15711580

6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
361
Bigger JT Jr, Dresdale FJ, Heissenbuttel RH et al (1977) Ventricular arrhythmias in

ischemic heart disease: mechanism, prevalence, significance, and management.
Prog Cardiovasc Dis 19:255300
Eldar M, Sievner Z, Goldbourt U et al (1992) Primary ventricular tachycardia in
acute myocardial infarction: clinical characteristics and mortality. Ann Intern Med
117:3136
Heidbuchel H, Tack J, Vanneste L et al (1994) Significance of arrhythmias during
the first 24 hours of acute myocardial infarction treated with alteplase and effect of
early administration of a b-blocker or a bradycardic agent on their incidence.
Mont L, Cinca J, Blanch P et al (1996) Predisposing factors and prognostic value of
sustained monomorphic ventricular tachycardia in the early phase of acute myocardial infarction. J Am Coll Cardiol 28:16701676
Newby KH, Thompson T, Stebbins A et al (1998) for the GUSTO Investigators.
Sustained ventricular arrhythmias in patients receiving thrombolytic therapy:
Incidence and outcomes. Circulation 98:25672573
Gorgels AP, Vos MA, Letsch IS et al (1988) Usefulness of the accelerated idioventricular rhythm as a marker for myocardial necrosis and reperfusion during thrombolytic therapy in acute myocardial infarction. Am J Cardiol 61:231235
Volpi A, Cavalli A, Santoro L et al on behalf of the GISSI-2 Investigators. (1998)
Incidence and prognosis of early primary ventricular fibrillation in acute myocardial infarction results of the Gruppo Italiano per lo Studio della Sopravvivenza
nellInfarto Miocardico (GISSI-2) database. Am J Cardiol 82:265271
Day CP, McComb JM, Campbell RW (1990) QT dispersion: an indication of
arrhythmia risk in patients with long QT intervals.Br Heart J 63:342344
Okin PM, Devereux RB, Howard BV et al (2000) Assessment of QT interval and QT
dispersion for prediction of all-cause and cardiovascular mortality in American
Indians. The Strong Heart Study. Circulation:101:6166
Kudaiberdieva G, Gorenek B, Timuralp B et al (2002) Value of combination of QT
variability and late potentials in identification of patients with ventricular tachycardia after myocardial infarction. Int J Cardiol 83:263 265
Wolf MM, Varigos GA, Hunt D, Sloman JG (1978) Sinus arrhythmia in acute myocardial infarction. Med J Australia 2:5253
Cripps TR, Malik M, Farrell FG, Camm AJ (1991) Prognostic values of reduced
heart rate variability after myocardial infarction: clinical evaluation of a new analysis method. Br Heart J 5:1419
Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ (1987) The Multicenter Post-infarction
Research Group. Decreased heart rate variability and its association with increased
mortality after acute myocardial infarction. Am J Cardiol 59:256262
La Rovere MT, Bigger JT Jr, Marcus FL et al (1998) Baroreflex sensitivity and heart
rate variability in prediction of total cardiac mortality after myocardial infarction.
ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction)
Task Force of the European Society of Cardiology and the North American Society
of Pacing and Electrophysiology (1996) Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 17(3):354381
Armoundas AA, Tomaselli GF, Esperer HD (2002) Pathophysiological basis and clinical application of T-wave alternans. J Am Coll Cardiol 40:207217
362
23.
Ikeda T, Sakata T, Takami M et al (2000) Combined assessment of T-wave alternans

and late potentials to predict arrhythmic events after myocardial infarction. A prospective study. J Am Coll Cardiol 35:722730
Sanjiv M, Narayan SM (2006) T-wave alternans and the susceptibility to ventricular
arrhythmias. J Am Coll Cardiol 47:269281
Bloomfield DM, Bigger JT, Steinman RC et al (2006) Microvolt T-wave alternans
and the risk of death or sustained ventricular arrhythmias in patients with left
ventricular dysfunction. J Am Coll Cardiol 47:456463
Chow T, Kereiakes D, Bartone C et al (2006) Prognostic utility of microvolt T-wave
alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll
Cardiol 47:18201827
Hood MA, Pogwizd SM, Peirick J, Cain ME (1992) Contribution of myocardium
responsible for ventricular tachycardia to abnormalities detected by analysis of
signal-averaged ECGs. Circulation 86:18881901
Gomes JA, Cain ME, Buxton AE et al (2001) Prediction of long-term outcomes by
signal-averaged electrocardiography in patients with unsustained ventricular
tachycardia, coronary artery disease, and left ventricular dysfunction. Circulation
104:436441
Arora R, Ferrick KJ, Nakata T et al (2003) I-123 MIBG imaging and heart rate variability analysis to predict the need for an implantable cardioverter defibrillator. J
Nucl Cardiol 10:121131
Farrell TG, Odemuyiwa O, Bashir Y et al (1992) Prognostic value of Baroreflex sensitivity testing after acute myocardial infarction. Br Heart J 67:129137
Schmidt G, Malik M, Barthel P et al (1999) Heart-rate turbulence after ventricular
premature beats as a predictor of mortality after acute myocardial infarction.
Lancet 353:13901396
Denniss AR, Richards DA, Cody DV et al (1986) Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed
potentials detected on the signal-averaged electrocardiograms of survivors of
acute myocardial infarction. Circulation 74:731745
Vaitkus PT, Kindwall KE, Marchlinski FE et al (1991) Differences in electrophysiological substrate in patients with coronary artery disease and cardiac arrest or ventricular tachycardia. Insights from endocardial mapping and signal-averaged electrocardiography. Circulation 84:672678
Martinez-Rubio A, Shenasa M, Borggrefe M et al (1993) Electrophysiologic variables characterizing the induction of ventricular tachycardia versus ventricular
fibrillation after myocardial infarction: relation between ventricular late potentials
and coupling intervals for the induction of sustained ventricular tachyarrhythmias. J Am Coll Cardiol 21:16241631
Ommen SR, Hammill SC, Bailey KR(1995) Failure of signal-averaged electrocardiography with use of time-domain variables to predict inducible ventricular
tachycardia in patients with conduction defects. Mayo Clin Proc 70:132136
Steinberg JS, Prystowsky E, Freedman RA et al (1994) Use of the signal-averaged
electrocardiogram for predicting inducible ventricular tachycardia in patients with
unexplained syncope: relation to clinical variables in a multivariate analysis. J Am
Anonymous (1996) Signal-averaged electrocardiography. J Am Coll Cardiol
27:238249
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.

39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
363
Haghjoo M, Kaini R, Fazelifar AF et al (2007) Early Risk stratification for

Arrhythmic death in Patients with ST-Elevation Myocardial Infarction. Indian
Pacing Electrophysiol J 7:1925
Watanabe MA, Schmidt G (2004) Heart rate turbulence: a 5 year review. Heart
Rhythm 1:732738
Schmidt G, Malik M, Barthel P et al (1999) Heart-rate turbulence after ventricular
premature beats as a predictor of mortality after acute myocardial infarction.
Lancet 353:13901396
Barthel P, Schneider R, Bauer A et al (2003) Risk stratification after acute myocardial infarction by heart rate turbulence. Circulation 108:12211226
Leclerq JF, Maison-Blanche P, Cauchemez B, Coumel P (1988) Respective role of
sympathetic tone and cardiac pauses in the genesis of 62 cases of ventricular fibrillation recorded during Holter monitoring. Eur Heart J 9:12761283
El-Sherif N, Caref EB, Chinushi M, Restivo M (1999) Mechanism of arrhythmogenicity of the shortlong cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome. J Am Coll Cardiol 3:14151423
Gorenek B, Kudaiberdieva G, Birdane A et al (2004) Clinical importance of the initiation pattern of monomorphic ventricular tachycardia. Int J Cardiol 93:325327
Crenshaw BS, Ward SR, Granger CB et al for the GUSTO-1 Trial Investigators (1997)
Atrial fibrillation in the setting of acute myocardial infarction: The GUSTO-1 experience. J Am Coll Cardiol 30:406413
Pizzetti F, Turazza FM, Franzosi MG et al (2001) Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data. Heart
86:527532
James TN (1961) Myocardial infarction and atrial arrhythmias. Circulation
24:761776
Gorenek B, Bakar S, Kudaiberdieva G et al (2003) Predicting atrial fibrillation after
mitral valve replacement. Ann Noninvasive Electrocardiol 8:97
Wong CK, White HD, Wilcox RG et al (2000) New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO-III experience. Am
Heart J 140:878885
Turhan H, Yetkin E, Sahin O et al (2003) Comparison of P-wave duration and
dispersion in patients aged > or =65 years with those aged < or =45 years J
Electrocardiol 36:321326
Dilaveris PE, Gialafos JE (2001) P-wave dispersion: a novel predictor of paroxysmal
atrial fibrillation. Ann Noninvasive Electrocardiol 6:159165
Gorenek B, Parspur A, Timuralp B et al 2006) Atrial Fibrillation after percutaneous
coronary intervention: predictive importance of clinical, angiographic features and
P-wave dispersion. Cardiology 107:203208
Vikman S, Makikallio TH, Yli-Mayry S et al (2003) Heart rate variability and recurrence of atrial fibrillation after electrical cardioversion. Ann Med 35:3642
Ishimoto N, Ito M, Kinoshita M (2000) Signal-averaged P-wave abnormalities and
atrial size in patients with and without idiopathic paroxysmal atrial fibrillation.
Am Heart J 139:684689
Darbar D, Jahangir A, Hammill SC, Gersh BJ (2002) P wave signal-averaged electrocardiography to identify risk for atrial fibrillation. Pacing Clin Electrophysiol
25:14471453
Gorenek B, Kudaiberdieva G, Goktekin O et al (2003) Long-short sequence may
predict immediate recurrence of atrial fibrillation after external cardioversion.
Europace 5:1116
The Routine ECG as a Marker of Sudden Cardiac Death

LUIGI DE AMBROGGI
Introduction
The incidence of sudden cardiac death (SCD) in industrialized countries is
around 1 per 1,000 inhabitants per year, thus representing a major public
health problem [1]. In the majority of cases, SCD occurs in the presence of
coronary artery disease, and in about 10% of cases it is associated with
arrhythmogenic cardiomyopathies or with primary electrical defect in the
absence of cardiac structural abnormalities.
The identification of subjects prone to malignant ventricular arrhythmias
and SCD is a difficult problem still unsolved. Different indices of vulnerability to arrhythmias, based on electrocardiographic recordings or hemodynamic data, have been studied but no marker has proved sufficiently sensitive in
predicting high risk. In the last decade, various methods of analysis of short
or long periods of electrocardiographic recordings have been proposed in
order to detect information not deducible by traditional analysis of the standard 12-lead ECG, such as body surface potential mapping, signal averaging
ECG, T wave alternans, heart-rate variability, and heart-rate turbulence.
Nevertheless, the routine ECG still plays an important role in identifying
subjects at risk for SCD. The ECG can reveal signs of heart diseases that are
potentially arrhythmogenic and generic markers of susceptibility to arrhythmias.
The importance of the 12-lead ECG in the diagnosis of ischemic heart
disease and in hypertrophic and dilated cardiomyopathies is well-recognized. This presentation focuses only on the diagnostic role of the ECG in
primary arrhythmogenic heart diseases. Particular attention is given to pri-
Division of Cardiology, IRCCS Policlinico San Donato, University of Milan, San Donato
Milanese (MI), Italy
366
Luigi De Ambroggi
mary electrical disorders that are not associated with structural heart disease. For such patients, no other imaging methods can provide relevant
information.
Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial
heart-muscle disease characterized by atrophy of the right ventricular
myocardium with fibro-fatty replacement and by electric instability of the
right ventricle. These changes predispose such patients to malignant ventricular arrhythmias and SCD [2, 3].
Several ECG features have been described in ARVC, but their sensitivity
and specificity are far from satisfactory. The most frequent are negative T
waves in lead V2V3, and in the most severe forms in V4, V5; right ventricular conduction defect (QRS duration 110 ms in right precordial leads,
incomplete or complete right bundle branch block); epsilon wave (in the
most severe forms); prolonged PR interval; and the presence of premature
ventricular beats with left bundle branch block morphology. In most
patients, the ventricular tachycardia shows a left bundle branch block pattern on 12-lead ECG.
The predictive value for life-threatening arrhythmias and SCD of each
abnormality is still not well established.
Ventricular Pre-excitation
Ventricular pre-excitation is due to the presence of an accessory atrioventricular (AV) pathway, which can be located anywhere along the AV annuli
and constitutes the anatomic substrate of AV re-entry tachycardias (WolffParkinson-White syndrome). When the refractory period of the accessory
AV pathway is very short, the occurrence of atrial fibrillation can precipitate
ventricular fibrillation and SCD even in young healthy individuals.
Therefore, the electrocardiographic recognition of ventricular pre-excitation
is quite important for preventing SCD in athletes.
The typical electrocardiographic findings of ventricular pre-excitation
are a short P-Q interval and a delta wave. The approximate location of the
accessory pathway can be deduced by the delta wave and the QRS morphology in the different leads. Actually, the pre-excited QRS complex represents a
fusion between activation of the ventricles over the normal AV conduction
system and the accessory AV pathway. In some subjects, accessory pathways
367
may be incapable of continuous anterograde conduction, giving rise to an

intermittent pre-excitation. Such patients are at low risk for sudden death
caused by rapid pre-excited ventricular rates, as can occur during atrial fibrillation [4].
Primary Electrical Heart Diseases

Long QT Syndrome
The long QT syndrome (LQTS) is a familial disease characterized by an
abnormally prolonged QT interval and life-threatening ventricular arrhythmias. Different genes encoding subunits of cardiac ion channels have been
associated with LQTS. The most frequent subtypes are LQT1 and LQT2,
which involve two genes (KCNQ1 and ERG) encoding major potassium currents (IKs and IKr), and LQT3, which involves SCN5A, the gene encoding the
sodium current.
The diagnosis of LQTS is obviously based on prolongation of the QT
interval. A value of QTc > 450-460 ms in the absence of drug or electrolyte
abnormality is suggestive of the diagnosis. However, it is well known that the
absence of a prolonged QT does not exclude the possibility that the subject
may be genetically affected [5].
Characteristic features of the ECG in the three forms, LQT1, LQT2, and
LQT3, have been described [6]. LQT1 is usually associated with the presence
of broad-based T waves, LQT2 is characterized by low-amplitude T waves,
and LQT3 shows late-peak T waves (long ST segment).
Priori et al. reported that all mutation carriers with a QTc > 500 ms are at
high risk for syncope and SCD [5]. It was recently reported that the overall
risk in 200 LQTS family members increased nearly exponentially by QTc
interval deciles, i.e., the longer the QTc the greater the risk for cardiac events
[7].
In some individuals, macroscopic T wave alternans have been observed
on routine ECG, suggesting severe electrical instability [8], but this finding is
exceptional.
Catecholaminergic Polymorphic Ventricular Tachycardia

This condition usually manifests in children older than 10 years in the form
of exercise- or emotion-induced palpitations or syncope. CPVT is characterized by adrenergically induced polymorphic ventricular tachycardia in the
368
Luigi De Ambroggi
absence of structural cardiac abnormalities. The genetic defect consists of

overactivity of the ryanodine receptor gene (RYR2), which regulates calcium
exchange [9]. Other genes, such as calsequestrin 2, may also be involved.
The electrocardiographic pattern during tachycardia typically shows a bidirectional pattern of the QRS complex that can be reproduced by exercise
or isoproterenol infusion. Unfortunately, the ECG at rest is usually normal.
Brugada Syndrome
Brugada syndrome (BS) is characterized by ST-segment elevation in the
right precordial leads and a high incidence of SCD in patients with a structurally normal heart. BS is estimated to be responsible for about 4% of all
SCDs and at least 20% of SCDs in patients with structurally normal hearts.
Since the ECG pattern can be dynamic and is often concealed, it is difficult to
evaluate the true prevalence of the disease in the general population, which
should be approximately 510 per 10,000 inhabitants [10].
In BS, three ECG patterns of ventricular repolarization in the right precordial leads are recognized, and they are often associated with a QRS having incomplete or complete right bundle branch block morphology. Only
type 1 is considered definitely diagnostic of BS; this type is characterized by
a coved ST-segment elevation 0.2 mV followed by a negative T wave in
leads V1V3. In types 2 and 3, the ST-segment elevation has a saddleback
aspect. These types are considered suspicious but not diagnostic of BS.
Moreover, all three patterns can be observed in serial ECG tracings in the
same patient.
Placement of the right precordial leads in a superior position (2nd, 3rd
intercostal space) can increase the sensitivity of the ECG for detecting the
typical aspects of BS.
The diagnosis of BS is considered positive when a type 2 or type 3 STsegment elevation observed in more than one right precordial lead under
baseline conditions converts to a type 1 pattern following the administration
of a sodium-channel blocker.
The ECG manifestations of BS, when concealed, can be unmasked in particular situations, such as febrile state or increase vagal tone or, as noted
above, by administration of sodium-channel blockers (flecainide, ajmaline,
procainamide).
Approximately 20% of patients w ith BS develop supraventricular
arrhythmias, mainly atrial fibrillation.
369
Short QT Syndrome
The association between a familiar history of SCD and short QT interval has
only recently been recognized [11]. Subsequently, short QT syndrome (SQTS)
was found to be related to various genetic disorders [1214]. Up to now, the
published data have included only a limited number of patients and little is
known about the clinical presentation of SQTS [15].
The ECG obviously provides the main diagnostic clue, i.e., a short QTc
value (ranging from 250 to 340 ms). Although it would be reasonable to suppose that a shorter QT interval could predispose to a higher risk of ventricular arrhythmias, at multivariate analysis the QTc value was not found to be a
significant risk factor for cardiac arrest [15], probably due to the small number of patients studied.
Electrocardiographic Markers of Vulnerability to Arrhythmias

Many investigations have focused on the key role played by ventricular repolar izat ion abnor malit ies in the genesis of cardiac ar rhy thmias.
Schematically, vulnerability to arrhythmias can arise from two conditions of
the repolarization process: (1) a state of heterogeneity of repolarization, i.e.,
a greater than normal dispersion of recovery times, and (2) a dynamic (beat
to beat) variation of the repolarization sequence. This last condition can seldom be detected by visual inspection of a routine ECG, because the beat to
beat variations are usually very subtle (in the order of microvolts); rather,
sophisticated computerized analyses of multiple beats of an ECG tracing are
required (analysis of T wave alternans, RR/QT relation variations). However,
repolarization heterogeneity can be detected by analyzing even a single beat,
using the 12-lead ECG. In recent years, various methods to quantify this condition from the standard 12-lead ECG have been proposed.
QT Interval
Ventricular repolarization was traditionally quantified by measuring the QT
interval on the 12-lead ECG and correcting for the heart rate using the Bazett
formula.
General population studies have shown that a QTc > 440 ms doubles the
SCD risk. In particular, the QT duration has been found to predict all-cause
and cardiovascular mortality in subjects at high cardiovascular risk, such as
Luigi De Ambroggi
370
those with previous myocardial infarction [16] and arterial hypertension

[17]. As mentioned above, in congenital LQTS, the QTc duration showed a
positive significant correlation with SCD risk [7].
QT Dispersion
The measurement of 12-lead QT-interval dispersion was at one time widely
used as an index of repolarization heterogeneity, mainly because of its simplicity, but this approach has several limitations. The major limitation is that
this measure cannot be related to the true spatial heterogeneity of repolarization, since each surface lead is influenced by the electrical activity of the
entire heart. Moreover, there are other well-known methodological limitations (e.g., accuracy of measurements, inter-/intra-observer variability, number of leads used) that can partly explain the controversial results reported
in the literature [18]. In summary, whereas initial results of small retrospective studies seemed to prove the predictive value of QTd as a risk stratifier,
more recent prospective trials have not confirmed these data [19, 20].
Actually, QTd represents only a gross estimate of repolarization abnormalities and inconsistently shows a positive correlation with arrhythmic risk.
In order to identify more reliable ECG predictive markers, principalcomponent analysis of ST-T waves and a set of new descriptors of the 12lead T wave morphology have been proposed. These measure the spatial and
temporal variations of T-wave morphology, the difference in the mean wavefront direction between ventricular depolarization and repolarization, and
the non-dipolar component of repolarization [2125]. The advantage of
these variables is that they are not critically dependent on time-domain
measurements (for instance, identification of the end of the T wave) and
show good reproducibility. Nevertheless, they cannot be deduced directly by
visual analysis of the ECG, but instead require appropriate computer analysis. For these reasons, they have remained substantially confined to the clinical research setting.
References
1.
2.
3.
Priori SG, Aliot E, Blomstrom-Lundqvist C et al (2001) Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J 22:13741450
McKenna WJ, Thiene G, Nava A et al (1994) Diagnosis of arrhythmogenic right
ventricular dysplasia/cardiomyopathy. Br Heart J 71:215218
Corrado D, Basso C, Thiene G et al (1997) Spectrum of clinico-pathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 30:15121520

4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
371
Klein GJ, Gulamhusein SS (1983) Intermittent pre-excitation in the WolffParkinson-White syndrome. Am J Cardiol 52:292296
Priori SG, Schwartz PJ, Napolitani C et al (2003) Risk stratification in the long QT
syndrome. N Engl J Med 348:18661874
Moss AJ, Zareba W, Benhorin J et al ( 1995) ECG T-wave patterns in genetically
distinct forms of the hereditary long QT syndrome. Circulation 92:29292934
Monnig G, Eckardt L, Wedekind H et al (2006) Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J 27:20742080
Schwartz PJ, Malliani A (1975) Electrical alternation of the T wave: clinical and
experimental evidence of its relationship with the sympathetic nervous system and
with the long QT syndrome. Am Heart J 89:4550
Priori SG, Napolitano C, Memmi M et al (2002) Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.
Antzelevitch C, Brugada P, Borggrefe M et al (2005) Brugada syndrome: report of
the second consensus conference. Circulation 111:659670
Gaita F, Giustetto C, Wolpert C et al (2003) Short QT syndrome. A familial cause of
sudden death. Circulation 108:965970
Brugada R, Hong K, DumaineR et al (2004) Sudden death associated with short QT
syndrome linked to mutation in HERG. Circulation 109:3035
Bellocq C, van Ginneken AC, BezzinaCR et al (2004) Mutation in the KCNQ1 gene
leading to the short QT interval syndrome. Circulation 109:23942397
Priori GS, Pandit SV, Rivolta I et al (2005) A novel form of short QT syndrome
(SQT3) is caused by mutation in the KCNJ2 gene. Circ Res 96:800807
Giustetto C, Di Monte F, Wolpert C et al (2006) Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 27:24402447
Locati E, Schwartz PJ (1987) Prognostic value of QT interval prolongation in post
myocardial infarction patients. Eur Heart J 8(Suppl A):121126
Schillaci G, Pirro M, Ronti T et al (2006) Prognostic impact of prolonged ventricular repolarization in hypertension. Arch Intern Med 166:909913
Malik M (2000) QT dispersion: time for an obituary? Eur Heart J 21:955957
Zabel M, Klingenheben T, Franz MR, Hohnloser S (1998) Assessment of QT dispersion for prediction of mortality or arrhythmic events after myocardial infarction.
Results of a prospective, long-term follow-up study. Circulation 97:25432550
Brendorp B, Elming H, Jun L et al (2001) QT dispersion has no prognostic information for patients with advanced congestive heart failure and reduced left ventricular systolic function. Circulation 103:831835
De Ambroggi L, Aim E, Ceriotti C et al (1997) Mapping of ventricular repolarization potentials in patients with arrhythmogenic right ventricular dysplasia.
Principal component analysis of the ST-T waves. Circulation 96:43144318
Okin PM, Devereux RB, Fabsitz RR et al (2002) Principal component analysis of the
T wave and prediction of cardiovascular mortality in American Indians. The
Strong Heart Study. Circulation 105:714719
Zabel M, Acar B, Klingenheben T et al (2000) Analysis of T wave morphology for
risk stratification after myocardial infarction. Circulation 102:12521257
Kardys I, Kors JA, van der Meer IM et al (2003) Spatial QRS-T angle predicts cardiac death in a general population. Eur Heart J 24:13571364
Zabel M, Malik M, Hnatkova K et al (2002) Analysis of T wave morphology from
the 12-lead electrocardiogram for prediction of long-term prognosis in male US
veterans. Circulation 105:10661070
ACUTE CORONARY SYNDROMES
International Guidelines on Acute Coronary Syndrome:

Practical Application and Current News in Cardiology
GIACOMO CHIARAND, GIUSEPPA STRANO, ANGELA LAZZARO, MARTA CHIARAND
Introduction
For the last few years, the main scientific international societies have enacted
guidelines regarding the treatment of acute coronary syndrome (ACS), with
the aim of promoting the best diagnostic and therapeutic methods in cardiology. These guidelines have been frequently revised according to scientific
evidence of randomized clinical studies [1, 2]. Among other issues, they have
addressed the use of glycoprotein IIb/IIIa inhibitors, low-molecular-weight
heparin, the prescription of clopidogrel, and criteria for the selection of
patients for very aggressive or less aggressive early treatment.
Risk Stratification
Risk stratification is made up of a simple score [3, 4], such as the thrombolysis in myocardial infarction (TIMI) risk score or that of the European Society
of Cardiology (ESC). Determination of risk is very important because it
increases the advantages of very aggressive and expensive therapy in highrisk patient groups.
The TACTICS-TIMI 18 Study demonstrated an absolute reduction of risk
(death, infarction, etc.) increases with increasing calculated individual risk
(actual number of patients needed to be treated with interventionist therapy
or glycoprotein IIb/IIIa inhibitors to save one life increases from 100 for TRS
0-2, to 25 for TRS 3-4, to 9 for high-risk patients with TRS 5-7) [5]. In addition, in patients with ACS with ST elevation (STE), Kent et al. showed the
Cardiology Operative Unit, Muscatello Hospital, AUSL 8 Syracuse, Augusta (SR), Italy
376
benefits of primary percutaneous transluminal coronary angioplasty (PTCA)

over thrombolysis in high-risk patients [6].
Role of Guidelines in Clinical Practice

While guidelines in clinical practice are important in therapeutic decisionmaking, the use of a specific set of guidelines is limited. This is due to the
fact that developments in the treatment of ACS occur very rapidly, such that
the time needed to establish guidelines based on the consolidation of scientific findings and then review and implement them in clinical practice may
soon make them obsolete [7].
Nonetheless, the main problem in daily clinical practice is a lack of
awareness of existing guidelines or the failure to adhere to them. The use of
guidelines in the clinical practice of Coronary Intensive Therapy Unit
(CITU) is the main objective of several medical professional societies. A few,
such as the ESC, have elaborated definite standards for the realization and
development of guidelines in order to increase their scientific credibility and
practitioners awareness of them.
Observational studies carried out by many researchers, such as in the
form of patient registers or surveys, ultimately means an improved daily
clinical reality and better large-scale clinical trials. These have provided
important data concerning the management of ACS and the therapeutic
implications of patient outcome, but also about adhesion or non-adhesion to
guidelines.
Registers
Information obtained from patient registers demonstrates the discrepancy
between current guidelines and actual clinical/therapeutic management of
ACS, in that an opposite relationship between a patients individual risk factor and the degree of therapeutic aggressiveness has been demonstrated.
Moreover, reports in the literature have shown that coronarography within
48 h of the beginning of symptoms is very important for correct management of patients with cardiovascular risk in ACS and non-ST-elevation
(NSTE) [28].
In another recent study of patients at low risk and with TRS 0-2 who were
treated conservatively, outcome, as measured by survival, was 11.8% vs
12.8% with invasive therapy; while in high-risk patients with TRS 5-7 who
were treated conservatively, outcome was 30.6% vs 19.5% in patients treated
International Guidelines on Acute Coronary Syndrome: Practical Application and Current News
377
with invasive therapy [5]. While the literature confirms that early and invasive treatment is most effective in low-risk patients, this is often not applied
in clinical practice.
The CRUSADE study demonstrated that early coronarography in ACS
NSTE patients is frequently adopted in patients at low risk (young and few
comorbidities) as in those at high risk (elderly, diabetes, high TRS) [913].
The Italian register BLITZ-2 confirmed that a large number of ACS in
patients at high risk and with high TRS (female, diabetes, elderly) were seldom treated with coronarography, primary PTCA, or glycoprotein IIb/IIIa
inhibitors [14]. Moreover, it also found that, in general, cardiologists do not
take into consideration risk stratification; rather, the selection of invasive vs
conservative treatment depends on the availability of equipment in the
department. An invasive approach was practiced in 76% of patients hospitalized in departments with a hemodynamic laboratory but only in 36% of
patients hospitalized in departments without one. Conservative treatment
was practiced in 64% of patients hospitalized in departments with a hemodynamic laboratory. This study found that complications occurred in 23%
of patients at low risk who were treated with PTCA. The implications of this
value are adverse, because patients with low TRS 0-3 have a mortality of only
12% and ischemic complications occur in just 5% of patients after 30 days.
The Italian register ROSAI-2 (1,581 patients, 76 of CITU during 2002)
demonstrated that patients admitted to a hospital with a hemodynamic laboratory were more often treated with invasive therapy (41 vs 19%; p < 0.001)
than patients admitted to a hospital without one. Coronarography was most
often used in patients at low risk: young (66 vs 77 years; p < 0.001), male (71
vs 65%; p < 0.01) and somewhat less frequently in patients with elevated ST
(44 vs 49%; p < 0.001) [15].
Thus, it is evident that the presence of a hemodynamic laboratory in a
hospital leads to a high number of invasive treatments in low-risk patient,
without an overall improvement in prognosis (therapeutic paradox).
Is Prognosis Dependent on Hospital Complexity or Adhesion to

Guidelines?
Several studies have found that the availability of a hemodynamic laboratory
does not improve ACS patient prognosis, while adhesion to guidelines does
positively influence survival. The American register CRUSADE found that
mortality in patients with ACS NSTE during hospitalization was 5.9% if adhesion to guidelines was < 65%, 5.0 if 6575%, 4.6 if 7580%, and 3.6 if > 83%.
378
Moreover, this register found that an adhesion to guidelines of 10% reduced

mortality by 11%, while the reduction in mortality during hospitalization for
acute myocardial infarction was 40% in hospitals that nearly completely
adhered to current guidelines [16, 17].
Drug Therapy
Poor adhesion to guidelines is also related to the use of drug therapy.
According to the French register PREVENIR, the use of statins, ASA, and
beta-blockers 6 months after admission is much greater in patients treated
with PTCA during recovery than in patients not treated with PTCA [18].
The CRUSADE register also found that highly qualified centers use PTCA
therapy, while poorly qualified ones often use anti-aggregating therapy combined with an anticoagulant [aspirin (95 vs 82%), beta-blocker (89 vs 69%),
statins (81 vs 64%), clopidogrel (60 vs 36%)] [16]. In the BLITZ-2 register,
more patients treated with PTCA also received anti-aggregating/anticoagulant
therapy than patients treated with conservative drug therapy (60 vs 40%).
In the GRACE study, 30% of high-risk patients (elderly, diabetes, heart failure or aortocoronary bypass) were not treated with perfusion therapy [19].
The most up-to-date Canadian register (NRMI) consists of 200,000
patients with ACS STE myocardial infarction (MI) and NSTEMI (14.3 vs
12.5%). It was found that in this population, NSTEMI patients have a 20-40%
reduced probability of being treated with ASA, beta-blocker; ACE-I, or
statins than STEMI patients [20].
Optimal adhesion to guidelines, with subsequent improvement of therapies and prognosis, is obtained with an increased number of guidelines as
well as feedback to researchers regarding their implementation, as demonstrated by CHAMP [21].
The German registers MITRA/MIR found that continuous improvement
in adhesion to guidelines was associated with improved prognosis [22].
Is It Necessary To Shape Risk Stratification into Organizational Ability?

Eighty percent of patients with ACS NSTEMI in BLITZ- 2 and 75% of
patients with ACS STEMI in BLITZ-1 were found to be at high risk and
require invasive therapy. This percentage, however, was not compatible with
the organized system for ACS treatment established by European hub and
spoke centers. Moreover according to the TIMI risk score, 14% of patients at
low risk, 50% at middle risk, and 36% at high risk received early invasive
379
therapy. Identification of patients at high risk should be based on the use of

prognostic information, such as heart failure, ST shifts, ECG findings, and
improvement of myocardial necrosis markers. When confronted with limited
means, it is very important that hub and spoke centers for ACS treatment use
a qualified classification risk, one that is consistent with the local availability
of resources and technology. When resources are limited, it is important to
reserve resources for patients at high risk [23].
What Difficulties Arise in the Application of Guidelines?

There are many reasons for non-adhesion to guidelines:
1. Few and poorly known or unknown guidelines.
2. Limitation acceptance of criticism; hurried acceptance of recent, nondefinitive, and poorly confirmed trials.
3. Personal beliefs of clinicians based on randomized studies.
4. Local treatment preferred by departmental leaders.
5. Poor logistical technological conditions, since the recommended treatments sometimes are very expensive or not available.
The application of guidelines in clinical practice is complex and difficult,
and their elaboration and publication in scientific reviews is not enough to
guarantee their use. Therefore, in Europe and in the USA programs have
been developed to improve the acceptance and use of clinical guidelines.
These programs are based on information from physicians, non-physician
clinical professionals, patients, and the public and make use of several strategies (protocols; algorithms; multimedia systems, outsourcing, pathology
management, case histories) to provide continuous feedback to researchers
as well as those involved in clinical practice [1620]. The application of
guidelines to the treatment of patients with acute or chronic ACS could save
many lives, with annual costs that are lower than those arising from the
development of new therapies [21].
What Can Be Expected from the Next Guidelines?

1. Increase loaded dose of clopidogrel from 300 mg to 600900 mg in ACS
NSTEMI treatment.
2. Combine the use of clopidogrel and aspirin in ACS STEMI treatment.
3. Revised statin dose (atorvastatine 80 mg) in ACS NSTEMI treatment (see
PROVIT TIME, REVERSAL and ALLIANCE results).
380
4. ARB use in ACS NSTEMI in patients with FE< 40%.

5. Cholesterol LDL target < 7080 mg in management of ACS STEMI and
chronic ischemic cardiopathy.
6. Use low molecular heparin in ACS STEMI.
7. Clear definition of use of metallic stent or drug-releasing stents.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Van de Werf D, Ardissimo D, Betriu A et al (2003) Management of acute myocardial

infarction in patients presenting with ST segment elevation. The Task Force on the
Management of Acute Myocardial Infarction of the European Society of
Cardiology. Eur Heart J 24:2866
Bertrand ME, Simoons MI, Fox KA et al, on behalf of the Task Force on the
Management of Acute Coronary Syndromes of the European Society of Cardiology
(2002) Management of acute coronary syndromes in patients presenting without
persistent ST segment elevation. Eur Heart J 223:18091840
Antman EM, Cohen M, Bernink PJ et al (2000) The TIMI risk score for unstable
angina/non ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 284:835842
Oltrona L, Ottani F, Galvani M, on behalf of the Working Group on Atherosclerosis,
Thrombosis, and Vascular Biology and Associazione Nazionale Medici Cardiologi
Ospedalieri (ANMCO) (2004) Clinical significance of a single measurement of troponin-I and C-reactive protein at admission in 1,773 consecutive patients with
acute coronary syndromes. Am Heart J 148:405415
Cannon CP, Weintraub WS, Demopoulos LA et al, for the TACTICS Investigators
(2001) Comparison of early invasive and conservative strategies in patients with
unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 344:18791887
Kent DM, Schimd CH, Lau J et al (2002) Is primary angioplasty for some as good as
primary angioplasty for all? J Gen Intern Med 17:887894
Bassand JP (2000) Improving the quality and dissemination of guidelines: the
quest for the Holy Grail. Eur Heart J 21:12891290
Braunwald E, Antman EM, Beasley JW et al (2002) ACC/AHA guideline update for
the management of patients with unstable angina and non ST-segment elevation
myocardial infarction 2002: summary article. A report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines
(Committee on the management of patients with unstable angina). Circulation
106:18931900
Peterson ED (2005) Management of patients with NSTE ACS: latest insights from
CRUSADE, a National Quality Improvement Initiative. American College of
Cardiology, Scientific Sessions
Alexander HP, Roe MP, Chen AY et al (2005) Evolution in cardiovascular care for
elderly patients with non ST-segment elevation acute coronary sondromes: results
fron the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol
46:1447914487
Blomkalns AL, Chen AY, Hochman JS et al () Gender disparities in the diagnosis
and treratment of non ST-segment elevation acute coronary syndromes: largescale observations fron the CRUSADE National Quality Improvement Initiative. J
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
381
Am Coll Cardiol 2005 45:832837

Tricoci P, Peterson EP, Mulgund J et al () Temporal trends in the use of early cardiac
catheterization in patients with non ST-segment elevation acute coronary syndromes (results from CRUSADE). Am J Cardiol 2006 98:11721176
Bhatt DL, Roe MT, Peterson ED et al, for the CRUSADE Investigators (2004)
Utilization of early invasive management strategies for high-risk patients with non
ST-segment elevation acute coronary syndromes: results from CRUSADE Quality
Improvement Initiative. JAMA 292:20962104
Di Chiara A, Fresco C, Savonitto S et al (2006) Epidemiology of non ST elevation
acute coronary syndromes in the italian cardiology network: the BLITZ-2 study.
Eur Heart J 27:393405
The Registro Osservazionale Angina Instabile (ROSAI-2) Investigators (2003)
Treatment modalities of non-ST elevation acute coronary syndromes in the real
world. Results of the prospective ROSAI-2 registry. Ital Heart J 4:782790
Ohman EM, Roe MT, Smith SC et al, for the CRUSADE Investigators (2004) Care of
non ST-segment elevation patients: insights fron the CRUSADE national quality
improvement initiative. Am Heart J 148(Suppl):S34-S39
Peterson E, Parsons L, Pollack C et al (2002) Variation of AMI care quality across
1,085 US hospital and its association with hospital mortality rates. Circulation
106:II722 (Abstract)
Danchin N, Grenier O, Ferrieres J et al (2002) Use of secondary preventive drugs in
patients with acute coronary syndromes treated medically or with coronary angioplasty: results from the nationwide French PREVENIR survey. Heart 88:2024
Eagle KA, Goodman SG, Avezum A et al (2002) Practice variations and missed
opportunities for reperfusion in ST-segment elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE). Lancet
359:373377
Roe MT, Parson LS, Pollack CV et al, for the National Registry of Myocardial
Infarction Investigators (2005) Quality of care by classification of myocardial
infarction. Treatment patterns for ST-segment elevation vs non ST-segment elevation myocardial infarction. Arch Intern Med 165:16301636
Mehta RH, Montoye CK, Gallogly M et al, for the GAP Steering Committee of the
American College of Cardiology (2002) Improving quality of care for acute myocardial infarction: the Guidelines Applied in Practice (GAP) initiative. JAMA
287:12691276
Gottwik M, Zahn R, Schiele R et al, for the Myocardial Infarction Registry (MIR)
Study Group (2001) Differences in the treatment and outcome of patients with
acute myocardial infarction admitted to hospitals with compared to without
departments of cardiology: results from the pooled data of the Maximal Individual
Therapy in Acute Myocardial Infarction (MITRA 1-2) Registres and Myocardial
Infarction Registry (MIR). Eur Heart J 22:17941801
Topol EJ, Kereiakes DJ (2003) Regionalization of care for acute ischemic heart
disease: a call for specialized centers. Circulation 107:14631466
Is There a Limit to PTCA in Elderly Patients?

FRANCESCO BOVENZI, ROBERTO LORENZONI, MAURO LAZZARI, ANDREA BONI,
CRISTINA GEMIGNANI
Introduction
Life expectancy in the western world is steadily increasing; as result,
ischemic cardiopathy has a higher incidence in the population. Moreover,
highly effective therapies have become available for treating this disease,
which has led to an increase in the number of chronically ill patients. It can
therefore be presumed that within the next few years the number of patients
in their 80s and 90s will be much greater than today.
Medical therapy has undoubtedly not only improved the quality of life of
elderly patients with ischemic cardiopathy, but it has also prolonged survival
[1]. Unfortunately, however, there are situations when medical therapy alone
is not sufficient to keep the symptoms under control, and in these cases
interventional procedures are necessary. It has been demonstrated that coronary-artery bypass grafting (CABG) is better able than medical therapy
alone to prolong the life of patients in their eighties. However, the mortality
rate during surgery is very high for these patients, as is the incidence of complications following surgery, such as stroke and renal failure [2].
Angioplasty is far less invasive than CABG in the elderly and is thus the
preferred procedure for revascularization in these patients [35]. Nonetheless,
despite supportive research findings, cardiologists prefer to avoid invasive procedures in patients over the age of 80, with the result that angioplasty is performed much less in this group than in younger patients [6].
There are, undoubtedly, a number of problems to be faced when considering angioplasty in an elderly patient, but very little research has been carried out in this particular area, including a lack of specific trials. Such stud-
Division of Cardiology, Campo di Marte Hospital, Lucca, Italy
384
Francesco Bovenzi, Roberto Lorenzoni, Mauro Lazzari, Andrea Boni, Cristina Gemignani
ies as well as patient registries are needed to confirm the possibility of positive results, such as those obtained when angioplasty is performed on
younger patients with acute coronary syndrome.
Invasive Strategy
There is a general widespread tendency in medical practice to reduce symptoms and offer good quality of life rather than intervene to prolong the same
in very elderly patients. This approach persists in spite of the fact that side
effects of drugs are more common in older patients and that elderly patients
frequently have co-morbidities, such as diabetes mellitus and chronic renal
failure. If an elderly patient is in good general health, CABG can be performed. However, the sternotomy is more traumatic in elderly patients, and
chronic obstructive bronchopathy and renal failure are frequent factors that
increase the risk of further complications. In addition, the extent of cognitive
deterioration following extracorporal circulation should not be underestimated [7]. Furthermore, the administration of radiographic contrast agents
(in invasive strategies) often causes renal damage in elderly patients [8].
Another risk is linked to bleeding caused by an aggressive use of antithrombotic therapy [9].
Despite these drawbacks, coronary revascularization with bypass surgery
or angioplasty has been shown to prolong life by 4 years compared to the
administration of medical therapy alone in patients over 80 [4].
Stable Angina
The latest guidelines for the management of patients with chronic stable
angina do not take age into consideration [1]. The TIME trial demonstrated
that coronary revascularization with bypass surgery or angioplasty is superior to medical therapy [5].
Non-ST-Segment-Elevation Acute Coronary Syndrome

In these patients an invasive strategy proved to be advantageous compared
with medical therapy even in older patients. The ROSAI-2 registry demonstrated that the mortality rate after 30 days in the elderly that is patients
over 75 is four times higher than in younger patients. Nonetheless, a conservative rather than an invasive strategy is usually preferred in the elderly
[10]. The TACTICS-TIMI 18 trial demonstrated, in fact, that an aggressive
385
approach was advantageous above all in the elderly [11]. Furthermore, in

that study, there were fewer strokes, but an increased number of hemorrhagic events.
In many risk scores (TIMI, GRACE, PURSUIT), age is considered an
important factor that leads to the decision for a therapeutic invasive strategy
[12]. Unfortunately, the choice often depends on the availability of a cardiac
catheterization lab, rather than on the risk score or age of the patient [10].
Acute ST-Segment-Elevation Myocardial Infarction

Age is fundamental when calculating the TIMI risk score in acute ST-segment-elevation myocardial infarction, for which primary angioplasty,
according to the latest guidelines, remains the best therapeutic choice even
in elderly patients [1316]. It is known, however, that the incidence of hemorrhagic stroke increases following thrombolytic therapy, thus reducing the
positive effects of treatment on outcome [17]. Primary angioplasty can be
carried out safely and effectively in the elderly [18] and above all in patients
with shock [19], even if shock, such as induced by heart-muscle rupture, is a
frequent complication with acute ST-segment-elevation myocardial infarction [20].
Antithrombotic Therapy
Studies have shown that combined antiplatelet and anticoagulant therapy is
effective in patients during percutaneous coronary intervention. It is, however, necessary to pay attention to the risk of minor and major bleeding in
elderly patients. The early administration of aspirin has proved to be effective for the prevention and treatment of acute coronary syndrome [21].
Clopidogrel has been shown to reduce complications during percutaneous
coronary intervention in elderly patients and should therefore be administered upstream of the procedure [22].
The intravenous use of GP IIb/IIIa inhibitors, in addition to aspirin,
clopidogrel, and unfractionated heparin, is also important as part of the initial medical management of patients with acute coronary syndrome who are
at high risk. However, in elderly patients, the risk of bleeding increases with
these drugs; consequently, their downstream use, when complications arise,
is more opportune [23].
The REPLACE-2 study showed that, in non-ST-segment-elevation acute
coronary syndrome, bivalirudin with provisional GP IIb/IIIa blockade during elective percutaneous transluminal coronary angiography (PTCA)
386
proved superior to heparin alone with respect to protection from ischemic

events and bleeding complications. The therapy was not inferior to that of
heparin plus a GP IIb/IIIa inhibitor and was associated with fewer bleeding
complications, above all in elderly patients (over age 75). As a result,
bivalirudin with provisional GP IIb/IIIa inhibitors was validated as an anticoagulant strategy during contemporary PTCA [24, 25].
Drug-Eluting Stents
Very few indications are available regarding the use of drug-eluting stents in
patients over 80, since most of the studies were carried out on patients who
were younger than 75 years. However, according to a report presented at the
2004 American Heart Association Scientific Sessions, elderly patients treated
with the CYPHER Sirolimus-eluting coronary stent should expect the same
benefit in repeat coronary procedures as seen with younger patients. The
data were taken from the e-CYPHER Registry [26], which was designed to
better understand the safety and clinical benefits of the CYPHER stent in the
therapy of coronary artery disease in difficult-to-treat patient groups. In this
octogenarian group, 505 patients age 80 years or older had a low targetlesion revascularization rate, which was similar to the rate in the patient
group under the age of 80 (0.8 vs 1.3%). It is certain, however, that double
prolonged antiplatelet therapy is not auspicious in those who are at high risk
of bleeding and who undergo surgery frequently.
Technical Aspects
As far as percutaneous vascular access in the elderly patient is concerned, it
is preferable to use a radial rather than a femoral approach. Radial access is
often associated with fewer puncture-site bleeding complications, as the
radial artery is smaller and more superficial and therefore much easier to
compress. Consequently, it is preferable not only in elderly patients who
need to undergo percutaneous coronary intervention [27], but also in obese
patients.
Conclusions
The number of over 80-year-olds suffering from ischemic cardiopathy is
increasing, and hospitals must shoulder the burden of care. However, these
387
patients are not always managed according to current guidelines. The need
for clear clinical indications as to how to manage this population clashes
with the difficulties encountered when random trials are carried out and
with often-incomplete registry information. The effectiveness of therapeutic
choices, on the one hand, and the iatrogenic risk (risk/benefit-damage/benefit), on the other, must be evaluated and adjusted according to the protocol in
use (guidelines) and to the clinical and biohumoral checks carried out. The
effectiveness of invasive therapy is indeed significant in high-risk cases and
in particular in those involving acute coronary syndrome. However, as the
clinical features of the individual elderly patient are extremely variable and
as these patients often present with co-morbidities, a personalized evaluation is fundamental to effective and safe treatment.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Fox K, Garcia MA, Ardissino D et al (2006) Guidelines on the management of stable

angina pectoris: executive summary: the Task Force on the Management of Stable
Angina Pectoris of the European Society of Cardiolog y. Eur Heart J
27(11):13411381
MacDonald P, Johnstone D, Rockwood K (2000) Coronary artery bypass surgery for
elderly patients: is our practice based on evidence or faith? Can Med Ass J
162(7):10051006
Graham MM, Norris CM, Galbraith PD et al (2006) Quality of life after coronary
revascularization in the elderly. Eur Heart J 27(14):16901698
Graham MM, Ghali WA, Faris PD et al (2002) Survival after coronary revascularization in the elderly. Circulation 105(20):23782384
Anonymous (2001) Trial of invasive versus medical therapy in elderly patients with
chronic symptomatic coronary-artery disease (TIME). A randomised trial. Lancet
358(9286):951957
Di Chiara A, Chiarella F, Savonitto S et al (2003) Epidemiology of acute myocardial
infarction in the Italian CCU network: the BLITZ study. Eur Heart J
24(18):16161629
Newman MF, Kirchner JL, Phillips-Bute B et al (2001) Longitudinal assessment of
neurocognitive function after coronary-artery bypass surgery. N Engl J Med
344(6):395402
Tepel M, Aspelin P, Lameire N (2006) Contrast-induced nephropathy: a clinical and
evidence-based approach. Circulation 113(14):17991806
Shaw RE, Anderson HV, Brindis RG et al (2002) Development of a risk adjustment
mortality model using the American College of Cardiolog y-National
Cardiovascular Data Registry (ACC-NCDR) experience: 1998-2000. J Am Coll
Cardiol 39(7):11041112
De Servi S, Cavallini C, Dellavalle A et al (2004) Non-ST-elevation acute coronary
syndrome in the elderly: treatment strategies and 30-day outcome. Am Heart J
147(5):830836
388
11.
Bach RG, Cannon CP, Weintraub WS et al (2004) The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation
acute coronary syndromes. Ann Intern Med 2004 141(3):186195
de Araujo Goncalves P, Ferreira J, Aguiar C, Seabra-Gomes R (2005) TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with
revascularization in NSTE-ACS. Eur Heart J 26(9):865872
Morrow DA, Antman EM, Charlesworth A et al (2000) TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment
at presentation. An intravenous nPA for treatment of infarcting myocardium early
II trial substudy. Circulation 102(17):20312037
Silber S, Albertsson P, Aviles FF et al (2005) Guidelines for percutaneous coronary
interventions. The Task Force for Percutaneous Coronary Interventions of the
European Society of Cardiology. Eur Heart J 26(8):804847
Van de Werf F, Ardissino D, Betriu A et al (2003) Management of acute myocardial
infarction in patients presenting with ST-segment elevation. The Task Force on the
Management of Acute Myocardial Infarction of the European Society of
Cardiology. Eur Heart J 24(1):2866
Holmes DR Jr, White HD, Pieper KS et al (1999) Effect of age on outcome with primary angioplasty versus thrombolysis. J Am Coll Cardiol 33(2):412419
Thiemann DR, Coresh J, Schulman SP et al (2000) Lack of benefit for intravenous
thrombolysis in patients with myocardial infarction who are older than 75 years.
Circulation 101(19):22392246
Antoniucci D, Valenti R, Santoro GM et al (1999) Systematic primary angioplasty in
octogenarian and older patients. Am Heart J 138(4 Pt 1):670674
Migliorini A, Moschi G, Valenti R et al (2006) Routine percutaneous coronary intervention in elderly patients with cardiogenic shock complicating acute myocardial
infarction. Am Heart J 152(5):903908
Wang YC, Hwang JJ, Hung CS et al (2006) Outcome of primary percutaneous coronary intervention in octogenarians with acute myocardial infarction. J Formos
Med Assoc 105(6):451458
Antiplatelet Trialists Collaboration (1994) Collaborative overview of randomized
trials of antiplatlet therapy. I: prevention of death, myocardial infarction, and
stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J
308:81106
Cannon CP, Turpie AG (2003) Unstable angina and non-ST-elevation myocardial
infarction: initial antithrombotic therapy and early invasive strategy. Circulation
107(21):26402645
Iakovou I, Dangas G, Mehran R et al (2003) Comparison of effect of glycoprotein
IIb/IIIa inhibitors during percutaneous coronary interventions on risk of
hemorrhagic stroke in patients 75 years of age versus those < 75 years of age. Am
J Cardiol 92(9):10831086
Lincoff AM, Bittl JA, Harrington RA et al (2003) Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein
IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 289(7):853863
Lincoff AM, Kleiman NS, Kereiakes DJ et al (2004) Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 292(6):696703
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.

26.
27.
389
Urban P, Gershlick AH, Guagliumi G et al; e-Cypher Investigators (2006) Safety of

coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of
the e-Cypher registry. Circulation 113:14341441
Archbold RA, Robinson NM, Schilling RJ (2004) Radial artery access for coronary
angiography and percutaneous coronary inter vention. Brit Med J
329(7463):443446
When Should Patients with Ischemic Mitral Regurgitation

Undergo Cardiac Surgery?
SCIPIONE CARERJ, CONCETTA ZITO, GIUSEPPE DATTILO, GIANLUCA DI BELLA, CARMELO
NIPOTE,ANNALISA LAMARI, ROSSELLA GARUFI, SALVATORE MICCIULLA, FRANCESCO ARRIGO
Introduction
Ischemic mitral regurgitation (MR) is a frequent entity that is often overlooked in the setting of acute or chronic coronary disease [1, 2]. The prevalence of this disorder varies between 10 and 30% of MR cases. The papillary
muscles are particularly jeopardized by acute ischemia, and the posteromedial muscle (perfused by the posterior descending coronary artery) is more
vulnerable than the anterolateral one (perfused by branches of the anterior
and circumflex coronary arteries). The posteromedial muscle is perfused by
one vessel in 63% of patients, whereas the anterolateral muscle receives
blood from the two major coronary branches in 73% of patients [3]. MR following acute myocardial infarction (AMI) develops in 15% of patients suffering from an anterior insult as compared to 40% of those with an inferior
infarction. Functional MR after the ischemic insult, or induced by myocardial ischemia and transient papillary-muscle-related myocardial wall dysfunction, is therefore characterized by preserved valve integrity.
The major determinant of functional MR is systolic valve tenting, which
is directly caused by the local remodeling and, particularly, by the apical and
posterior papillary muscle displacement. Previous studies have shown that
posterior infarctions involving the posterior papillary muscle can produce
severe MR, by asymmetric tethering, whereas large anterior myocardial
infarctions with involvement of the anterior papillary muscle do not lead to
this condition. Moreover, in almost half of the patients with chronic ischemic
MR due to anterior infarction and symmetric tethering, the anterior papillary muscle is not involved, but the left ventricle is always markedly dilated
[46]. Indeed, MR secondary to asymmetric tethering represents the conse-
Cardiology Department, University of Messina, Messina, Italy
392
Scipione Carerj et al.
quence of a limited posterior infarction and causes displacement of the posterior papillary muscle and prevalent posterior tethering of both leaflets. In
symmetric tethering, MR generally represents progressive global left ventricular remodeling that is determined by a previous anterior myocardial infarction and which also involves remote zones.
Evaluation of Ischemic Mitral Regurgitation

Acute MR due to rupture of the papillary muscle should be considered in a
patient presenting with shock during AMI. The murmur may even be inaudible, which stresses the importance of performing echocardiographic examination as soon is possible in this setting. It should be remembered that
chronic ischemic MR is a dynamic condition and its severity may vary from
time to time in relation to arrhythmias, ischemia, hypertension, or exercise.
In patients with coronary disease, echocardiographic examination is useful for establishing the diagnosis and for differentiating true ischemic MR, in
which the valves are normal, from organic MR. The use of quantitative methods adds valuable information. In ischemic MR, lower thresholds of regurgitation severity, using quantitative methods, have been proposed (20 mm2 for
effective regurgitant orifice and 30 ml for regurgitant volume) [1, 7].
Preliminary studies have shown that quantitation of MR during exercise is
feasible, provides a good evaluation of dynamic characteristics, and has
prognostic importance [7]. Limited studies using low-dose dobutamine or
positron emission tomography have explored preoperative myocardial viability as a predictor of outcome [8].
Indications for Cardiac Surgery

There has been progressive improvement in our understanding of the variable mechanisms of MR in relation to different etiologies. Better knowledge
of mitral-valve anatomy and pathophysiology in different MR etiologies has
been paralleled by substantial advances in surgical management and postoperative results [2, 911]. Enormous progress has been made in the surgical
procedures for MR, with a trend towards tailored reconstructive operations
according to the specific valvular pathology [911]. Indeed, conservative
techniques, such as the treatment of MR by prosthetic valve replacement
alone, have emerged as the gold standard and applied in MR to restore proper valve function and to improve postoperative outcome by maintaining the
valve-ventricle relationship and avoiding the well-known complications
associated with prosthetics [911].
When Should Patients with Ischemic Mitral Regurgitation Undergo Cardiac Surgery?
393
Data concerning the results of surgery are far more limited in ischemic
MR than in organic MR. Operative mortality is higher than in organic MR
and the long-term prognosis is less satisfactory, with a higher recurrence
rate of MR after valve repair [12]. These less favorable results are partially
due to the more severe comorbidities in ischemic MR patients.
Acute MR secondary to papillary muscle rupture has a dismal short-term
prognosis and requires urgent surgical treatment, after stabilization of the
patients hemodynamic status, using an intra-aortic balloon pump and
vasodilators.
In patients with chronic ischemic MR, although coronary artery disease
and left ventricular dysfunction have prognostic importance, the presence
and severity of MR are independently associated with increased mortality
[1]. The limited data in the field of chronic ischemic MR has resulted in less
evidence-based management (Table 1). While chronic severe MR should be
corrected at the time of bypass surgery, there is continuing debate on the
management of moderate ischemic MR. In such patients, valve repair is
preferable and the decision must be made pre-operatively, since intraoperative echocardiographic assessment underestimates the severity of ischemic
MR. In patients with low ejection fraction, surgery is more likely to be considered if myocardial viability is present and if comorbidity is low.
There are no data to support surgically correcting mild MR due to
ischemia when the patient is asymptomatic, from the point of view of MR,
and, particularly, when coronary revascularization can be carried out by percutaneous coronary intervention. However, these patients should be carefully
followed, by clinical and echocardiographic examination, to detect any
change in the degree and the consequences of ischemic MR.
Table 1. Indications for surgery in patients with chronic ischemic mitral regurgitation
(Modified from [13])
Clinical indications
Class
Patients with severe MI, LVEF > 30% undergoing CABG
IC
Patients with moderate MI undergoing CABG if repair is feasible
IIaC
Symptomatic patients with severe MI, LVEF < 30% and option for CABG
IIaC
Patients with severe MR, LVEF >30%, no option for CABG, refractory to
medical therapy, and low comorbidity
IIbC
CABG, Coronary artery bypass grafting; MR, mitral regurgitation; LV, left ventricle; EF,
ejection fraction
Scipione Carerj et al.
394
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Grigioni F, Enriquez-Sarano M, Zehr KJ et al (2001) Ischemic mitral regurgitation:

long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 103:17591764
Levine RA, Scwammenthal E (2005) Ischemic mitral regurgitation on the threshold
of a solution: from paradoxes to unifying concepts. Circulation 112:745758
Voci P, Bilotta F, Caretta O et al (1995) Papillary muscles perfusion pattern. A
hypothesis for ischemic papillary muscle dysfunction. Circulation 91:17141718
Gorman 3rd JH, Gorman RC, Plappert T et al (1998) Infarct size and location determine development of mitral regurgitation in the sheep model. J Thorac Cardiovasc
Surg 115:615622
Gorman 3rd JH, Jackson BM, Gorman RC et al (1997) Papillary muscle discoordination rather than increased annular area facilitates mitral regurgitation after
posterior myocardial infarction. Circulation 96(Suppl):II124-II127
Agricola E, Oppizzi M, Maisano F et al (2004) Echocardiographic classification of
chronic mitral regurgitation caused by restricted motion according to tethering
pattern. Eur J Echocardiogr 5:326334
Lancellotti P, Lebois F, Simon M et al (2003) Prognostic importance of exerciseinduced changes in mitral regurgitation in patients with chronic ischaemic left
ventricular dysfunction. Circulation 108:17131717
Pu M, Thomas JD, Gillinov MA et al (2003) Importance of ischaemic and viable
myocardium for patients with chronic ischaemic mitral regurgitation and left ventricular dysfunction. Am J Cardiol 92:862864
Enrique-Sarano M, Schaff HV, Frye RL (2003) Mitral regurgitation: what causes the
leakage is fundamental to the outcome of valve repair. Circulation 108:253256
Yacoub MH, Cohn LH (2004) Novel approaches to cardiac valve repair: from structure to function. Part I. Circulation 109:942950
Al-Radi OO, Austin PC, Tu JV et al (2005) Mitral repair versus replacement for
ischemic mitral regurgitation. Ann Thorac Surg 79:12601267
Lung B (2003) Management of ischaemic mitral regurgitation. Heart 89:459464
The Task Force on the Management of Valvular Heart Disease of the European
Society of Cardiology (2007) Guidelines on the management of valvular heart
disease. Eur Heart J 28:230268
Minimally Invasive Techniques in Cardiac Surgery:

An Opportunity for All Patients?
LEONARDO PATAN, ALFIO CAVALLARO
Introduction
Cardiac operations have traditionally been carried out through the median
sternotomy approach and cardiopulmonary by-pass (CPB). However, the
procedures are associated with complications, such as infection, dehiscence,
mediastinitis, and neurological problems, some of which have an unacceptably high mortality rate. CPB, in particular, is responsible for diverse objective problems, such as hemolysis, heparin rebound phenomena, complement activation, and deterioration of the immune system, as well as subjective factors related to the degree of surgical invasiveness, such as poor
appetite, insomnia, depression, visual, memory, intellectual deficits, and loss
of sexual ability.
The experience gained through less invasive surgery in other specialties
has influenced clinical thinking regarding minimally invasive cardiac
surgery (MICS), a term initially used to describe small-incision approaches
to the heart [1]. Limited access was initially used only in coronary artery
bypass graft (CABG) surgery, but today minimally invasive approaches are
being applied to a number of other cardiac procedures as an alternative to
conventional median sternotomy. While the advantages of MICS have been
well-documented, it remains clear that a successful outcome requires a close
working relationship between surgeons, anaesthetists, and perfusionists.
Supporters of minimally invasive techniques in cardiac surgery claim significant improvements in patient comfort, lower procedural costs, and
decreased operative morbidity [25]. In this article, we review the current
minimally invasive techniques that are available and discuss whether they
represent an opportunity for all or only a select group of patients.
Centro Cuore Morgagni, ISCAS, Pedara (CT), Italy
396
Background
Cardiac surgery was the last of the surgical specialties to embrace the principles of minimal invasiveness. The complexity of the procedures presents
both obstacles and opportunities to make them less invasive. However, since
the mid-1990s, MICS has rapidly gained popularity through pioneers in the
field, such as F.J. Benetti and H. Vanermen [6, 7]. The first Port-Access single
CABG surgery procedure was done at Stanford University, California, in
April 1995. In 1996, Colvin, Galloway, Ribakove, and Grossi, performed the
worlds first minimally invasive mitral-valve repair, at the NYU School of
Medicine. The heart was accessed via small chest incisions, allowing the
patient to recover more quickly than would have been the case with traditional open-heart surgery [8]. Robotic-surgery clinical trials of minimally
invasive surgical procedures, particularly those involving repair of the mitral
valve, began that same year.
MICS Procedures: Techniques and Results

There are benefits in avoiding both median sternotomy and CPB. While in
MICS procedures this is not always possible, there is no question that they
reduce the degree of invasiveness. Besides having different degrees of invasiveness, MICS procedures may also introduce additional risk, make the conversion to conventional surgery more or less difficult, and have different
learning curves. The possibility of additional risk and the length of the
learning curve are affected by changes in instrumentation, including stabilizers, special retractors, trocar ports, and smaller-shafted instruments, the
change in visualization to partial or complete video assistance, and new ways
to carry out CPB.
To compare the different ways to lessen the aggression in cardiac surgery,
a definitive classification of this type of surgery is needed. We distinguish
five different types of MICS procedures.
Direct CABG Surgery Without CPB (Off-Pump CABG or OPCAB)

Coronary-artery bypass graft (CABG) surgery through a complete sternotomy without CPB is, for the most part, conventional and can only be considered less invasive because the CPB complication is avoided. The heart keeps
beating during the procedure and stabilizers are necessary to immobilize the
Minimally Invasive Techniques in Cardiac Surgery: An Opportunity for All Patients?
397
distal anastomotic site. Anastomoses are performed using conventional forceps and visualization. Hence, the learning curve is fairly short. This procedure carries the risk of partial revascularization but conversion to conventional surgery is not difficult. Specific indications for this type of surgery
include single-vessel disease, such as disease of the left anterior descending
artery (LAD) or right coronary artery; previous or current malignancy,
hemodialysis, severe pulmonary insufficiency, advanced age, poor ejection
fraction, calcified aortic root and arch, redo situations, recent history of
cerebral hemorrhage, and a patient who is a Jehovahs Witness [9].
Several companies have developed technologies that stabilize the anastomotic site in the same way as the Cardiac Thoracic System (CTS) or the
Octopus stabilizer. In many centers, both surgeons and anesthesiologists
have elaborated techniques to work on the beating heart without compromising the patients hemodynamic status. It remains to be seen whether full
revascularization using the same number of arterial grafts and results as
good as those obtained with CPB can be achieved.
As yet, there is no clear evidence of significant benefits for those patients
undergoing OPCAB, except for in high-risk situations (for example, elderly
patients, or patients with low ejection fraction, renal failure, etc.) [10].
Limited or Modified Approaches with CPB

An increasing array of surgical corrections have involved a limited or modified alternative approach, thus lessening the damage to the thoracic cavity.
These include: hemisternotomy, partial T, J or L sternotomy through the 3rd
or 4th intercostal space, reversed-T sternotomy, transverse sternotomy,
parasternotomy with excision of two or more costal cartilages (as in the
Dresden technique), and various types of anterolateral minithoracotomies
[11, 12]. The surgical techniques are fairly conventional so the learning curve
is short, but conversion to conventional surgery is more difficult. CPB can be
done either in the conventional manner or with the EndoCPB System.
Visualization is conventional, but special retractors are required.
Specific indications for such procedures include redo situations, previous
sternitis and mediastinitis, severe pulmonary insufficiency, and disorders of
the ventilatory muscles. These approaches reduce the injury to the thoracic
cavity and the amount of pain. The thoracic cavity is more stable after
hemisternotomy or J sternotomy, which will most certainly benefit some
patients. Comfort and cosmesis may also be improved, and some patients
will have a shorter rehabilitation period.
398
Minimally Invasive Direct CABG Surgery without CPB (MIDCAB)

This approach consists of the anastomosis of a pedicle of an arterial graft,
most commonly the internal mammary artery (IMA), to a coronary branch
(usually the LAD) on the beating heart via a parasternal or left anterior
small thoracotomy (LAST operation). The value, even in the extended 18- to
20-year follow-up, of a bypass from an IMA to the LAD is well-documented
in the literature, and in the off-pump and mini-thoracotomy setting the procedure is extremely cost-effective. Thus, it is a valid alternative for endovascular procedures. In two- or three-vessel disease, it may be a part of a welldesigned hybrid therapy protocol. It is most definitely minimally invasive,
and epidural anesthesia can provide additional comfort to the patient.
However, the learning curve is difficult, and conversion to conventional
surgery can be cumbersome. Special retractors and stabilizers are required,
although visualization may be conventional or video-assisted, particularly in
the take-down of the IMA to obtain a full-length view of the graft [13].
Keyhole Approaches with Endo-CPB System (True Port-Access or Heartport)

For some surgical procedures, an endoscopic or keyhole approach, also
referred to as true Port-Access or Heartport surgery, or video-assisted
surgery, may be performed [7, 8, 1416]. In this approach, surgery is
through one to four small (510 mm) incisions or ports and a 57 cm
working port in the chest wall between the ribs. An endoscope or thoracoscope and surgical instruments are placed through the incisions. Since the
large vessels are not easily accessible, new methods to install the CPB and to
arrest the heart are necessary to allow surgery in a gold-standard setting. A
CPB system that does not require a large access and that uses endovascular methods is called endo-CPB. The Seldinger technique is used to introduce Heartports arterial and venous cannula in the femoral artery and
femoral and internal jugular veins, respectively. Since endo-CPB is not
appropriate for all patients, it is important to take into account the preoperative thresholds indicating the presence of good peripheral arteries. During
surgery, it is essential to know exactly when to retreat and/or to convert in
order to exclude additional risk. Transesophageal echocardiography (TEE)
will clearly show the right lumen, the passage through the right vessel, and
the exact positioning of, for example, the endo-aortic balloon. Safe cardiac
ar rest is a challenge in Por t-Access surger y. The technolog y of the
Heartport Endo-aortic clamp allows endo-aortic balloon inflation to
occlude the lumen and the delivery of antegrade cardioplegia, under TEE
positioning and monitoring.
399
In some centers, a large percentage of Port-Access mitral or tricuspid

valve procedures have been carried out on the beating heart. This is an
advanced technique that uses Endo-CPB and better preserves heart function
than when the heart is stopped during surgery.
The types of MICSs that are possible using the innovative Port-Access or
keyhole approach include: valve surgery, atrial-septal defects (ASD) and
myxoma surgery, biventricular pacemaker lead placement on the surface of
the left ventricle, and minimally invasive surgery for atrial fibrillation [8,
1416]. The ability to perform an endoscopic anastomosis, if not robotically
assisted, still remains the rate-limiting step for totally endoscopic CABG
surgery [17].
Robotic-Assisted Cardiac Surgery

Robotic-assisted cardiac surgery may change the way certain heart surgeries,
such as valve surgery and single-vessel or multi-vessel CABG surgery, are
performed in the future [17]. In this type of MICS, the cardiac surgeon uses a
computer to control surgical instruments on thin robotic arms. The technology allows surgeons to perform certain types of complex heart surgeries
with smaller incisions and precise motion control. The surgeons hands control the movement and placement of the endoscopic instruments. The robotic arm and wrist movements mimic those of the surgeon. The surgeon is
always in control during the surgery, and there is no chance that the robotic
arms will move on their own. In several centers, robotic-assisted surgical
technique is used in select patients during CABG surgery (with single-vessel
disease), biventricular pacemaker lead placement on the surface of the left
ventricle, and catheter ablation for the treatment of paroxysmal atrial fibrillation. Robotic technology is a prerequisite in totally endoscopic CABG
surgery. During the implementation phase, several surgeon-related technical
difficulties may be encountered. Technical difficulties associated with this
type of surgery translate into markedly increased operative time, moderately
prolonged postoperative ventilation time, and slightly increased hospital
stay. Short-term survival and freedom from angina, however, do not seem to
be compromised.
Benefits of Minimally Invasive Surgery and Patient Selection

Several studies have demonstrated that the aforementioned techniques offer
several patient benefits [25, 18]. The documented advantages of MICS
400
include a smaller incision and a smaller scar. Incisions are 34 inches instead
of 68 inches, as required for traditional surgery. Other possible benefits of
MICS, compared to open-chest surgery, are listed in Table 1.
According to Vaca et al. patients experience less pain and return to normal activities faster [19].
Hospital stays are shortened to 45 days or less, compared to 812 days
for conventional heart surgery.
The recovery period is reduced to 24 weeks instead of 812 weeks. Other
patient benefits in CABG surgery include the decreased incidence of atrial
fibrillation (1015% vs 3550% post-conventional), therefore lowering morbidity. Although, on balance, the techniques require larger amounts of disposable items and have higher revenue costs, intensive care and hospital stay
are shorter. This, along with more rapid rehabilitation, results in lower
healthcare costs.
MICS is appropriate and effective for the treatment of many congenital or
acquired cardiac conditions, including such complex and demanding clinical
cases as mitral and tricuspid valvulopathies, single-vessel CABG surgery,
myxomas, epicardial lead placement in cardiac resynchronization therapy,
paroxysmal atrial fibrillation, and ASDs. Also, harvesting of the saphenous
vein and radial artery may be performed using small-incision approaches.
At this early stage, not all patients are candidates for a minimally invasive
approach [9, 16], as there are some relative contraindications. These include
a previous right or left thoracotomy with an adherent lung, severe mitral
valve annulus calcification, a dilated ascending aorta greater than 4.5 cm in
Table 1. Minimally invasive cardiac surgery: benefits
Less damage to tissue and muscle
Reduced risk of infection
Less bleeding
Elimination, in some patients, of the need for cardiopulmonary bypass
Lower risk of complications
Less pain and trauma
Shorter hospital stay, quicker return home
Quicker recovery
Improved quality of life and heart function
Easier mobility and walking
Faster return to normal life (often in 2 weeks)
Minimal assistance, once home
Earlier, more consistent cardiac rehabilitation program
401
diameter, and severe pulmonary hypertension. Thus, each patient must be

individually assessed prior to surgery.
Discussion
Unquestionably, MICS benefits both CABG and heart valve surgeries [25].
In all cases, the emerging data suggest that these less-invasive operative techniques provide measurable clinical and physiologic benefits.
CPB and the access represent the two sources of invasiveness. Whenever a
revascularization is needed, it should be as least invasive as possible, and a
complete armamentarium suited to the procedure must be at hand.
Nonetheless, CPB must be avoided in several specific cases, such as renal,
recent cerebrovascular accident, calcified aorta, malignant tumor, the patient
being a Jehovahs Witness, and in elderly people in whom the number of targets is low.
Important advantages (such as less pain, less systemic stress response,
and recovery in approximately half the time, based on the Duke activity
index score) have been seen in patients who have undergone OPCAB and
MIDCAB compared to those who had conventional surgery for multi-vessel
CABG. Since these techniques avoid CPB, the risk of stroke and other bypassrelated complications is diminished. At NYU School of Medicine, approximately 2530% of patients requiring CABG are currently treated with a lessinvasive operative approach. A study of high-risk patients with atheromatous
disease of the aortic arch requiring CABG surgery demonstrated that
patients who received OPCABG or MIDCABG had half the risk of stroke and
death compared to those receiving conventional surgery.
MIDCAB is an excellent surgical procedure when LIMA to LAD is the
only aspect to be considered, although the learning curve is probably the
most important factor. In complete revascularization through a small access
on- or off-pump, such as important lesions of the LAD and its tributaries, the
alternative of leaving the rest to the cardiologists in a hybrid-therapy strategy, should also be considered. Whenever complete and/or arterial revascularization is mandatory and the patient would be at risk with either technique, opting for the conventional approach is the best option.
Small-access is the best choice for those patients in whom fast rehabilitation and/or cosmesis are important to return to work and/or sport, and the
number of target is not impressive.
These strategies, which allow risk stratification based on anatomy and
risk factors such as severe vascular disease or renal failure, have led to
improved overall results and a reduced risk.
402
The impact of minimally invasive approaches on valvular surgery has

been even more striking than those of coronary bypass surgery. Cohn et al.
[11] recently reported results of 100 patients who underwent minimally
invasive mitral valve repair or replacement using a right parasternal incision. The operation was successfully completed in all patients. Sixty percent
of the patients did not require blood transfusion and the mean hospital stay
was only 5 days. The authors observed that post-operative pain and return to
normality were improved compared to sternotomy patients.
Cosgrove et al. [12] reported results from 115 patients who underwent
isolated mitral or aortic valve surgery using a parasternal incision. The operative risk in this series was 1%. Seventy-seven percent of the patients did not
receive blood and the mean hospital stay was 5 days. The authors concluded
that the less invasive approach reduced surgical trauma, the need for blood
transfusion, and length of hospital stay.
Although less invasive, MICS is still major heart surgery, with the potential for risks and complications, including stroke and death. A patients particular anatomy, clinical circumstance, or tendency for excessive bleeding
may cause the surgeon to switch to a conventional sternotomy approach to
complete the operation safely and effectively.
Risks and complications of any type of heart surgery include damage to
major blood vessels or adjacent structures, chest wound pain or infection,
bleeding from the wound or internal organs, irregular heartbeat, stroke, or
death. Risks associated with MICS include damage to major blood vessels,
especially aortic dissection, and potential damage to the ribs.
Results of MICS have been extremely good, with a very low operative
risk, less bleeding, less risk of infection, and shorter overall recovery. Followup studies have shown that valve repair durability is equivalent to that
achieved with conventional surgery. Thus, the short-term risks are reduced
with equivalent to long-term results.
The minimally invasive approach has become the standard of care for
most patients requiring isolated valve repair or replacement, with the PortAccess approach being used for virtually all mitral-valve surgery.
In summary, the large and extremely favorable experience with MICS
suggests that this form of less-traumatic surgery is now preferred for most
patients requiring aortic- or mitral-valve surgery, for ASD repair, and for
atrial myxoma excision. Patients requiring CABG surgery are risk-stratified
for either conventional surgery, MIDCAB, or OPCAB, which has lowered the
overall risk significantly. MICS patients require less blood, have fewer infections, and recover more quickly. Emerging new technologies are having a
dramatic impact on patient care by lowering the overall morbidity, pain, and
403
suffering associated with heart surgery.

Costs can be phenomenal as instruments are disposable, with new instruments being required for each operation. Thus, the initial cost of setting up a
theatre with the correct equipment must also be considered.
Long-term costs will be lower due to reduced hospitalization and
improved recovery times.
Conclusions
Since 1996, the use of MICS has expanded dramatically, and this surgical
strategy has become an accepted and established alternative to conventional
surgery. Many groups are developing minimally invasive techniques for all
types of heart surgery. In each of these procedures, every effort is made to
limit the trauma to the patient. The experience to date has demonstrated that
MICS is a safe and broadly applicable technique for performing a wide range
of complex cardiac procedures with highly reproducible results and several
benefits. CABGs and mitral-valve replacement are examples of the successful
surgeries performed using minimally invasive techniques. However, risks
and complications remain. Currently, not all patients are suitable for MICS.
Technical, anatomical, and organizational aspects associated with the surgical learning curve and the high initial costs influence the indications for
these approaches. Heartports technology has the potential to change cardiac
surgery in much the same way that laparoscopic techniques have revolutionized gall-bladder surgery. It is likely that over the next few years the term
minimally invasive will be replaced with minimally invasive and innovative to encompass all forms of innovative cardiac surgery that carry less
invasion of tissues, thus reflecting the true meaning of MICS.
References
1.
2.
3.
4.
5.
6.
Mack MJ (2006) Minimally invasive cardiac surgery. Surg Endosc Suppl 2:S488-492
King RC, Reece TB, Hurst JL et al (1997) Minimally invasive coronary artery bypass
grafting decreases hospital stay and cost. Ann Surg Jun 225:805811
Del Rizzo DF, Boyd WD, Novick RJ et al (1998) Safety and cost-effectiveness of
MIDCABG in high-risk CABG patients. Ann Thorac Surg 66:10021007
Magovern JA, Benckart DH, Landreneau RJ et al (1998) Morbidity, cost, and sixmonth outcome of minimally invasive direct coronary artery bypass grafting. Ann
Thorac Surg 66:12241229
Arom KV, Emery RW, Flavin TF et al (1999) Cost-effectiveness of minimally invasive coronary artery bypass surgery. Ann Thorac Surg 68:15621566
Benetti FJ, Ballester C, Sani G et al (1995) Video assisted coronary bypass surgery. J
Card Surg 10:620625
404
7.
Vanermen H, Wellens F, De Geest R et al (1999) Video-assisted Port-Access mitral

valve surgery: from debut to routine surgery. Will Trocar-Port-Access cardiac surgery ultimately lead to robotic cardiac surgery. Semin Thorac Cardiovasc Surg
11:223234
Schwartz DS, Ribakove GH, Grossi EA et al (1997) Minimally invasive mitral valve
replacement Port-Access technique, feasibility and miocardial functional preservation. J Thorac Cardiovasc Surg 113:10221031
Diegeler A, Matin M, Falk V et al (1999) Indication and patient selection in minimally invasive and off-pump coronary artery bypass grafting. Eur J Cardiothorac
Surg Suppl 1:S79-S82
Acuff TE, Landreneau RJ, Griffith BP, Mack MJ (1996) Minimally invasive coronary
artery bypass grafting. Ann Thorac Surg 61:135137
Cohn LH, Adams DH, Couper GS et al (1997) Minimally invasive cardiac valve surgery improves patient satisfaction while reducing costs of cardiac valve replacement and repair. Ann Surg 226:421426
Cosgrove DM 3rd, Sabik JF, Navia JL (1998) Minimally invasive valve operations.
Ann Thorac Surg 65:15351539
Mack MJ, Acuff T, Osborne J (1998) Minimally invasive direct coronary artery
bypass: technical considerations and instrumentation. J Card Surg 13:290296
Chitwood R Jr (2000) Video-assisted mitral valve surgery using the Chitwood
clamp. Oper Techn Thorac Cardiovasc Surg 5:176189
Fann JI, Pompili MF, Stevens JH et al (1997) Port-Access cardiac operations with
cardioplegic arrest. Ann Thorac Surg Jun 63(6 Suppl):S35-S39
Glower DD, Landolfo KP, Clements F et al (1998) Mitral valve operation via Port
Access versus median sternotomy. Eur J Cardiothorac Surg 14:S143-S147
Bonatti J, Schachner T, Bonaros N et al (2006) Technical challenges in totally endoscopic robotic coronary artery bypass grafting. J Thorac Cardiovasc Surg
131:146153
Schroeyers P, Wellens F, De Geest R et al (2001) Minimally invasive video-assisted
mitral valve repair: short and mid-term results. J Heart Valve Dis 10:579583
Vaca KJ, Daake C, Lambrecht DS (1997) Nursing care patients undergoing thorascopic minimally invasive bypass grafting. Am J Crit Care 6:281286
Chitwood WR Jr, Nifong LW (2003) Minimally invasive and robotic valve surgery.
In: Cohn LH, Edmunds LH Jr (eds) Cardiac surgery in the adult. McGraw-Hill, New
York, pp 10751092
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
GLOBAL CARDIOVASCULAR RISK PREVENTION
Cardiovascular Risk Management: An Overview

A NDREA B ONI , R OBERTO LORENZONI , M AURO L AZZARI , C RISTINA G EMIGNANI ,
FRANCESCO BOVENZI
Introduction
Cardiovascular disease (CVD) is a leading cause of mortality and is responsible for one-third of all global deaths annually. This translates into the deaths of
17 million people each year [1, 2]. Despite research-based gains in the treatment of CVDs, they remain the leading killer in the USA and in most developed areas of the world. Coronary heart disease (CHD) accounts for the majority of CVD deaths, disproportionately afflicts racial and ethnic minorities, and
is a prime target for prevention. Hypertension is the most prevalent CVD,
affecting at least 600 million people, and is an important contributor to cardiovascular mortality and morbidity [3]. Nearly 85% of the global mortality and
disease burden from CVD is borne by low- and middle-income countries.
In India, for example, approximately 53% of CVD deaths are in people
younger than 70 years of age; in China, the corresponding figure is 35%. The
majority of the estimated 32 million heart attacks and strokes that occur
every year are caused by one or more cardiovascular risk factors hypertension, diabetes, smoking, high levels of blood lipids, and physical inactivity
and most of these CVD events are preventable if meaningful action is taken
against these risk factors.
The Challenges of Effective Cardiovascular Risk Management

The prevention of CVDs too frequently focuses on single risk factors, rather
than on comprehensive cardiovascular risk. For many years, individual car-
Division of Cardiology, Campo di Marte Hospital, Lucca, Italy
408
Andrea Boni, Roberto Lorenzoni, Mauro Lazzari, Cristina Gemignani, Francesco Bovenzi
diovascular risk factors have been dealt with in isolation, often by specialists
with an interest in one particular risk factor, for example hypertension or
hypercholesterolemia. There has recently been a move to emphasize the
importance of reducing global cardiovascular risk. This requires clinicians to
address any one of a number of different risk factors. The interplay between
these various factors is important in our understanding of development of
CVD and, similarly, the synergistic effects of targeting different risk factors
is important in risk reduction.
Evidence based, cost-effective interventions are available for addressing
comprehensive cardiovascular risk, and the challenge now is to use what we
know, particularly in low- and middle-income countries. Advances in cardiovascular epidemiology in developed countries provide the knowledge base
necessary to understand the underlying biological processes that account for
these emerging epidemics [4, 5]. This calls for resource-sensitive, innovative
strategies.
Barriers to Comprehensive Cardiovascular Risk Assessment

and Management
Health Policy
The overriding barrier to CVD risk-management programs in low- and middle-income countries is that there are no formal policies that target CVD as a
major health issue. In 2001, a survey of 167 countries in the six WHO regions
found that 57% of the countries lacked a non-communicable-disease policy,
and 65% had no CVD plan [6]. Several factors explain the absence of formal
policies in such settings: a paucity of epidemiological data documenting the
scope of CVD; a focus on communicable diseases; a lack of knowledge about
the cost-effectiveness of CVD prevention; and limited human and physical
resources. The per capita health expenditures vary from US$ 4,055 in the
USA, to US$ 34 in China and US$ 1 in Liberia.
Health-care Systems
The lack of a health policy for CVDs can have many downstream effects,
most notably the inadequate allocation of resources to local health systems
for CVD management. Other factors that limit CVD risk management at the
system level include: under-equipped health facilities; a lack of continuity
between primary health-care and the secondary- and tertiary-care sectors
409
[7]; poorly developed information systems; a lack of awareness of the potential health benefits and cost savings of CVD programs; and the influence of
commercial interests on resource allocation.
This situation needs to be rectified, such that primary health facilities,
which are most accessible to patients, are equipped to provide basic CVD
care. This sector has been developed for treating acute, time-limited illnesses
and thus does not have information systems to support the patient follow-up
necessary for CVD risk management. Finally, the commercial interests that
shape the purchase of pharmaceuticals and devices have a strong impact on
the current provision of CVD care in under-resourced settings.
Hypertension:A Gateway to Risk Factor Management

Several studies have demonstrated that conventional management of hypertension leaves patients at an unacceptably high risk of cardiovascular and
other complications, such as myocardial infarctions, strokes, cardiac failure,
renal failure and death [7, 8]. This appears to be due mainly to suboptimal
blood-pressure control and failure to address other coexistent risk factors
that contribute to total cardiovascular risk [9]. People with high blood pressure frequently have other risk factors for CVD. These include the common
occurrences of dyslipidemia, impaired glucose tolerance, and target organ
damage. Thus, the identification of hypertension should prompt the physician to search for other risk factors and consider them as part of a comprehensive strategy to reduce a patients cardiovascular risk. This concept is
important because the simple measurement of blood pressure provides what
has been described as a gateway to risk factor management, i.e., a simple
means of identifying people at risk for CVD prior to the onset of diseaseassociated symptomatology and events. These findings demand a paradigm
shift from treatment of hypertension to management of comprehensive
cardiovascular risk. In addition, the cost-effectiveness of treating hypertension is also determined by the overall cardiovascular risk and not by blood
pressure alone [10, 11].
The Way Forward

Guideline developers may continue to focus their guidelines around traditional gateways of CVD risk management, notably, the detection of high
blood pressure, dyslipidemia, or diabetes. Nevertheless, whatever the gateway, the objective of treatment must be the same, to optimize CVD risk
410
reduction. The force of evidence from clinical trials has led to an evolution
in thinking with regard to CVD prevention. It is rare to find an individual
patient who has only a single risk factor for CVD; instead, the vast majority
has multiple risk factors that conspire to increase their risk. The only effective strategy to optimize CVD risk reduction is to formally assess risk in
each patient by using one of the many CVD risk calculators currently available. If risk is elevated, then optimal therapy must involve the use of multiple
strategies aimed at reducing risk rather than focusing on individual risk factors. In the example of hypertension, an individuals risk is not determined
solely by his or her blood pressure. Or, to benefit from a statin, all a hypertensive patient needs is an elevated risk, not necessarily an elevated cholesterol value. This is an important shift in thinking, but a shift that is consistent with long-established evidence from epidemiologic studies. Although
the concept of applying evidence-based medicine to clinical practice seems
simple, there are many issues to consider. Several studies, for example, have
demonstrated low rates of compliance with evidence-based treatment guidelines for managing hypertension [12, 13]. Furthermore, conventional management of hypertension leaves patients at an unacceptably high risk of cardiovascular events, due to suboptimal blood pressure control and failure to
address coexistent cardiovascular risk factors [8, 10]. In many settings, the
management of hypertension is suboptimal, mainly due to barriers related to
patients, health-care providers, and the health system [13]. Furthermore, the
management of cardiovascular risk, compared to treating elevated blood
pressure per se, demands more skills and better-maintained and betterequipped facilities. To meet these demands, flexible tools need to be developed that can be applied in many situations.
The Objective of CVD Prevention in Clinical Practice

The specific objective of CVD prevention for individuals at high risk is to
reduce the risk of CVD and its complications, including the need for percutaneous or surgical revascularization procedures in any arterial territory, and
to improve quality of life and life expectancy. The broader objective of CVD
prevention is to reduce the risk of a non-fatal or fatal atherosclerotic cardiovascular event and to improve both quality and length of life. These broader
goals can be achieved through lifestyle and risk-factor interventions and
appropriate drug therapies to lower blood pressure, modify lipids, and
reduce glycemia. For the high-risk population, a number of drugs from different classes will reduce the risk of recurrent disease and increase life expectancy. These drugs include: anti-thrombotics as well as blood-pressure-, lipid-,
411
and glucose-lowering therapies. CVD prevention should be provided in clinical practice and with equal access to: (1) people with any form of established
atherosclerotic CVD; (2) asymptomatic people without established CVD but
who have a combination of risk factors that put them at high total risk (estimated multifactorial CVD risk 20% over 10 years) of developing atherosclerotic CVD for the first time; (3) people with diabetes mellitus (type 1 or 2).
Individuals in these three groups require professional lifestyle and multifactorial risk-factor management of defined lifestyle and risk factor targets. In
addition, the elevation of a single risk factor is also an indication for CVD
prevention because affected individuals are also at high cardiovascular risk,
regardless of the presence of other risk factors. These single risk factors are:
(1) elevated blood pressure 160 mmHg systolic or 100 mmHg diastolic, or
lesser degrees of blood pressure elevation with target-organ damage; (2) elevated total cholesterol to high density lipoprotein (HDL) cholesterol ratio
6.0; (3) familial dyslipidemia, such as familial hypercholesterolemia or familial combined hyperlipidemia. Finally, anyone with a family history of premature CVD should be assessed for their cardiovascular risk and then managed
appropriately.
Identifying Those at Risk

All adults from 40 years onwards who have no history of CVD or diabetes
and who are not already on treatment for blood pressure or lipids should be
considered for an opportunistic comprehensive CVD risk assessment in primary care. Younger adults (< 40 years) with a family history of premature
atherosclerotic disease should also have their cardiovascular risk factors
measured. Risk assessment should include ethnicity, smoking habit history,
family history of CVD, and measurements of weight, waist circumference,
blood pressure, non-fasting lipids (total cholesterol and HDL cholesterol),
and non-fasting glucose. The new Joint British Societies CVD risk prediction
chart should be used to estimate total risk of developing CVD (CHD and
stroke) over 10 years based on five risk factors: age, sex, smoking habit, systolic blood pressure, and the ratio of total cholesterol to HDL cholesterol.
This is the estimated probability (percentage chance) of developing CVD
over the next 10 years. Total CVD risk should be estimated for the persons
current age group: < 50 years, 5059 years, or 60 years. A total CVD risk of
20% over 10 years is defined as high risk and requires professional lifestyle
intervention and, where appropriate, drug therapies to achieve the lifestyle
and risk-factor targets. Numerous methods [14] to calculate a patients
absolute cardiovascular risk have been described (Table 1).
Mean blood pressure; total cholesterol;

diabetes mellitus; smoking; family history;
anginal symptoms
5,203 men age 4059 (UK heart disease

prevention project)
4,400 men and women age 4065

(workplace study)
Dundee coronary risk

disk (UK)
PROCAM risk function

(Germany)
British regional heart

735 men age 4059 (from general
study risk function (UK) 7practitioner practices)
LDL, Low density lipoprotein; HDL, high density lipoprotein
Age; systolic blood pressure; total and HDL

cholesterol; diabetes mellitus; smoking;
family history; anginal symptoms

(lipid research clinics follow-up cohort)
Cardiovascular disease
life expectancy model
(USA and Canada)
Total cholesterol; systolic blood pressure;
smoking
Age; sex; mean blood pressure; total and

HDL cholesterol; diabetes mellitus;
smoking; cardiovascular disease
Age; sex; systolic and diastolic blood

pressure; total, LDL, and HDL cholesterol;
diabetes mellitus; smoking

(original and offspring Framingham
studies)
Framingham (USA)
Variables incorporated
Population derived in
Risk prediction model
Table 1. Tools for determining cardiovascular prognosis in individual patients
No
Not in women
Not in women
Yes
Yes
Validated in other data sets?
412
413
For people with established atherosclerotic CVD, hypertension with target-organ damage, familial dyslipidemias such as familial hypercholesterolemia, or diabetes, formal risk estimation is not necessary since all of
them are at high total CVD risk.
The Targets in CVD Prevention

Lifestyle
Lifestyle intervention, i.e., to discontinue smoking, make healthier food
choices, increase aerobic physical activity, and achieve optimal weight and
weight distribution, is central to CVD prevention in all high-risk individuals. Involvement of the entire family may be helpful, together with community resources. Lifestyle measures consist of:
Maintaining normal weight for adults (body mass index 2025 kg/m2)
Reducing salt intake to < 100 mmol/day (< 6 g NaCl or < 2.4 g Na+/day)
Limiting alcohol consumption to 3 units/day for men and 2 units/day for
women
Engaging in regular aerobic physical exercise (brisk walking rather than
weightlifting) for 30 min per day, ideally on most of days of the week but
at least on 3 days of the week
Consuming at least five portions/day of fresh fruit and vegetables
Reducing the intake of total and saturated fat
Blood Pressure
The optimal blood pressure target is < 140 mmHg systolic and < 85mm Hg
diastolic. In selected higher-risk people (established atherosclerotic disease,
diabetes, and chronic renal failure) a lower blood-pressure target of < 130
mmHg and < 80mm Hg may be more appropriate. These targets can usually
be achieved with antihypertensive drugs prescribed at doses (and in combinations) that were shown in clinical trials to be efficacious and safe. An
audit standard of < 150 mmHg systolic and < 90 mmHg diastolic is also
recommended. For higher-risk people with atherosclerotic disease, diabetes,
or renal failure, the recommended audit standard is < 140 mmHg systolic
and < 80 mmHg diastolic. However, these audit standards are considered to
be the minimum standard of care for this population. Wherever possible, the
optimal treatment targets should be achieved.
414
Blood Lipids and Dyslipidemia

The optimal total cholesterol target is < 4.0 mmol/l and low density lipoprotein (LDL) cholesterol < 2.0 mmol/l, or a 25% reduction in total cholesterol
and a 30% reduction in LDL cholesterol, whatever results in the lowest
absolute value. HDL cholesterol and triglyceride values should also be considered in overall lipid management. Total and LDL cholesterol targets are
usually achieved with lipid-lowering drugs prescribed at doses shown to be
efficacious and safe in trials. An audit standard for total cholesterol of < 5.0
mmol/l (or a 25% reduction in total cholesterol) and for LDL cholesterol of <
3.0 mmol/l (or a 30% reduction in LDL cholesterol), whatever results in the
lowest absolute level, is also recommended. This audit standard is considered
to be the minimum standard of care for all individuals at high risk.
Whenever possible, the optimal treatment targets should be achieved.
Blood Glucose and Diabetes

In all those at high risk, optimal fasting glucose is 6.0 mmol/l. If the non-fasting glucose is < 6.1 mmol/l it does not need to be repeated. If it is 6.1 mmol/l
then fasting glucose should be measured for evidence of impaired glucose
regulation or new-onset diabetes. If this measurement is normal (6.0 mmol/l)
there is no need to repeat it. If it is abnormal (6.16.9 mmol/l) but not
indicative of diabetes (7.0 mmol/l), either it should be repeated on a separate
occasion or an oral glucose tolerance test (OGTT) should be administered. If
the second fasting glucose is still abnormal (6.16.9 mmol/l) the patient has
impaired fasting glycemia (IFG). If fasting glucose values are 7.0 mmol/l on
separate occasions, the diagnosis of diabetes is made regardless of symptoms. In the presence of diabetic symptoms (thirst, polyuria, and weight loss)
a fasting glucose 7 mmol/l on one occasion is considered diagnostic of diabetes. An OGTT is the only way to diagnose impaired glucose tolerance (IGT)
(2-h glucose 7.8 mmol/l but < 11.1 mmol/l) and is the conventional standard
for the diagnosis of diabetes mellitus (2-h glucose 11.1 mmol/l).
For individuals with impaired glucose regulation (either IFG or IGT) the
aim is to prevent progression to diabetes and CVD through lifestyle intervention and, where appropriate, drug therapy. These patients should be followed up annually to reassess glucose regulation and all other cardiovascular
risk factors. With a diagnosis of type 1 and 2 diabetes mellitus, rigorous control of glycemia is recommended with treatment.
415
Conclusions
The enormous treatment opportunities available must be balanced against
the magnitude of the health challenges. Although heart attacks and strokes
are leading causes of death and disability, they represent only the tip of an
iceberg. Indeed, all societies that adopt an industrialized lifestyle have seen
the emergence of CVD risk factors on a mass scale. These modifiable risk
factors (i.e., smoking, unhealthy diet, and lack of physical activity) are
expressed as hypertension, diabetes, obesity, and high blood-lipid levels.
Together they contribute to the total cardiovascular risk and are the root
causes of the global CVD epidemic. Deaths mainly due to CVD and lung cancer are largely preventable. Although the relative importance of CVD risk
factors may vary in different populations, they account for 75% of the CVD
epidemic worldwide. Not only do we understand the causal pathways
between these risk factors and CVD, we have extensive evidence that, when
action is taken against the risk factors, the catastrophic consequences of this
rapidly growing problem can be avoided.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Mathers CD, Stein C, Ma Fat DM et al (2002) Global burden of disease 2000. Version
2: methods and results. World Health Organization, Geneva
World Health Organization (2002) The World Health Report 2002 Reducing risks
and promoting healthy life. World Health Organization, Geneva
Mensah GA (2002) The global burden of hypertension: good news and bad news.
Cardiol Clin 20(2):181185
Yusuf S, Reddy S, Ounpuu S, Anand S (2001) Global burden of cardiovascular
diseases. Part I: general considerations, the epidemiologic transition, risk factors,
and impact of urbanization. Circulation 104:27462753
Yusuf S, Reddy S, Ounpuu S, Anand S (2001) Global burden of cardiovascular
diseases. Part II: variations in cardiovascular disease by specific ethnic groups and
geographic regions and prevention strategies. Circulation 104:28552864
Alwan A, Maclean D, Mandil A (2001) Assessment of national capacity for noncommunicable disease prevention and control. The report of a global survey. World
Health Organization, Geneva
World Health Organization (2001) Innovative care for chronic conditions. World
Health Organization, Geneva
Klungel OH, de Boer A, Paes AH et al (1998) Undertreatment of hypertension in a
population-based study in the Netherlands. J Hypertens 9:13711377
Hedner T (1998) Treating hypertension effect of treatment and cost-effectiveness
in respect to later cardiovascular diseases. Scand Cardiovasc J 47:S31-S35
Trilling JS, Froom J (2000) The urgent need to improve hypertension care. Arch
Fam Med 9:794801
416
11.
Pocock SJ, McCormack V, Gueyffier F et al (2001) A score for predicting risk of

death from cardiovascular disease in adults with raised blood pressure, based on
individual patient data from randomised controlled trials. BMJ 2001 323:7581
World Health Organization (2001) Adherence to long-term therapies: policy for
action. World Health Organization, Geneva
Feldman R, Bacher M, Campbell N, Drover A, Chockalingam A (1998) Adherence to
pharmacologic management of hypertension. Can J Public Health 89(5):116118
Van Den Hoogen PCW, Feskens EJM, Nagelkerke NJD et al for the Seven Countries
Study Research Group (2000) The relation between blood pressure and mortality
due to coronary heart disease among men in different parts of the world. N Engl J
Med 342:18
12.
13.
14.
Is Arterial Pressure Self-Measurement Better Than Ambulatory

24-Hour Pressure Monitoring?
CARLO FERNANDEZ
Hypertension is an important risk factor for cardiovascular disease, which is

the second leading cause of death in the world. The overall reduction of
absolute risk factors for cardiovascular disease is the therapeutic goal, with
blood pressure (BP) management being a key component. Thus, accurate
diagnosis and treatment of hypertension are necessary to improve a patients
prognosis [1]. The bulk of our knowledge about the risks of hypertension
and the benefits of treatment has been based on the traditional method of
taking a small number of BP readings with the auscultatory technique in
medical setting. However, such measurements, which are of enormous value
on a population basis, often provide a poor estimate of risk in an individual
patient for various reasons, such as poor technique of the observer, the
white-coat effect (the transient but variable elevation of BP in a medical
setting), and the inherent variability of BP [1, 2].
Any clinical measurement of BP may be regarded as a surrogate measure
for the true BP of the patient, which may be defined as the mean level over
prolonged periods. Two techniques have been developed to improve the estimate of true BP: ambulatory monitoring and home monitoring (or selfmonitoring). In addition, the BP measurement techniques used to determine
whether a patient has hypertension have undergone substantial changes in
the past 30 years [3].
Self-measurement of BP at home can accomplish several of the advantages of ambulatory BP monitoring, such as a greater number of readings, an
avoidance of the white-coat effect, and, when automated devices are used, an
absence of observer bias. Furthermore, self-measurement of BP may also
increase compliance with antihypertensive therapy and reduce the number
College of Practice Cardiology ANCE, Palermo, Italy
418
Carlo Fernandez
of visits required for the diagnosis and treatment of hypertension [4, 5].
Nonetheless, self-measurement of BP at home can only become a useful
instrument in the management of hypertension if the technique is wellstandardized and complies with defined quality criteria. Most national and
international hypertension guidelines include recommendations for home
BP measurement. In principle, these guidelines are not different from those
of BP measurement in general, but some points deserve special attention [6].
Experts have not yet reached a general consensus about a standard protocol (how many measurements and on how many days) patients should follow
to measure their BP at home. In a recent editorial in the Jour nal of
Hypertension, Parati et al. [7] described two different methods to define the
most suitable schedule for home BP measurement, namely, a statistical
approach and a clinical approach. In the statistical approach, the reproducibility and stability over time of home BP values and their relation with
ambulatory BP values are used as criteria for defining the best frequency of
home BP measurement. The clinical approach is based on the power of home
BP values to predict cardiovascular outcome, and the reproducibility of
home BP depends on the number of measurements. However, Brook [8]
reported that if the accuracy of the average home BP was determined by
agreement with average ambulatory BP values, the total number of measurements and total duration of monitoring were not important and that most
benefits of home BP monitoring could be achieved by obtaining as few as
two home BP measurements on one day. The advantage of home BP monitoring thus does not seem only to lie in the statistical advantages associated
with the availability of many measurements but also in obtaining information on BP levels away from the clinical setting [7].
Ambulatory BP monitoring was first described more than 40 years ago.
The currently available ambulatory monitors are fully automatic and can
record BP for 24 h or longer, while patients go about their normal daily
activities. Most monitors use the oscillometric technique. They measure
about 4 x 3 x 1 inches (10 x 8 x 3 cm) and weigh about 4 pounds (2 kg). 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. Subjects are asked to
keep their arm still while the cuff is inflating and to avoid excessive physical
exertion during monitoring. The monitors are typically programmed to take
readings every 1530 min throughout the day and night. At the end of the
recording period, the readings are downloaded into a computer. Standard
protocols are used to evaluate the accuracy of the monitors, and approved
devices are usually accurate within 5 mmHg of readings taken with a mercury sphygmomanometer.
Is Arterial Pressure Self-Measurement Better Than Ambulatory 24-Hour Pressure Monitoring?
419
Three types of clinically valuable information are provided by ambulatory BP monitoring: an estimate of the true, or mean, BP level; the diurnal
rhythm of BP; and BP variability. Currently, clinical guidelines exist only for
estimating true, or mean, BP levels [46, 9].
The correlation coefficient between ambulatory measurements and clinically based measurements of BP is usually about 0.50.7, but the relationship
is such that at low clinical BP levels the ambulatory blood pressure is higher,
and at high clinical BP levels the ambulatory blood pressure is lower [2]. The
daytime level of ambulatory BP that is usually considered the upper limit of
normal is 135/85 mmHg [6]. This cut-off is reasonable because it corresponds approximately to a clinical blood pressure of 140/90 mmHg; furthermore, it is the threshold above which cardiovascular risk appears to increase
markedly [10]. Evaluation of the time course of BP over a 24-h period can be
achieved only with the use of ambulatory BP monitoring.
Subjects with normotension have a pronounced diurnal rhythm of BP
[11]. During the first few hours of sleep, BP falls to its lowest level while in
the morning there is a marked surge that coincides with the transition from
sleep to wakefulness. The average difference between waking and sleeping
systolic and diastolic pressure is 1020%. Patients with hypertension usually
have the same pattern, but the diurnal profile of BP is set at a higher level
[10]. In some subjects, whether they have normotension or hypertension, the
normal nocturnal fall of BP is diminished (< 10%). This is referred to as a
nondipping pattern, in contrast to the normal dipping pattern. In extreme
cases (patients with autonomic insufficiency), BP rises during the night. The
nondipping pattern is common in blacks but also has multiple causes, such
as a high level of activity during the day, poor quality of sleep, highly active
sympathetic nervous system, use of glucocorticoids, and the presence of
renal disease. Nondipping has been proposed as one reason why blacks are at
higher risk for cardiovascular disease than are members of other races or
ethnic groups.
There are many different ways of measuring BP, ranging from beat-tobeat changes to changes over periods of weeks or months [12]. Since the
readings are taken intermittently, ambulatory BP monitoring can yield only a
crude estimate of the true variations of BP, rather than the changes related to
sleep vs wakefulness. The clinical significance of BP variability remains
uncertain.
One trial comparing ambulatory BP with conventional clinical BP included patients whose hypertension had been treated at the time of the initial
measurements [13]. Most such studies, however, have included patients
whose hypertension was untreated at the time of the initial measurements
420
Carlo Fernandez
but was treated according to the clinical BP during the follow-up period,
which ranged from 2 to 8 years. The general finding has been that cardiovascular events are more accurately predicted with ambulatory BP than with
clinical blood pressure [14, 15].
In addition, the majority of the studies used some measure of the mean
level of ambulatory BP as the predictor variable, but it remains uncertain
which component of the 24-h BP profile gives the best prediction of risk. The
most widely used has been the mean 24-h BP. Many studies have compared
the predictive value of daytime BP with that of night-time pressure; some
have shown no difference, whereas others have reported that the best prediction of risk comes from night-time BP.
The main clinical indications for ambulatory blood-pressure monitoring
(ABPM) is the diagnosis of white-coat hypertension. This requires the
demonstration that the patients BP is normal outside the clinic, which can
be established using self blood-pressure monitoring (SBPM) and confirmed
by ABPM. Even though ABPM may save drug costs in patients with whitecoat hypertension, its use may also lead to increased drug expenditure in
others in whom it demonstrates suboptimal BP control. SBPM has the potential to reduce the number of clinical visits and also to improve BP control.
The ultimate validation of these two procedures will depend on whether
either one can prevent cardiovascular morbidity. There have been suggestions that a nondipping pattern of nocturnal BP may carry a poor prognosis,
but this may apply only to certain disease end-points. The greater recognitions of the relevance of dipping status should provide an additional stimulus to the use of ABPM and SBPM. Moreover, it is anticipated that hypertension will eventually be managed by the virtual hypertension clinic, in
which ABPM is used for the initial diagnosis and SBPM, through electronic
linkage between the patient and the health-care provider, for maintenance
and follow-up [16].
Twenty-four-hour ABPM has emerged as an important tool supporting
physicians in the diagnosis and management of arterial hypertension compared with office measurements and self-measurements; however, it shows
the lowest patient acceptance. Nonetheless, a number of interacting factors
have resulted in the increased clinical use of ABPM and SBPM. These include
the phasing out of mercury, evidence of the unreliability of clinically based
measurements, technical advances in automated BP measurement, increasing
evidence that out-of-office measurements give the best risk assessment, and
gradual recognition by insurance providers of the clinical utility of ABPM
and SBPM. Both techniques have been endorsed by the two major guidelines
for manag ing hy per tensive pat ients ( World Health Organizat ion,
421
International Society of Hypertension and Join National Committee VI). The

use of SBPM has grown enormously over the past few years, mostly because
of direct sales to patients. Although SBPM may give a better estimate of the
true BP than obtained with clinical readings, there are concerns about the
accuracy of the monitors in individual patients.
The following situations are considered to indicate the use of ABPM:
1. Labile hypertension. This is something of a misnomer because all
hypertension is labile. However, ABPM may prove helpful in some patients
with a history of paroxysmal hypertension.
2. Resistant hypertension. An exaggerated white-coat effect may be
suspected in some patients whose clinic BP remains high even though they
are taking three or more antihypertensive drugs.
3. Masked hypertension. Recently, interest has increased in the phenomenon of masked hypertension, defined as a normal clinical BP and a
high ambulatory BP. This condition is the reverse of white-coat hypertension. The clinical BP levels of patients with masked hypertension may underestimate the risk of cardiovascular events. A study of patients with treated
hypertension showed that about one-third of those seen in a hypertension
clinic had masked hypertension, and over a 5-year follow-up period their relative risk of cardiovascular events was 2.28 times higher than that of patients
whose BP was adequately controlled according to the criteria for both clinically based and ambulatory BP measurements [17].
4. Postural hypotension. This is a not uncommon finding in older
patients who become dizzy when standing for long periods and who may
also have syncopal episodes. The BP of patients with postural hypotension is
unusually labile and depends on their body position. When such patients are
supine, their BP may be quite high, particularly during the night [18].
Treatment with vasopressor drugs and antigravity stockings is a compromise
between permitting the BP to go too low and making it go too high.
Therefore, in these patients, ABPM is essential for evaluating optimal BP
control.
Conclusions
Currently, ABPM is used only in the minority of patients with hypertension,
but its use is gradually increasing. Compared with isolated clinically based
measurements, ABPM provides insight into BP changes in everyday life.
Cross-sectional evidence suggests a direct and significant relationship
between ambulatory BP and organ damage. There is also longitudinal evidence for a superior predictive value of 24-h ambulatory BP in relation to the
422
Carlo Fernandez
risk for cardiovascular morbidity and mortality as opposed to clinical BP.

Ambulatory monitors are reliable, reasonably convenient to wear, and
generally accurate. Ambulatory monitoring can be regarded as the gold standard for the prediction of risk related to BP, since prognostic studies have
shown that it predicts clinical outcome better than conventional BP measurements. Therefore, a good case can be made for using this technique in all
patients in whom hypertension has been newly diagnosed by means of clinical BP measurements. The role of ABPM for diagnosing masked hypertension is uncertain.
The usefulness of ABPM in pharmacologic studies aimed at evaluating
the 24-h antihypertensive efficacy of different drugs and drug combinations
is now acknowledged. Among the mathematical indices available to explore
24-h BP coverage by treatment, the ABPM-derived smoothness index provides a superior measure of the homogeneity of BP control compared with
episodic peak ratios. The main applications of this technique in clinical
practice should be: (1) in identifying patients with isolated office hypertension and those who are nonresponders to treatment, (2) in assessing coverage of the 24-h BP profile in high-risk patients, and (3) in diagnosing suspected treatment-related hypotension.
Although ambulatory monitoring is relatively expensive compared with
other methods of measuring BP, its ability to diagnose white-coat hypertension may reduce health-care costs. ABPM is also invaluable for assessing the
efficacy of antihypertensive treatments and should be included in studies
designed to compare the effects of various drugs.
Night-time blood pressure can be assessed only with ABPM, and evidence
suggests that a failure of BP to decrease at night is associated with an adverse
prognosis. Also unresolved is the extent to which ABPM can be supplanted
by home monitoring an aspect that was not included in most of the studies
documenting the superiority of ambulatory monitoring over traditional
clinical BP measurements.
In some hypertensive patients on adequate antihypertensive treatment
there is a significant difference between clinical and ambulatory BP measurements. This difference (white-coat effect) is greater in elderly patients
and in men. Although clinical BP values in these patients are significantly
increased, the majority have controlled BP on ambulatory monitoring. In
this population, ABPM has been of great value to identify a misdiagnosis of
refractory hypertension, which could lead to improper decisions in the therapeutic management of elderly patients (increasing treatment) and compromise cerebrovascular or coronary circulation.
423
References
1.
Pickering TG, Phil D, Shimbo D, Haa SD (2006) Ambulatory blood-pressure monitoring. N Engl J Med 354:23682374
2. Armitage P, Rose GA (1966) The variability of measurements of causal blood pressure. I.A. Laboratory study. Clin Sci 30:325335
3. Wite WB (2003) Ambulatory blood-pressure monitoring in clinical practice. N Engl
J Med 348:23772378
4. Staessen JA, Wang J, Bianca G (2003) Essential hypertension. Lancet 361:12691641
5. Staessen JA, Dean Hond E, Celis H et al (2004) Antihypertensive treatment based
on blood pressure measurement at home or in the physicians office: a randomized
controlled trial. Treatment of Hypertension Based on Home or Office Blood
Pressure (THOP) Trial Investigators. JAMA 291:995964
6. OBrien E, Asnear R, Beilin L et al (2003) European Society of Hypertension recommendation for conventional, ambulatory and home blood pressure measurement. J
Hypertens 21:821848
7. Parati G, Stergiou G (2004) Self blood pressure measurement at home: how many
times. J Hypertens 22:10751079
8. Brook RK (2000) Home blood pressure: accuracy is independent of monitoring
schedules. Am J Hypertens 13:625631
9. Little P, Barnet J, Barnsley L et al (2002) Comparison of agreement between different measures of blood pressure in primary care and daytime ambulatory blood
pressure. BMJ 325:254254
10. Verdecchia P (2000) Prognostic value of ambulatory blood pressure: current evidence and clinical implications. Hypertension 35:844851
11. Pickering TG, Harshfield GA, Kleinert HD et al (1982) Blood pressure during normal daily activities, sleep, and exercise: comparison of values in normal and hypertension subjects. JAMA 247:992996
12. Parati G, Valentini M (2006) Prognostic relevance of blood pressure variability.
Hypertension 47:138138
13. Clement DL, De Buyzere ML, De Bacquere DA et al (2003) Prognostic value of
ambulatory blood-pressure recordings in patients with treated hypertension. N
Engl J Med 348:2407-2415
14. Sega R, Facchetti R, Bombelli M et al (2005) Prognostic value of ambulatory and
home blood pressure compared with office blood pressure in the general population: follow-up results from the Pression Arteriose Monitorate e Loro Associazioni
(PAMELA) study. Circulation 111:17771783
15. Dolan E, Stanton A, Thijs L et al (2005) Superiority of ambulatory over clinic blood
pressure measurement in predicting mortality: the Dublin outcome study.
Hypertension 46:156161
16. Pickering T (2005) Future developments in ambulatory blood pressure monitoring
and self-blood pressure monitoring in clinical practice. Blood Press Monit 7:2125
17. Pierdomenico SD, Lapenna D, Bucci A et al (2005) Cardiovascular outcome in treated hypertensive patients with responders, masked, false resistant, and true resistant hypertension. Am J Hypertens18:14221428
18. Man S, Altman DG, Raftery EB, Bannister R (1983) Circadian variation of blood
pressure in autonomic failure. Circulation 68:477483
Role of Angiotensin-Receptor Blockers in the Prevention of

Cardiovascular Risk: Clinical Guidelines
PASQUALE P ERRONE -F ILARDI , P IERLUIGI C OSTANZO, A NTONIO M ARZANO, PAOLO
CESARANO, PAOLA GARGIULO, ENRICO VASSALLO, CATERINA MARCIANO, TERESA LOSCO,
MASSIMO CHIARIELLO
Introduction
The development and progression of cardiovascular disease can be regarded
as a continuum (Fig. 1) [1]. Targeting different points within this continuum
is therefore of major importance for reducing cardiovascular morbidity and
mortality. Inhibition of the renin-angiotensin-aldosterone system (RAAS)
has become a key target in this regard, given that angiotensin II (Ang II) has
been implicated as a pathogenic factor at many steps in the development and
progression of cardiovascular disease [2, 3].
Fig. 1. The cardiovascular continuum showing key clinical trials with angiotensin
receptor. Reproduced from [2], with permission
Department of Internal Medicine, Cardiovascular & Immunological Sciences, Federico

II University, Naples, Italy
426
Pasquale Perrone-Filardi et al.
Current Evidence for the Prevention of Cardiovascular Risk with

Angiotensin-Receptor Blockers
Patients with Hypertension
Three clinical trials have investigated the cardioprotective effects of
angiotensin-receptor blockers (ARBs) in patients with hypertension. The
Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial compared valsartan (80160 mg diuretic) with amlodipine (510 mg diuretic) in more than 15,000 patients with hypertension who were at high risk for
a cardiac event. Even though amlodipine-based treatment resulted in a
greater reduction in blood pressure (BP) in the early stages of the trial, the
primary endpoint (a composite of cardiac mortality and morbidity) was not
significantly different between the treatment groups at 66 months of followup [4]. The Losartan Intervention For Endpoint reduction in hypertension
(LIFE) trial demonstrated the advantage of losartan, titrated to 100 mg once
daily, compared with atenolol for reducing the composite endpoint (most
notably stroke), despite similar BP reductions. Moreover, losartan induced a
greater reduction of left ventricular mass than atenolol [5]. Similar findings
have been observed for other ARBs, including valsartan and irbesartan [5].
These results indicate that the cardioprotective benefits of ARBs extend
beyond BP reduction alone [6]. In addition, a subgroup analysis of hypertensive patients with left ventricular hypertrophy (LVH) who did not have clinically evident vascular disease showed that losartan was more effective than
atenolol in preventing cardiovascular morbidity and death, with no difference between treatment groups regarding the lowering of BP. Similar to the
reduction in stroke among the entire LIFE study sample, losartan reduced
the rate of fatal and nonfatal stroke by 34% in this analysis [7]. Another
recently published study compared the effectiveness of losartan vs atenolol
for regression of LVH in patients enrolled in the LIFE study [8]. After a 6month follow-up, losartan resulted in greater regression of LVH according to
electrocardiographic criteria than did atenolol [9].
Prevention of Diabetes
As with the ACE inhibitors, the ARBs are known to exert positive metabolic
effects. Also like the ACE inhibitors, initial evidence of the effects of ARBs on
new-onset diabetes came from studies in which these drugs were compared
with conventional therapies. At the end of the LIFE study, there was a 25%
risk reduction in new-onset diabetes in patients in the ARB arm compared
Role of Angiotensin-Receptor Blockers in the Prevention of Cardiovascular Risk: Clinical Guidelines 427
with those in the beta-blocker arm [10]. In the Antihypertensive Treatment

and Lipid Profile, a North of Sweden Evaluation (ALPINE), patients were randomized to receive either candesartan (16 mg) or hydrochlorothiazide
(HCTZ; 25 mg), and both regimens reduced blood pressure effectively.
However, fasting levels of both serum insulin and plasma glucose increased
in HTCZ-treated patients but remained unchanged in the candesartan-treated group, and significantly more patients in the HCTZ group were diagnosed
with diabetes during follow-up [11]. Additional evidence of the anti-diabetic
effects of ARB therapy came from the VALUE study, in which, after a mean of
4.2 years, new-onset diabetes was diagnosed in significantly fewer patients in
the valsartan group than in the amlodipine group [12]. Similar to ALLHAT,
which compared an ACE inhibitor with amlodipine, the results from VALUE
suggested that the reduced incidence of diabetes associated with ARB was
due to a positive effect on metabolic control rather than a negative effect of
the comparator amlodipine, as this drug is considered metabolically neutral.
More recently, the Candesartan in Heart Failure-Assessment of Reduction in
Mortality and Morbidity (CHARM) program included the reduction of newonset diabetes in heart failure (HF) patients treated with candesartan compared with placebo as a prespecified secondary endpoint. After 3.5 years,
patients who received candesartan had a significant reduction in relative risk
of developing diabetes compared to placebo. The reduction in new-onset
diabetes was even greater among patients in the CHARM-Preserved trial
[13]. The Study on Cognition and Prognosis in the Elderly (SCOPE) also
reported a 25% relative risk reduction in new-onset diabetes with candesartan compared with placebo [14]. Although this finding did not achieve statistical significance, it does, nevertheless, provide further support that ARBs
can help to reduce the risk of diabetes in high-risk patients, such as those
with hypertension. However, the recent disappointing results of the DREAM
trial, which was specifically designed to test the anti-diabetic hypothesis of
ACE-inhibitor therapy, raised caution about a significant anti-diabetic action
of these drugs [15].
Renoprotective Activity of ARBs

Agents that delay the progression of renal disease are likely to be cardioprotective by lessening the systemic consequences of renal dysfunction [16]. A
number of recent clinical studies with ARBs reported renal benefits in
patients with type 2 diabetic nephropathy. The beneficial effects on microalbuminuria and renal function went beyond those attributed to the decrease
in BP alone. The Irbesar tan in Patients w ith Type 2 Diabetes and
428
Microalbuminuria 2 (IRMA-2) trial, which compared irbesartan to placebo,

demonstrated a reduction in relative risk of diabetic nephropathy in the
irbesartan group. The Irbesartan Diabetic Nephropathy Trial (IDNT), in
which patients were randomized to receive either irbesartan or amlodipine
or placebo, reported a reduced lower risk with irbesartan therapy of doubling serum creatinine concentration and developing end-stage renal disease
(ESRD) [17]. In the Microalbuminuria Reduction with Valsartan (MARVAL)
trial, there was a greater reduction in baseline urinary albumin excretion
rate with valsartan than with amlodipine [18]. The Reduction of Endpoints in
Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist
Losartan (RENAAL) trial, in which patients were randomized to receive
either losartan or placebo, demonstrated a reduction in the doubling of
serum creatinine concentration, onset of ESRD, and in risk of primary composite endpoint by losartan. The trial also reported a significant reduction in
the pre-specified secondary endpoint of new HF development in diabetic
nephropathic patients [19]. The COOPERATE trial tested trandolapril, losartan, or both and demonstrated that an ARB in addition to ACE-inhibitor
therapy is more renoprotective than either ARBs or ACE inhibitors alone in
patients with non-diabetic renal disease [20].
ARBs and Heart Failure

Recent clinical studies have evidenced improvements in morbidity and mortality by treating HF with ARBs in addition to conventional therapy. The
Valsartan Heart Failure Trial (Val-HeFT), with primary endpoints of allcause mortality and cardiovascular morbidity, compared valsartan to placebo [21]. This was the first study demonstrating a significant benefit of combination therapy, mostly driven by a reduced number of hospitalizations.
Most recently, in the CHARM trials, candesartan reduced both all-cause
mortality and composite endpoint of cardiovascular mortality and hospitalization for HF. The trial consisted of three separate studies with the same
protocol conducted in different but complementary populations. All patients
recruited to the study had symptomatic HF, but those in the CHARMAlternative had a LVEF 40% and were ACE-inhibitor intolerant, those in
CHARM-Added also had LVEF 40% but were treated with ACE inhibitors,
and patients recruited to CHARM-Preserved had LVEF > 40% [13]. Above
all, these last two studies demonstrated the clinical efficacy of ARBs in
decreasing morbidity and mortality in patients with HF and led to the introduction of ARB therapy indication in recently released HF guidelines [22].
ARBs in Patients After Myocardial Infarction

Left ventricular dysfunction and HF are common complications of myocardial infarction (MI) and place patients at high risk for cardiovascular mortality. The VALIANT results demonstrated the statistical non-inferiority of
valsartan vs captopril in these high-risk patients, but also unlike in
patients with chronic HF no advantage of combination therapy [23]. In
contrast, the Optimal Trial in Myocardial Infarction with the Angiotensin II
Antagonist Losartan (OPTIMAAL) trial demonstrated a non-significant difference in total mortality in favor of captopril, although losartan was better
tolerated [24]. Current guidelines recommend the use of ARBs, specifically
valsartan and candesartan, as an alternative to ACE inhibitors in high-risk,
post-MI patients [25].
ARBs and Atrial Fibrillation

Secondary analysis of the findings of the LIFE and CHARM trials evidenced
that losartan and candesartan reduced the incidence of atrial fibrillation
(AF) in hypertensive patients with LVH and symptomatic HF, respectively
[2628]. These results, together with the favorable safety profiles of these two
drugs compared with anti-arrhy thmic agents, suggest a role for ACE
inhibitors or ARBs in the primary prevention of initial or recurrent episodes
of AF associated with hypertension, MI, HF, or diabetes mellitus. An
overview of 11 clinical trials involving more than 56,000 patients with different underlying cardiovascular diseases suggested that ACE inhibitors or
ARBs can reduce the occurrence and recurrence of AF [28]. Additional
prospective research is ongoing to determine the impact of ACE inhibitors or
ARBs in reducing AF occurrence.
Cardiovascular Risk and ARBs: Future Perspectives

Prevention of new-onset diabetes is currently under further investigation in
the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes
Research (NAVIGATOR) trial. This study compares valsartan to nateglinide
with the aim of evaluating the development of type 2 diabetes and cardiovascular disease in people with impaired glucose tolerance who are at high cardiovascular risk [29].
Two ongoing studies are examining the use of ARBs in patients at high
risk of cardiovascular disease. The Ongoing Telmisartan Alone and in
430
Combination with Ramipril Global Endpoint Trial (ONTARGET) compares

telmisartan monotherapy, ramipril monotherapy, and combination therapy
with telmisartan plus ramipril. In a parallel study, patients who are unable to
tolerate an ACE inhibitor will be randomized to receive either telmisartan or
placebo (the Telmisartan Randomized Assessment Study in ACE-Intolerant
Patients with Cardiovascular Disease, TRANSCEND). The primary endpoint
in each trial is a composite of cardiovascular death, MI, stroke, and hospitalization for HF [30, 31].
Other ongoing trials include Irbesartan in Heart Failure with Preserved
Systolic Function (I-PRESERVE) and the Diabetic Retinopathy Candesartan
Trials (DIRECT) [32, 33]. In particular, the I-PRESERVE study is currently
enrolling patients with chronic HF and preserved systolic function (ejection
fraction 45%), a patient population for which fewer data are available. The
primary aim of the study is to evaluate whether irbesartan is superior to
placebo (i.e., existing therapy) for reducing mortality and morbidity. In contrast, DIRECT has been designed to examine the efficacy of candesartan for
primary and secondary prevention of diabetic retinopathy in normoalbuminuric, normotensive patients with type 1 diabetes. This trial will also
examine secondary prevention in normoalbuminuric, normotensive or treated patients with type 2 diabetes and hypertension [33].
Ongoing trials will determine the impact of the use of ACE inhibitors or
ARBs in patients with AF. The irbesartan arm of the Atrial Fibrillation
Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVEI) trial will randomize 9,000 patients with a history of AF, with or without a
history of hypertension, to receive an ARB, irbesartan, or placebo. A substudy of this trial will examine the effects of irbesartan on the recurrence of
paroxysmal AF [34]. Finally, the Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarto Miocardico Atrial Fibrillation (GISSI-AF) will
evaluate the addition of valsartan to standard therapy or placebo (i.e., standard therapy) in reducing the recurrence of AF [35].
References
1.
2.
3.
Dzau V, Braunwald E (1991) Resolved and unresolved issues in the prevention and
treatment of coronary artery disease: a workshop consensus statement. Am Heart J
121:12441263
Weber MA (2003) Angiotensin receptor blockers and the cardiovascular continuum: what future is indicated by recent successes? Eur Heart J Supplements
5(Suppl C):C1-C4
Burnier M, Brunner HR (2000) Angiotensin II receptor antagonists. Lancet
355:637645
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Julius S, Kjeldsen SE, Weber M et al (2004) Outcomes in hypertensive patients at

high cardiovascular risk treated with regimens based on valsartan or amlodipine:
the VALUE randomised trial. Lancet 363:20222031
Dahlf B, Devereux RB, Kjeldsen SE et al (2002) Cardiovascular morbidity and
mortality in the Losartan Intervention For End point reduction in hypertension
study (LIFE): a randomised trial against atenolol. Lancet 359:9951003
Thurmann PA, Kenedi P, Schmidt A et al (1998) Influence of the angiotensin II
antagonist valsartan on left ventricular hypertrophy in patients with essential
hypertension. Circulation 98:20372042
Malmquist K, Kahan T, Edner M et al (2001) Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens 19:11671176
Devereux RB, Dahlf B, Kjeldsen SE et al (2003) Effects of losartan or atenolol in
hypertensive patients without clinically evident vascular disease: a substudy of the
LIFE randomized trial. Ann Intern Med 139:169177
Okin PM, Devereux RB, Jern S et al (2003) Regression of electrocardiographic left
ventricular hypertrophy by losartan versus atenolol: the Losartan Intervention For
Endpoint reduction in hypertension (LIFE) study. Circulation 108:684690
Lindholm LH, Ibsen H, Borsch-Johnsen K et al (2002) Risk of new-onset diabetes in
the Losartan Intervention For Endpoint reduction in hypertension study. J
Hypertens 20:18791886
Lindholm LH, Persson M, Alaupovic P et al (2003) Metabolic outcome during 1
year in newly detected hypertensives: results of the Antihypertensive Treatment
and Lipid Profile in a North of Sweden Evaluation (ALPINE study). J Hypertens
21:15631574
Montalescot G, Collet JP (2005) Preserving cardiac function in the hypertensive
patient: why renal parameters hold the key. Eur Heart J 26:26162622
Pfeffer MA, Swedberg K, Granger CB et al (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362:759766
Lithell H, Hansson L, Skoog I et al (2003) The Study on Cognition and Prognosis in
the Elderly (SCOPE): principal results of a randomized double-blind intervention
trial. J Hypertens 21:875886
DREAM Trial Investigators (2006) Effect of ramipril on the incidence of diabetes. N
Engl J Med 355:15511562
Lewis EJ, Hunsicker LG, Clarke WR et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2
diabetes. N Engl J Med 345:851860
Parving HH, Lehnert H, Brochner-Mortensen J et al (2001) The effect of irbesartan
on the development of diabetic nephropathy in patients with type 2 diabetes. N
Engl J Med 345:870878
Viberti G, Wheeldon NM for the Microalbuminuria Reduction with Valsartan
(MARVAL) Study Investigators (2002) Microalbuminuria reduction with valsartan
in patients with type 2 diabetes mellitus. Circulation 106:672678
Keane WF, Lyle PA (2003) Recent advances in management of type 2 diabetes and
nephropathy: lessons from the RENAAL study. Am J Kidney Dis 41(Suppl 3):S22S25
Nakao N, Yoshimura A, Morita H et al (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet
361:117124
432
21.
Krum H, Carson P, Farsang C et al (2004) Effect of valsartan added to background

ACE inhibitor therapy in patients with heart failure: results from Val-HeFT. Eur J
Heart Fail 6:937945
ESC Task Force (2005) Guidelines for the diagnosis and treatment of chronic heart
failure: executive summary (update 2005). Eur Heart J 26:11151140
Pfeffer MA, McMurray JJ, Velazquez EJ et al (2003) Valsartan, captopril, or both in
myocardial infarction complicated by heart failure, left ventricular dysfunction, or
both. N Engl J Med 349:18931906
Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group (2002) Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 360:752760
ACC/AHA Task Force (2004) ACC/AHA guidelines for the management of patients
with ST-elevation myocardial infarction executive summary. J Am Coll Cardiol
44:671719
Wachtell K, Lehto M, Gerdts E et al (2005) Angiotensin II receptor blockade reduces
new-onset atrial fibrillation and subsequent stroke compared to atenolol: the
Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J
Am Coll Cardiol 45:712719
Maggioni AP, Latini R, Carson PE et al (2005) Valsartan reduces the incidence of
atrial fibrillation in patients with heart failure: results from the Valsartan Heart
Failure Trial (Val-HeFT). Am Heart J 149:548557
Healey JS, Baranchuk A, Crystal E et al (2005) Prevention of atrial fibrillation with
angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a
meta-analysis. J Am Coll Cardiol 45:18321839
McMurray JJ, Califf R, Holman R et al (2004) Cardiologists should care about glucose: most people with cardiovascular disease or risk factors have diabetes or
significant glycaemic abnormalities. Results of screening over 39,000 subjects for
NAVIGATOR. Eur Heart J 25(Suppl):239 (abs)
Yusuf S (2002) From the HOPE to the ONTARGET and the TRANSCEND studies:
challenges in improving prognosis. Am J Cardiol 89:18A-26A
Teo K, Yusuf S, Anderson C et al (2004) Rationale, design, and baseline characteristics of 2 large, simple randomized trials evaluating telmisartan, ramipril and their
combination in high-risk patients: the Ongoing Telmisartan Alone and in
Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized
Assessment in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND). Am Heart J 148:52 61
Carson P, Massie BM, McKelvie R et al (2005) The irbesartan in heart failure with
preserved systolic function (I-PRESERVE) trial: rationale and design. J Cardiol Fail
11:576585
Chaturvedi N, Sjoelie AK, Svensson A for the DIRECT Programme Study Group
(2002) The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design. J Renin Angiotensin Aldosterone Syst 3:255261
The Active Steering Committee; ACTIVE Investigators (2006) Rationale and design
of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of
vascular events. Am Heart J 151:11871193
Disertori M, Latini R, Maggioni AP, Delise P (2006) Rationale and design of the
GISSI-Atrial Fibrillation Trial: a randomized, prospective, multicentre study on the
use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial
fibrillation recurrence. J Cardiovasc Med 7:2938
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
New Evidence about the Beneficial Effects of AngiotensinReceptor Blockers on the Heart and the Kidney
CLAUDIO BORGHI1, MARCO MANCA2
Introduction
Historically, renal dysfunction has been considered separately from the cardiovascular risk profile, and has been treated as such. In particular, cardiologists, concerned with treating the heart and vasculature, did not routinely
consider the impact of disturbed renal function on the progression toward
cardiac events. However, the landscape of cardiovascular disease has changed
dramatically in recent years, most notably with the publication in 2003 of a
joint statement by a panel of cardiologists and nephrologists illustrating the
importance of kidney disease as a risk factor for the development of cardiovascular disease [1]. Recent evidence clearly showed that both microalbuminuria and glomerular filtration rate (GFR), even in the very earliest and
otherwise asymptomatic stages of renal disease, are risk factors for cardiovascular disease, and there are numerous links between renal dysfunction
and other common risk factors.
Microalbuminuria is surprisingly prevalent, even in patients without
common comorbidities that are conventionally thought to cause nephropathy, and is strictly linked to many important cardiovascular end points. For
instance, of the 1,499 participants without diabetes or hypertension in the
Framingham Heart Study, 15% developed hypertension and 33% progressed
to a high blood pressure category over the 2.9-year follow-up period. After
adjusting for other risk factors, patients in the highest quartile of baseline
urinary albumin-to-creatinine ratio had a 2.2-fold higher risk of developing
new hypertension and a 1.5-fold higher risk of hypertension progression
than those in the lowest quartile.
1 Unit of Internal Medicine, Department of Clinical Medicine and Applied

Biotechnology, University Hospital St. Orsola, Bologna; 2Descovich Atherosclerosis and
Metabolic Disease Study Centre, Department of Clinical Medicine and Applied
Biotechnology, University Hospital St. Orsola, Bologna, Italy
434
One of the most important studies of the natural course of microalbuminuria and its relation to renal and cardiovascular disease is the Prevention
of Renal and Vascular End-Stage Disease (PREVEND) study, which collected
postal questionnaires and morning urine samples from > 40,000 residents of
the Dutch city of Groningen [2]. Although 7.2% of residents had microalbuminuria (20200 mg/l) and 0.2% had macroproteinuria (> 200 mg/l), a further 16.6% had high-normal albuminuria (1020 mg/l). In other words, nearly 25% of the population had increased urinary albumin excretion rates,
despite the fact that in this population the prevalence of diabetes was only
2.6% and that of hypertension was 11.2%. The high prevalence of high-normal albuminuria is a concern because it has been shown that the cardiovascular risk due to albuminuria is continuous.
Inhibition of the renin-angiotensin system (RAS) by administration of an
angiotensin-receptor blocker (ARB) reduces blood pressure (BP) in hypertensive patients [3]. ARBs also slow the progressive decline in renal function that
marks renal injury, particularly in patients with diabetic nephropathy [4, 5].
The renoprotective effects of these drugs relate, in part, to their capacity to
moderate protein excretion [6]. ARB therapy has been shown to decrease the
cardiovascular event rate in high-risk cardiac patients [7, 8]. Moreover, ARBs
are of proven benefit in systolic forms of heart failure (HF) [9].
Effects on the Kidneys

Angiotensin-II-receptor blockers have been repeatedly shown to reduce microalbuminuria and proteinuria to a greater degree than expected from their
effect on blood pressure alone. This has been well-documented for patients with
diabetes [4, 5, 10] (although not so well-documented in nondiabetic individuals); thus, ARBs are an established first-line treatment for diabetic kidney disease or kidney disease with significant proteinuria [11]. However, several issues
demand further investigation, one of the most important being establishment
of the optimal dose. Data from animal models have suggested that the doses of
ARBs required for full renal protection are greater than those required for
maximal lowering of blood pressure. In SpragueDawley rats subjected to
subtotal surgical renal ablation, subsequent treatment with high-dose enalapril
(48 mg/kg, equivalent to a dose of approximately 3 g in humans) significantly
reduced the resultant glomerulosclerosis and tubulointerstitial and vascular
damage [12]. Not only was renal damage reduced compared with untreated controls, but it was also reduced compared with baseline (i.e., 4 weeks after renal
ablation), suggesting that appropriately high doses of ARBs may even have the
potential to reverse preexisting glomerulosclerosis.
New Evidence about the Beneficial Effects of ARBs on the Heart and the Kidney
435
Some evidence of the renoprotective effects of high-dose ARB treatment

has come from clinical studies. The Irbesartan in Patients with Type 2
Diabetes and Microalbuminuria (IRMA-2) trial compared irbesartan (150 or
300 mg daily) with placebo in 590 patients over a 2-year period [13]. Both
irbesartan doses significantly reduced the progression to overt proteinuria
compared with placebo. However, the percentage of patients who progressed
to proteinuria with the higher dose (5.2%) was almost 50% of that in the
lower-dose arm (9.7%), despite the fact that mean arterial BP reductions
were almost identical in the two groups. Similar effects were seen in the
mean urinary albumin excretion rate (UAER), which was reduced by 34% in
the low-dose arm and 60% in the high-dose arm.
Higher doses of ARBs may have a progressive effect that takes months to
be fully manifested. In one study, 78 patients with nondiabetic hypertensive
and proteinuric chronic nephropathy received telmisartan (80 mg) either
once daily (which is the dose that produces maximal reduction in BP) or
twice daily for 18 months, with all patients remaining in the study for 12
months [14]. At 6 months, both groups had a similar reduction in proteinuria. However, there were further reductions in the high-dose group by
month 12, with the result that total reduction was significantly greater than
in the lower-dose group. BP control was similar in the two groups.
If ARBs truly do reduce the progression of kidney disease independently
of their hemodynamic effects, then treatment withdrawal should be accompanied by at least partial maintenance of the effects. Such an analysis was
conducted in IRMA-2, in which patients were followed for 1 month after
withdrawal of treatment [13]. In the placebo and irbesartan 150-mg and 300mg groups, BP returned to baseline values during this follow-up period, and
albuminuria in the placebo and irbesartan 150-mg arms increased to
approximately 10% greater than baseline [15]. In the 300-mg arm, however,
albuminuria was still 47% lower than baseline 1 month after treatment discontinuation, strongly suggestive of prolonged, non-hemodynamic effects.
In patients with diabetes, blockade of the RAS reduced not only the level
of microalbuminuria but also the risk of developing new-onset microalbuminuria compared with other antihypertensives. In the subset of 1,195
patients with type 2 diabetes in the Losartan Intervention for Endpoint
Reduction in Hypertension (LIFE) study, new-onset albuminuria (identified
as albuminuria reported as an adverse event during the study period)
occurred in 7% of patients in the losartan arm compared with 13% of
patients in the atenolol arm [7]. More recently, in the Bergamo Nephrologic
Diabetes Complications Trial (BENEDICT) of patients with hypertension,
type 2 diabetes, and normalbuminuria, 6% of the trandolapril arm pro-
436
gressed to persistent microalbuminuria, compared with 10% of patients in

the placebo arm and 11% of patients in the verapamil arm [16].
Effects on the Heart

Persistent morbidity and mortality benefits of chronic angiotensin-converting enzyme (ACE) inhibition have established ACE inhibitors as the first-line
therapy for patients with reduced left ventricular function and symptoms of
HF in both acute infarction and chronic HF patients. The concept that more
complete inhibition of the RAS system by blocking angiotensin II receptors
might lead to similar or further benefits provided the rationale for clinical
trials with ARBs, such as OPTIMAAL [17], ELITE II [18], Val-HEFT [19],
CHARM [20], and VALIANT [21].
The first trial to directly compare an ARB with an ACE inhibitor in HF
patients was the Evaluation of Losartan in the Elderly (ELITE) trial [22],
which compared the potential renal benefits of an ARB with an ACE
inhibitor in elderly patients with HF. Approximately 700 patients were randomized to losartan (50 mg daily) or to captopril (50 mg three times daily).
While no benefit in terms of renal function was observed in either arm,
there was a statistically significant and unexpected mortality benefit in
patients receiving losartan, albeit with a small number of events in each
group. Despite the initial enthusiasm regarding these findings, this study was
clearly underpowered to assess mortality. The subsequent and properly powered Evaluation of Losartan in the Elderly (ELITE) II study failed to show a
benefit of losartan in reducing mortality or morbidity in HF patients, with a
slight non-significant benefit to patients in the captopril group. While these
findings provided no support for the notion that angiotensin-receptor blockade was superior to ACE inhibition in the treatment of HF, many clinicians
criticized this study for using too low a dosage (50 mg daily) of losartan.
In contrast to ELITE II, the Val-HeFT study compared the ARB valsartan
with standard therapy in HF patients. The majority of patients enrolled in ValHeFT (92%) were already on ACE inhibitors. Val-HeFT demonstrated no mortality benefit, but a reduction in a combined endpoint of morbidity and mortality that was primarily driven by a reduction in HF-related hospitalization.
In the subset of patients not receiving ACE inhibitors in VALIANT, there
was a substantial mortality benefit associated with valsartan. Val-HeFT, however, raised concerns about an increase in adverse outcomes in those patients
receiving the combination of an ARB, an ACE inhibitor, and a beta-blocker
simultaneously. This is a concern that would linger until the results of
CHARM and VALIANT.
437
The CHARM program studied the benefits of candesartan in a broad

range of chronic HF patients. The study consisted of three component trials:
CHARM-Alternative [9], which enrolled patients with symptomatic HF and
left ventricular dysfunction who were intolerant to ACE inhibitors; CHARMAdded [23], which enrolled symptomatic HF and left ventricular dysfunction
patients who were already taking optimal doses of ACE inhibitors; and
CHARM-Preserved [24], which enrolled patients with symptomatic HF but
with preserved (LVEF > 40%) systolic function.
In CHARM-Alternative, candesartan reduced the primary endpoint of
cardiovascular mortality and HF-related hospitalizations by 23% (p <
0.0001) in patients with left ventricular systolic dysfunction and intolerance
to ACE inhibitors. In CHARM-Added, which enrolled patients already on
optimal doses of ACE inhibitors, the composite endpoint was reduced by
14% (p < 0.01).
CHARM-Preserved demonstrated a non-significant trend towards
improved outcome in patients with symptomatic HF and preserved systolic
function. Importantly, patients enrolled in CHARM-Added who received the
combination of ARB, ACE inhibitor, and beta-blockers had better outcomes
than patients receiving ARB and ACE inhibitors but without beta-blockers.
These findings, along with similar lack of concern regarding triple therapy in VALIANT, helped to allay many of the fears raised by the VAL-HeFT
results. Thus, the CHARM studies suggested a benefit of ARB therapy both in
HF patients who are intolerant to ACE inhibitors and in patients already
receiving optimal doses of ACE inhibitors.
In myocardial infarction patients, ARBs have been tested in two large outcome studies. The Optimal Trial in Myocardial Infarction with Angiotensin II
Antagonist Losartan (OPTIMAAL) was designed similarly to ELITE II, and
compared losartan (50 mg daily) with captopril (50 mg three times daily) in
patients with high-risk myocardial infarction. Similarly to the findings of
ELITE II, OPTIMAAL failed to show a benefit of losartan over the ACE
inhibitor at that dose. Patients treated with losartan (50 mg) had a borderline increase in mortality (odds ratio [OR] 1.13, 95% confidence interval [CI]
0.991.28, p < 0.069) and significant increase in cardiovascular death (OR
1.17, 95% CI 1.101.34, p < 0.032). As was the case with ELITE II, this study
was criticized because of the low dose of losartan administered.
In contrast to the head-to-head approach of OPTIMAAL, the Valsartan in
Acute Myocardial Infarction Trial (VALIANT) tested the hypothesis that the
ARB valsartan, either alone or in combination with captopril, would be better than captopril alone at reducing mortality following myocardial infarction. In addition, VALIANT was designed as a non-inferiority trial, and was
438
powered to determine whether valsartan, if not superior to captopril, would

be non-inferior to captopril in reducing morbidity and mortality after
myocardial infarction. VALIANT enrolled 14,703 patients who were randomized to valsartan (160 mg twice daily), captopril (50 mg three times daily) or a
combination of captopril (50 mg three times daily) and valsartan (80 mg
twice daily). VALIANT showed no differences among the three treatment
arms, with virtually superimposable mortality curves. Nevertheless, VALIANT
was able to effectively test the non-inferiority hypothesis and demonstrated
that valsartan was as effective as captopril in reducing mortality.
Conclusions
The studies discussed above demonstrated clearly that microalbuminuria is
an important cardiovascular and renal risk factor. In patients with microalbuminuria, RAS blockade is an effective tool to reduce cardiovascular risk.
For these reasons, estimation of albuminuria will certainly become an
important component of cardiovascular risk profiling.
Common pathologic mechanisms underlie the progression of cardiovascular and renal damage. This fact, coupled with evidence that renal damage
can precipitate cardiovascular damage, reinforces the importance of targeting early renal disease with appropriate therapy in order to reduce the prevalence of cardiovascular disease. As succinctly summarized by de Zeeuw et al.,
we should treat the kidney to protect the heart [25] or, better, we should
treat them both at once, as a logical and clinical unit. Clinical studies demonstrating sustained efficacy and tolerability identify ARBs as a rational choice
of antihypertensive therapy for the prevention of stroke, chronic heart disease, and target-organ damage in a wide range of patients. Furthermore, several large-scale, prospective controlled trials revealed that ARBs simultaneously confer both cardiovascular and renal protective effects, beyond their
ability to lower BP. By utilizing the large body of accumulated evidence,
practitioners can deliver meaningful benefits to their patients in terms of
survival, prognosis, and quality of life.
References
1.
Sarnak MJ, Levey AS, Schoolwerth AC et al (2003) Kidney disease as a risk factor
for development of cardiovascular disease: a statement from the American Heart
Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure
Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation
108:21542169
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
439
Hillege HL, Janssen WM, Bak AA et al (2001) Microalbuminuria is common, also in

a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 249:519526
Elliott WJ (2000) Therapeutic trials comparing angiotensin converting enzyme
inhibitors and angiotensin II receptor blockers. Curr Hypertens Rep 2:402411
Brenner BM, Cooper ME, Zeeuw D (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med
345:861869
Lewis EJ, Hunsicker LG, Clarke WR (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851860
Keane WF, Brenner BM, Zeeuw D (2003) The risk of developing end-stage renal
disease in patients with type 2 diabetes and nephropathy: the RENAAL study.
Kidney Int 63:14991507
Lindholm LH, Ibsen H, Dahlof B (2002) Cardiovascular morbidity and mortality in
patients with diabetes in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): a randomised trial against atenolol. Lancet
359:10041010
Julius S, Kjeldsen SE, Weber M (2004) Outcomes in hypertensive patients at high
cardiovascular risk treated with regimens based on valsartan or amlodipine: the
VALUE randomised trial. Lancet 363:20222031
Granger CB, McMurray JJ, Yusuf S et al (2003) Effects of candesartan in patients
with chronic heart failure and reduced left-ventricular systolic function intolerant
to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet
362:772776
Viberti G, Wheeldon NM (2002) Microalbuminuria reduction with valsartan in
patients with type 2 diabetes mellitus: a blood pressure-independent effect.
Kidney Disease Outcomes Quality Initiative (K/DOQI) (2004) K-DOQI clinical
practice guidelines on hypertension and antihypertensive agents in chronic kidney
disease. Am J Kidney Dis 43(Suppl 1):S1-S290
Adamczak M, Gross ML, Krtil J et al (2003) Reversal of glomerulosclerosis after
high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol
14:28332842
Parving HH, Lehnert H, Brchner-Mortensen J et al (2001) The effect of irbesartan
on the development of diabetic nephropathy in patients with type 2 diabetes. N
Engl J Med 345:870878
Aranda P, Aranda FJ, Frutos MA et al (2004) Comparative long-term renoprotective
effects of usual versus high dose of telmisartan in nondiabetic nephropathies. J
Hypertens 22(Suppl 2):S81-S82
Andersen S, Brochner-Mortensen J, Parving HH (2003) Kidney function during
and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care 26:32963302
Ruggenenti P, Fassi A, Ilieva AP et al (2004) Preventing microalbuminuria in type 2
diabetes. N Engl J Med 351:19441951
Dickstein K, Kjekshus J (2002) Effects of losartan and captopril on mortality and
morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL
randomised trial Optimal Trial in Myocardial Infarction with Angiotensin II
Antagonist Losartan. Lancet 360:752760
Pitt B, Poole-Wilson PA, Segal R et al (2000) Effect of losartan compared with cap-
440
19.
20.
21.
22.
23.
24.
25.

topril on mortality in patients with symptomatic heart failure: randomised trial
the Losartan Heart Failure Survival Study ELITE II. Lancet 355:15821587
Cohn JN, Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker
valsartan in chronic heart failure. N Engl J Med 345:16671675
Pfeffer MA, Swedberg K, Granger CB et al (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362:759766
Pfeffer MA, McMurray JJ, Velazquez EJ et al (2003) Valsartan, captopril, or both in
myocardial infarction complicated by heart failure, left ventricular dysfunction, or
both. N Engl J Med 349:18931906
Pitt B, Segal R, Martinez FA et al (1997) Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly
Study, ELITE). Lancet 349:747752
McMurray JJ, Ostergren J, Swedberg K et al (2003) Effects of candesartan in
patients with chronic heart failure and reduced left-ventricular systolic function
taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet
362:767771
Yusuf S, Pfeffer MA, Swedberg K et al; CHARM Investigators and Committees
(2003) Effects of candesartan in patients with chronic heart failure and preserved
left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 362:777781
de Zeeuw D, El Nahas AM (2005) Albuminuria, a new target for therapy: treat the
kidney to protect the heart. In: El Nahas AM (ed) Kidney Diseases in the
Developing World and Ethnic Minorities. Marcel Dekker, New York
Lercanidipine, Enalapril, and Their Combination in the

Treatment of Elderly Hypertensive Patients
JUAN GARCIA PUIG1, CARLOS CALVO2, OLAVI LUURILA3, HARRI LUURILA3, SAKARI
SULOSAARI4, ARTO STRANDBERG4, CRISTINA GHEZZI5
Introduction
Several trials have shown that hypertensive patients whose blood pressure
(BP) is brought under control (< 140/90 mmHg) have significantly fewer cardiovascular events than patients whose BP remains uncontrolled [1].
However, despite the availability of multiple antihypertensive drugs, BP is
difficult to control, especially systolic BP and in elderly patients [2]. In most
clinical trials aimed at controlling BP, more than two antihypertensive drugs
are almost always required. The importance of combination therapy has
been emphasized in current guidelines [3]. Adding a second antihypertensive drug may be a better option in non-controlled patients than switching to
a different drug or increasing the dose of the first compound.
Aim
In this study, we tested the hypothesis that combination therapy with lercanidipine [4], a lipophilic dihydropyridine calcium antagonist with long
duration of action, and enalapril [5] is more effective than either drug alone
in reducing 24-h systolic BP in hypertensive elderly patients.
Methods
Patients aged 6085 years with an office systolic BP (SBP) of 160179 mmHg, an
office diastolic BP (DBP) < 110 mmHg and a mean daytime SBP > 135 mmHg
1 La Paz University Hospital, Madrid; 2 Hospital Clinico Universitario, Santiago de

Compostela, Spain; 3Kaisaniemen Lkariasema Oy, Helsinki; 4Keravan Lkrikeskus,
Kerava, Finland; 5Medical Department, Recordati S.p.A., Milan, Italy
442
Juan Garcia Puig et al.
were included in the study. Patients with severe hypertension, diabetes mellitus, or prior cardiovascular events were excluded because the study design involved the administration of placebo for 4 weeks.
This was a randomized, double-blind, placebo-controlled, four-way crossover study, balanced for first-order carry-over. Four centers participated, two
in Finland and two in Spain. After a 2-week run-in period, eligible patients
were randomly assigned to receive a 4-week treatment with placebo (P); lercanidipine 10 mg (L); enalapril 20 mg (E); and a combination of the two
drugs (L/E). All patients were scheduled to receive one of the four treatments. Double-blind medications were taken once-daily in the morning. At
the end of each treatment period, office trough (24 2 h post-dose) sitting
blood pressure was measured. A 24-h ambulatory blood pressure monitoring
(ABPM) was obtained on the last day of drug intake.
The primary efficacy parameter was the mean reduction in 24-h SBP of
active treatment vs placebo. The 24-h SBP was chosen as the primary efficacy
variable since the mean 24-h BP is the most solid information provided by
ABPM.
Results
Of the 103 patients who were screened, 75 patients (40 males, 54%) with a
mean age of 66 years were randomized to the study. Of these 75 patients, 71
received P, 69 L, 70 E and 72 L/E. The intention to treat (ITT) population consisted of 72 patients of which 62 patients completed the four ABPMs foreseen
after randomization. Mean seated office BP was 168/92 mmHg. Mean baseline 24-h SBP was 151 mmHg. The administration of P, L, E and L/E was associated with a mean 24-h SBP of 144, 137, 133, and 127 mmHg, respectively
(Fig. 1). Compared to the mean 24-h SBP reduction observed with P, active
antihypertensive therapy significantly decreased the mean 24-h SBP by a
mean of 8.2 (L), 12.9 (E), and 17.9 (L/E) mmHg (p < 0.0001 compared to 24-h
SBP with P). Office BP values were similarly reduced. A seated SBP < 140
mmHg was recorded in 11% (P), 18% (L), 23% (E), and 48% (L/E) of the
patients, and a seated BP < 140/90 mmHg in 8% (P), 18% (L), 19% (E), and
45% (L/E) of the patients.
Two patients on P and two on L/E were withdrawn from the study.
Adverse events were recorded in 9% (P), 12% (L), 16% (E), and 14% (L/E) of
the patients.
Combination Therapy in the Elderly
443
Fig. 1. Mean 24-h blood pressure. SBP, Office systolic blood pressure; DBP, office diastolic blood pressure; L, Lercanidipine (10 mg); E, enalapril (20 mg)
Conclusions
This study showed that in elderly hypertensive patients combination therapy
with L/E is significantly more effective than either placebo or the two
monotherapies in reducing ambulatory and clinic systolic and diastolic BP.
The finding that combination therapy with enalapril and lercanidipine
decreased 24-h BP by a mean of 17.9/9.2 mmHg supports the JNC 7 recommendation to initiate therapy with two agents in patients whose BP is > 20
mmHg above the SBP goal or > 10 mmHg above the DBP goal [3]. In fact,
combination therapy with L and E was associated with a BP < 140/90 mmHg
in 45% of the patients and monotherapy with L or E in < 20% of the patients.
Since a prompt reduction of BP values is associated with a significant reduction in the number of cardiovascular events [6], the achievement of BP values < 140/90 mmHg within a 4-week period may be of substantial benefit.
Acknowledgements
The study was presented in abstract form at the XVI European Meeting on
Hypertension (J Hypertension 2006, 24(Suppl 4):S420). The study was supported by a
grant from Recordati S.p.A. Milan, Italy
Juan Garcia Puig et al.
444
References
1.
2.
3.
4.
5.
6.
Benetos A, Thomas F, Bean KE, Guize L (2003) Why cardiovascular mortality is

higher in treated hypertensives versus subjects of the same age, in the general
population. J Hypertens 21:16351640
Mancia G, Grassi G (2002) Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens 20:14611464
Chobanian AV, Bakris GL, Black HR et al (2003) The seventh report of the joint
national committee on prevention, detection, evaluation and treatment of high
blood pressure. JAMA 289:25602572
Borghi C (2005) Lercanidipine in hypertension. Vasc Health Risk Manag 1:173182
Todd PA, Goa LG (1992) Enalapril: a reappraisal of its pharmacology and therapeutic use in hypertension. Drugs 43:346381
Julius S, Kjeldsen E, Weber M et al (2004) Outcomes in hypertensive patients at
high cardiovascular risk treated with regimens based on valsartan or amlodipine:
the VALUE randomised trial. Lancet 363:20222031
Subject Index
Ablation 8, 20, 2325, 2931, 33, 34, 41, 4347,

4953, 5761, 63, 66, 68, 69, 7678, 82, 83,
9495, 111, 326, 328, 399, 434
Acute coronary syndrome 355, 360, 375,
384, 385, 387
Acute heart failure 125127
Age and sex dependency 342
Ambulatory monitoring 159, 417, 422
Angioplasty 58, 206, 376, 383385
Antiarrhythmic drugs 4, 5, 8, 13, 1821, 23,
24, 43, 76, 87, 227, 229, 257, 260, 265
Anti-interference protection 319, 320
Application 46, 61, 76, 129, 160, 218, 299,
311, 344, 352, 375, 379
ARBs 106, 246, 426430, 434438
Arrhythmias 18, 19, 23, 24, 45, 46, 67, 93,
94, 109, 111, 160, 161, 173, 179, 180,
182184, 186, 201, 206208, 216, 218,
223, 240242, 245, 247, 255, 257258,
260, 261, 265, 266, 270, 355, 357360,
365369, 392
Arrhythmogenic heart diseases 365
Atrial arrhythmias 67, 241, 359
Atrial fibrillation 3, 11, 17, 1921, 23, 24,
33, 41, 43, 44, 49, 54, 57, 63, 64, 75, 78, 79,
82, 83, 87, 93, 107, 108, 113, 122, 127, 138,
147, 169, 172, 191, 240242, 247, 250, 297,
310, 317, 326, 327, 332, 359, 360, 366368,
399, 400, 429, 430
Atrial flutter 1113, 19, 23, 29, 41, 93, 240
Atypical atrial flutter 41
AV block 64, 106, 119, 161, 250, 280, 281,
288, 290, 291, 295, 310, 311, 322, 325, 328
AV node ablation 69, 326, 328
Blood pressure management 417
Brugada syndrome 94, 217, 255, 257, 368
Capture surveillance 320

Cardiac function 33, 281, 294, 328
Cardiac resy nchronization therapy
patients 125
Cardiac surgery 25, 32, 41, 42, 296, 391,
392, 395, 396, 399, 403
Cardiomyopathy 25, 29, 94, 111, 169, 173,
175, 180182, 184186, 191, 197, 199201,
206, 215217, 227, 258, 263, 358, 366
Cardiovascular disease 4, 89, 407, 417, 419,
425, 429, 430, 433, 434, 438
Cardiovascular risk 210, 369, 376, 407411
414, 415, 419, 425, 426, 429, 433, 434, 438
Carotid sinus syndrome 145, 148, 153, 155
Catecholaminergic polymorphic ventricular tachycardia 255, 257, 367
Catheter ablation 3, 7, 11, 2326, 3033, 41,
42, 44, 45, 76, 94, 95, 111, 399
Cavotricuspid isthmus 23, 24, 26, 30, 41
Competitive athletes 9395
Continuous monitoring 126, 283
Contractility 120123, 132, 134, 135, 288,
289, 295, 298, 299, 304, 305, 311, 317, 318
Coronary care unit 355
Cost-effectiveness 30, 38, 263271, 408, 409
Cryoablation 45, 46
Delay optimisation 120
Diabetes 172, 207, 333, 377, 378, 384, 407,
409, 411, 413415, 426430, 433435, 442
Diagnosis 30, 58, 60, 61, 102, 103, 114, 126,
133, 146, 148150, 153, 159162, 202, 258,
288, 345, 365, 367, 368, 392, 414, 417, 418,
420
Drug eluting stent 386
Dual cardioverter defibrillator 79, 80
Dual chamber device 239241
Subject Index
446
Dyslipidemia 409, 411, 413, 414
Loop recorder 149, 153, 155, 159162
Echocardiographic examination 392, 393

Echocardiography 58, 60, 117, 120, 121,
123, 138, 296, 297, 310, 311, 398
Elderly patients 89, 146, 331, 332, 334336,
383386, 397, 422, 436, 441
Electrocardiogram (ECG) 29, 145, 347, 356
Electrocardiographic monitoring 12
Electrocardiographic risk stratifiers 370
Epidemiology 205, 408
Magnetic resonance imaging 44, 58, 347

Mapping systems 44, 59
Midcab 398, 401, 402
Middle-aged 95
Minimally invasive cardiac surgery 397
Mitral valve 122, 134, 295, 396, 400, 402
Monitoring 12, 25, 120123, 125127, 131,
135, 137140, 145, 147, 159162, 172,
173, 175, 194, 223, 226, 240, 258, 283, 303,
306, 307, 313, 335, 398, 417420, 422, 442
Mortality 4, 20, 43, 75, 79, 82, 87, 88, 101,
109111, 113, 114, 125, 126, 131, 137, 140,
169, 172173, 179181, 184186, 191,
197201, 206209, 215, 216, 218, 235,
241, 245247, 252, 263269, 272, 297,
298, 325, 334, 335, 356358, 269, 377, 378,
383, 384, 393, 395, 407, 422, 425430,
436438
Myocardial infarction 75, 89, 106, 107, 111,
168, 172, 179, 180, 216, 247, 266, 269, 296,
333, 334, 341, 342, 345, 247352, 355, 370,
375, 378, 385, 391, 392, 429, 437, 438
Flecainide 5, 8, 1113, 1921, 368

Forensic pathology 199
Functional status 111, 113, 132, 182, 216,
218, 328, 333
Guidelines 3, 7, 14, 20, 24, 25, 81, 101104,
108, 110114, 147, 153, 157, 182, 192, 205,
207, 211, 215218, 250, 260, 263, 271, 341,
345, 375379, 381, 385, 387, 409, 410,
418420, 425, 428, 429, 441
Heart failure 5, 25, 43, 63, 66, 69, 75, 76, 88,
101104, 109, 111, 113, 117, 119,
125127, 129, 137, 140, 167, 173, 181, 185,
187, 191, 200, 206, 218, 227, 234, 241, 245,
247, 261, 266, 267, 272, 279, 282, 294, 295,
297, 298, 303, 309, 310, 326, 332, 356, 357,
359, 378, 379, 427, 428, 430, 434
Heart rate turbolence 167, 358
Heart rate variability 130, 167, 207, 357
Hemodynamics 240, 293294, 296, 298,
300, 304, 309, 310, 313, 325326
Hypertension 14, 89, 333, 370, 392, 401,
407410, 413, 415, 417422, 426, 427,
429, 430, 433435, 442, 443
Implantable cardioverter defibrillator 79,
109, 179, 192, 201, 239, 245, 263
Inappropriate therapies 240, 247
Indications 2426, 80, 89, 90, 129, 147, 148,
192, 215, 217, 218, 234, 240, 241, 246,
250252, 263, 279, 294, 303, 306, 326, 331,
386, 387, 392, 397, 403, 420
Intrathoracic impedance 126, 132, 137,
138, 141, 303
Ischemic mitral regurgitation 391, 392
Long QT syndrome 183, 317, 255, 367
3D Navigation 44
Neuromediated syncope 145
New developments 3, 44, 376
Normal limits 342, 343
Off-pump 396, 398, 401
Pacemaker 41, 63, 64, 66, 77, 78, 82, 106,
131, 132, 147, 149, 150, 155157, 159, 167,
281, 283, 288291, 294, 295, 299, 307,
309311, 313
Pacing 20, 61, 63, 64, 6669, 7779, 82, 83,
95, 109, 112, 113, 119122, 138, 148, 150,
155, 174, 181, 183, 192, 218, 222, 240252,
245247, 248252, 279284, 286, 288,
290, 291, 293300, 303, 304, 306, 307,
309311, 313, 317322, 325328, 331336
Peak endocardial acceleration 121, 134
PortAccess 396, 398, 399, 402
Predictors 89, 118, 172, 173, 185, 193, 227,
232, 327, 333334, 355, 357, 360
Preload 295, 298, 299, 304306, 311, 318
Prevention 24, 5860, 63, 6668, 75, 78, 79,
82, 109111, 113, 157, 192, 193, 201,
205211, 215218, 232, 234, 241, 247,
Subject Index
255, 260, 261, 263, 266269, 271, 272, 309,
385, 407, 408, 410, 411, 413, 425, 426, 429,
430, 434, 438
Propafenone 5, 8, 1113, 1921
Pulmonary vein ablation 76, 77, 82, 83
QT dinamicity 167, 173
Right ventricular pacing 66, 68, 69, 77, 78,
241, 249, 251, 252, 279, 281, 284, 286, 288,
290, 291, 295, 297, 326328, 336
Risk stratification 167, 169, 174, 179, 182,
184186, 191193, 201, 211, 259, 269,
357, 358, 375, 377, 378, 401
Self-measurement 417, 418
Sensors 121, 123, 127, 129, 130, 132, 134,
135, 280, 281, 294, 298, 310, 317
Short QT syndrome 94, 217, 255, 257, 369
ST amplitude 342344
Stereotaxis 46, 47
Substratebased ablation 50
447
Sudden cardiac death 109, 111, 169, 179,
181, 191, 205, 217, 245, 259, 263, 267,
355358, 365
Sudden death 18, 173, 179, 181, 183, 186,
191, 193, 197, 205207, 209211, 217,
235, 255, 257260, 263, 266268, 270,
298, 357, 367
Syncope 12, 14, 110, 145150, 153157,
159132, 191, 193, 194, 200, 217, 258261,
367
Transvalvular impedance 132, 283, 286,
288, 298, 304, 317
Triggerbased ablation 49, 50
Ventricular desynchronization 310, 311
Ventricular fibrillation 18, 109, 179, 191,
200, 201, 206, 216, 221, 222, 227, 231, 257,
264, 322, 355356, 366
Ventricular tachycardia 45, 109, 162, 173,
179, 194, 200, 207, 216, 217, 229, 239, 255,
257, 264, 356, 357, 359, 366, 367
Printed in May 2007

Current News in Cardiology

Uploaded by

Copyright:

Available Formats

Current News in Cardiology

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Current News in Cardiology

Uploaded by

Copyright:

Available Formats

To my beloved wife Luisa

Someone said Love, pleasant folly,

Michele M. Gulizia (Editor)

Library of Congress Control Number: 2007927712

Springer is a part of Springer Science+Business Media

ATRIAL FIBRILLATION AND ATRIAL FLUTTER

Complications of Atrial Fibrillation Ablation: How To Prevent Them . . . . . . . 57

PACING IN THE PREVENTION AND THERAPY OF ATRIAL ARRHYTHMIAS

PRACTICAL ISSUES IN MANAGING ATRIAL FIBRILLATION PATIENTS

MANAGING PATIENTS WITH IMPLANTABLE CRT DEVICES FOR HEART FAILURE

Predicting Heart Failure Events in CRT Patients: Future Challenges . . . . . . . . 129

CURRENT NEWS IN PREVENTION OF SUDDEN DEATH BY IMPLANTABLE

Electrocardiographic Predictors of Arrhythmias In CCU Patients . . . . . . . . . . 355

ACUTE CORONARY SYNDROMES

GLOBAL CARDIOVASCULAR RISK PREVENTION

New Evidence about the Beneficial Effects of Angiotensin-Receptor

CHIARIELLO M., 425

GHEZZI C., 441

MOCCIA E., 221

SOLDATI E., 303

VALLE A., 245

ATRIAL FIBRILLATION AND ATRIAL FLUTTER

Anti-arrhythmic Drugs in Atrial Fibrillation:

Minimal Heart Disease

Fig. 1. From guidelines to individual treatment and maintenance of sinus rhythm.

Department of Medicine - Cardiology, University of Bonn, Bonn, Germany

The fear of thromboembolism in a patient compels the physician to

Table 1. Introduction of antiarrhythmic drugs: chronological overview

Anti-arrhythmic Drugs in Atrial Fibrillation: Historical Perspectives and New Developments

Table 2. New class III antiarrhythmic drugs

i.v. and p.o.

i.v. and p.o.

i.v. and p.o.

i.v. and p.o.

i.v. and p.o.

i.v. and p.o.

Dronedarone Multiple effects

Concerning pharmacological rate control, we recommend digitalis as the

Fig. 2. Paroxysmal atrial fibrillation (PAF): pharmacological management

Rhythm Control or Rate Control and Anticoagulation

Anti-arrhythmic Drugs in Atrial Fibrillation: Historical Perspectives and New Developments

capacity are increased. This improved cardiovascular performance enhances

ns, Not significant

heart, were important considerations. The analysis of the (peripheral) pulse

Anti-arrhythmic Drugs in Atrial Fibrillation: Historical Perspectives and New Developments

Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic

Department of Cardiology, SantAnna Hospital, Como, Italy

Gianluca Botto, Mario Luzi, Giovanni Russo, Barbara Mariconti

Defining the Risk of Proarrhythmic Events

Table 1. Various forms of proarrhythmic events

Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic Treatment

tricular fibrillation has been reported with most anti-arrhythmic agents,

Gianluca Botto, Mario Luzi, Giovanni Russo, Barbara Mariconti

What Is the True Incidence of Proarrhythmia in Atrial Fibrillation?

Which Drugs Maintain Sinus Rhythm in Lone Atrial Fibrillation?

Lone Atrial Fibrillation: Prophylactic Anti-arrhythmic Treatment

Out-of-Hospital Administration of Anti-arrhythmic Drugs

Feinberg WM, Blackshear JL, Laupacis A et al (1995) Prevalence, age distribution,

Gianluca Botto, Mario Luzi, Giovanni Russo, Barbara Mariconti

The Cardiac Arrhy thmia Suppression Trial (CAST) Investigators (1989)