Interventional

Cardiology
Imaging

An Essential Guide

Amr E. Abbas
Editor

123
Interventional Cardiology Imaging
Amr E. Abbas
Editor

Interventional
Cardiology Imaging
An Essential Guide
Editor
Amr E. Abbas, MD, FACC, FSCAI, FSVM, FASE, RPVI
Interventional Cardiology Research
Beaumont Health System
Royal Oak, MI
USA

ISBN 978-1-4471-5238-5 ISBN 978-1-4471-5239-2 (eBook)

DOI 10.1007/978-1-4471-5239-2

Library of Congress Control Number: 2015942528

Springer London Heidelberg New York Dordrecht

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This book is dedicated to my parents, El-Sayed and Raifa, who
I owe everything to and then more, my wife, Mona, who I love
dearly and lots, my children, Zane and Layla, who are my life
and then some, and my co-authors, who without them, this book
would not be possible.
Preface

Ever since the establishment of invasive coronary angiography, the limita-

tions of the technique have not gone unnoticed. As a result, multiple invasive
imaging modalities have been developed in an attempt to characterize the true
severity of coronary artery disease as well as guide the percutaneous coronary
interventions.
Invasive imaging modalities have included ultrasound, optical, and che-
mographic technologies. Moreover, physiological assessment of the degree
of the coronary blood flow has also been performed through fractional and
coronary flow assessments.
This book provides an overview of the current available invasive coronary
imaging modalities in an attempt to present a concise review of their current
technologies, indications, appropriate use, and pitfalls. It is an invaluable tool
for interventional cardiologists and cardiologists in training who wish to have
a concise and practical review of all these modalities.

Royal Oak, MI, USA Amr E. Abbas, MD, FACC, FSCAI, FSVM, FASE, RPVI

vii
Contents

1 Basic Coronary Artery Anatomy and Histology. . . . . . . . . . . . 1

Alfred C. Burris II and Mazen Shoukfeh
2 Physiology of Coronary Blood Flow. . . . . . . . . . . . . . . . . . . . . . 13
Elvis Cami
3 Pathophysiology of Coronary Artery Disease . . . . . . . . . . . . . . 29
Jason George
4 Qualitative and Quantitative Coronary Angiography . . . . . . . 47
Julian J. Barbat
5 Imaging of Coronary Artery Anomalies . . . . . . . . . . . . . . . . . . 75
Benjamin T. Ebner and Kavitha M. Chinnaiyan
6 Coronary Flow Resistance and Reserve. . . . . . . . . . . . . . . . . . . 95
James L. Smith, Mark C. Pica, and Amr E. Abbas
7 Fractional Flow Reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Ivan Hanson, Mazen Shoukfeh, and Amr E. Abbas
8 Intravascular Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Rolf Graning
9 Optical Coherence Tomography. . . . . . . . . . . . . . . . . . . . . . . . . 153
Amr E. Abbas and Justin E. Trivax
10 Intracoronary Imaging for Plaque Characterization . . . . . . . . 175
Ryan D. Madder
11 Intracoronary Imaging for PCI Planning
and Stent Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Ryan D. Madder
12 Non-invasive Correlation of Invasive Imaging . . . . . . . . . . . . . 203
A. Neil Bilolikar, Amr E. Abbas, and James A. Goldstein
13 Intra-cardiac Echocardiography-Guided
Interventional Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Frances O. Wood and George S. Hanzel
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

ix
Contributors

Amr E. Abbas, MD, FACC, FSCAI, FSVM, FASE, RPVI Department of

Cardiovascular Medicine, Beaumont Health, Oakland University/William
Beaumont School of Medicine, Royal Oak, MI, USA
Julian J. Barbat, MD Department of Cardiology,
Beaumont Health System, Royal Oak, MI, USA
A. Neil Bilolikar, MD Department of Cardiovascular Medicine,
William Beaumont Hospital, Royal Oak, MI, USA
Alfred C. Burris II , MD Department of Cardiology,
William Beaumont Hospital, Royal Oak, MI, USA
Elvis Cami, MD Department of Cardiology, William Beaumont Hospital,
Royal Oak, MI, USA
Kavitha M. Chinnaiyan, MD Department of Cardiovascular Medicine,
William Beaumont Hospital, Royal Oak, MI, USA
Benjamin T. Ebner, MD Heart and Vascular Center of Excellence,
William Beaumont Hospital, Royal Oak, MI, USA
Jason George, MD Department of Cardiology,
William Beaumont Hospital, Royal Oak, MI, USA
James A. Goldstein, MD Department of Cardiovascular Medicine,
Beaumont Health System, Royal Oak, MI, USA
Rolf Graning, MD Department of Cardiology,
William Beaumont Hospital, Royal Oak, MI, USA
Ivan Hanson, MD Department of Cardiovascular Medicine,
William Beaumont Hospital, Royal Oak, MI, USA
George S. Hanzel, MD Department of Cardiovascular Medicine,
William Beaumont Hospital, Royal Oak, MI, USA
Ryan D. Madder, MD, FACC Department of Cardiovascular Medicine,
Frederik Meijer Heart & Vascular Institute, Spectrum Health,
Grand Rapids, MI, USA
Mark C. Pica, BS, CCRP Department of Cardiology/Research Institute,
Beaumont Health System, Royal Oak, MI, USA

xi
xii Contributors

Mazen Shoukfeh, MD Department of Cardiovascular Medicine,

Beaumont Health System, Royal Oak, MI, USA
James L. Smith, MD Department of Cardiovascular Disease,
Beaumont Health System, Royal Oak, MI, USA
Justin E. Trivax, MD, FACC, FSCAI Department of Cardiovascular
Medicine, Beaumont Health System, Birmingham, MI, USA
Frances O. Wood, MD Department of Cardiovascular Medicine,
Beaumont Health System, Royal Oak, MI, USA
 Basic Coronary Artery Anatomy
and Histology 1
Alfred C. Burris II and Mazen Shoukfeh

Abstract
An interest in coronary anatomy dates back to the sixteenth century when
Renaissance scholars began anatomic investigation. This was preceded by
philosophical and theological teachings of Greek and Arabic scholars such
as Aristotle (384–322 BC) and Galen of Pargamum (129–199 AD). Prior
to the twentieth century, anatomic analysis of the coronary arteries were
based solely on gross anatomic inspection. With the advent of catheter
based selective coronary angiography in 1962 by Mason Sones, there has
been an increased awareness of variation in the “normal” coronary anat-
omy. This has been further clarified most recently by computed tomogra-
phy angiography. A thorough understanding of normal coronary anatomy
and variations are imperative in making accurate diagnoses and providing
effective management.

Keywords
Coronary vascular anatomy • Coronary histology • Anatomic analysis of
coronary arteries • Normal coronary anatomy • Myocardial bridging •
Right coronary artery • Left main artery • Left anterior descending artery
• Left circumflex artery

Introduction

An interest in coronary anatomy dates back to the

sixteenth century when Renaissance scholars
A.C. Burris II, MD (*)
Department of Cardiology, William Beaumont began anatomic investigation. This was preceded
Hospital, Royal Oak, MI, USA by philosophical and theological teachings of
e-mail: [email protected] Greek and Arabic scholars such as Aristotle
M. Shoukfeh, MD (384–322 BC) and Galen of Pargamum (129–199
Department of Cardiovascular Medicine, Beaumont AD) [1]. Prior to the twentieth century, anatomic
Health System, Royal Oak, MI, USA analysis of the coronary arteries were based
e-mail: [email protected]

© Springer-Verlag London 2015 1

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_1
2 A.C. Burris II and M. Shoukfeh

solely on gross anatomic inspection. With the studies, both invasive and noninvasive, have shown
advent of catheter based selective coronary angi- some common anatomical variation within the
ography in 1962 by Mason Sones, there has been “normal” anatomy.
an increased awareness of variation in the “nor-
mal” coronary anatomy [2]. This has been further
clarified most recently by computed tomography Origin from the Sinus of Valsalva
angiography [3–5]. A thorough understanding of
normal coronary anatomy and variations are The aortic root is the initial part of the ascending
imperative in making accurate diagnoses and aorta that consists of three sinuses of Valsalva:
providing effective management. right, left, and posterior. The posterior sinus is also
referred to as the non-coronary sinus. Each sinus
correlates with a leaflet of a tri-leaflet aortic valve.
Normal Coronary Anatomy The right and left sinus of valsalva lie anteriorly,
and are the site or origin for the right and left coro-
Coronary arteries are the only branches of the nary arteries, and lie adjacent to the pulmonary
ascending aorta. Traditionally a coronary artery root (Fig. 1.1). The aortic root begins at the aortic
has been described as any artery or arterial branch annulus and extends distally to the sinotubular
that carries blood to the cardiac parenchyma [1]. junction; an area of circumferential thickening that
The cardiac parenchyma is defined as any struc- divides the aortic root from the ascending aorta.
ture located in the pericardial cavity and includes Coronary ostia typically arise from the middle
not only the myocardium but also structures such of the right and left sinus of valsalva; below the
as the pulmonary truck, the superior vena cava, sinotubular junction and above the free margin of
and the semilunar valves. Coronary arteries are the corresponding open aortic valve leaflet [1, 8].
located on the epicardial surface of the heart. This allows for maximal coronary filling during
Septal perforators would be the exception and diastole. A coronary ostium that that arises above
run intramuscularly in the ventricular septum. or below the sinus of valsalva is termed to be a
Coronary arteries are named based on the ves- variant of normal anatomy (Fig. 1.2). If the
sels’ distal vascularization territory but not its ostium of a coronary artery takes off >1 cm above
origin [1]. This would explain the description of the sinotubuluar junction, it is considered a high
coronaries with anomalous origin: a right coro- take off or ectopic position [9]. This has been
nary artery that arises from the left coronary cusp described to be associated with decreased dia-
remains a right coronary artery. The left anterior stolic filling and chronic ischemia in the absence
descending artery (LAD) is defined as the artery of epicardial stenosis [10].
that runs within the interventricular septum, the Normally, there are two to three coronary ostia
right coronary artery is defined as the artery sup- [11]. Two ostia are more common and corre-
plying the major blood supply to the right ven- spond with the left and right coronary arteries.
tricle, and the circumflex is defined as the third The third typically comes from a separate ostium
major epicardial artery. for the conus or infundibular branch that is pres-
“Normal” coronary anatomy is that which ent in 23–51 % or normal hearts [1, 12] and has
occurs in greater than 99 % of the general popula- been referred to as the “third coronary artery”.
tion [6], and any variation is considered an anom- Less commonly, there is an absence of the left
aly. The true incidence of coronary anomalies has main with separate ostia of the left anterior
been reported from 0.3 % to 1.6 % by autopsy or descending and the left circumflex arteries
cardiac catheterization, respectively and are dis- (Fig. 1.3). The ostial orientation is generally
cussed elsewhere [7]. However, gender differences orthogonal to the aortic root or ascending aorta
have not been well described. Newer imaging [6]. Although there is some variation, the right
modalities such as coronary CTA may be a better coronary artery ostium generally arises in the
representation of the population; as it represents a vertical plane and the left coronary in the hori-
more diverse patient population [3]. Angiographic zontal plane (Figs. 1.4, 1.5, and 1.6).
1 Basic Coronary Artery Anatomy and Histology 3

Aortic valve

NC
LC Coronary ostia Tubular portion
LM
L Sinotubular
junction
R
R NC L
Sinus portion
(P)
LAD
R

Sinotubular junction
AV
cusp
R

Pulmonic valve

Fig. 1.1 Figure displaying normal ostia of the left and The coronary arteries include: R right coronary, L left cor-
right coronary arteries arising from the left and right coro- onary, LM left main, LAD Left anterior descending. The
nary cusps, respectively. Notice the ostia arise between the aortic valve cusps: R right, L left, NC noncoronary (or pos-
margin of the aortic valve leaflets and sinotubular junction. terior) (From Waller et al. [8] with permission)

Fig. 1.2 Figure displays the normal take off of the left and left coronary arteries arise from the right and left cor-
main and high takeoff off of the right coronary artery. onary cusps, respectively. R right, L left, LM left main, AV
Each artery arises from the proper coronary cusp-the right aortic valve (From Waller et al. [8] with permission)
4 A.C. Burris II and M. Shoukfeh

a b

Fig. 1.3 Figures demonstrate an absent left main with the left anterior descending and left circumflex arteries arising
from separate ostia in the left sinus of valsalva (a) left coronary CTA and (b) right selective coronary angiography

Aorta

vp

hp
R L

Fig. 1.4 This figure represents the coronary orientation

in regard to the aortic root and ascending aorta. The right
and left coronary artery ostia are oriented in a vertical 2
plane (vp) and horizontal plane (hp), respectively (From
Angelini [6] with permission)
1

Fig. 1.5 This represents a cross sectional view of the

variable right coronary ostium orientation. (1) Normal
and remains orthogonal to the aorta in the vertical plane
(2) Upward takeoff (3) Downward takeoff (4) Horizontal
orientation (From Angelini [6] with permission)
1 Basic Coronary Artery Anatomy and Histology 5

3
3
2

1 2

a
b

Fig. 1.6 The orientation of the left coronary artery ostium in the frontal (a) and horizontal (b) planes. (1) Inferior tilt
(2) Normal orthogonal orientation (3) Superior tilt (From Angelini [6] with permission)

Myocardial Bridging The Coronary Arteries

Normal epicardial coronary arteries occasion- Right Coronary Artery

ally take a short intramyocardial course. This
causes arterial compression during systole The right coronary artery (RCA) arises anteriorly
referred to as milking or systolic “myocardial from the right coronary cusp and travels anteri-
bridging”. Although this can occur in any ves- orly and posteriorly in the atrioventricular groove
sel, it is most commonly seen in the [18, 19] (Figs. 1.7 and 1.8). If the RCA is the
LAD. Myocaridal bridging is reported as fre- dominant vessel, it travels posteriorly and
quently as 25 % by autopsy studies and 2 % provides branches along the interventricular
angiographically [13–15]. Generally, myocar- groove and lateral wall of the left ventricle; the
dial bridging is considered a benign phenome- posterior descending artery and posterolateral
non, as the 5-year survival remains high with branch, respectively.
rare reports of sudden cardiac death. Despite the The usual dominant RCA is 12–14 cm in
fact that much of the coronary compression length prior to giving off a PDA [20]. The lumi-
occurs during systole and the majority of coro- nal diameter generally ranges from 1.5 to 5.5 mm
nary perfusion occurs during diastole, there are with a mean of 3.2 mm [20]. While the LAD and
reports of underlying ischemia driven by myo- LCX tend to taper as they progress distally, the
cardial bridging [16, 17]. This has been diameter of the RCA remains relatively constant
described in patients with long segments of an until just prior to the take off of the PDA. The
intramyocardial course. Increased heart rates first branch of the RCA is the infundibular or
and decreased diastolic filling pressures contrib- conus branch in 50 % of the population. This sup-
ute to ischemia by decreasing diastolic filling plies the right ventricular outflow tract and often
time and increased systolic coronary compres- anastomoses with an infundibular branch of the
sion, respectively. left anterior descending artery forming the circle
6 A.C. Burris II and M. Shoukfeh

a b nodal artery [22]. In the remaining 40 %, the

sinus nodal artery is a branch from the circumflex
artery. The RCA then gives off small branches
supplying the right atrium and ventricle. The
largest of these is the acute marginal artery;
which supplies much of right ventricular free
wall [23]. If the RCA is dominant, it supplies two
several major branches: (1) the posterior descend-
ing artery (2) posterolateral branch. The posterior
descending artery travels in the posterior inter-
ventricular grove and supplies the posterior infe-
rior septum. If the left anterior descending artery
Fig. 1.7 Wire model of coronaries (a) RCA in LAO does not reach the apex of the heart, the PDA can
projection; (b) the Left coronary system in the RAO supply the distal third of the interventricular
projection septum. The posterolateral branch (es) supply the
lateral wall. Just distal to the PDA, the RCA
occasionally supplies an AV nodal branch [8].

Left Main Artery

The left main (LM) artery originates from the left

sinus of Valsalva and travels anteriorly and left-
ward (Figs. 1.7 and 1.8). It is positioned between
the left atrial appendage and the pulmonary trunk
[5]. This divides into two major branches: the left
anterior descending (LAD) and left circumflex
(LCX) arteries. The LM varies in length from 0.5
to 2.5 cm but remains uniform in caliber
throughout its length [20, 24, 25]. The LM can
trifurcate providing a third branch referred to as a
ramus intermedius (RI) (Fig. 1.9). The RI origi-
nates between the LAD and the LCX and sup-
plies the territory of the obtuse marginal and/or
the diagonal [25]. The luminal diameter of the
LM is usually 2.0–5.5 mm with a mean of 4 mm
Fig. 1.8 This figure demonstrates normal coronary anat- [20].
omy. The left and right coronary arteries arise from the
respective aortic cusps. The left anterior descending artery
courses anteriorly between the left and right ventricles.
The left circumflex and right coronary arteries travel in Left Anterior Descending Artery
the left and right atrioventricular grooves, respectively.
LAD left anterior descending, RCA right coronary artery
The LAD extends from the left main and curves
around the pulmonary trunk prior to entering the
of Vieussens [21]. In the other half, the conus anterior interventricular groove and extending
branch arises from a separate ostium in the right to the apex [26]. The left anterior descending
coronary sinus of Valsalva. In 60 % of the popu- artery then extends distally to the apex within
lation, the second branch of the RCA is the sinus the inferior interventricular sulcus towards the
1 Basic Coronary Artery Anatomy and Histology 7

crux of the heart. It then provides branches to from the anterior descending artery and supply
the inferior walls of both ventricles [26]. The the anterior two thirds of the intraventricular
vessel terminates in the interventricular groove septum [22]. The diagonal branches are typi-
prior to the posterior (inferior) descending cally larger than the septal perforators and sup-
artery (Figs. 1.7 and 1.8). The anterior descend- ply the lateral wall of the left ventricle. The
ing artery provides two major branches: septal diagonal branches are sequentially numbered as
perforator arteries and diagonal branches. The they arise from the LAD. The anterior descend-
septal perforator arteries branch at right angles ing artery can also produce an infundibular/
conal branch. The LAD is generally has a lumi-
nal area from 2.0 to 5.0 mm with an average of
3.6 mm [20].

Left Circumflex Artery

The left circumflex artery has a branching angle

from the main stem that is variable. It then courses
through the left atrioventricular groove [26]. This
artery provides obtuse marginal branches that are
sequentially numbered as they arise from the LCX
Fig. 1.9 Ramus Intermedius. In some individuals, and supply the posterior and lateral wall of the left
instead of the typical bifurcation into the LAD and LCX, ventricle (Figs. 1.7 and 1.8). If this is the dominant
the left main trifurcates into an LAD, LCX, and ramus vessel, it provides the PDA and PLB; rather than
intermedius (RI), the RI coursing between the LAD and
LCX. This can be difficult at times to differentiate from a
the right coronary artery (Fig. 1.10). The luminal
early diagonal branch of the LAD or obtuse marginal of area of the LCX is generally 1.5–5.5 mm with an
the LCX average of 3.2 mm [20].

a b

Fig. 1.10 Coronary Dominance. Coronary dominance is and PLB as seen in (a). The left circumflex is considered
determined by the vessel that supplies the posterior dominant if it supplies both as seen in (b). It is considered
descending (PDA) and posterolateral branches (PLB) to a co-dominant system if the RCA supplies the PDA and
the inferior wall of the left ventricle. The right coronary the LCX supplies the PLB
artery is considered dominant if it supplies both the PDA
8 A.C. Burris II and M. Shoukfeh

Dominance LCX:
Proximal-Segment from the ostium to the first
The vessel that supplies the PDA and PLB OM
determines coronary dominance (Fig. 1.10). Distal-Segment distal to the first OM
The artery that supplies both vessels is consid-
ered the dominant vessel. If one provides the
PDA and the other provides the PLB, it is con-
sidered to be co-dominant or have balanced Histology
dominance. In the general population, domi-
nance of the right coronary artery is most com- Vessel Wall
mon and has been described in up to 89 % of the
population. The left coronary artery is dominant The normal vessel wall is described as a trilami-
in approximately 7–8 % of the population [27– nar structure. The three layers include: tunica
30]. A co-dominant system was noted in approx- intima or interna, tunica media, and tunica adven-
imately 4 % of the population. The clinical titia (Fig. 1.11). Understanding the histological
significance of dominance is not entirely clear, structure of the coronary arteries is essential in
though there have been data suggesting selecting and identifying the structures in the
increased adverse events (cardiovascular related various coronary imaging modalities.
mortality and non-fatal MI) with those who are
left dominant [30]. Some data suggest increased
incidence of perfusion defects on nuclear Tunic Intima
studies.
The intima is the innermost layer of the normal
arterial wall. The intima consists of three layers:
Segmental Anatomy (1) a lining layer of endothelial cells (2) a suben-
dothelial layer of connective tissue with smooth
Segmental anatomy of coronary arteries is have muscle cells (3) a fenestrated internal elastic lam-
been developed by the American Heart ina (Figs. 1.11 and 1.12).
Association [31, 32] and is used for both research Arterial endothelial cells play a critical role
and anatomy reporting The coronary arteries are in vascular homeostasis. Although previously
divided into proximal, mid, and distal segments. believed to predominately play a passive bar-
rier role, it is now recognized as playing a criti-
RCA: cal role in vascular tone, vascular permeability,
Proximal-Segment from ostium to the acute balancing thrombosis and thrombolysis,
marginal branch inflammation/local immune response, and
Mid-Segment that curves around the acute angiogenesis [33–36]. Disruption of these pro-
margin cesses lead to vascular pathology ranging from
Distal-Posterior atrioventricular groove atherosclerosis to thrombosis and aneurysmal
LAD: dilatation.
Proximal-Segment from the ostium of the The endothelium is a single layer of cells
LAD to either the first septal perforator of that serves as a semipermeable barrier between
the first diagonal branch the blood plasma and interstitial tissue fluid.
Mid-Segment from the proximal segment to These cells are squamous, polygonal, and elon-
the second diagonal branch gated with the long axis and direction of blood
Distal-Segment from the mid segment to the flow [8]. Endothelial cells are connected through
terminal vessel occluding and gap junctions that, along with its
1 Basic Coronary Artery Anatomy and Histology 9

Lumen

Endothelial cells Intima

Internal elastic lamina
Smooth muscle cells Media

External elastic lamina

Adventitia

Fig. 1.11 Arterial vessel wall: The arterial wall consists of elastic lamellae and smooth muscle cells. The inner and
of three major layers: tunica intima, tunica media, and outer boarders are the internal and external elastic mem-
tunica adventitia. The tunic intima has an endothelial branes, respectively. The tunica adventitia contains con-
layer, connective tissue with a basement membrane, and nective tissue and vasa vasorum
an internal elastic membrane. The tunica media consists

basal lamina, helps to regulate bidirectional nonfibrillar collagen (type IV collagen), lam-
exchange of molecules by processes such as, inin, fibronectin, and other extracellular matrix
simple and active diffusion, receptor-mediated molecules [34–38]. This subintimal supporting
endocytosis, and transcytosis [33]. Vascular tissue contains fibroblasts and other cells with
tone is regulated through the conversion of structural features similar to smooth muscle
angiotensin I to angiotensin II and the produc- cells known as myointimal cells. With age,
tion of vasoactive agents such as nitrous oxide arteries develop a thicker, more complex intima
and endothelins. It also allows for blood to containing smooth muscle cells and fibrillar
remain in a liquid state by expression of heparin forms of interstitial collagen (type I and II).
sulfate proteoglycan molecules. Contained This more complex intima is often referred to by
within endothelial cells is thrombomodulin, pathologists as diffuse intimal thickening, which
which binds thrombin. If needed, the endothe- does not necessarily correlate with lipid accu-
lium can also produce tissue and urokinase-type mulation. It is currently unclear if this diffuse
plasminogen activators with catalyze the activa- thickening reflects atherosclerotic burden. The
tion of plasminogen to plasmin for fibrinolysis. intimal thickening is not uniform across the
Vascular endothelial growth factor (VEGF) also entire vascular bed. Atherosclerosis is a disease
helps to maintain vasculature during tissue of the intima and is thought to be secondary to
repair, growth, and regeneration. Vascular endo- an increase in lipid accumulation of the myo-
thelium plays a vital role in inflammation and intimal cells.
the local immune response through the migra- The intima is separated from the media by an
tion of inflammatory cells to the site of injury. internal elastic membrane referred to as the
The next layer within the tunica intima is the basal lamina [34–36]. This is described as a
subendothelial space. At birth, this contains fenestrated structure composed of elastin. With
10 A.C. Burris II and M. Shoukfeh

The internal and external borders of the tunica

media are the internal and external elastic
lamina (Figs. 1.11 and 1.12). The composition
of the media differs depending on the location
and size of the vessel. Depending on the char-
acteristics of the media, arteries are classified
as elastic or muscular.
Elastic arteries such as the aorta and pulmo-
nary artery are describes as those that receive
blood from the heart. The main branches such as
aortic arch vessels and iliac arteries are included.
These vessels are often greater than 10 mm in
diameter and have a media containing a high den-
sity of elastic lamellar that are interspersed with
smooth muscle. It has been describes as both
contributing to the arterial structural integrity and
storage of the kinetic energy produced by left
ventricular contraction. This is imperative in
maintaining forward flow of blood during dias-
tole. The adult aorta contains approximately 50
elastic lamellae; this is higher in patients with
hypertension [34]. The highly pulsatile blood
flow through elastic arteries decreases with age
causing the increased peripheral resistance and
higher systolic blood pressure. Because of the
Fig. 1.12 Tunics of the vascular wall: This represents the
layers of the aorta. The arrows represent the simple squa- dense elastic lamellae, the internal elastic lamina
mous epithelium and the intima (I). This is separated from is not easily visualized.
the media (M) by loose connective tissue and the internal Muscular arteries such as the epicardial cor-
elastic lamina (IEL). The media (M) contains elastic onary arteries are typically those that perfuse end
lamellae and elastic fibers alternating with layers of
smooth muscle. Elastic fibers are also present in the organs and generally measuring between 1 and
adventitia (A). The vasa vasorum (V) are seen in the 10 mm. These vessels have a media that is com-
adventitia (From Mescher [33] with permission) posed of less elastic lamellae and more smooth
muscle [39, 40]. The media contains up to 40 lay-
ers of large smooth muscle cells interspersed in a
aging or intimal disease, this can be fragmented, variable amount of elastic lamellae. This allows
duplicated, or focally lost [8]. Disruption of the for vasodilatation and constriction to maintain
internal elastic membrane can also represent pre- steady perfusion.
vious angioplasty. Normal medial thickness averages 200 μm
with a range of 125–350 μm [41]. In the setting of
underlying disease of the intima, the medial
Tunica Media thickness decreases to 16–190 μm with a mean of
80 μm [41]. Of note, in normal arteries smooth
The media is the middle layer that serves muscle cells rarely proliferate. The extracellular
mainly as the muscular layer of vessel wall. It matrix remains homeostatic. The media is sepa-
consists of multiple helically arranged layers rated from the adventitia by an external elastic
of smooth muscle cells and connective tissue. membrane.
1 Basic Coronary Artery Anatomy and Histology 11

Tunica Adventitia 2. Sones FM, Shirey EK. Cine coronary arteriography.

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 Physiology of Coronary Blood Flow
2
Elvis Cami

Abstract
Coronary blood flow is responsible for providing nutrients and oxygen to
the heart thus enabling it to pump blood to itself and the rest of the circula-
tory system. Given this important task, oxygen supply must be matched
very closely to the demands of the myocardium. This is accomplished
through various regulatory mechanisms that can have deleterious effects if
interrupted due to the presence of coronary stenosis or other factors that
affect basal and hyperemic blood flow. As such, knowledge of these mech-
anisms is imperative in understanding the physiological assessment of
coronary stenosis and in treating various cardiac conditions.

Keywords
Coronary blood flow • Physiology of coronary blood flow • Coronary
artery resistance • Coronary vasospasm • Pathophysiology of coronary
artery stenosis

Introduction that can have deleterious effects if interrupted

due to the presence of coronary stenosis or other
Coronary blood flow is responsible for providing factors that affect basal and hyperemic blood
nutrients and oxygen to the heart thus enabling it flow. As such, knowledge of these mechanisms is
to pump blood to itself and the rest of the circula- imperative in understanding the physiological
tory system. Given this important task, oxygen assessment of coronary stenosis and in treating
supply must be matched very closely to the various cardiac conditions.
demands of the myocardium. This is accom-
plished through various regulatory mechanisms
Mechanical Determinants
of Coronary Blood Flow
E. Cami, MD
Department of Cardiology,
William Beaumont Hospital,
Coronary blood flow comprises about 4 % of the
Royal Oak, MI, USA cardiac output (250 ml/h). It is normally supplied
e-mail: [email protected] by the right and left coronary arteries, which

© Springer-Verlag London 2015 13

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_2
14 E. Cami

a b

Fig. 2.1 Still frame of an angiogram showing a left ante- the bottom of the picture demonstrates this is occurring
rior descending artery and its septal branches. (a) Flow is during diastole. (b) Different frame from the same angio-
seen in the septal branches which course through the myo- gram now shows no flow in the same small arteries during
cardium demonstrated by the red arrows. The tracing at systole

arise at the root of the aorta. Similar to other dium. This degree of compression is related to the
organ systems, the coronary circulation is com- intraventricular and intramyocardial pressure. The
posed of epicardial arteries, smaller intramyocar- epicardial arteries themselves are not affected by
dial arteries, arterioles, capillaries, venules, and the myocardial compression as they do not course
veins. through the myocardium. The myocardial wall
The two major determinants of coronary blood pressure is highest near the endocardium and lowest
flow are: in the epicardium and, during contraction, the endo-
cardium experiences the greatest force compared to
1. The perfusion pressure at the head of the the outer muscle layers [1]. As a result, the suben-
system (the aorta), & docardium is the region most vulnerable to isch-
2. The downstream resistance residing primar- emia. Myocardial compression plays a role on the
ily in the arteriolar bed, which will be dis- coronary venous system as well leading to increased
cussed in detail later on. venous return during systole (Fig. 2.2) [2].
In diastole, normal ventricular pressure is less
than 10 mmHg and does not impede flow in the
small arteries and arterioles which are coursing
Coronary Artery Perfusion Pressure through the myocardium and have a pressure
equal to that of aortic diastolic pressure. Thus,
The coronary circulation, however, is unique in that the perfusion pressure in the coronary arteries
the heart generates the arterial pressure required to can be assumed to be the diastolic arterial
perfuse the systemic circulation but at the same pressure. Diastolic myocardial compressive
­
time, its own perfusion is impeded during systole. effects on coronary perfusion, however, become
The heart, therefore, receives most of its blood sup- significant when ventricular diastolic pressure
ply during diastole (Fig. 2.1). This occurs because rises as in decompensated heart failure, restric-
the arterioles and capillaries (microcirculation ves- tive cardiomyopathy, or hypertrophic cardiomy-
sels) are compressed by the contracting myocar- opathy. These conditions may result in ventricular
2 Physiology of Coronary Blood Flow 15

Fig. 2.2 Myocardial Diastole

a Artery Vein
compression effects on
transmural perfusion. 80 4–8
(a) Compressive effects 0 0
during diastole decrease in
going from subendocardium Epi
to epicardium. At signifi-
cantly elevated ventricular 5 5
diastolic pressures of >20
and low diastolic aortic
pressures of <60, the
subendocardial region is at 10 10
risk for ischemia during
diastole. (b) During systole,
ventricular contraction Endo
increases intramyocardial 5–10 mm Hg
tissue pressure which cancels LV cavity
the arteriolar systolic
pressure. Compression of
venules increases venous
outflow (From Mann et al.
[2] and McCormack et al. b Systole
Artery Vein
[25] with permission)
120 20–50
20 20
Epi

65 65

120 120

Endo
120 mm Hg
LV cavity

diastolic pressures of up to 40 mmHg. These dia- Conditions such as hypotension or aortic regur-
stolic compressive effects are also most promi- gitation can decrease perfusion pressure by
nent in the subendocardium making this area lowering diastolic pressure which leads to a
most prone to ischemia. decrease in oxygen supply. In normal condi-
tions however aortic diastolic pressure does
not change in order to increase coronary perfu-
Coronary Artery Resistance sion. Even during strenuous physical exercise,
aortic diastolic pressure does not change sig-
Coronary arterial flow (Q) is directly propor- nificantly whereas systolic arterial pressure
tional to the perfusion pressure of the coronary may rise considerably. This is due to fluctua-
arteries (P) and inversely proportional to the cor- tions in vascular resistance. Coronary vascular
onary vascular resistance (R). resistance, therefore, is the other determinant
of coronary blood flow and is inversely propor-
Q∞P / R
tional to flow.
As noted earlier, the coronary perfusion pres- Blood flow through any artery is directly pro-
sure is equal to the diastolic arterial pressure. portional to the fourth power of the vessel radius
16 E. Cami

a Normal artery

Artery
Wall

Normal
blood flow

Abnormal
b blood flow Plaque
Norrowing Normal radius
of artery

Decreased Plaque
radius

Fig. 2.3 Example of epicardial coronary artery with nor- and Blood Institute; National Institutes of Health;
mal vessel radius (a). And decreased vessel radius due U.S. Department of Health and Human Services)
atheroslerosis (b) (Modified from National Heart, Lung,

according to Poiseullie’s law, where r is the vessel R = 8× η× L / π × r4

radius, ΔP is the pressure difference between the
two points, η is the blood viscosity, and L is the As we can see, given that the radius is raised to
vessel length. the fourth power, its importance in determining
resistance and blood flow is essential. A 50 %
Q = π × r 4 × ∆P / 8 × η × L
decrease in the vessel radius will increase the
Therefore, the resistance of a vessel is directly resistance in that vessel by 16 times. This
proportional to the vessel length and inversely becomes important in determining the resistance
proportional to the fourth power of the vessel of the epicardial coronary arteries which are
radius. prone to atherosclerosis (Fig. 2.3) [3]. Resistance
2 Physiology of Coronary Blood Flow 17

cross-sectional area (cm2) 3000

20
Total aggregate

Area Velocity

Velocity (cms/)
2000

10
1000
2
0 0

Coronary sinus
Arterioles
Coronary

Capillaries

Venules
arteries

Veins
Aorta

Psystolic
120
Pressure(P) Relative
80

resistance
resistance
Pressure
(mm Hg)

Relative
Pdiastolic
40

Fig. 2.4 Pressure, resistance, velocity, and flow in different parts of the coronary circulation (Modified from Stouffer
[4] with permission)

also relates to the length of the vessel. This how- resulting in a high cross-sectional area and low
ever is only a linear relationship whereas the total resistance. Finally, as a result of the pressure
radius is an exponential relationship. Furthermore, drop in the arteriolar bed, blood flow in the
the length of the vessel cannot be changed physi- microcirculation is no longer pulsatile but
ologically but the radius can change through dif- continuous.
ferent mediators that will be explained below. As Given that the greatest resistance is in the arte-
a result, the most regulated variable for control of riolar bed then it is logical that the most regula-
coronary blood flow is vessel radius. tion also happens in the arteriolar bed through
Similarly to other systems, in the coronary cir- constriction or dilation of coronary arterial vas-
culation, the greatest resistance is at the arteriolar cular smooth muscle. Capillaries do not have
bed and this is where we see the largest drop in smooth muscle therefore their resistance cannot
pressure. There is a significant decrease in vessel be regulated that way.
diameter going from the epicardial arteries to
arterioles where the vessels are mainly connected
in series leading to a large increase in the resis-  yocardial Oxygen Demand
M
tance of each individual vessel and increase in the and Supply
total resistance of the system (at the arteriolar
bed) (Fig. 2.4) [4]. While going from arterioles to In normal hearts, oxygen demand by the myocar-
capillaries, there is only a small decrease in ves- dium equals oxygen supply by the coronary
sel radius but a high degree of branching, equiva- arteries through autoregulatory mechanisms that
lent to a system connected in parallel. The total are explained below [5] (Fig. 2.5). The three main
number of capillaries in a circulation bed, there- determinants of myocardial oxygen demand are
fore, greatly exceeds the number or arterioles heart rate, contractility, and left ventricular
18 E. Cami

18 valvular regurgitation will also cause an increase

Myocardial oxygen consumption

in wall stress and conversely an increase in oxy-

16
gen demand. The third component of the equa-
14
tion (ventricular wall thickness) is inversely
(mL/min/100g)

12 proportional to wall stress. In disease states such

10 as chronic hypertension or aortic stenosis ven-
8 tricular wall thickness will increase as a compen-
satory mechanism to attempt to decrease wall
6
stress. Conditions that decrease wall thickness
4 including myocardial infarction will result in
2 increased wall stress and increased oxygen
20 30 40 50 60 70 80 90 100110120 demand.
Coronary blood flow Oxygen delivery to the myocardium depends
(mL/min/100g) on coronary arterial oxygen content and coronary
Fig. 2.5 Myocardial oxygen consumption and coronary
blood flow. Oxygen content is in turn determined
blood flow relationship at different metabolic rates (From by the hemoglobin concentration and degree of
Pappano et al. [5] and Berne and Sperelakis [26] with systemic oxygenation. In absence of anemia or
permission) lung disease, coronary arterial oxygen content
remains fairly constant so increases in oxygen
wall stress. Increased heart rate leads to increased supply have to be met by increased coronary
metabolic rate and higher oxygen demand while blood flow.
decreasing heart rate has the opposite effect. Furthermore, unlike other organs, oxygen
Contractility describes the force of contraction extraction by the myocardium at rest is near max-
by the myocardium. This can be increased by imum at about 65–75 % of arterial oxygen con-
sympathetic stimulation or positive inotropic tent. The heart at that point cannot simply
medications such as dobutamine. Wall stress is increase oxygen extraction to increase oxygen
the tension or stress that develops in the wall of supply to the myocardium. Instead, increased
the ventricle throughout the cardiac cycle and oxygen demand such as during exercise must be
acts to pull the myocardial fibers apart. This met by increasing blood flow to the
stress during systole is called afterload and dur- myocardium.
ing diastole is termed preload. The wall stress is
better described using the law of Laplace where σ
is ventricular wall stress, P is ventricular pressure,  ontrol of Coronary Flow
C
r is ventricular radius, and h is ventricular wall and Autoregulation
thickness.
The heart has the ability to maintain a constant
s = ( P ´ r ) / 2h
blood flow at a range of coronary arterial pres-
sures [6] (Fig. 2.6). Autoregulation of coronary
Wall stress, therefore, is directly proportional to vascular resistance makes this possible. Other
ventricular wall pressure and radius. Disease states organs that exhibit significant autoregulation are
such as hypertension cause increased wall stress the brain and kidneys. Autoregulation helps the
by increasing left ventricular (LV) wall pressure body to divert oxygen supply to organs (e.g. the
during systole, diastole, or throughout the cardiac heart) that need it the most in conditions when
cycle. This, in turn, leads to increased oxygen perfusion pressure may fall as in hypotension.
demand. Antihypertensive medications decrease Factors that participate in the regulation of coro-
LV wall stress thus decreasing oxygen demand. nary vascular resistance include local metabo-
Other conditions that result in increased ventricu- lites, endothelium derived substances, and
lar radius including dilated c­ardiomyopathy or neurohormonal innervation.
 2 Physiology of Coronary Blood Flow 19

5.0 then binds to A2 receptors on smooth muscle

cells, increasing cyclic adenosine monophos-
phate (cAMP) which leads to vasodilation. At
high levels, adenosine also activates endothelial
Flow reserve
normal
adenosine triphosphate (ATP)-sensitive K+ (KATP)
channels, vascular smooth muscle KATP channels,
as well as calcium-activated potassium channels.
Coronary flow (mL/min/g)

Maximum
vasodilation These lead to decreased calcium entry into the
3.0
vascular smooth muscle cells and vasodilation.
During basal conditions, adenosine does not play
a significant role in coronary vascular tone but
the amount of adenosine generated during severe
Maximum arterial hypoxia is sufficient to cause strong coro-
vasoconstriction
nary vasodilation [7]. Conversely, when there is
40
no mismatch in oxygen supply and demand, ATP
mm Hg
1.0
levels are high and adenosine levels are much
lower thus the amount of vasodilator substances
Autoregulatory
range
is decreased.
Oxygen levels also affect regulation of coro-
nary blood flow. Decrease of coronary arterial
Coronary pressure pO2 is one of the most powerful stimuli for coro-
nary vasodilation. Coronary artery hypoxia can
Fig. 2.6 Graph showing pressure-flow curve relationship occur because of coronary artery stenosis, ane-
in the coronary arteries. Coronary flow is maintained con-
stant across a large range of perfusion pressures. The blue mia, decreased ambient oxygenation like high
line represents maximal coronary flow also known as altitude exposure, or blood flow impairment.
hyperemic flow (which will be discussed later on) (From Low myocardial tissue oxygen levels, whether
Mann et al. [2] with permission) resulting from reduction in O2 supply or
increased demand, lead to opening of ATP sensi-
Metabolic Factors tive K+ channels present in vascular smooth
muscle cells. The latter then causes hyperpolar-
Local metabolic factors play the most important ization of the cell membrane thus preventing
role in regulation of coronary blood flow. Some Ca2+ channels from opening and leading to low
of these key local mediators include adenosine, cytosolic calcium levels [8]. This, in turn, causes
ATP, oxygen, pH level, K+, and CO2. Myocardial smooth muscle relaxation and decreased vascu-
metabolic activity parallels coronary blood flow lar resistance.
and this is found in denervated hearts as well. Furthermore, during hypoxia, aerobic metabo-
Myocytes release vasodilatory substances in pro- lism and oxidative phosphorylation are inhibited
portion to their level of work thus ensuring ade- and ATP cannot be generated. Consequently
quate supply to meet metabolic demands of the ADP and AMP are converted to adenosine which
cells. also leads to vasodilation as mentioned above. In
Adenosine is directly derived from hydrolysis endothelial cells, hypoxia activates KATP channels
of AMP (adenosine monophosphate) or from that signal release of NO causing vascular smooth
hydrolysis of adenine nucleotides. During oxy- muscle relaxation as a result. This oxygen imbal-
gen supply/demand mismatch or increased ance either from decrease in arterial oxygen con-
metabolism, adenosine levels rise sharply as high tent, decrease in coronary blood flow, or increase
energy phosphate bonds are consumed and ATP in cardiac metabolic rate decreases the oxygen
is converted to adenosine in cardiac myocytes or supply/demand ratio and affects other vasodilator
from adenine nucleotide hydrolysis. Adenosine substances like pH and carbon dioxide levels. It
20 E. Cami

Agonists

Ca2+
R

Ca
Ca2+
SR
Ca2+ Ca2+ -calmodulin X
AA
Endothelial Cyclo- L-Arg +NOS +
cell oxygenase
PGI2 NO EDHF

PGI2 NO EDHF

K+

Soluble
guanylate cyclase K+

Smooth muscle A denylate hyperpolarization

cell cyclase cGMP GTP

ATP cAMP Ca2+

Relaxation

Fig. 2.7 Endothelium-derived vasoactive substances and hyperpolarizing factor (EDHF) (From Vanhoutte [10]
their regulators. These include vasodilators including with permission)
nitric oxide (NO), prostacyclin, and endothelium-derived

should be stressed that a critical fall of coronary Endothelial Factors

myocardial oxygenation likely does not occur in
normal hearts under physiological conditions Vascular endothelial cells also produce vasoregu-
even during conditions of strenuous exercise. It lators that can act independently of cardiac
may however be common if there is significant metabolism to influence blood flow. Vasoactive
coronary stenosis. substances produced by the endothelium include
Carbon dioxide is a byproduct of metabolism nitric oxide (NO), prostacyclin, endothelium
of pyruvate in the citric acid cycle. Increased lev- derived hyperpolarizing factor (EDHF), and
els of carbon dioxide will result in increased pro- endothelin1 (Fig. 2.7) [10].
ton concentration and acidosis by the following NO is produced in the endothelial cells by the
equation ( CO 2 + H 2 O « H + + HCO3- ) . Some actions of the enzyme type III NO synthase which
experiments in animals have shown that increases converts L-arginine to citrulline. NO then activates
in arterial carbon dioxide levels results in vasodi- guanylate cyclase in the vascular smooth muscle
lation and decreases in arterial carbon dioxide cells which causes an increase in the intracellular
levels result in vasoconstriction [9]. However, its production of cyclic guanosine monophosphate
significance is not yet known in the autoregula- (cGMP). This initiates a signaling cascade which
tion process. results in decreased cytosolic calcium levels and
2 Physiology of Coronary Blood Flow 21

Fig. 2.8 Effects of Intracoronary acetylcholine

intracoronary acetylcholine Atherosclerotic Normal
in normal arteries and 150
epicardial arteries with Prestenotic segment *
atherosclerosis. Stenotic segment
*

Vessel diameter (% control)

Acetylcholine leads to *
vasodilation in a normal
artery whereas in an 100
atherosclerotic artery it leads
to vasoconstriction that is *
most pronounced at the
stenotic segment (From 50
Mann et al. [2] and Kern and
Normal segment
Samady [23] with
permission) * P <0.01 vs. C1

*
0
C1 C2 AChmax C3 NTG C1 C2 AChmax C3 NTG

dephosphorylation of myosin light chains leading coronary diameter, there is uncertainty whether
to smooth muscle relaxation in blood vessels and they significantly contribute to control of coro-
therefore vasodilation. Diseases such as athero- nary flow. Experiments in dogs did now show a
sclerosis may lead to oxidative stress and creation change in coronary flow during exercise in the
of superoxide anion generation which inactivates presence of a cycloocygenase inhibitor [14].
nitric oxide therefore impeding the NO mediated Endothelins are produced by endothelin con-
vasodilation. The discovery that NO was in fact verting enzymes from large precursors and lead
the endothelium derived relaxing factor lead to the to vasoconstriction. Their effects are mediated by
award of the Nobel Prize in physiology in 1998. ETA and ETB receptors. ETA mediated constric-
Experiments have shown that after the NO and tion is caused by the activation of protein kinase
prostacyclin pathways have been inhibited, there C in vascular smooth muscle. ETB mediated
is still another factor which causes vessels to actions also lead to vasoconstriction but result in
dilate [11]. This has been termed EDHF and, as NO production and indirect vasodilation as well.
the name implies, it is released by endothelial Unlike the shorter acting effects of NO, EDHF,
cells. It opens calcium activated potassium chan- and prostacyclin, the effects of endothelin are
nels (KCa) on vascular smooth muscle cells hyper- thought to be longer lasting and leading to long
polarizing them and leading to relaxation. Its term changes. It has been suggested that endothe-
chemical structure, however, is still unknown. It lin does not play a significant role in regulating
is thought to be stimulated by similar factors that blood flow in normal hearts but can regulate vas-
also stimulate NO production. cular tone in disease states like heart failure.
Prostacyclin is a metabolite of arachidonic Furthermore, in the dysfunctional endothelium,
acid. Arachidonic acid is converted to prostaglan- as seen in the hearts of smokers or coronary ath-
din by cyclooxygenase which is then converted to erosclerosis, the production of vasodilatory
prostacyclin (PGI2) by prostacyclin synthase in mediators is compromised; therefore, the net
endothelial cells. It is released from endothelial effect is endothelin mediated vasoconstriction.
cells in response to decreases in arterial oxygen
partial pressures [12, 13]. Its release is also stim-
ulated by acetylcholine and shear stress. Neurohormonal Factors
Prostacyclin then results in smooth muscle relax-
ation by a cAMP dependent pathway. While there The sympathetic and parasympathetic nervous sys-
is evidence that prostacyclins affect epicardial tems both can affect coronary vascular resistance,
22 E. Cami

a b

Fig. 2.9 Still frame of a left circumflex artery angiogram i­ntracoronary nitroglycerin was given, the occlusion
and its branches in a patient without any known prior ­completely resolved and there was TIMI-III flow with
coronary artery disease who had suffered a ventricular complete filling of the distal posterolateral branch
fibrillation cardiac arrest. The rest of the coronary arteries (red arrowheads). Flow was then seen in an obtuse mar-
did not have any stenosis. (a) There is a subtotal occlusion ginal branch (yellow arrowheads) as well. The occlusions
of the large posterolateral branch demonstrated by the red were due to vasospasms. The patient had a long smoking
arrows. There was TIMI-II flow in the distal posterolat- history which likely contributed to the vasospasms
eral branch (red arrowheads). (b) After 200 mcg of

however, under basal conditions there is very little leads to alpha1 receptor mediated vasoconstriction
to no sympathetic tone in the heart and the parasym- and beta2 receptor mediated vasodilation. The vaso-
pathetic innervation predominates. Parasympathetic dilating properties of the beta receptor activation,
stimulation from the vagus nerve leads to acetyl- however, predominate. Sympathetic stimulation
choline release which has two opposing effects on also increases heart rate and contractility by means
the coronary circulation (Fig. 2.8). of beta1 receptors leading to increased metabolic
Acetylcholine interacts on arterial endothelial demands which further potentiates the vasodilating
cells through muscarinic receptors which then effects. Thus, in normal hearts, sympathetic stimu-
release nitric oxide (NO), leading to vasodilation. lation induces coronary dilation mainly secondary
When acetylcholine interacts directly with arte- to increased metabolic demand. People with endo-
rial vascular smooth muscle cells through musca- thelial dysfunction such as atherosclerosis have
rinic receptors, it leads to vasoconstriction. In impaired NO mediated vasodilation, thus alpha1
healthy patients, the net effect is vasodilation mediated vasoconstriction predominates which
because the direct muscarinic constriction of vas- results in an increase in stenosis severity.
cular smooth muscle is overcome by the endothe-
lium mediated vasodilation through nitric oxide.
However, in patients with endothelial dysfunc-  achycardia and Bradycardia Effects
T
tion (e.g. in smokers or those with significant ath- on Coronary Flow
erosclerosis), the vasoconstriction effect will
predominate as NO production is attenuated. At a heart rate of 60 beats per minute, 60 % of the
Sympathetic activation results in release of nor- cardiac cycle is spent in diastole. In tachycardia,
epinephrine from cardiac sympathetic nerves. This however, diastole shortens to a greater proportion
2 Physiology of Coronary Blood Flow 23

than systole; therefore, the proportion of the car- v­ asospasms may last long enough to be present
diac cycle that is spent in diastole is less. This during coronary angiogram if emergent cardiac
mechanical reduction in coronary flow is how- catheterization is performed (Fig. 2.9). If clinical
ever overridden by coronary vasodilation which concern for coronary spasm is high and spasms
results from the increased metabolic activity are not observed during angiography, then
from the increased heart rate. In bradycardia, the ­provocation can be attempted in the cardiac cath-
heart spends more time in diastole than systole so eterization lab. The two main pharmacological
coronary flow is less restricted but the metabolic agents used to induce coronary artery spasms are
requirements are also being diminished. acetylcholine or ergonovine [18]. In the dysfunc-
Ultimately, it is the local metabolic requirements tional endothelium, acetylcholine causes vaso-
which have the largest impact in vascular tone constriction as was discussed earlier. Ergonovine
and coronary flow. activates serotonergic receptors on vascular
smooth to produce vasoconstriction. Endothelial
cells, in turn, release prostacyclin inhibitors in
Coronary Vasospasm response to ergonovine further potentiating the
vasoconstriction effect. Both agents can be given
Coronary vasospasm is a sudden, transient, and intravenously or intracoronary to achieve the
reversible occlusion of the coronary arteries. desired effect; however, intracoronary administra-
During episodes of vasospasms, oxygen supply tion is thought to be safer as it avoids peripheral
to the myocardium is reduced resulting in angina. effects while allowing provocation of the right
This particular type of angina is known as and left coronary arteries separately. Intracoronary
Prinzmetal or variant angina. The exact mecha- nitroglycerin may be used if needed to relieve the
nism of coronary vasospasm is not clearly defined spasms. A positive test is defined as more than
but some risk factors that may lead to it are 90 % transient occlusion of the artery associated
known. with angina symptoms or ST segment changes.
Coronary vasospasm occurs more frequently Studies have suggested that provocative testing
in coronary artery stenosis or in coronary arteries for coronary artery spasm is relatively safe [19]
with endothelial dysfunction such as in smokers however its practice is uncommon and varies by
but can also occur in normal coronary arteries. centers due to safety concerns [20] given case
Alcohol consumption or recreational drug use reports of prolonged spasms or infarction.
has also been linked to coronary vasospasms and
an example of this is cocaine. Cocaine is a pow-
erful stimulant of sympathetic effects by block-  athophysiology of Coronary
P
ing the reuptake of norepinephrine. This increase Artery Stenosis
in norepinephrine causes activation of alpha1 and
beta1 adrenergic receptors therefore leading to Hemodynamic Significance
vasoconstriction as well as increased heart rate of Coronary Stenosis
and contractility. The alpha mediated vasocon-
striction can be strong enough to cause complete In normal coronary arteries, the epicardial arter-
occlusion of the coronary arteries and lead to ies have minimal resistance and pass blood with-
myocardial infarction [15]. The vasospastic out a drop in pressure. In coronary artery disease,
effects of cocaine can be reversed with an alpha1 there may be stenotic segments in the epicardial
receptor antagonist like phentolamine. vessels leading to increased resistance in those
Over the past two decades, there has been segments. The increase in resistance then causes
increasing evidence that coronary vasospasm, a drop in pressure distal to the stenosis. The pres-
regardless of the cause, does not carry a benign sure drop is proportional to the severity of the
prognosis but can lead to myocardial infarction or stenosis. The relationship between the coronary
cardiac arrest [16, 17]. Diagnosis is difficult given flow across a stenosis and pressure drop can be
that episodes are transient, but occasionally described using Bernoulli’s principle (Fig. 2.10).
24 E. Cami

Fig. 2.10 The pressure drop

across a stenosis is
­determined by the length of
the stenotic segment, cross
sectional luminal are at the
most stenosed segment, and
the cross sectional area distal
to the stenosis, which are
then used to calculate the
viscous and separation
coefficients. The other
determinant in the equation
is flow (Modified from Mann
et al. [2] and Kern and
Samady [23] with
permission)

As is implied by the equation, luminal area at the 5

stenosis has the biggest effect on the pressure Maxima blood flow
drop. This is because resistance is inversely pro- 4
Coronary flow reserve

portional to the cross sectional area squared;

therefore, a small increase in the stenosed lumi- 3
nal area will lead to a large pressure drop. In
order to compensate for the increased resistance 2
at the stenosed segment, the distal vessel dilates Basal flow
through autoregulatory mechanisms so that flow 1
to that area of the myocardium is not affected.
However, as stenosis severity continues to 0
increase beyond a certain threshold, blood flow 0 20 40 60 80 100
distal to the stenosis will be impaired even with (%) Diameter narrowing
maximal vasodilation (Fig. 2.11). Hyperemic
Fig. 2.11 Graph demonstrating epicardial artery stenosis
blood flow starts to become impaired when an versus flow relationship. Basal coronary flow is repre-
upstream coronary stenosis narrows the luminal sented by the red line and hyperemic flow is represented
diameter by more than 50 % while the basal by the purple line. The difference between the two curves
blood flow (flow at rest) remains unaffected. demonstrates the coronary flow reserve
When a stenosis narrows the luminal diameter by
more than 90 %, then the basal blood flow strenuous exercise, coronary blood flow can
becomes impaired so ischemia can develop at increase up to three to five times above levels at
rest. This happens even with maximum vasodila- rest by mechanisms that were discussed earlier.
tory mechanisms. This magnitude of blood flow increase relative to
flow values at rest is termed coronary blood flow
reserve. Coronary flow reserve is also the ratio of
Coronary Flow Reserve hyperemic flow to basal flow and can become
impaired as the stenosis severity exceeds 50 % of
Coronary hyperemia is defined as the maximum the luminal diameter. Therefore, given that coro-
increase in coronary blood flow above the basal nary flow reserve is a ratio of two values, it is
level. This can happen during exercise, pharma- affected if there is a decrease in hyperemic flow
cologic stimulation, or relief of ischemia. During like in coronary artery stenosis or if there is a
2 Physiology of Coronary Blood Flow 25

Left ventricular hypertrophy Table 2.1 Pharmacologic agents used to achieve hyper-
emic coronary blood flow during stress testing or to mea-
400
sure fractional flow reserve in the catheterization lab
mL/min Normal
50% and LVH Substance Mechanism Effect
320 Adenosine Activates A2 Vasodilation
Coronary flow (mL/min)

receptors on
vascular smooth
240
muscle
70%
Regadenoson Activates A2 Vasodilation
160 receptors with
higher affinity
LVH
than adenosine
80 Dipyridamole Inhibits cAMP Vasodilation
Normal
breakdown
Nitroglycerin Converted to Vasodilation
0
nitric oxide in
0 20 40 60 80 100
mitochondria
Fig. 2.12 Comparison of basal (purple line) and hyper- Sodium Releases nitrick Vasodilation
emic coronary flow (yellow line) in normal hearts and nitrupruside oxidine in
ventricular hypertrophy. The latter leads to increased circulation
basal flow though the maximum or hyperemic flow Papaverine Inhibits cAMP Vasodilation
remains unchanged. Therefore coronary flow reserve is breakdown
decreased in ventricular hypertrophy (From Mann et al. Dobutamine Primarily B1 Increases
[2] with permission) adrenergic metabolic
receptor agonist demands
weak B2 and leading to
change in resting flow. Resting coronary flow can alpha1 activity hyperemia
vary based on hemoglobin content, oxygen satu-
ration, and baseline hemodynamics. Disease
states like left ventricular hypertrophy will result through exercise or pharmacologic agents which
in increased basal flow. In left ventricular hyper- include agents that produce direct vasodilation
trophy, the myocardial muscle mass increases and agents that lead to indirect vasodilation by
without proliferation of the coronary circulation. increasing metabolic demands. These are further
As a result, there is increased basal flow to meet explained in Table 2.1. Hyperemic blood flow
the increased metabolic demands of the hypertro- can then be assessed noninvasively or invasively.
phied myocardium. The hyperemic flow, how- Noninvasive methods include evaluation of myo-
ever, is not changed in the absence of other cardial wall motion through the use of echocar-
conditions (Fig. 2.12). The net result then is diography or by assessing tissue perfusion with
decreased coronary flow reserve [21]. imaging such as SPECT, PET, MRI, or CT.
Invasive methods to evaluate the significance
of a coronary stenosis are performed in the car-
 ssessing Significance of Coronary
A diac catheterization lab by measuring, coronary
Stenosis flow reserve (CFR), fractional flow reserve [22]
(FFR), and instantaneous wave-free ratio (iFR).
Given that resting blood flow is not significantly A pressure-sensor wire is passed through a ste-
impaired until stenosis severity reaches 90 % of notic segment. The blood pressure is then mea-
the luminal diameter, measuring resting blood sured in the distal and proximal segments to the
flow or imaging resting perfusion will not iden- stenosis and the ratio of the two values is known
tify hemodynamically significant stenosis. as the fractional flow reserve (FFR). This must be
Instead, perfusion images or blood flow measure- done during hyperemic flow to eliminate the
ments need to be obtained during hyperemic resistance in the microcirculation so that flow is
blood flow. Hyperemic flow can be achieved limited solely by the resistance of the stenotic
26 E. Cami

segment in the epicardial artery. Hyperemic flow 6. Gould KL, Lipscomb K. Effects of coronary stenoses
on coronary flow reserve and resistance. Am J Cardiol.
in the catheterization lab is induced with drugs
1974;34:48–55.
such as papaverine, adenosine, dipyridamole, 7. Sato A, Terata K, Miura H, et al. Mechanism of vaso-
nitroglycerin, or nitroprusside. If there is no drop dilation to adenosine in coronary arterioles from
in pressure across the stenosis, the distal blood patients with heart disease. Am J Physiol Heart Circ
Physiol. 2005;288:H1633–40.
pressure will be the same as the proximal blood
8. Deussen A, Ohanyan V, Jannasch A, Yin L, Chilian W.
pressure. A normal FFR therefore is equal to 1.0 Mechanisms of metabolic coronary flow ­regulation. J
and decreases progressively as the stenosis sever- Mol Cell Cardiol. 2012;52:794–801.
ity increases [23]. 9. Wexels JC, Myhre ES, Mjos OD. Effects of carbon
dioxide and pH on myocardial blood-flow and metab-
olism in the dog. Clin Physiol (Oxford Engl). 1985;5:
575–88.
Future 10. Vanhoutte PM. Vascular biology. Old-timer makes a
comeback. Nature. 1998;396(213):5–6.
11. Luksha L, Agewall S, Kublickiene K. Endothelium-
Over the past half century, an increase in knowl-
derived hyperpolarizing factor in vascular physiology
edge about the physiology of coronary blood and cardiovascular disease. Atherosclerosis. 2009;
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understanding cardiovascular disease processes 12. Busse R, Forstermann U, Matsuda H, Pohl U. The
role of prostaglandins in the endothelium-mediated
and treatments. For example, the discovery that
vasodilatory response to hypoxia. Pflugers Arch Eur J
NO was in fact the endothelial derived relaxing Physiol. 1984;401:77–83.
factor lead to a better understanding and imple- 13. Kalsner S. The effect of hypoxia on prostaglandin
mentation of medications like nitroglycerin and output and on tone in isolated coronary arteries. Can J
Physiol Pharmacol. 1977;55:882–7.
other nitrates. Furthermore, the understanding of
14. Dai XZ, Bache RJ. Effect of indomethacin on coro-
stenosis and pressure flow relationship has led to nary blood flow during graded treadmill exercise in
better outcomes with FFR guided percutaneous the dog. Am J Physiol. 1984;247:H452–8.
coronary interventions [24]. Coronary blood flow 15. Rezkalla SH, Kloner RA. Cocaine-induced acute
myocardial infarction. Clin Med Res. 2007;5:
indeed is very complex and several unknowns
172–6.
remain. We need to better understand the signifi- 16. Wang CH, Kuo LT, Hung MJ, Cherng WJ. Coronary
cance of the determinants that have been identi- vasospasm as a possible cause of elevated cardiac tro-
fied. We also need to learn more about the other ponin I in patients with acute coronary syndrome and
insignificant coronary artery disease. Am Heart J.
unknown determinants of autoregulation. With
2002;144:275–81.
ongoing research, these unknowns can become 17. MacAlpin RN. Cardiac arrest and sudden unexpected
the focus for continued expansion in treating car- death in variant angina: complications of coronary
diac diseases. spasm that can occur in the absence of severe organic
coronary stenosis. Am Heart J. 1993;125:1011–7.
18. Zaya M, Mehta PK, Merz CN. Provocative testing for
coronary reactivity and spasm. J Am Coll Cardiol.
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flow reserve versus angiography for guiding
 Pathophysiology of Coronary
Artery Disease 3
Jason George

Abstract
Coronary artery disease (CAD) generally refers to condition that involve
impairment or blockage of coronary artery blood flow that can result in
silent ischemia, angina pectoris, acute coronary syndromes, or sudden car-
diac death. Acute coronary syndromes (ACS) represent a clinical spec-
trum disease ranging from ST-segment elevation myocardial infarction
(STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), or
unstable angina (UA). The clinical manifestation of CAD depends on
many factors and is heavily influenced by the pathophysiology of the dis-
ease process. The most common cause of CAD is atherosclerosis. Less
frequent causes include coronary spasm, aneurysm, dissection, embolic
occlusion, vasculitis, and restenotic disease. This chapter will review the
pathophysiology of CAD.

Keywords
Pathophysiology of coronary artery disease (CAD) • Acute coronary syn-
dromes (ACS) • ST-segment elevation myocardial infarction (STEMI) •
Non-ST-segment elevation myocardial infarction (NSTEMI) • Unstable
angina (UA) • Stable angina • Atherosclerosis • Atherosclerotic plaques

Introduction

Coronary artery disease (CAD) generally refers

to condition that involve impairment or blockage
of coronary artery blood flow that can result in
silent ischemia, angina pectoris, acute coronary
J. George, MD syndromes, or sudden cardiac death. Acute coro-
Department of Cardiology,
nary syndromes (ACS) represent a clinical
William Beaumont Hospital,
Royal Oak, MI, USA spectrum disease ranging from ST-segment
e-mail: [email protected] elevation myocardial infarction (STEMI),

© Springer-Verlag London 2015 29

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_3
30 J. George

Table 3.1 ACC/AHA/ACP clinical classification of Table 3.2 Canadian cardiovascular society grading of
chronic stable angina angina pectoris
Typical angina Grade Ordinary physical activity does no cause
1. Substernal chest discomfort with a characteristic 1 angina, such as walking and climbing stairs.
quality and duration Angina with strenuous or rapid or prolonged
exertion at work or recreation
2. Worse with exertion or emotional stress
Grade Slight limitation of ordinary activity.
3. Relieved by rest or nitroglycerin
2 Walking or climbing stairs rapidly, walking
Atypical angina: meets two of the characteristic above uphill, walking or stair climbing after meals,
Noncardiac chest pain: meets ≤1 of the characteristic or in cold, in wind or under emotional stress,
above or only during the few hours after
Data from Gibbons et al. [1] and Diamond [30] awakening. Walking more than two blocks
on the level and climbing more than one
flight of ordinary stairs at a normal pace and
in normal conditions
non–ST-segment elevation myocardial infarction
Grade Marked limitation of ordinary physical
(NSTEMI), or unstable angina (UA). The clinical 3 activity. Walking one or two blocks on the
manifestation of CAD depends on many factors level and climbing one flight of stairs in
and is heavily influenced by the pathophysiology normal conditions and at normal pace
of the disease process. The most common cause Grade Inability to carry out any physical activity
of CAD is atherosclerosis. Less frequent causes 4 without discomfort; angina may be present at
rest
include coronary spasm, aneurysm, dissection,
embolic occlusion, vasculitis, and restenotic From Campeau [31] with permission
disease. This chapter will review the
pathophysiology of CAD. Unstable angina (USA) is type of angina that
has pattern of increasingly frequent pain, longer
duration, and change in quality and is a warning
Definitions: Angina sign that an acute MI may be imminent. USA of
most often caused by disruption of an atheroscle-
As outlined in the ACC/AHA/ACP Guidelines rotic plaque, partial thrombus formation, emboli-
“Angina is a clinical syndrome characterized by zation, and/or coronary vasospasm. The
discomfort in the chest, jaw, shoulder, back, or characteristic features of USA include: (1)
arm. It is typically aggravated by exertion or Occurs are rest or with minimal exertions, (2)
emotional stress and relieved by nitroglycerin. New onset within 1 month, and (3) Occurs with a
Angina usually occurs in patients with CAD crescendo pattern (more severe, prolonged, or
involving ≥1 large coronary artery. However, increased frequency than previously) [2–4].
angina can also occur in individuals with valvular Prinzmetal variant angina is an uncommon
heart disease, hypertrophic cardiomyopathy, and form myocardial ischemia caused by coronary
uncontrolled hypertension. It can be present in vasospasm. It is important to note that Prinzmetal
patients with normal coronaries or in patient with angina may occur in patients with or without sig-
myocardial ischemia related to spasm or endo- nificant coronary atherosclerosis. Multiple etiol-
thelial dysfunction” [1]. There are different clas- ogies have been identified as the cause of
sification of angina that will are outlined coronary artery spasm and include smoking,
(Table 3.1) and graded below (Table 3.2). cocaine use, and stress although many cases
Stable angina (also called typical angina) is the occur spontaneously without any identifiable
most common form of angina pectoris and is cause. The clinical presentation of Prinzmetal
caused by an imbalance of coronary perfusion rela- angina is characterized by chest discomfort that
tive to myocardial oxygen demand. Stable angina occurs at rest (rather than on exertion) thus
is usually relieved by factors that decrease myocar- patient may exhibit a circadian pattern of symp-
dial oxygen demand (such as rest) or increase coro- toms with episodes occurring at night or during
nary perfusion (such as vasodilator) [2]. the early morning hours [2, 3, 5].
3 Pathophysiology of Coronary Artery Disease 31

Definition: Myocardial Infarction Table 3.4 Universal classification of myocardial

infarction
Myocardial infarction is defined as a clinical Type 1: Spontaneous myocardial infarction
event caused by ischemia in which there is evi- Spontaneous myocardial infarction related to
atherosclerotic plaque rupture, ulceration,
dence of myocardial injury or necrosis. Evidence
erosion, or dissection with resulting intraluminal
of ischemia is met when there is a rise and fall of thrombus in one or more of the coronary arteries
cardiac biomarkers with supportive evidence leading to decreased myocardial blood flow or
including patient symptoms, ECG findings, and/ distal platelet emboli with myocyte necrosis. The
patient may have underlying severe CAD but on
or imaging findings (such as wall motion abnor-
occasion non-obstructive or no CAD
mality on an echocardiogram). Elevated tropo-
Type 2: Myocardial infarction secondary to an
nins due to myocardial injury may be due to ischemic imbalance
multiple causes included primary myocardial In instances of myocardial injury with necrosis
ischemia, supply/demand ischemia, myocardial where a condition other than CAD contributes to
injury not related to ischemia, or multifactorial an imbalance between myocardial oxygen supply
and/or demand, e.g. coronary endothelial
(Table 3.3). In 2012 the Third Universal dysfunction, coronary artery spasm, coronary
Definition of MI was release and is outlined in embolism, tachy-/brady-arrhythmias, anemia,
Table 3.4. respiratory failure, hypotension, and hypertension
Commonly the clinical diagnosis and treatment with or without LVH
of a myocardial infarction is based on ECG findings Type 3: Myocardial infarction resulting in death when
biomarker values are unavailable
as a means of distinguishing between two types of
Cardiac death with symptoms suggestive of
myocardial ischemia and presumed new ischemic
ECG changes or new LBBB, but death occurring
Table 3.3 Causes of elevated cardiac troponins
before blood samples could be obtained, before
Myocardial injury related to primary coronary artery cardiac biomarker could rise, or in rare cases
injury cardiac biomarkers were not collected
Plaque rupture Type 4a: Myocardial infarction related to
Coronary artery thrombus formation percutaneous coronary intervention (PCI)
Coronary vasculitis Myocardial infarction associated with PCI is
Myocardial injury related to supply/demand mismatch defined by elevation of troponins >5 times the
upper limit of normal in patients with normal
Coronary spasm baseline values or a rise of troponins by 20 % if
Severe hypertension or hypotension the baseline values are elevated and are stable or
Tachy/brady – arrhythmia falling
Severe aortic stenosis In addition, one for the following must be present:
Severe anemia Symptoms suggestive of myocardial ischemia
Respiratory failure New ischemic ECG changes or new LBBB
Coronary emboli Angiographic loss of patency of a major coronary
Myocardial injury not related to ischemia artery or a side branch or persistent slow or
no-flow or embolization
Myocarditis
Imaging demonstration of new loss of viable
Cardiac contusion
myocardium or new regional wall motion
Defibrillator shock abnormality
Surgery Type 4b: Myocardial infarction related to stent
Cardiotoxic drugs thrombosis
Multifactorial Myocardial infarction associated with stent
Takotsubo cardiomyopathy thrombosis is detected by coronary angiography
Sepsis or autopsy in the setting of myocardial ischemia
and with a rise and/or fall of cardiac biomarkers
Heart failure values with at least one value above the upper
Pulmonary emboli limit of normal URL
Infiltrative diseases (continued)
Data from Thygesen et al. [6]
32 J. George

Table 3.4 (continued) and is primary branches. The function of the

Type 5: Myocardial infarction related to coronary adventitia is to stretch and recoil in response to
artery bypass grafting (CABG) systolic pressures produced by the heart.
Myocardial infarction associated with CABG is
defined by elevation of cardiac biomarker values
10 times the upper limit of normal in patients
with normal baseline troponin values Atherosclerosis
In addition, one for the following must be present:
New pathological Q waves or new LBBB The most common cause of heart disease and
Angiographic documented new graft or new CAD is caused by atherosclerosis. “The term
native coronary artery occlusion atherosclerosis is derived from the Greek word
Imaging evidence of new loss of viable “athero”, meaning gruel, or wax, corresponding
myocardium or new regional wall motion to the necrotic core area at the base of the ath-
abnormality
erosclerotic plaque, and “sclerosis” for harden-
From Thygesen et al. [6] with permission ing, or induration, referring to the fibrous cap of
the plaque’s luminal edge” [7]. Atherosclerosis
MI, one that is marked by ST elevation (STEMI) is a slowly progressive chronic disease that is
and one that is not (NSTEMI). The terms transmu- due to the build up of lipid within the artery
ral and nontransmural (subendocardial) MI are no wall resulting in thickening and hardening of
longer used because ECG findings in patients with the vessel. The development of atherosclerosis
this condition do not closely correlated with patho- is asymptomatic until it reaches an advanced
logic changes in the myocardium. The presence of stage or is triggers by an acute cardiovascular
Q waves or ST elevation is associated with higher event.
early mortality and morbidity; however, the absence Atherosclerotic CAD is the leading cause of
of these two findings does not confer better long- morbidly and mortality worldwide [8] and is
term mortality and morbidity [4, 6]. responsible for about one in every six deaths in
the United States [9]. The economic burden of
cardiovascular disease (CVD) is rapidly grow-
Coronary Artery Anatomy ing compromising the national health care
expenditure and cost the US economy over $100
As discussed in Chap. 1, the normal coronary billion each year. It is estimated that by 2030
artery wall consists of three layers called the 40 % of the US population will have some form
intima, media, and adventitia (See Fig. 3.1). The of CVD [10].
intima is separated from the media by a thin mem-
brane call the internal elastic membrane. The
media is separated from the adventitia by a thin Theories of Atherogenesis
membrane call the external elastic membrane. The
intimal layer is closest to the arterial lumen and Several theories have been proposed over the past
consists of a single layer of cells called the endo- two centuries to explain the pathogenesis and
thelium. The endothelium is a highly metaboli- development of atherosclerotic plaques. As our
cally active barrier of tissue that serves multiple knowledge has rapidly increased we have found
functions with the most notable being maintenance that the individual proposed theories are not mutu-
of hemostasis and immune cell recruitment. The ally exclusive, and are linked to each other.
media is the thickest layer of tissue and contains Leonardo da Vinci (1452–1519AD) was one of the
mostly smooth muscle cells as well as the extracel- first to document the macroscopic findings of an
lular matrix. The media enable the vessel to dilate atherosclerotic artery when he illustrated the artery
and constrict in order to control blood flow. The of a human autopsy specimen and suggested that
adventitia is the outermost layer and consists the thickening of the vessel wall might be due to
mostly of fibro-elastic tissue. The adventitia is “excessive nourishment” [11]. In the nineteenth
more prominent in larger vessels such as the aorta century a physician by the name of Carl von
3 Pathophysiology of Coronary Artery Disease 33

Fig. 3.1 Arterial wall

structure (From Lilly [27]
with permission)

Lumen

Endothelial cells Intima

Internal elastic lamina
Smooth muscle cells Media

External elastic lamina

Adventitia

Rokitansky documented the macroscopic findings accumulation of lipids in the vessel wall. The
of multiple plaques in the aorta. He hypothesized lipids from these lesions are believed to be
that degenerated blood bound proteins deposit into derived from plasma lipoproteins (i.e. low den-
the arterial wall and formed pseudomembranes that sity lipoproteins, LDL), which is consistent with
had both thrombogenic and calcific characteristics the role of hyperlipidemia being a risk factor for
[12]. Several years later Rudolf Virchow (1821– atherosclerosis and acute coronary syndrome.
1902) built upon his work by studying microscopic The LDL particle is too large to penetrate the
sections of diseased vessels. Virchow concluded tightly closed junctions between adjacent endo-
that atherosclerotic lesions were located in the inti- thelial cells. However, endothelial cells have
mal layer of blood vessels and that despots within receptors for LDL and are able to transport these
this layer was associated with connective tissue lipids across an intact endothelium by receptor-
proliferation resulting in vessel wall degeneration mediated uptake. Lipids may also be engulfed by
[13]. In the early twentieth century several scientist monocytes while in the circulation and then
contributed to identifying the content of arterial transport into the intima as they transmigrate
plaques. The most notable was a German scientist into the wall between dysfunctional endothelial
by the name of Adolf Windaus who won a Nobel cells. Lipids that are in the extracellular space
prize in 1910 after showing that cholesterol was within the intima become trapped within the
present in atherosclerotic lesions [14]. Throughout extracellular matrix where they accumulate over
the nineteenth century as people began to live lon- time.
ger, interest grew to determine the clinic implica-
tions cause atherosclerosis. Several theories were
proposed during this time, and as our understand- Encrustation Theory
ing of the pathophysiology of atherosclerosis
increased, we have recognized that process is of This theory initially proposed that material from
increasing complexity with a multitude of vari- the blood was deposited on the inner surface of
ables. Below we will outline several of the most arteries and lead to thickening of the inner lining
pertinent theories of atherosclerosis. creating a mural thrombus. It was thought that
platelets and fibrin of thrombi initiated athero-
sclerosis. Although mural thrombosis is not the
Insudation Theory initial event in atherogenesis, it is likely to pro-
mote the later progression of the atherosclerotic
This theory proposes that the primary event that lesion and is the major event leading to vascular
triggers the development atherosclerosis is focal occlusion, especially in coronary arteries.
34 J. George

Reaction to Injury Theory

The reaction to injury theory is the most widely

excepted among scientific and medical scholars.
This theory states that the initial event in the
pathogenesis of atherosclerosis is injury to the
endothelium that compromises the integrity of
the endothelial barrier. The nature of the injury is
likely to involve numerous factors and is different
in different people depending on genetic and
environmental conditions. Injured endothelium
triggers an inflammatory response with migration Fig. 3.2 Electron micrograph image of aorta from a
of inflammatory cells (predominantly macro- experimental animal that received intravenous injection of
human low-density lipoprotein (LDL). Round LDL parti-
phages and lymphocyte). Inflammatory cell cles seen trapped in the extracellular matric of the intima
migration along with oxidized low-density lipo- (From Douglas et al. [3]. with permission)
proteins within the lesion is thought to be the key
player during the development of an atheroscle-
rotic plaque [13, 15]. Accumulation of extracellular lipoprotein
particles is one of the first morphologic changes
to occur. Lipoprotein particles become trapped
Atherosclerosis: Pathophysiology in the strands of proteoglycan within the suben-
dothelial region of the intima where they begin
Microscopic Description to accumulate. Proteoglycan-associated lipo-
of the Development proteins appears particularly are susceptible to
of an Atherosclerotic Lesion oxidative modification. In response to oxidized
lipoproteins, cellular injury occurs and triggers
Endothelial injury and dysfunction is the corner- an immune respond with the recruitment of
stone for the initiation of atherosclerosis. The spe- monocytes that migrate into the intima of the
cific mechanism contributing to endothelial artery wall (Fig. 3.3). Once monocytes have
dysfunction is not completely understood, although migrated into the intima they differentiate into
the most important culprits that trigger endothelial macrophages and engulf the harmful oxidized
dysfunction include hypertension, hyperlipidemia, lipoproteins form intracellular lipid filled vacu-
diabetes, and toxin from cigarette smoking. oles. These macrophages that are filled with
Regardless of the cause of endothelial dysfunction vacuoles of lipoproteins are referred to as foam
this lead to increased vascular permeability. cells. Although, the foam cells serve a theoreti-
In the presence of a lipoprotein abnormality cally protective function the oxidized lipopro-
lipids begin to accumulate on the endothelial teins within these cells augments cellular
cells lining the endothelium. As the lipid parti- activation and cytokine production resulting in
cles accumulate they migrate into the intima and additional recruitment of mononuclear cells.
coalesce into the proteoglycan of the extracellu- Activate macrophages also produce reactive
lar matrix (ECM) were they get “trapped” oxygen species that further augments oxidation
(Fig. 3.2). Lipoproteins that accumulate in the of lipoproteins within the cell. Over time the
ECM are susceptible to oxidative stress. The oxi- macrophages and foams cells die releasing the
dized lipoproteins produce free radicals that lipid content into the intercellular space. As a
causes localize cellular injury and dysfunction. result of this cyclic chronic inflammatory state
This stimulates the release of growth factors, (with local tissue injury, endothelial dysfunc-
cytokines, and chemokines by endothelial cells, tion, and breakdown of the vessel wall endothe-
and hinders the vessels vasodilator activity. lial barrier), T lymphocyte recruitment occurs
3 Pathophysiology of Coronary Artery Disease 35

Hyperlipidemia, hypertension,
smoking, toxins, hemodynamic
factors, immune reactions, viruses

Endothelial injury/dysfunction

Monocyte adhesion and Cholesterol efflux via HDL

emigration into intima

Lumen
Extracellular
matrix synthesis
LDL

Macrophage
Endothelium
Proliferation of
LDL Foam
Lipid smooth muscle
Cytokines cells
uptake cells
(e.g., IL-1, MCP-1)
+
lntima Oxidized LDL

T cell Cytokines Growth factors Extracellular lipids

(e.g., interferon-γ) and necrotic cells
Internal Recruitment and
elastic migration of
membrane smooth muscle
cells
Smooth musle cells
Media

Normal vessel Progressive development of

artherosclerotic plaque

Fig. 3.3 “Hypothetical sequence of cellular interactions from the vessel lumen, particularly in the presence of
in atherosclerosis. Hyperlipidemia and other risk factors hypercholesterolemia, and also from degenerating foam
are thought to cause endothelial injury, resulting in adhe- cells. Smooth muscle cells migrate to the intima, prolifer-
sion of platelets and monocytes and release of growth fac- ate, and produce extracellular matrix” (From Vinay et al.
tors, which leads to smooth muscle cell migration and [2] with permission)
proliferation. Extracellular lipid is derived from insudation

resulting in additional release of cytokines that Macroscopic Description

further stimulates macrophages, endothelial of the Development
cells, smooth muscle cells, and proliferation of of an Atherosclerotic Lesion
the extracellular matrix. With the accumulation
of foam cells and the proliferation of intimal In the early stages of the development of coronary
smooth muscle cells and extracellular matrix atherosclerosis the plaque does not protrude into
the earliest grossly visible lesion sign of an ath- the coronary lumen, thus can escape detection by
erosclerotic lesion develops called a fatty coronary angiography. Early atherosclerotic
streak. Over time the lesions further mature plaques, which are filled with lipid, are more
into an atheroma and will progressively grow likely to rupture and cause coronary events then
with the development of a lipid core. During the more stable advance plaques with thick fibrous
the lesion maturation process the smooth mus- caps that cause narrowing of the lumen. A fibrous
cle cells synthesizing extracellular matrix cap consists mostly of collagen that forms over
(notably collagen) in an attempt to stabilize the the lipid core. The fibrous cap is an attempt by the
atherosclerotic plaques. Many times this is body to contain the lesion. Continued plaque
unsuccessful resulting in an unstable plaque growth cause by the accumulations of lipids
that is prone to rupture [2]. within the intima causes the external elastic
36 J. George

Fig. 3.4 Relationship

between plaque formation
and arterial remodeling. With
development of atheroscle-
rotic plaque positive or
negative remodeling occurs.
When positive remodeling
occurs vessel lumen in
preserved until remodeling is
no longer to compensate for
the growing plaque. When
negative remodeling occur
vessel lumen area is reduced
compromising blood flow
(From van Varik et al. [28]
and Leon J. Schurgers, MD
with permission)

membrane to expand outward. This compensatory expands while the lumen retains its normal shape
enlargement is known as arterial remodeling and allowing the vessel to maintain blood flow.
allows the vessel to maintain adequate luminal However as the burden of plaque increases over
area for blood flow. For this reason angiography, time the artery can no longer expand outward and
which visualizes only plaques that encroach upon the plaque begins to occupy the lumen. Plaque
the lumen, will under-represent the extent of ath- rupture sets the stage for thrombus formation,
erosclerosis. As the burden of plaque increases the which can lead to a clinical event. Recurrent
artery can no longer compensate by expanding plaque rupture and healing leads to slowly pro-
outward and the plaque begin to protrude into the gressive luminal narrowing and manifest with
lumen. This generally occurs when plaque clinical symptoms as blood flow is obstructed.
involvement reaches about 40 % of the vessel cir-
cumference [16]. As the lipid burden of an athero-
sclerotic lesion grows the risk of plaque rupture Arterial Remodeling and Coronary
increases. When plaque rupture occurs the lipid Artery Disease
core comes into contact with the blood. This sets
the stage for the formation of a thrombus or clot. Coronary artery remodeling refers to changes in
The thrombus may partially or totally block an the size, shape, structure, and physiology of a
artery causing an acute reduction in blood flow. coronary artery in an attempt to preserve luminal
This reduction in blood flow may cause symp- area and thus blood flow to the myocardium.
toms such as angina. Complete prolonged block- Positive (outward) arterial remodeling refers to
age will cause an acute myocardial infarction. radial enlargement of a vessel in order to com-
To summarize, during the early stages of ath- pensate for the growth of atherosclerotic lesions.
erosclerosis plaques accumulates within the intima Negative (inward) arterial remodeling refers to a
without protruding into the lumen. As the plaque reduction in vessel luminal cross-sectional area
initially does not protrude into the lumen it tradi- resulting in vessel stenosis (Fig. 3.4).
tional escapes detection by coronary angiography, Glagov was the first to describe the concept of
however, may be detected by advances coronary arterial remodeling in 1987 after studying cross
imaging modalities. The initial adaptive response section specimens of coronary artery lesions.
an artery undergoes to growing plaque is called Glagov found that many of the autopsy specimens
arterial remodeling. The external elastic membrane had normal coronary artery lumen cross-sectional
3 Pathophysiology of Coronary Artery Disease 37

area despite the presence of advanced atheroscle- endothelial growth factor for reasons not com-
rosis. He also identified that luminal narrowing pletely understood. The rise in intracellular cal-
only occurred when the lesion occupied 40 % or cium triggers apoptosis of smooth muscle cells.
greater of the area circumscribed by the internal The release of growth factors attracts smooth
elastic lamina (internal elastic lamina area) [16]. muscle cell migration and proliferation within
Since Glagov proposed his arterial remodeling the lesion, and promotes collagen production
model further research has focus to delineate the with a net effect resulting in negative
mechanism of this process. remodeling.
The pathophysiology of coronary artery
remodeling is a complex adaptive response that is
influenced by a number of factors including coro- Lesion Morphology/Type
nary risk factors, plaque composition, vessel size,
shear stress, hemodynamic factors, vasoactive AHA Classification (Fig. 3.5)
substances, and growth factors. This process
involves a interplay between cell growth, cell The histologic and morphologic features catego-
death, and the migration, production, and degra- rize atherosclerotic lesions. Atherosclotic lesions
dation of extracellular matrix. Endothelial cells are categorized as early (type I–II lesions), inter-
play a key role in the structural changes of mediate (type III lesion), advanced (type IV–V
remodeling. As atherosclerotic lesions evolve lesions), and complicated (Type VI lesions).
they alter the flow of blood through the vessel Early and intermediate lesions are typically
lumen. This sustained change in blood flow stim- asymptomatic, whereas advanced and compli-
ulates the endothelial cells to produce a variety of cated lesion may result in significant morbidity
growth factors. This results in the proliferation and mortality. Atherosclerotic lesions are consid-
and migration of smooth muscle cells, the release ered advanced when there is an accumulation of
of proteases that break down matrix proteins, and lipid, cells, and matric components within the
the expression of cellular adhesion molecules intima leading to structural disorganization and
that facilitate migration of inflammatory cells. As thickening of the arterial wall. Although, lesions
macrophages migrate into atherosclerotic lesions that are considered advanced by histology they
in response to oxidizing lipids and growth factors may not cause symptomatic narrow of the arterial
they produced matrix metalloproteinase (such as lumen or be visible by angiography. Despite
collagenase) which function to reabsorb extracel- these lesions not causing clinical symptoms or
lular matrix components. evidence of severe disease on invasive imaging
Conditions that cause sustained increase blood they are still clinically significant as complica-
flow or sustained low blood flow influence tions may develop suddenly. Below we will
whether positive or negative remodeling occurs. briefly discuss each type of atherosclerotic lesion
When sustained increased blood flow occurs as defined by the American Heart Association
across a lesion this stimulates smooth muscle cell [17, 18].
proliferation and collagenase release with a net
effect resulting in positive remodeling. The pre-
dominant feature of positive remodeling is Type I
increased matrix degradation by metalloprotein-
ase as the vessel remodels outward. Although, Type I lesions represent the very early initial
this is meant to be a protective adaptation the changes and are characterized by microscopic
remodeling process weakens the vessel wall thus lipid deposit with associated cellular reactions.
making it prone to plaque rupture. Sustained low At this initial stage small isolated groups of mac-
blood flow across a lesion causes a rise in intra- rophages containing lipid droplets develop within
cellular calcium within smooth muscle cells lin- the intimal layer of an artery. Type I lesions have
ing the intima, and this triggers the release of been described as early as infancy with autopsy
38 J. George

Fig. 3.5 Flow diagram

Nomenclature and main Sequences in progression Main growth mcchanism
indicating the evolution histology
and progression of
atherosclerosis. The roman
Type I Iesion: Isolated
numerals indicate the macrophage and foam cells
histological characteristic I
types and the arrows indicate
the sequence in which
characteristic morphologies Type II Iesion: mainly
may change. The loop intracellular lipid
between Type V and VI accumulation II Growth mainly by lipid
lesions illustrate how lesions accumulation
may increase in thickness Type III Iesion: Type II
when non-obstructive changes & small
thrombus occurs. The extracellular lipid pools III
thrombotic deposits may
form repeatedly over time
and may be the principal Type IV Iesion: Type II
changes & core of
mechanism for gradual extracellular lipid IV
stenosis of a vessel
(From Stary et al. [19] with
permission) Type V Iesion: Lipid core & Accelerated smooth muscle
fibrotic layer, or multiple and collagen increase
lipid cores & fibrotic layers,
V
or mainly calcific, or mainly
fibrotic

Type VI Iesion: Surface Thrombus, Hematoma

defect, hematoma-
VI
hemorrhage, thrombus

studies reporting that 45 % of infants within the whether a type II lesion progress that includes:
first 8 months of life have macrophage foam cells cardiac risk factors, mechanical forces that act on
in there coronary arteries. the vessel wall, circulating lipoprotein levels, and
adaptive changes (abundance of smooth muscle
cells, extracellular matrix, and macrophage accu-
Type II mulation). As a type II lesion begin to mature mac-
rophages accumulate near the endothelial surface,
Type II lesions are characterized by several foam cells accumulate further into the intima at the
changes within the intimal layer which include: bottom of the proteoglycan layer, and the extracel-
layering of macrophage foam cells, lipid droplets lular lipids begin to accumulate even deeper.
within smooth muscle cells, and small amounts of
heterogeneous droplets of extracellular lipids.
Macroscopically a visible fatty streak may be pres- Type III: “The Intermediate Lesion”
ent, although not all type II lesions have visible
fatty streaks. Most of the lipids in type II lesions Type III lesions, also called the intermediate
are intracellularly contained within the macro- lesion, are characterized by pools of extracellular
phages and smooth muscle cells. Compared to lipids that form among the layers of smooth mus-
type I lesions there is an influx of macrophages. cle cells. These lipid pools displace intercellular
The majority of type II lesions either do not prog- matrix and drives smooth muscle cells apart. At
ress or progress slowly. A small subset will pro- this stage a well-delineated accumulation of
ceed to type III lesions and then to advanced extracellular lipid (i.e. lipid core) has not yet
lesions. There are many factors that influence developed.
3 Pathophysiology of Coronary Artery Disease 39

development of the lipid core along with intimal

disorganization results in what is called ather-
oma. Atheromas are typically large enough to be
visible by the unaided eye on autopsy specimens.
Many times atheromas fail to narrow the artery
lumen. Instead, they are associated with an
increase in size of the external boundary of the
artery, which is a characteristic of vessel remod-
eling [19].

Type V

Type V lesions are characterized by the formation

of a thick layers of fibrous connective tissue. The
development of connective tissue in and around
regions of the intima is thought to be a reparative
mechanism in response to accumulation of extra-
cellular lipids and intimal cellular disorganiza-
tion. The new tissue that forms consists
predominantly of collagen and smooth muscle
cells. Although this is considered to be a repara-
tive response, many times the connective tissue
formation is exaggerated resulting in a fibrous
cap that is thicker then the underlying lipid accu-
mulation. Type V lesions are further subcatego-
rized into Type Va (fibroatheroma), Type Vb
Fig. 3.6 Photomicrograph of atheroma (type IV lesion) (calcific), and Type Vc (fibrotic).
in proximal left anterior descending coronary artery. The • Type Va or fibroatheroma is when a type IV
formation of a lipid core is seen with a fibrous cap separat-
lesion develops a layer of fibrous connective
ing it from the vessel lumen. The region between the core
and the endothelial surface contains macrophages and tissue. Type Va lesions may also be multilay-
macrophage foam cells (fc). A adventitia, M media (From ered or multilobular with several lipid cores
Stary et al. [19] with permission) separated by thick layers of fibrous connective
tissue. These are termed multilayered
Type IV fibroatheroma.
• Type Vb (fibrocalcific) lesion is when the lipid
Type IV lesions, also called the “The Atheroma” core or other parts of the lesion become heav-
is the first to be considered an advanced lesion ily calcified. Calcified lesions generally
due to its increased risk of sudden lesion develop when there is an abundance of fibrous
progression and ischemia events. Histologically, connective tissue overlying the lipid core.
type IV lesions are characterized by intimal dis- Calcific deposition occurs where there are
organization, arterial deformity, and well-defined accumulated remnants of dead cells through-
dense extracellular accumulation of lipids creat- out the lesion.
ing what is called a lipid core (Fig. 3.6). The • Type Vc (fibroltic) lesion is when the lipid core
development of a lipid core results in severe inti- is minimal or absent. Type Vc lesion are not
mal disorganization. The intimal smooth muscle typically seen in coronary arteries, although are
cells and extracellular matrix become displaced often evident in the arteries of the lower extrem-
by the accumulation of extracellular lipid. The ities. In these lesions the intima is replaced with
40 J. George

fibrous connective tissue in the absence of lip- Plaque Rupture

ids or minimally present. The development of
these lesions may result from the organization When the fibrous cap of a vulnerable plaque rup-
of thrombi, extension of fibrous from an adja- tures the highly thrombogenic contents (includ-
cent fibroatheroma, or resorption of lipid core. ing tissue factor) of the necrotic core comes into
contact with blood causing the activation of
platelets and the clotting cascade. A platelet rich
Type VI plug develops over the rupture site forming what
is grossly called a white thrombus.
Type VI or Complicated lesions are characterized Morphologically, a plaque that has ruptured
as a type IV or type V lesion in which there is develops an intraluminal thrombus overlying a
disruption in the lesion surface, hematoma, and/ thin disrupted fibrous cap. Proximal and distal to
or thrombus. The underlying morphology of type the plaque rupture thrombus rich in fibrin and red
VI lesions is similar to Type IV and V lesions blood cells form creating what is grossly called
with the addition of a complicating feature. Type red thrombus. The clinical presentation of a
VI lesion are subdivided by there superimposed plaque rupture can range from asymptomatic to
feature. Type VIa lesion indicates disruption of death depending on the location of the lesion and
the luminal surface (i.e. fissure, ulcerations). the degree of luminal obstruction that occurs. In
Type VIb lesion indicates the presence of a hema- severe cases atheroma tissue debris and thrombus
toma-hemorrhage. Type VIc lesion indicates the obstruct blood flow at the level of the lesion or
present of a thrombus. Type VIabc indicates the obstruct smaller downstream branches leading to
presents of all three features. myocardial ischemia. Plaque rupture may also
result in bleeding from the lumen or from rupture
of neovessels (intraplaque hemorrhage) into the
The Vulnerable Plaque inner tissue of the lesion resulting in the ather-
oma to suddenly protrude into the lumen of the
A vulnerable plaque is a type Va (fibroatheroma) artery, producing lumen narrowing or even total
lesion with a thin fibrous cap separating the necrotic obstruction. Thrombotic deposits that are not
core from the vessel lumen that is particularly fatal and are not lysed undergo what is called
unstable and prone to sudden rupture. Characteristic thrombus healing. Infiltration of smooth muscle
features of a vulnerable plaque include a large cells, accumulation of extracellular matrix, and
necrotic core that represents about 25 % of the eventual overgrowth of the thrombus by endothe-
plaque area and a thin fibrous cap of <65μmm in lial cells characterize thrombus healing. Multiple
thickness. The mechanisms that compromise the layers of necrotic cores interspersed by fibrous
integrity of the fibrous cap include heavily infiltra- tissue (so-called buried caps) characterize healed
tion of macrophages and loss of smooth muscle ruptures. Healed ruptures contribute to an
cells within the fibrous cap. Therefore, thin-cap increase in lesion plaque burden and narrowing
fibroatheromas or vulnerable plaques represent inti- of the lumen [19, 20].
mal changes that occur prior to the onset of rupture.
A variety of factors may trigger vulnerable plaques
to rupture and include release of toxic substances Plaque Erosion
into the circulation, proteolytic enzymes by macro-
phages within the lesion, coronary spasm, shear Plaque erosion is a cause of coronary thrombosis
stress, or structural weakness related to lesion com- and is many times responsible for acute coronary
position. It important to note that majority of vul- syndrome and sudden cardiac death in patients
nerable plaques do not cause severe arterial luminal who do not exhibit plaque rupture (Fig. 3.7).
stenosis, with over 80 % of thin-cap fibroatheromas They are unique in that they typically involve
causing <75 % coronary artery stenosis [20]. early atherosclerotic lesion with pathologic
3 Pathophysiology of Coronary Artery Disease 41

Progression of Human Coronary Atherosclerosis

Pathologic
Non-progressive (Intimal) Intimal Fibrous Thin-cap
thickening xanthoma thickening cap atheroma fibroatheroma

Erosion
Rupture Calcified nodule Healed rupture

Fig. 3.7 This represents a spectrum of coronary artery represent eruptive fragments of calcium that protrude into
lesions taken from a sudden death population. The two the lumen caused by a prior thrombotic event. Healed
non-progressive lesions (AHA Type II) show intimal plaque ruptures are lesions with smaller necrotic cores
thickening and intimal xanthomas. The Pathologic intimal and focal areas of calcifications. Recurrent healing of
thickening (AHA Type III) represent the progression of plaque rupture are thought to cause progressive luminal
plaque as they advance to an fibroatheromas. Thin-cap narrowing. Ca2+ calcium, EL extracellular lipid, FC
fibroatheromas are consider the precursor to plaque rup- fibrous cap, NC necrotic core, Th luminal thrombus (From
ture. Erosions can occur in lesions with pathologic intimal Virmani et al. [29] with permission)
thickening or thin-cap fibroatheromas. Calcified nodules

intimal thickening but without an extensive Superficial plaque erosion by them self do not
necrotic core, hematoma-hemorrhage, or calcifi- cause critical luminal obstruction. Although
cation. Plaque erosions are more common in when there is significant endothelial erosion with
younger patients, females, and smokers. The pri- intima dysfunction this may precipitate the devel-
mary characteristics of plaque erosion are an opment of a large thrombus resulting in luminal
abundance of smooth muscle cells and extracel- obstruction [20, 21].
lular matrix formation with a disrupted endothe-
lium overlying the plaque. There is no
communication between the lumen and the Coronary Dissection
necrotic core of the lesion. Endothelial erosion
exposes the underlying intima allowing blood to Coronary artery dissection results from a tear in
come in contact with collagen and this induces a vessel endothelium allowing blood to penetrate
platelet rich thrombus adherent over the lesion. down into the intima and media. As blood
42 J. George

accumulates in the arterial wall it propagates Table 3.5 Etiologies of coronary artery aneurysms
into surrounding tissue with displacement of Atherosclerosis
adjacent endothelium into the vessel lumen Congenital malformation
reducing blood flow, which may cause a myo- Inflammatory disorders
cardial infarction and/or sudden cardiac death. Kawasaki disease
Iatrogenic coronary dissection infrequently Takayasu’ arteritis
occurs during percutaneous coronary interven- Giant cell arteritis
tions as a complication with varying degrees of Polyarteritis nodosa
severity. Spontaneous coronary dissection is a Lupus
rare life-threatening emergency. It occurs more Rheumatoid arthritis
frequently in females and it thought to be due to Inflammatory bowel disease
alterations in arterial connective tissue in Connective tissue disorders
response to hormones. Treatment of coronary Marfan syndrome
artery dissection varies depending on the nature Ehlers-Danlos
of the dissection and severity of the case Fibromuscular dysplasia
although are predominantly coronary artery Polycystic kidney disease
stenting or coronary artery bypass surgery in Infectious
severe cases. Endocarditis (septic emboli)
Mycotic aneurysm
Syphilis
Drug related
Coronary Aneurysm
Cocaine
Amphetamines
Coronary artery aneurysm is defined as coronary
Protease inhibitors
dilatation which is greater than the diameter of
Iatrogenic
normal adjacent segments or the diameter of the
List not all inclusive
patient’s largest coronary vessel by 1.5 times.
The pathophysiology of coronary artery aneu-
rysms involves destruction of the vessel media.
The molecular mechanism underlying coronary
aneurysm is not fully understood, although there
is evidence that overexpression of matrix metal-
loproteinases may play a role [22]. As the integ-
rity of the vessel wall is compromised wall stress
increased and subsequent dilation occurs. The
etiologies of coronary artery aneurysms is diverse
and includes atherosclerosis, congenital, inflam-
matory disorders (e.g. Kawasaki disease), con-
nective tissue disorders (e.g. Marfan syndrome),
infectious, drug related (e.g. cocaine, amphet-
amines), traumatic, and iatrogenic (Table 3.5).
Despite the multiple etiologies it is estimated that
50 % of coronary aneurysms are due to athero-
sclerosis and 20–30 % are congenital. A host of
inflammatory and connective tissue disorders
have also been associated with coronary aneu-
rysms with the most well know being Kawasaki Fig. 3.8 Coronary aneurysm of the right coronary artery
disease (Fig. 3.8). in a patient with a Kawasaki’s disease
3 Pathophysiology of Coronary Artery Disease 43

Coronary Vasculitis

Coronary Vasculitis is a rare form of coronary

artery disease that is typically associated with
various forms of systemic vasculitis or infectious
agents such as infective endocarditis, tuberculo-
sis, and syphilis. The pathophysiology and clini-
cal presentation of the arteritis depends on the
etiology of the vasculitis. Regardless of the etiol-
ogy coronary vasculitis results in destruction of
the vessel intima and/or media that may manifest
as coronary artery sclerosis, coronary aneurysms,
coronary rupture, and/or myocardial infarction.

Coronary Artery Restenosis Fig. 3.9 Coronary stent restenosis (black arrow)

Percutaneous coronary intervention and Coronary

Artery Bypass Grafting surgery are the mainstay
treatment for advanced coronary artery disease.
Although these treatments are lifesaving they confer
some amount of injury to the coronary vessel. The
clinical manifestation of coronary artery dysfunction
varies depending on the type of coronary interven-
tion. This section will briefly review the type of
native coronary artery and graft dysfunction.

Restenosis

In-stent restenosis is typically a gradual narrow-

ing of the stented segment of the coronary artery. Fig. 3.10 Coronary stent thrombosis (black arrow)
Although coronary artery stents function to main-
tain luminal patency they also enhance neointimal
formation (re-endothelialization), which is princi- cardiac death or a large myocardial infarction
pally responsible for in-stent restenosis. The use (Fig. 3.10). Stent thrombosis can occur acutely
of drug-eluting stents (DESs) dramatically (within 24 h), subacutely (within 30 days), late
reduced in-stent restenosis, although increased (30 days–1 year) or very late (greater than 1 year)
the incidence of stent thrombosis. Clinically, in- after stent placement. As per the Academic
stent restenosis typically manifest as recurrent Research Consortium, definite stent thrombosis is
angina within the first few years after stent place- defined by the clinical syndrome of acute coronary
ment, although may occur at any time (Fig. 3.9). syndrome along with angiographic or pathologic
evidence of acute thrombosis. Probable stent
thrombosis is defined as unexplained death occur-
Stent Thrombosis ring with 30 days after stent placement or evidence
of an acute myocardial infarction in the territory of
In contrast to in-stent restenosis, stent thrombosis the implanted stent with out angiographic confir-
is a catastrophic event that often results in sudden mation. Possible stent thrombosis is defined as an
44 J. George

Table 3.6 Risk factors for stent thrombosis

Procedure related Patient related Lesion related
Stent underexpansion Acute presentation Necrotic cores
Stent malapposition Diabetes Bifurcation lesion
Stent length Renal failure Diffuse disease
Multiple stents Smoker Small vessel diameter
Strut fracture Low ejection fraction Long segment disease
Reduced TIMI flow Cancer Chronic total occlusion
Stent drug DAPT nonresponsiveness
Stent polymer Premature cessation of DAPT
BMS vs DES Thrombocythaemia

unexplained death occurring more then 30 days

after stent placement. The exact mechanism of
stent thrombosis is not completely understood
although multiple risk factors have been identified
and are outlined in the table below (Table 3.6).

Graft Failure

The use of vein graft and/or arterial grafts during

coronary artery bypass graft surgery is largely
dependent of the anatomic obstructions of the
native coronary arteries. Despite the benefits
patients received after undergoing CABG sur-
gery graft failure is common. Atrial grafts are
preferred over vein grafts due to their long-term
patency and reduced need for repeat revascular-
ization, although due to availability vein grafts Fig. 3.11 Left internal mammary graft failure due to ste-
nosis at the anastomosis site. Then patent presented sev-
(such as the saphenous vein) are frequently used. eral month after CABG surgery with extensional angina
About 50 % of vein grafts occlude at 10 years
post CABG and an additional 25 % will show
evidence of restenosis [23]. Arterial grafts (such as kinks from excessive length of grafts), con-
are internal mammary artery) have a much lower duit characteristics (such as graft diameter,
rate of failure with patency rates as high as 98 % graft-target mismatch, or diseased graft), or
at 10 years [24, 25], although early graft failure poor distal runoff [26].
may occur due to technical factors (Fig. 3.11). • Midterm vein graft failure is caused by exag-
Vein graft failure can be divided into three gerated intimal hyperplasia that due to dam-
temporal categories: early (<30 days), midterm age to the vein graft at the time of
(30 days–1 year), or late (>1 year). transplantation, higher mechanical pressures
of the arterial system, and changes in flow pat-
• Early vein graft failure occurs in about terns within the venous graft (i.e. shear stress).
10–15 % of vein grafts and is due to factors • Late vein graft failure is relatively low
that contribute to status within the graft lead- although when it occurs it is typically due to
ing to thrombosis. The most common recog- intimal hyperplasia. The vein grafts develop
nized factors included technical failure (such atherosclerotic like plaque predisposing the
3 Pathophysiology of Coronary Artery Disease 45

vessel to plaque rupture. Veins graft that 7. Ladich ERM. Atherosclerosis pathology. 2012. 25
Nov 2014. Available from: http://reference.medscape.
remain patent after 1 years have about a 2 %
com/article/1612610-overview.
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ischaemic heart disease by country, region, and age:
statistics from World Health Organisation and United
Conclusions Nations. Int J Cardiol. 2013;168(2):934–45.
9. Murphy SL, Kochanek KD. Deaths: final data for
Atherosclerosis remains the most common 2010. National Vital Statistics Reports CDC report,
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vascular disease in the United States: a policy statement
ity of cases. However, multiple imaging
from the American Heart Association. Circulation.
modalities are available to identify and guide 2011;123(8):933–44.
interventional techniques of patients with 11. Lorkowski S. Atherosclerosis. 2006. 25 Nov 2014.
CAD. The following chapters will review the Available from: http://www.infarktforschung.de/arte-
riosclerosis.html.
most commonly available interventional
12. Steiner I, Laco J. Rokitansky on atherosclerosis. Cesk
imaging technologies. Patol. 2008;44(1):23–4.
13. Haimovici H, Ascher E. Haimovici’s vascular surgery.
6th ed. Chichester: Wiley-Blackwell; 2012.
14. Fuster V, Topol E, Nabel E. Atherothrombosis and
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 Qualitative and Quantitative
Coronary Angiography 4
Julian J. Barbat

Abstract
In patients with coronary artery disease (CAD), cardiac catheterization
remains the gold standard in evaluating the degree of luminal narrowing
and assessing the appropriateness of a patient’s medical regimen, the need
for percutaneous coronary intervention (PCI), or coronary artery bypass
grafting (CABG).
Cardiac catheterization involves the insertion of catheters

1. Into different heart chambers to measure pressures (hemodynamics), and

2. Into coronary arteries to measure degree of stenosis (SCA).

In order to better understand current cardiac catheterization, it is impor-

tant to understand how it has evolved. Werner Forssman in 1929 inserted a
catheter into the vein of his own forearm and guided it all the way into his
right atrium. Subsequently, Andre Cournand and Dickinson Richards per-
formed more systemic measurements of the hemodynamics of the heart.
The Nobel Prize in Physiology or Medicine in 1956 was awarded to these
three pioneers for their contributions to the development of cardiac cath-
eterization. Mason Sones performed the next major milestone in the path
to modern-day heart catheterization in 1958 when he inadvertently
engaged the right coronary artery and injected contrast. Subsequently,
Andreas Gruentzig performed the first balloon angioplasty on an awake
human in 1977 in San Francisco.

J.J. Barbat, MD
Department of Cardiology, Beaumont Health System,
Royal Oak, MI, USA
e-mail: [email protected]

© Springer-Verlag London 2015 47

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_4
48 J.J. Barbat

Keywords
Coronary artery disease (CAD) • Percutaneous coronary intervention
(PCI) • Coronary artery bypass grafting (CABG) • Cardiac catheterization •
Selective coronary angiography (SCA)

Introduction Selective Coronary Angiography

In patients with coronary artery disease (CAD), Routes of Access

cardiac catheterization remains the gold standard
in evaluating the degree of luminal narrowing The most frequently used sites of access are the
and assessing the appropriateness of a patient’s femoral artery, radial artery, and the brachial
medical regimen, the need for percutaneous coro- artery. Each has their own risks and benefits. The
nary intervention (PCI), or coronary artery site of access is pre-determined by the anticipated
bypass grafting (CABG). anatomic and pathological condition of the
Cardiac catheterization involves the insertion patient. In short, femoral access is quicker but
of catheters has more complications. Traditionally, the bra-
chial artery was the alternative to the femoral
1. Into different heart chambers to measure pres- approach, however compromise of this vessel can
sures (hemodynamics), and cause severe ischemic injury to the forearm and
2. Into coronary arteries to measure degree of ste- hand since it is provides the only circulation to
nosis selective coronary angiography (SCA). the hand. Whereas radial access is potentially
more difficult and takes more time but has fever
In order to better understand current cardiac complications and does not pose as high of a risk
catheterization, it is important to understand how of ischemic complications when the correct pre
it has evolved. Werner Forssman in 1929 inserted procedure evaluation is undertaken. The radial
a catheter into the vein of his own forearm and access approach has since taken over the brachial
guided it all the way into his right atrium. artery approach and is much more widely used.
Subsequently, Andre Cournand and Dickinson The advocates of the femoral artery approach
Richards performed more systemic measure- state that there is a perceived shorter procedure
ments of the hemodynamics of the heart. The time, and shorter duration of radiation (Table 4.1)
Nobel Prize in Physiology or Medicine in 1956 [2]. In addition, they state there is no limitation to
was awarded to these three pioneers for their con- the size of the guide catheter and should the need
tributions to the development of cardiac catheter- arise for hemodynamic support devices, it can be
ization [1]. Mason Sones performed the next an easy transition. However, patients that are
major milestone in the path to modern-day heart obese and those with significant peripheral vas-
catheterization in 1958 when he inadvertently cular disease pose a challenge to femoral artery
engaged the right coronary artery and injected approach. Advocates of the radial artery approach
contrast. This was the first SCA performed in taut the lower incidence of vascular complica-
humans. Subsequently, Andreas Gruentzig per- tions, less patient discomfort, and decreased
formed the first balloon angioplasty on an awake bleeding. However, the limitations of the radial
human in 1977 in San Francisco. This is consid- artery approach are the inability to use larger
ered by some as the first revolution in interven- French guide catheters, and the need for left
tional cardiology, the second being the radial to engage access to the left internal mam-
introduction of bare metal stents, the third as mary artery (LIMA), although, access from the
drug eluting stents, and the fourth is drug eluting right radial approach has been performed in
biovascular scaffolds. selective cases.
4 Qualitative and Quantitative Coronary Angiography 49

Table 4.1 Pros and cons of both the radial and femoral artery approach
Radial Femoral
Access site bleeding 0–0.6 % 3–4 %
Artery complications Rare local irritation, pulse loss 3–9 %, forearm hematoma Pseudoaneurysm
Patient discomfort Significantly reduced Increased
Ambulation Immediate 2–4 h
Extra costs Band Closure device
Procedure time Perceived longer Perceived shorter
Use of artery for CABG Unknown n/a
Estimated radiation exposure Perceived longer Perceived shorter
Access to LIMA Harder (usually requires left radial approach) Easier
Learning curve Longer Short
>8 F guide catheter Maximum 7 French No issue
PVD, obese No issue Problematic
Modified from Kern [2]. pp 37–38 with permission
Abbreviations: LIMA Left Internal Mammary Artery

site aortic wall, and Amplatzer catheters provide

Equipment Selection the maximum support through contact with the
aortic root and opposite aortic wall. The majority
Arterial sheaths commonly used for interventional of coronary interventional and imaging proce-
procedures range from 5 to 8 F. Larger sheaths are dures are performed through a 6 F guide.
required for valvuloplasty (12 F), Impella (14 F), However, they may be performed with guide
and ECMO cannulation (18–22 F). Long sheaths catheters between 5 and 8 F sizes. As a general
may be utilized in patients with tortuous femoral rule, the outer diameter (OD) of the guiding cath-
and iliac arteries, which provide guiding catheter eter is the same dimension as the inner diameter
support and improve torque control. (ID) of the sheath. This means that a 6 French
Selection of catheter is an elementary deci- guiding catheter will fit inside a 6 French sheath.
sion, however, it can be the difference between However, the ID of a 6 French sheath is the same
success and failure. Diagnostic and guiding cath- as the ID of a 8 French guiding catheter.
eters come in multiple preformed shapes and
sizes (Fig. 4.1) [3]. Diagnostic catheters are used
for diagnosing coronary stenosis. However, a Judkins Catheters
diagnostic catheter is exchanged for a guiding
catheter when an intervention needs to be done The Judkins left catheter is preformed with two
and equipment needs to be passed through the curves and the length of the segment between
catheter. Guiding catheters are preformed and the primary and secondary curve is what deter-
generally constructed from polyethylene or mines the size of the catheter (Fig. 4.2) [4]. The
polyurethane and contains a wire mesh within the length and size of the aorta is what is used to
distal aspect that allows torque to be applied to determine the correct size of catheter to choose.
the catheter while minimizing kinking. In addi- However, for the majority of adult patients the
tion, they have a stiffer shaft and larger internal JL4 catheter is optimum. Short tip Judkin cathe-
diameter, which are the properties necessary to ters are available and may be helpful for patients
perform successful PCI. Guiding catheters can with short left main.
provide variable levels of support depending on The Judkins Right coronary catheter (JR) is
their structure. Judkin catheters provide the least sized by the secondary curve (Fig. 4.3). Access is
amount of support, HB and EBU catheters pro- gained into the right coronary ostium via any vas-
vide more support through contact with the oppo- cular access point by clockwise rotation.
50 J.J. Barbat

JR3.5 JR4 JR5 JR6 JL3.5 JL4 JL4.5 JL5 JL6 AR I AR II AR III AR Mod AL I AL II AL III MPA 1

155° 145°

MPA 2(1) MPA 2 MPB 1 MPB 2 SK PIG PIG PIG PIG LCB SON I SON II SON III CAS I CAS II CAS III

Flow-direction baloon catheters

LUM
Cardiac
MH PIG MPA 2 JL 4 JR 4 RCB CB IM multipacks

Fig. 4.1 Commonly used catheters. AL Amplatz left, AR modified, MP multipurpose, NIH National Institutes of
Amplatz right, CAS Castillo, CB coronary bypass cathe- Health, PIG pigtail, RCB right coronary bypass graft,
ter, IM internal mammary, JL Judkins left, JR Judkins SON Sones (From Bonow et al. [3] and Cordis with
right, LCB left coronary bypass graft, LUM lumen, Mod permission)

Engagement of the Left Coronary catheter is at the level of the ostium but not
Artery Using Judkins Left (JL) engaged, a small degree of torque either clock-
Catheter (Femoral Approach) wise or counterclockwise, could be attempted to
allow for engagement. In cases where the ostium
Engaging of the left coronary artery should be is not cannulated properly, a different size Judkins
performed in the left anterior oblique projection or alternative catheter can be used. The smaller
(LAO). In the LAO projection, the ascending the JL catheter, the more likely the tip will
aorta and Sinus of Valsalva are not superimposed point upwards and vice versa.
on the coronary ostium. There is minimal manip-
ulation needed to engage the left coronary artery
using the JL catheter, and in the words of Judkins, Engagement of Right Coronary
“the catheter knows where to go if not thwarted Artery Using Judkins Right Catheter
by the operator.” A J-tipped wire, either a 0.035 (Femoral Approach)
or 0.038 in., is advanced to the level of the aortic
valve. The catheter is then seated in a position to The right coronary artery is engaged in the LAO
face the left coronary ostium. The wire is then projection as well, for the same reasons mentioned
subsequently removed, the catheter is connected above. In an approach similar to that of the JL tech-
to a pressure line to assess for dampening, and a nique, the JR catheter is advanced into the right
test injection is given. If the test injection reveals coronary cusp facing to the left. The catheter can
that the catheter is below the coronary ostium, it then be rotated 45–90 so that the tip is facing the
is gently withdrawn, which will allow for engage- right. Simultaneously the catheter should be with-
ment. If the test injection demonstrates that the drawn back 2–3 cm [2]. If difficulty is encountered
4 Qualitative and Quantitative Coronary Angiography 51

Fig. 4.3 Judkins right catheter which has a sharp primary

curve and shallow secondary curve

Fig. 4.2 Judkins left catheter with 4 cm distance from the

primary curve to the secondary curve

engaging the right coronary ostium, the same tech-

nique can be employed at different levels.

Engagement of the Left Coronary

Artery Using Amplatz (Femoral)

The Amplatz left catheter is a half circle with the

distal tip extending perpendicular to the curve
(Fig. 4.4). The catheter size indicates the diame-
ter of the half circle. The AL catheter is advanced
with the secondary curve sitting in the right coro-
Fig. 4.4 Amplatz left catheter
nary cusp, with the tip pointing at the left aortic
cusp (Fig. 4.5). Once it is advanced into this posi-
tion, alternating between advancement and with- allow the catheter to travel cranially along the left
drawal is performed while simultaneously Sinus of Valsalva to allow for coaxial engage-
applying slight clockwise torque. These motions ment of the left main coronary artery.
52 J.J. Barbat

Fig. 4.5 Catheterization of the left coronary artery using 2 The catheter is then retracted or advanced until it is
Amplatz technique. 1 The catheter is advanced until the engaged in the coronary ostium (From Kern [2] with
secondary curve is sitting in the right or non coronary permission)
cusp with tip pointing towards the left coronary ostium.

Engagement of the Right Coronary

Artery Using Amplatz (Femoral)

The Amplatz Right (AR) catheter is similar to

the AL in that has a pre shaped half circle,
but the diameter is smaller than that of the AL
(Fig. 4.6) [4]. As with the Judkins technique, the
AR catheter is advanced in to the right coronary
cusp with its tip point at the left coronary cusp. It
is then rotated clockwise 45–90° while simulta-
neous withdrawing the catheter to allow for the
tip to point towards the right coronary artery
ostium. It is then advanced and withdrawn to
allow for engagement into the coronary ostium
(Fig. 4.7) [2].

Multipurpose Catheter

The multipurpose catheter (MP) has a gentler

curve with an end hole and two side holes placed
close to the tapered tip (Fig. 4.1). As the name
suggests, it can be used for cannulation of both
the right and left coronary ostiums, and also can
be used for left ventriculography but the pigtail
catheter is preferred. It is also useful in engaging
the saphenous vein graft to the RCA. Less com-
monly, it may be used to obtain pulmonary pres-
sures when the pulmonary catheter fails to Fig. 4.6 Amplatz right catheter
4 Qualitative and Quantitative Coronary Angiography 53

Fig. 4.7 Catheterization of the right coronary artery right coronary ostium and secondary curve is resting in
using Amplatz technique. 1 Catheter is advanced until left aortic cusp. 3 Catheter is advanced and withdrawn
secondary curve is sitting in right coronary cusp. 2 45–90 until it is engaging the ostium (From Kern [2] with
clockwise rotation so that tip of catheter is point toward permission)

Fig. 4.8 Tiger and Jacky radial catheters from left to right

advance. It is the catheter initially used to guide a additional preformed catheters that have been
wire across a patent foramen ovale during percu- developed. The Tiger and Jacky catheters are
taneous closure. two of the most commonly used radial catheters
(Fig. 4.8) [4]. They are designed to cannulate
both the left and right coronary arteries. Judkins
Radial Catheters left and right coronary catheters are commonly
used and can be utilized from either arm, how-
The radial artery technique also utlilizes the ever, when compared with the femoral approach,
Judkins catheters however there are also a left Judkins catheter of smaller curve typically
54 J.J. Barbat

0.5 cm less may be necessary with the left radial Radiation Dose Measurement
technique. An Amplatz catheter can also be used
effectively from either arm in a similar technique There are many different ways of measuring radia-
to that of the femoral approach. Another tion dosage and exposure but few are more pertinent
approach is to engage the left coronary ostium in the catheterization lab. In order to understand
with a guide catheter such as the XB or radiation dose measurement, it is important to
EBU. Other catheters include the Kimney and understand key definitions. When the X-ray beam
the multipurpose catheters. interacts with the atoms of different tissue, most
commonly the skin in the cath lab, there is a con-
centration of energy absorbed from that interaction
Special Considerations and this is called the dose. The unit of measurement
for dose in the lab is called the Gray, which is
Typically, the RCA is engaged in its normal posi- defined as the absorption of one joule of radiation
tion with a JR4, if extra backup is required, an energy divided by 1 kg of that specific substance.
AL1-2 or AR1-2 may e required. In Shepard’s Another important term to understand is Kerma,
crook origins of the RCA, an IMA catheter, a which is an acronym for kinetic energy released per
Hockey catheter, and an AL1-2 may be required. unit mass, which is measured in gray. Air Kerma is
With low origin and horizontal course, a JR4 or term that describes exposure, and this is a measure
an AR1-2 may be required. Finally, in patients of strength of the radiation field at some point in air.
with anterior take off of the RCA, an AL1-2, non- The fluoroscopic output during a case is deter-
torque, and RDC catheters may be required. mined by this exposure.
Standard left main catheters include the XB, The point at which the radiation enters the
EBU, or AL1, while short left main trunks may skin of the patient is important at determining the
require JL4 and JL4 or short tip SL4 catheters total amount of radiation exposure to the patient.
(Fig. 4.9). The fluoroscopic machine uses software to calcu-
late this dose to the patient, which is called the
dose-area product (DAP, gy-cm^2) which is cur-
Cineangiographic Imaging, rently named the Kerma air product (KAP).
Radiation Dose Measurement, KAP represents the product of air dose at the cen-
and Contrast Types ter of a certain plane of the X-ray beam multi-
plied by the cross sectional area of the beam at
Cineangiographic Imaging the same distance from X-ray tube. The KAP is a
good surrogate for the actual dose of radiation the
In order to perform heart catheterizations, high patient is exposed to as the majority of the X-ray
resolution X-ray imaging is necessary beam is absorbed by the patient. Another impor-
(Fig. 4.10). Cinefluorographic systems operate tant point at which measurements are taken is the
on two modes which are fluoroscopy and acqui- amount of radiation reaching the image intensi-
sition. Fluoroscopy mode provides real time fier. These measurements are important for image
imaging of sufficient quality to guide manipula- creation and determining image noise.
tion of various catheters and wires [5]. Once the
desired image is obtained on fluoroscopy, cine
can be used to acquire the image. Cine (acquisi- Contrast Types
tion) are of high enough quality for viewing and
require higher X-ray input doses in order to pro- All contrast agents contain iodine which absorbs
vide an image with less noise. The per-frame X-rays allowing the region containing the con-
dose of cine is approximately 15 times that of trast to show up on the angiographic projection.
fluoroscopy. The two main types of contrast agents are
4 Qualitative and Quantitative Coronary Angiography 55

Fig. 4.9 Special consider-

ations regarding guiding A Normal origin
catheters for PCI on the RCA
Standard choice
with normal (A), shepherd’s
crook (B), and low horizontal Judking right
© origins. Similarly, PCI on
the LAD or LCX in patients B Poor back up
with a normal (a) and short Amplatz left 1, 2
(b) left main arteries. As a A
or
general rule PCI of the LCX C Amplatz right 1, 2
may require a 1/2 size
greater catheter compared to
the LAD (From Giubilato B Shepherd’s crook origin C Low origin with horizontal course
et al. [14] with permission)
Standard choice Standard choice
Internal mammary Judking right
or or
Amplatz left 1, 2 Amplatz right 1, 2

Nornmal left main

standard choice

XB, EBU
or
Amplatz left

Short left main

standard choice

Judking JL

high-osmolar contrast media and low osmolar Angiographic Projections,

contrast agents (Tables 4.2 and 4.3). The high Recommended Views for Specific
osmolar contrast agents are salts, which in the Coronary Segments
aqueous phase become osmotically active. They
have an osmolality five to eight times greater than Angiographic Projections
that of plasma. The low osmolar agents have
osmolality that are two to three times that of Accurate diagnosis of coronary abnormalities
plasma. Within the low osmolar contrast agents requires visualization of the different arteries
you have contrast agents that are either ionic or from multiple angles. Manipulating the image
nonionic which do not ionize when in solution. intensifier allows you to create different views
56 J.J. Barbat

Fig. 4.10 Cardiac catheterization lab. 1 Monitor; 2 Image different angles. When the foot pedal (#4) is pushed,
intensifier; 3 Xray Tube; 4 Foot pedal; 5 Touch panel con- images are obtained and shown on the monitor (#1). The
trol; 6 Table. The fluoroscopic image comes from a C-arm patient is placed on the table (#6) with their head at the
noted on the left. It is a semicircular structure with the bot- center of C-arm which can then be manipulated 180° to
tom part serving as the x-ray tube (#3) and the image inten- create the desired angle with images being displayed on
sifier at the other end (#2). By rotating the C-arm, you are the monitor. The tables have bearings and brakes that can
able to obtain different fluoroscopic image over a range of be controlled by the positioning control (#5)

Table 4.2 High-osmolar agents

Osmolality Viscosity Iodine Sodium
Compound Brand name (MOSM/KG H20) at 37 °C (MG/ML) (MEQ/L) Additives
Sodium diatrizoate Hypaque 1690 9.0 37.0 160 Calcium
disodium EDTA
Sodium meglumine Renografin 1940 8.4 370 160 Sodium citrate,
diatrizoate disodium EDTA
From Bonow et al. [3] and Pepine et al. [16] with permission

Table 4.3 Nonionic or low-osmolar agents

Osmolality Viscosity Iodine Sodium
Compound Brand name (MOSM/KG H20) at 37 °C (MG/ML) (MEQ/L) Additives
Ioxaglate Hexabrix 600 7.5 320 150 Calcium disodium EDTA
Iohexol Omnipaque 844 10.4 350 5 Tromethamine calcium disodium
EDTA
Iopamidol Isovue 790 9.4 370 2 Tromethamine calcium disodium
EDTA
Ioversol Optiray 702 5.8 320 2 Tromethamine calcium disodium
EDTA
Iodixanol Visipaque 290 11.8 320 19 Tromethamine calcium disodium
EDTA + 0.15 mEq/l calcium
From Bonow et al. [3] and Pepine et al. [16] with permission

of the same coronary segments and improves patient, is in relation to the transverse plane.
diagnostic accuracy by minimizing foreshorten- The three main views obtained in the transverse
ing and vessel overlap. The first description, of plane are left anterior oblique (LAO), right
the relationship of the image-intensifier to the anterior oblique, and anterior-posterior (AP)
4 Qualitative and Quantitative Coronary Angiography 57

Fig. 4.11 Transverse view demonstrating the Left Image intensifier

position of the image-intensifier relative to the Right
anterior anterior
patient. I-I to the left of the patient is deemed oblique oblique
the left anterior oblique projection. I-I to the (LAO) (LAO)
right of the patient is deemed the right anterior 20° 20°
oblique projection

Patient head
Table

X-Ray generator

Fig. 4.12 In the sagittal cross section, the Image intensifier

I-I is deemed to be cranial when angled Cranial 30° Caudal 30°
towards the patient’s head. It is deemed
caudal when angled towards the patient’s
feet

Table Side of
patent

X-Ray generator

(Fig. 4.11). For example, right anterior oblique For example, the notation RAO 25 Caudal 25,
is a position in which the image-intensifier is indicates the image intensifier is positioned 25°
over the right anterior chest wall of the patient. from the midline in the transverse plane on the
The same description applies to left anterior patients right side, and 25° from the midline in
oblique in which the image intensifier is over the sagittal plane towards the patients feet.
the left anterior chest wall. In the AP position,
the image-intensifier is directly over the patient
and the X-ray beam is traveling from posterior Specific Coronary Segments
to anterior. The second description of the rela-
tionship of the image-intensifier to the patient The main coronary arteries may be considered
is in relation to the sagittal plane (Fig. 4.12). to be located in two planes: the plane of the
Cranial describes a position in which the image atrioventricular groove and the plane of the
intensifier is angled toward the patients head. interventricular septum as shown below
Caudal described a position in which the image- (Fig. 4.13). Various segments of the coronary
intensifier is angled towards the patient’s feet. arteries are noted below (Fig. 4.14).
58 J.J. Barbat

RAO 30 LAO 60

SN L main
L main OM D
D D RCA CX
SN
CX CB
CB S S LAD OM
LAD RV S
OM
RV S D

AcM D
AcM
PL
PD OM

PL
RCA D

Interventricular plane Atrioventricular

plane
PD
Atrioventricular
plane

Fig. 4.13 Planes of the coronary artery (From http://www.pcipedia.org/wiki/File:Coronary_anatomy1.png with

permission)

Fig. 4.14 Coronary artery 1. Proximal RCA

segments 2. Mid RCA
1 3. Distal RCA
5
4. Right PDA
6
11 5. Left Main
6. Proximal LAD
12 9 7. Mid LAD
8. Distal LAD
13 7 9. D1
2
10. D2
14 10 11. Proximal LCX
16 12. Intermediate/OM1
3 13. MID LCX
8 14. OM2
4 15 15. OM3
16. Right postero-lateral

Recommended Views for Specific Left Main

Coronary Segments The left main is best visualized in straight AP
or 5–10° RAO with caudal (Fig. 4.15). This
Left Coronary Artery projection demonstrates the entire perpendicu-
Obtaining fluoroscopic images of the left coro- lar length of the left main, in addition the
nary artery and its different branches requires a proximal LAD and circumflex can be seen as
multitude of different angiographic views. well.
4 Qualitative and Quantitative Coronary Angiography 59

Fig. 4.15 Left main demonstrated in the RAO caudal

Fig. 4.17 RAO caudal projection which best shows the
view
circumflex and its branches

Fig. 4.16 LAD-circumflex bifurcation as visualized in Fig. 4.18 The LAD and its branches are visualized well
the LAO cranial projection in the RAO cranial projection

Left Anterior Descending (LAD)-

Circumflex Bifurcation
Angling the I-I at 30–45° LAO and 20–30° best LAD and Diagonal Branches
shows the LAD-circumflex bifurcation. You will The LAD and its diagonal branches are best
still be able to visualize the left main but it is viewed in 5–30° RAO and 20–45° cranial. The
foreshortened as compared to the RAO caudal origins of the diagonal branches are clearly visu-
projection as seen in the previous image alized and project upward (Fig. 4.18).
(Fig. 4.16).
LAD-Circumflex Bifurcation,
Circumflex and Marginal Branches Circumflex, Marginal
The circumflex and its obtuse marginal branches Another good view to visualize the LAD-
are best viewed in 30–40° RAO and 20–30° cau- Circumflex bifurcation is the so called spider
dal [2]. This view is best to visualize the circum- view obtained with 50–60° LAO and 10–20°
flex as this projection demonstrates the origin and caudal (Fig. 4.19). In addition, to the bifurca-
course of the circumflex, and in addition clearly tion, this is a good view to visualize the ori-
demonstrates the obtuse marginal branches gins of the diagonal and obtuse marginal
(Fig. 4.17). branches.
60 J.J. Barbat

Fig. 4.21 Straight RAO view demonstrating RCA

branches including PDA and PLB

Fig. 4.19 LAO caudal projection (spider) demonstrating

the LAD-circumflex bifurcation and their associated
branches

Fig. 4.20 LAO cranial view demonstrating the origin of

the RCA, the proximal RCA and the entire length of the
mid RCA

Right Coronary Artery

Routine angiographic views of the right coronary Fig. 4.22 Common insertion sites of bypass grafts to the
artery and its branches are obtained in 30–45° right and left coronary artery to the anterior wall of the
LAO and 15–20° cranial (Fig. 4.20). This projec- aorta. The right coronary bypass grafts are lower and most
tion shows the origin of the RCA, the proximal anterior. Whereas the left coronary bypass grafts are
placed in a more posterolateral position with each subse-
RCA, and the entire length of the mid RCA. In quent graft placed in a more superior position (From Kern
addition it shows the crux where the posterior [2] with permission)
descending artery (PDA) originates.
Additional routine views of the right coronary
artery are the straight RAO view at 30–45° with Bypass Graft Angiography
no cranial or caudal angulation (Fig. 4.21). This In addition to native vessel angiography, many
view shows the mid RCA, the posterolateral patients undergoing angiography have had several
branches (PLB), and the posterior descending bypass grafts that require assessment (Fig. 4.22).
artery. Collaterals from septals off of the PDA to
the left system can easily be seen in this view as 1. The first approach to assessing bypass grafts
well. is to review the operative report in order to
4 Qualitative and Quantitative Coronary Angiography 61

know where and how many bypasses the

patient has had and to what native coronary
vessels they are attached to.
2. The next step is to review previous catheter-
ization films which will help to understand if
previous grafts have already occluded which
will help to save time and contrast exposure
for the patient.
3. A common way to approach imaging in
patients with bypass grafts is to first look at
the native vessels, then SVG imaging, fol-
lowed by internal mammary artery imaging,
left ventriculography, and lastly an aortogram
if it is felt that there are additional bypasses
not visualized.
4. When visualizing bypass grafts, it is impor-
tant to view the origin, the course, and site of Fig. 4.23 (a) Usual orientation of vein grafts to the distal
anastomosis to the native vessel. RCA. Superior to right sinus of valsalva from the lateral
wall of the aorta; (b) More anterior origin of vein grafts to
5. Bypass vein or free arterial grafts are usually the RCA; (c) Usual orientation of left coronary artery
anastomosed on the anterior wall on the aorta, bypass grafts which is on the anterior wall of the aorta
several centimeters above the Sinuses of superior to the left sinus of Valsalva; (d) More anterior
Valsalva with some surgeons placing markers origin of vein grafts to the left coronary artery (From
Safian and Freed [6] with permission)
on the vessels in order to allow easier visual-
izing during future cardiac catheterizations
(Fig. 4.22). The right coronary artery bypass the catheter is rotated clockwise in the LAO pro-
grafts are anastomosed usually most anteriorly jection until the tip of the catheter is superior to
and lower on the aorta. The left coronary the origin of the vein graft (Fig. 4.24). This will
bypasses are anastomosed in a more postero- place the catheter on the lateral wall of the aorta
lateral branch with each subsequent graft and by advancing the catheter down the aortic
placed more superiorly from LAD, to diago- wall you will be able to engage the ostium.
nal, with circumflex grafts and its branches
usually placed highest [2]. Left Coronary Artery Bypass Graft
Angiography
Left coronary artery guiding catheter selection
Right Coronary Bypass Graft is based on the orientation of the vein graft ori-
Angiography fice. In the typical position (Fig. 4.23) the JR or
Guiding catheter selection is based on the origin Hockey stick catheters can be used, with alterna-
of the vein grafts [6]. In the usual orientation of tives being the AL, left bypass, or multipurpose.
vein grafts to the RCA demonstrate as position A In the more anterior orientation of vein grafts to
in the figure below, a multipurpose or JR 4 can be the left coronary artery the primary guiding cath-
the primary catheter used (Fig. 4.23) [6]. eters are the AL and Hockey Stick, with alterna-
Alternative catheters that can be used are the AL, tives being the JR, left bypass, and multipurpose.
and right bypass. From position B, which is a The graft to the LAD is engaged in the RAO
more anterior origin, the AL becomes the pri- projection. If using the JR4 to engage the SVG to
mary catheter and the JR, multipurpose, and RCA, the SVG to LAD vein graft may simply be
Hockey Stick as alternatives. engaged by pulling back on the catheter from the
Typically the right coronary bypass grafts are SVG to RCA ostium (Fig. 4.25). If this is not suc-
engaged in the LAO projection. If using the JR 4, cessful, then clockwise rotation of the catheter
62 J.J. Barbat

Fig. 4.24 Clockwise rotation of the JR 4 catheter, in the

LAO projection, with subsequent advancement downward
on the lateral wall of the aorta, is a common approach to
engaging right coronary bypass grafts (From Kern [2]
with permission) Fig. 4.25 Engagement of the SVG to left coronary artery
vein graft orifice by clockwise rotation from a position
superior to the expected graft orifice using a JR-4 catheter
from a position superior to the SVG-RCA graft (From Kern [2] with permission)
ostium may be necessary.
An alternative way to engage this ostium is by projection. A JR 4 or a LIMA catheter can be used
placing the JR 4 at a position slightly superior to engage the LIMA. The catheter is positioned in
than the expected level of the SVG-LAD vein the aortic arch at the level of the brachiocephalic
graft orifice and applying a 30–45° clockwise trunk with the catheter tip pointing caudal
rotation (kern see below). (Fig. 4.26). The catheter is then pulled back while
Circumflex vein grafts can usually be engaged applying a counterclockwise torque. At this point,
by withdrawing the JR catheter upward from the some operators may perform angiography of the
LAD graft ostium. The same techniques men- subclavian artery to evaluate for any stenosis. The
tioned above can also be used. catheter can be advanced over a wire (J-tipped or
Wholey wire) into the subclavian beyond the ori-
Left Internal Mammary Artery Graft gin of the IMA. A small contrast injection at this
Catheterization point can help to visualize the origin of the IMA. It
The internal mammary artery originates anteri- is then slowly pulled back while applying a coun-
orly from the subclavian artery just after the ori- terclockwise torque. Once engaged, careful con-
gin of the vertebral artery. Catheterization of this trol of the catheter must be maintained as
artery is usually done in the AP or shallow RAO manipulation can lead to dissection.
4 Qualitative and Quantitative Coronary Angiography 63

Fig. 4.27 Engaging the RIMA. The JR 4 catheter is

advanced into the aortic arch and then advanced passed
the brachiocephalic trunk and withdrawn back while
Fig. 4.26 Engagement of the LIMA. The catheter is posi- applying counterclockwise torque. When the catheter
tioned in the aortic arch with tip pointing downwards (1). enters the brachiocephalic trunk it is then advanced into
It is then pulled back at rotated counterclockwise in order the subclavian (From Kern [2] with permission)
to enter the subclavian artery (2). The catheter is then
advanced over a wire passed the origin of the LIMA (3). It
is then slowly pulled back while applying counterclock- Technique: It is often performed using a pig-
wise torque to engage (4) (From Kern [2] and King et al. tail catheter which is placed over a 0035- in
[15] with permission)
J-tipped wire. In order to enter the left ventricle,
the catheter is advanced just superior to the aortic
Right Internal Mammary Artery Graft valve. It is then made to look like a “6” in the
Catheterization RAO projection. The catheter is then gently
Engaging the RIMA is similar to that of the LIMA advanced across the valve orifice into the ventri-
and the same catheters can be used (JR-4, LIMA). cle. Once it enters the ventricle, the tip of the pig-
The JR-4 catheter is advanced into the aortic arch tail should be position mid cavity with the loop
just past the origin of the brachiocephalic trunk. directed toward the apex (Fig. 4.28).
The trunk is then entered by applying counter-
clockwise rotation. Once it enters the brachioce-
phalic trunk it is then advanced into the subclavian Wall Motion Abnormalities
artery. The same manipulation as described for
LIMA cannulation using a wire is performed to Different wall motion abnormalities can be seen
engage the RIMA as well (Fig. 4.27). depending on the projection obtained (RAO
vs LAO). Wall motion abnormalities can be
described as normal, hypokinetic, dyskinetic, or
Ventriculography akinetic.
In the RAO view the apex of the heart is tipped
Left ventriculography provides important ana- downward. The segments these in this view are
tomic, valvular, and functional information. It anterior basal, anterior, apical, inferior, and infe-
provides information on ejection fraction, wall rior basal (Fig. 4.29). In the LAO projection, the
motion abnormalities, mitral regurgitation, and basal, lateral, apical and septal walls are seen
the presence of a VSD. (Fig. 4.30).
64 J.J. Barbat

Fig. 4.31 LV gram in the RAO projection demonstrating

Fig. 4.28 Pigtail positioned midcavity with loop directed 4+ MR with complete opacification of the left atrium to a
towards the apex seen in the RAO projection greater degree than that of left ventricle

range from 1+ to 4+ where 1+ is mild, 2+ is mod-

erate, 3+ is moderately severe, and 4+ is severe. In
1+ MR there is minimal opacification of the left
atrium and it clears with one beat. In 2+ MR there
is opacification of the entire left atrium after sev-
eral beats, and it does not clear with one beat. In
3+ MR the left atrium is completely opacified to a
degree that is equal to that of the left ventricle. In
4+ MR, there is complete opacification of the left
atrium to a greater extent than that of left ventricle,
Fig. 4.29 LV gram in the RAO projection. 1 Anterior and contrast material can be seen refluxing into the
basal, 2 Anterior, 3 Apex, 4 Inferior, 5 Inferior basal walls pulmonary veins during systole (Fig. 4.31).

Ventricular Septal Defect

VSD’s are best seen in the LAO projection as this

view shows the septal wall of the left ventricle.
A VSD is present if contrast is seen entering the
right ventricle (Fig. 4.32).

Calculation of LV Ejection Fraction

Overall LV function is characterized as hyper-

Fig. 4.30 LV gram in the LAO projection. 1 Basal, 2 dynamic (>70 %), normal (50–69 %), mildly
Lateral, 3 Apex, 4 Septum walls
hypokinetic (35–49 %), moderately hypokinetic
(20–24 %), or severely hypokinetic (<20 %) [5].
Mitral Regurgitation This assessment is most often made visually.
However, a quantitative assessment can also be
The degree of mitral regurgitation can also be computed to calculate the LV EF. Using the LV
characterized using ventriculography by noting gram, tracings can be done of the LV at the end
the degree of opacification of the left atrium and of diastole and end of systole. These tracings can
whether it clears with each beat. The scale is a then be used to calculate volume by assuming the
4 Qualitative and Quantitative Coronary Angiography 65

Fig. 4.33 Fusiform aneurysm of the right coronary artery

in a patient with previously diagnosed Kawasaki disease
Fig. 4.32 Contrast seen entering into the right ventricle
in the LAO projection indicative of a VSD

LV is an ellipse and plugging into a formula the

length and area of the left ventricle. Subtracting
end diastolic volume from end systolic volume
and dividing the total by the end diastolic vol-
ume will give you the EF. However, this method
is rarely done.

Identifying Specific Coronary

and Aortic Abnormalities

Coronary Artery Aneurysms (CAA) Fig. 4.34 Coronary thrombus visualized in the LAD in a
patient with acute anterior ST elevation myocardial
infarction
CAA is defined as dilatation that exceeds 50 % of
the diameter of normal adjacent coronary seg-
ments (Fig. 4.33). A vast majority of CAA’s are activation, aggregation, and adherence to the sub-
caused by atherosclerosis, however, in the pediat- endothelium. In addition, the coagulation cas-
ric population, Kawasaki disease is the most cade is activated with resultant thrombin
common etiology. Anatomically, CAA’s most formation, which subsequently leads to the for-
commonly occur in proximal LAD followed by mation of fibrin, which is one of the main con-
the proximal RCA and occur most commonly at stituents of thrombus.
branch points. These aneurysms can be fusiform, The TIMI classification of thrombus includes:
saccular, or ectatic.
• Grade 1: Possible thrombus with angiographic
findings as reduced contrast density, haziness,
Coronary Thrombus irregular lesion contour, or a smooth meniscus
at the site of occlusion
Most cases of acute coronary syndromes are the • Grade 2: Definite thrombus with greatest
result of atherosclerotic plaque rupture with dimension <½ vessel diameter
subsequent thrombus formation (Fig. 4.34). • Grade 3: Definite thrombus with greatest
When the contents of plaque are exposed to the dimension >½ vessel diameter but <2 vessel
blood stream this begins a cascade of platelet diameters
66 J.J. Barbat

Fig. 4.36 Calcified plaque seen in the LAD prior to con-

Fig. 4.35 Significant tortuosity seen in both circumflex trast injection
and LAD

• Grade 4: Definite thrombus with greatest

dimension >2 vessel diameters
• Grade 5: Total occlusion

Coronary Artery Tortuosity

Coronary artery tortuosity is a common anatomi-

cal variant that has unknown clinical importance
(Fig. 4.35). However, tortuosity can increase the
difficulty in patients requiring percutaneous cor-
onary intervention. Fig. 4.37 Spiral dissection of the circumflex artery
caused by a monorail guiding catheter

Calcified Coronary Artery Plaque coronary dissection as a result of angioplasty

should be stented to prevent acute vessel closure
Coronary artery calcification is a regulated and subsequent myocardial infarction.
process that occurs in the setting of atheroscle-
rosis (Fig. 4.36). It is a sensitive marker for
coronary stenosis that may be angiographically Calcified Aortic Valve
significant.
Aortic valve calcification is a slow progressive
disease and is a continuum. One end of the spec-
Coronary Artery Dissection trum is aortic sclerosis which is mild valve thick-
ening, with the other end of the spectrum being
Coronary artery dissection is separation of the aortic stenosis (Fig. 4.38).
arterial wall and may occur spontaneously or a
procedural complication of a PCI (Fig. 4.37).
Spontaneous coronary artery dissection is uncom- Procedural Complications
mon, but should be considered in any young
patients, in particular women, who are presenting Although cardiac catheterization is a relative safe
with a history consistent with an acute coronary procedure with procedural complications decreas-
syndrome or cardiac arrest. Iatrogenic complex ing over the years with new approaches such as
4 Qualitative and Quantitative Coronary Angiography 67

be used when appropriate. Management of hema-

toma requires prompt direct pressure either man-
ually, pneumatic (femstop), or a mechanical
clamp. Compression can help to prevent the
hematoma from expanding further and can
“soften” it, which can help to facilitate further
compression. Close attention must be paid to the
hemoglobin level and blood pressure with trans-
fusions of crystalloid or packed red blood cells in
patients with hemodynamic compromise.

Pseudoaneurysm
This is essentially an encapsulated hematoma that
Fig. 4.38 Calcified aortic valve seen on fluoroscopy in a communicates with the artery due to incomplete
patient with severe aortic stenosis sealing of the media. Patients with a new bruit, a
pulsatile mass, leg weakness, or a large and
the radial technique, it does still carry a low but expanding hematoma should be evaluated for this
significant risk of morbidity and mortality. clinical entity. Color flow duplex ultrasonography
is the method of choice for diagnosis.
Pseudoaneurysms less than 2 cm can be moni-
Local Complications tored. The treatment of choice is ultrasound
guided thrombin injection in to the pseudoaneu-
Local complications at the site of access include rysm. Additional treatment modalities are ultra-
hematoma, pseudoaneurysms, retroperitoneal sound guided compression although this is not as
hematoma, and arteriovenous fistula. The post successful as ultrasound guided thrombin injec-
catheterization assessment should include an tion. If these methods fail, or if there is femoral
examination of the site of access. nerve compression, surgical repair may be needed.

Hematoma Retroperitoneal Hematoma

Bleeding after a catheterization may be visual- Bleeding into the retroperitoneal space may occur
ized externally, however, if bleeding occurs inter- if femoral artery access occurs proximal to the
nally at the site of access this can create a inguinal ligament. Other causes of retroperitoneal
hematoma. Clinically, many patients with hema- hematoma from cardiac catheterization may be
toma will present with groin pain at the site of due to guidewire perforation of a small pelvic
access accompanied by swelling, focal bruising, vein or arteriole [6]. In addition, spontaneous ret-
and potentially hemodynamic compromise (low roperitoneal hematoma may occur secondary to
blood pressure, tachycardia) with more signifi- anticoagulation. Detection of retroperitoneal
cant hematomas. Additional complications from hemorrhage can be difficult. A high index of sus-
hematoma may be femoral nerve compression, picion should be kept in patients who experience
given its proximity to the femoral nerve, which hypotension and tachycardia without any obvious
typically presents with quadriceps weakness. In external signs of bleeding as can be seen in groin
order to minimize the chances of hematoma for- hematoma and pseudoaneurysm. Some patients
mation, meticulous attention to the access site may have bruising at the flanks or abdomen (Grey
and site of entry using fluoroscopy should be per- Turner sign) although this is rare. Whereas other
formed. The skin nick should be larger than the may just have a drop in the hemoglobin. Additional
size of the sheath to facilitate external expression possible clinical presentations depends on the site
of blood. Sheaths should be removed when the of retroperitoneal hematoma. If the hematoma is
activated clotting time falls to subtherapeutic adjacent to the psoas muscle, patients may have
levels (<170). In addition, radial approach should difficulty with hip flexion. Patients may complain
68 J.J. Barbat

of right lower quadrant pain if it compresses on which is a protocol of sliding-scale hydration

the ipsilateral ureter. It patients The most reliable based on the left ventricular end diastolic pres-
method of diagnosis is a non contrast CT although sure (LVEDP) obtained during cath [8]. This
often the diagnosis can be made clinically and strategy is employed in patients with underly-
should not be performed in unstable patients. If ing renal insufficiency (GFR <60) in which pre-
diagnosis is made, heparin should be discontin- procedure they are hydrated with 0.9 % normal
ued, and fluid, blood products, and pressors insti- saline at 3 ml/kg for 1 h pre-procedurally. During
tuted immediately in patients with hemodynamic and after procedure hydration is determined by
collapse. Many times retroperitoneal hemorrhage the LVEDP with patients getting 5 ml/kg/h for
stops spontaneously, however rarely patients may LVEDP <13, 3 ml/kg/h for LVEDP 13–18, and
require surgical exploration if continued bleeding 1.5 ml/kg/h for LVEDP greater than 18. This
occurs. is continued for 4 h post-procedurally. Overall,
however, the best strategy to minimize CIN is to
Arteriovenous (AV) Fistula minimize the contrast dose.
During vascular access, patients may have a femo-
ral vein that overlies the femoral artery which may
be punctured created a connection between the Coronary Complications
two vessels. Clinical manifestation include a swol-
len, tender leg secondary to venous insufficiency, There is a 0.05 % risk of MI from LHC and this
leg pain secondary to arterial insufficiency, and a is due to complications that may occur secondary
continuous bruit auscultated at the site of access to the procedure including coronary dissection,
Duplex ultrasonography is used to make the diag- coronary spasm, coronary perforation, and plaque
nosis. Many small, asymptomatic AV-fistulae disruption.
thrombose and resolve on their own. For large,
symptomatic AV fistulas that cause significant Coronary Artery Spasm
shunting, extremity swelling, congestive heart fail- Spasm occurs secondary to endothelial dysfunc-
ure, or deep vein thrombosis, surgical repair is pre- tion from percutaneous devices [6]. When endo-
ferred. However ultrasound guided compression, thelial dysfunction occurs there is a loss of nitric
endovascular repair with covered stents or coil oxide production causing an imbalance between
embolization are less invasive alternatives. vasodilating and vasoconstricting. Management
requires withdrawal of the percutaneous device.
Reengagement and intracoronary nitroglycerin
Contrast Induced Nephropathy (CIN) may be needed for rapid resolution of spasm. If
spasm is refractory to nitrates, intracoronary
CIN is defined as new onset renal failure, or wors- verapamil may be used.
ening of existing renal dysfunction secondary to
contrast administration. Renal failure is defined Coronary Artery Dissection
as either an increase in serum creatinine of 25 % Small intimal dissections secondary to angio-
from baseline, or an absolute increase by 0.5 mg/ plasty are frequent and usually have no associ-
dL. Typically CIN occurs 24–48 h are contrast ated adverse events. However, untreated complex
exposure [7]. Risks factors for CIN include dissections need to be treated with stents to pre-
chronic kidney disease, proteinuria, diabetes, vent coronary occlusion. Types A and B have no
advanced age, anemia, use of other nephrotoxic associated increase in procedural outcomes
medications and dehydration. The best strategy therefore they are considered minor (Fig. 4.39).
to reduce the chance of developing CIN is by Types C-F are considered major as they increase
adequate pre and post catheterization hydration. the risk of myocardial infarction and emergent
The Poseidon protocol is used at our institution, CABG and need to be stented.
4 Qualitative and Quantitative Coronary Angiography 69

Type Description Angiographic Accute

Appearance Closure (%)

A* Minor radiolucencies -
within the lumen during
contrast injection with no
persistence after dye
clearance

B* Parallel tracts or double 3

lumen seperated by a
radiolucent area during
contrast injection with no
persistence after dye
clearance

C* Extraluminal cap with

10
persistence of contrast
after dye clearance from
the lumen

D* Spiral luminal filling

30
defects

E** New persistent filling

9
defects

F** Non A-E types that lead

69
to impaired flow or total
occlusion

Fig. 4.39 Types of Coronary artery dissection (NHLBI increase in morbidity and mortality when compared to
Classification System). Abbreviations: NHLBI National patients without dissections, ** May represent thrombus
Heart, Lung, and Blood institute, – not reported, *No (From Safian and Freed [6] with permission)

Coronary Artery Perforation Additional Complications: Death,

Stroke, Arrhythmias, and Heart
• Class 1: A crater extending outside the lumen Failure
only in the absence of linear staining angio-
graphically suggestive of dissection Death
• Class 2: Pericardial or myocardial blush with- There is a 0.1 % chance of death from left heart
out a ≥1 mm exit hole catheterization, however this percentage is signifi-
• Class 3: Frank streaming of contrast through a cantly increased in patients undergoing catheteriza-
≥1 mm exit hole tion on an emergent basis for acute coronary
• Class 4: Cavity spilling into the coronary syndromes. Risk factors for increased mortality are
sinus, right ventricle, or other cardiac advanced age, severe/critical aortic stenosis, left
chamber main coronary disease, and severe LV dysfunction.
70 J.J. Barbat

Stroke Angiographic Evaluation

Occurs at a rate of one per thousand patients of Coronary Perfusion
under cardiac catheterization. Most strokes pres-
ent during the procedure or during the first 24 h. During acute coronary syndromes, it is important
Ischemic or hemorrhagic strokes may occur after to evaluate coronary perfusion at both the epicar-
a catheterization. Strokes may occur secondary to dial and myocardial level. Angiographic blood
inadvertent air embolus, or thrombus, or from flow of the major epicardial vessels can be quali-
dislodgement of aortic atheromatous debris. tatively assessed by Thrombolysis in Myocardial
Hemorrhagic strokes are secondary to anticoagu- Infarction (TIMI) flow grades (Table 4.4) [9].
lation in combination with antiplatelet agents. Determination of TIMI flow grades after perfu-
Patients with ischemic strokes that occur within sion is established during acute myocardial
the TPA window can be considered for this ther- infarction and has prognostic significance.
apy. In patients with hemorrhagic stroke, antico- Patents with TIMI 3 flow have been shown to
agulation should be reversed, BP control, and have improved clinical outcomes.
treatment of elevated intracranial pressure. TIMI flow is an important evaluation of epi-
cardial blood flow, however, it does not charac-
Arrhythmias terize perfusion to the myocardium. The
Ventricular fibrillation and bradycardia are myocardial blush score, which is an angiographic
arrhythmias that can occur during cardiac cath- parameter of myocardial perfusion, is a way of
eterization. Ventricular fibrillation can occur qualitatively evaluating blood flow reperfusing
during forceful contrast injection into the RCA the myocardium (Table 4.5). Myocardial blush
and is treated with defibrillation. Symptomatic grade is an important predictor of major adverse
bradycardia, which can occur secondary to con- cardiac events (MACE). Myocardial blush grade
trast dye, may require a transvenous pacer but 3, after reperfusion, has been shown to be a strong
usually more conservative approaches with atro- predictor of the absence of MACE events [10].
pine and having the patient cough should be
adequate.
Quantitative Coronary
Heart Failure Angiography (QCA)
In patients with cardiac or renal dysfunction, a
large osmotic dye load can put them into pulmo- QCA is an objective way of measuring coronary
nary edema. Care should be taken to minimize luminal narrowing and is an alternative to visual
contrast in these patients and non-ionic, low estimation, which has significant observer vari-
osmotic contrast should be used. ability and bias. Several processes are required

Table 4.4 Thrombolysis in Myocardial Infarction (TIMI) flow grades

TIMI flow grade Definition
TIMI 0 There is no antegrade flow beyond the point of occlusion
TIMI 1 The contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify
the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming
sequence
TIMI 2 The contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify
the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming
sequence
TIMI 3 The contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify
the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming
sequence
Data from Chesebro et al. [9]
4 Qualitative and Quantitative Coronary Angiography 71

Table 4.5 Myocardial blush grade

Myocardial blush grade Definition
0 No myocardial blush or contrast dye. Lack of contrast entering myocardium which
indicates a lack of tissue perfusion
1 Minimal myocardial blush or contrast density
2 Moderate myocardial blush or contrast density but less than that obtained during
angiography of a contralateral or ipsilateral non-infarct -related coronary artery
3 Normal myocardial blush or contrast density, comparable with that obtained during
angiography of a contralateral or ipsilateral non-infarct-related coronary artery
Data from van’t Hof et al. [10]

Fig. 4.40 Still frame from

quantitative coronary
angiography (QCA)
depicting the use of operator
determined lines through the
segment of interest to
calculate different QCA
variables (From Kern [2]
with permission)

for QCA, which includes film digitization, image Table 4.6 Quantitative Coronary Angiography (QCA)
calibration, and arterial contour detection [3]. variables
Image calibration is obtained by taking a contrast Minimal lumen diameter (MLD)
filled catheter with known dimensions, and then Reference vessel diameter
enlarging it for diameter measurement [2]. This Acute lumen gain after PCI (final MLD-baseline
diameter measurement is then used to create a MLD)
calibration factor in millimeters per pixel (mm/ Late lumen loss after PCI (follow-up MLD-final
MLD)
pixel), which is used to calculate vessel lumen
Percent diameter stenosis
size. Central lines are drawn through the area of
Data from Kern [2]
interest, which is then used to obtain the contour
of the catheter and vessel (Fig. 4.40). These lines
are examined by QCA software, which utilizes Assessment of Lesions
digital algorithms to calculate vessel diameter Characteristics and Suitability
from automatic border detection from the lines for PCI
drawn through the segment of interest. Different
values can be obtained using QCA to evaluate Several lesion classification models have been
angiographic success (Table 4.6). developed in an attempt to estimate PCI success
72 J.J. Barbat

Table 4.7 American College of Cardiology/American Heart Association Classification of Coronary Lesions
Type A lesions Type B lesions Type C lesions
High success >85 % Moderate success 65–85 % Low success <65 %
Low risk Moderate risk High risk
Discrete (<10 mm) Tubular (10–20 mm) Diffuse (>20 mm)
Concentric Eccentric
Readily accessible Moderate proximal tortuosity Excessive tortuosity of proximal segment
Smooth contour Irregular contour
Little or no calcification Moderate to heavy calcification
Less than total occlusion Total occlusion <3 months Total occlusion >3 months
Not ostial Ostial
No major branch involvement Bifurcation lesions requiring Inability to protect major side branch
double guidewires
Absence of thrombus Some thrombus present
Degenerated vein grafts with friable lesions
Data from Ryan and Faxon [11]

Table 4.8 Society for Cardiovascular Interventions (Table 4.7) [11] and the Society of Cardiovascular
(SCAI) classification of coronary lesions Imaging and Interventions (SCAI) classification
SCAI I (highest success expected, lowest risk) (Table 4.8). The association between angio-
Does not meet criteria for American College of graphic lesion complexity and long-term out-
Cardiology/American Heart Association (ACC/ comes after coronary revascularization with PCI
AHA) type C lesion
or CABG was evaluated in the SYNTAX
Patent
(Synergy between Percutaneous Coronary
SCAI II
Intervention with TAXUS and Cardiac Surgery)
Diffuse (>2 cm length)
trial [13].
Excessive tortuosity of proximal segment
Extremely angulated segments, >90°
The SYNTAX score is derived from angio-
Inability to protect major side branches
graphic variables and calculated by software that
Degenerated vein grafts with friable lesions integrates: (1) the number of lesions with their
Patent specific weighting factors based on the amount of
SCAI III myocardium distal to the lesion, and (2) the mor-
Does not meet criteria for ACC/AHA type C lesion phologic features of each single lesion (Table 4.9).
Occluded In the SYNTAX trial, at 3 years of follow-up,
SCAI IV patients with a low SYNTAX score (<22) had
Diffuse (>2 cm length) similar outcomes with PCI or CABG, whereas
Excessive tortuosity of proximal segment patients with intermediate (23–32) or high (>33)
Extremely angulated segments, >90° SYNTAX score suffered fewer adverse events
Inability to protect major side branches with revascularization by CABG compared
Degenerated vein grafts with friable lesions with PCI.
and Occluded The SYNTAX score is subject to the limita-
OR tions of coronary angiography in determining
Occluded more than 3 months lesion severity. When a “functional” SYNTAX
Data from Krone et al. [12] score was calculated, taking into account the frac-
tional flow reserve measurement of each lesion,
the number of higher-risk patients decreased and
and complication rates. These include the better discrimination of the risk for adverse events
American College of Cardiology/American was achieved in patients with multivessel coro-
Heart Association (ACC/AHA classification nary artery disease undergoing PCI.
4 Qualitative and Quantitative Coronary Angiography 73

Table 4.9 Lesion adverse characteristic scoring for the 2. Inadequate assessment of stenosis severity due
SYNTAX score
to spasm, foreshortening, vessel overlap with
Diameter reduction significant inter and intra observer variability
Total occlusion X5 3. There may be lack of a “normal” reference
Significant lesion (50–99 %) X2 vessel size due to diffuse atherosclerosis
Total occlusion
Age >3 months or unknown +1
Blunt stump +1 Conclusions
Bridging +1 Coronary angiography remains the final com-
First segment visible beyond TO mon pathway for assessment of coronary
+1 per non visible segment artery disease. Information of coronary steno-
Side branch
sis, myocardial perfusion, and ventricular
Yes <1.5 mm +1
function and morphology may be obtained as
Yes SB < and ≥1.5 mm +1
well as multiple hemodynamic parameters.
Trifurcations
However, it is subject to several limitations
1 Diseased segment +3
with inherent potential complications and
2 Diseased segments +4
invasive coronary imaging is often required to
3 Diseased segments +5
confirm stenosis severity or significance and/
4 Diseased segments +6
or PCI feasibility and success.
Bifurcations
Type A, B, C +1
Type D, E, F, G +2
Angulation <70° +1
Aorto-ostial stenosis References
Severe tortuosity +1
1. Mueller RL, Sanborn TA. The history of interven-
Length >20 mm +2 tional cardiology: cardiac catheterization, angio-
Heavy calcifications +1 plasty, and related interventions. Am Heart
Thrombus +2 J. 1995;129(1):146–72.
Diffuse disease/small vessel +2 2. Kern MJ. The cardiac catheterization handbook. 5th
ed. Philadelphia: Saunders; 2011.
+1
3. Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald
+1 per segment number E, editors. Braunwald’s heart disease. A textbook of
Data from Sianos et al. [13] cardiovascular medicine. 9th ed. Philadelphia:
Elsevier, Saunders; 2011.
4. Chatterjee K. Cardiology: an illustrated textbook, vol.
2. New Delhi: Jaypee Brothers Medical Pub; 2012.
Limitations of Coronary 5. Baim DS, Grossmans W. Grossmans cardiac catheter-
Angiography ization, angiography, and intervention. Philadelphia:
Lipincott Williams & Wilkins; 2006.
Coronary angiography is subjected to the inher- 6. Safian RD, Freed M. The manual of interventional
cardiology. Royal Oak: Physicians’ Press; 2001.
ent limitation that it is an assessment of the coro-
7. Di Mario C, Sutaria N. Coronary angiography in the
nary lumen “lumenogram” rather than an angioplasty Era: projections with a meaning. Heart.
assessment of the coronary vessel wall morphol- 2005;91(7):968–76.
ogy. As such, several limitations are encountered 8. Brar SS. Sliding scale hydration for the prevention of
contrast induced acute kidney injury: 6-month clinical
with angiography.
outcomes from the POSEIDON (Prevention of
Contrast Renal Injury with Different Hydration
1. Technical limitations: suboptimal visualiza- Strategies) trial. Lancet 2014;383(9931):1814–23.
tion due to patient body habitus, suboptimal 9. Chesebro JH, et al. Thrombolysis in Myocardial
Infarction (TIMI) trial, phase I: a comparison between
opacification with contrast due to sub-
intravenous tissue plasminogen activator and intrave-
selective coronary engagement or poor nous streptokinase. Clinical findings through hospital
injection. discharge. Circulation. 1987;76(1):142–54.
74 J.J. Barbat

10. van’t Hof AWJ, Liem A, Suryapranata H, Horntje complexity of coronary artery disease.
JCA, de Boer MJ, Zijlstra F, Zwolle myocardial EuroIntervention. 2005;1:219–27.
infarction study group. Angiographic assessment of 14. Simona Giubilato, Salvatore Davide Tomasello
myocardial reperfusion in patients treated with pri- and Alfredo Ruggero Galassi. Percutaneous.
mary angioplasty for acute myocardial infarction. Recanalization of Chronic Total Occlusion (CTO)
Myocardial blush grade. Circulation. 1998;97: coronary arteries: looking back and moving forward,
2302–6. what should we know about prevented, diagnostic, and
11. Ryan TJ, Faxon DP, Gunnar RM, et al. Guidelines for interventional therapy in coronary artery disease, Prof.
percutaneous transluminal coronary angioplasty. A Baskot Branislav, editor, ISBN: 978-953-51-1043-9,
report of the American College of Cardiology/ InTech, DOI: 10.5772/54079 2013. Available from:
American Heart Association Task Force on http://www.intechopen.com/books/what-should-we-
Assessment of Diagnostic and Therapeutic know-about-prevented-diagnostic-and-interventional-
Cardiovascular Procedures (subcommittee on percu- therapy-in-coronary-artery-disease/
taneous transluminal coronary angioplasty). J Am percutaneous-recanalization-of-chronic-total-occlusion-
Coll Cardiol. 1988;12:529–45. cto-coronary-arteries-looking-back-and-moving
12. Krone RJ, Laskey WK, Johnson C, et al. A simplified 15. King S, et al. Coronary arteriography and angioplasty.
lesion classification for predicting success and com- New York: McGraw Hill; 1984.
plications of coronary angioplasty. Registry 16. Pepine CJ, Hill JA, Lambert CA, editors. Diagnostic
Committee of the Society for Cardiac Angiography and therapeutic cardiac catheterization. Baltimore:
and Intervention. Am J Cardiol. 2000;85:1179–84. Williams & Wilkins; 1989.
13. Sianos G, Morel MA, Kappetein AP, et al. The
SYNTAX score: an angiographic tool grading the
 Imaging of Coronary Artery
Anomalies 5
Benjamin T. Ebner and Kavitha M. Chinnaiyan

Abstract
Although coronary anomalies are recognized as the second leading cause
of sudden death amongst young and seemingly healthy persons, they con-
stitute a diverse group of uncommon and poorly understood cardiac disor-
ders. Despite widely known implications of sudden cardiac death occurring
from malignant forms of coronary anomalies within the medical commu-
nity as well as among the general public, the pathophysiologic mecha-
nisms that characterize the clinical presentations, long-term clinical
repercussions and prognoses coronary anomalies are not well-defined.
Imaging remains a cornerstone in the diagnosis and prognostication of
these disorders. However, the optimal screening tool for these conditions
remains elusive. Larger, longer-term data are needed to understand these
entities with further clarity.

Keywords
Coronary anomalies • ACAOS • ALCAPA • Coronary CT angiography •
Echocardiography • IVUS

Introduction

Anomalies of the coronary arteries are uncom-

mon and poorly understood cardiac disorders.
Although the implications of sudden cardiac
B.T. Ebner, MD (*) death occurring from malignant forms of coro-
Heart and Vascular Center of Excellence, nary anomalies are widely known within the
William Beaumont Hospital, Royal Oak, MI, USA
medical community as well as among the general
e-mail: [email protected]
public, the pathophysiologic mechanisms that
K.M. Chinnaiyan, MD
characterize the clinical presentations, long-term
Department of Cardiovascular Medicine,
William Beaumont Hospital, Royal Oak, MI, USA clinical repercussions and prognoses of this
e-mail: [email protected] group of disorders are not well-defined [1].

© Springer-Verlag London 2015 75

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_5
76 B.T. Ebner and K.M. Chinnaiyan

Fig. 5.1 Distribution of Other (3%) Normal heart (3%)

causes of sudden death in Other congenital HD (2%)
1,435 young athletes (From Ion channelopathies (3%)
Maron [55] with permission) Aortic rupture (2%)
Sarcoidosis (1%)
Dilated C-M (2%)

AS (3%)

CAD (3%)
HCM (36%)
Tunneled LAD (3%)

%)
MVP (4
) )
4% %
V C( (6
AR tis
rdi
ca
yo
M Coronary artery
anomalies (17%)

Indeterminate LVH
- possible HCM
(8%)

Coronary anomalies are recognized as the second been suggested that any morphologic form
leading cause of sudden death amongst young observed in >1 % of an unselected general pop-
and seemingly healthy persons (Fig. 5.1) [2]. ulation falls within the “normal variant” cate-
Unfortunately, the natural history of even the gory [4]. An anomaly is an anatomic feature
most commonly recognized anomalies is poorly noted in <1 % of an unselected general popula-
understood and cardiac stress testing may fail to tion [5, 6].
identify dynamic obstruction, which is postulated Some researchers have suggested that there
to precipitate fatal arrhythmias. When coronary are two distinct parts of normal coronary circu-
anomalies are identified, the clinician and patient lation: the large, proximal epicardial vessels,
are left with the challenging decision of whether and the distal microvascular, high-resistance
or not to pursue revascularization. Although there vessels [7]. While the general assumption is that
are a handful anatomic features which are known the human heart comprises of the right and left
to confer an elevated risk of death, the underlying coronary arteries, the recommendation is to
absolute risk remains unknown. Prior to under- more accurately assume that the left anterior
taking cardiac surgery in complex congenital descending artery (LAD), left circumflex artery
heart disease, the coronary anatomy should be (LCX) and right coronary artery (RCA) are the
defined so as not to inadvertently damage a ves- fundamental units of coronary anatomy [7]. In
sel during the operation [3]. Cardiac imaging is this latter classification, the left main (LM) is
instrumental in identifying high risk features considered a mixed proximal trunk that may or
which warrant surgical consideration and can may not be present in all cases. The coronary
help guide surgical planning. orifices are located within the corresponding
aortic sinuses; usually two, and occasionally
three ostia are present. The conal branch of the
Normal Coronary Anatomy RCA may arise separately from the right coro-
nary sinus [8]. The LAD courses through the
A fundamental issue in the definition of coro- anterior interventricular groove while the LCX
nary anomalies lies in the large spectrum of and RCA traverse the left and right atrioventric-
what is considered normal variation. It has ular grooves, respectively.
5 Imaging of Coronary Artery Anomalies 77

Embronic Embryonic
week week
~4 ~6

Fig. 5.2 Embryologic development of coronary vasculature (From Lluri and Aboulhosn [10] with permission)

Embryology of Coronary Artery Table 5.1 Incidence of coronary anomalies

Development Overall % Frequency of
incidence all anomalies
Although the process of coronary embryogene- (%) (%)
sis is incompletely understood, it is postulated Probably benign 1.07 80.6
Separate origin of 0.41 30.4
that the primitive endocardium makes a signifi-
LAD and Cx from
cant contribution to coronary endothelium while LSV
the vascular smooth muscle layer derives largely Cx from RSV or RCA 0.37 27.7
from the epicardium [9]. The process is believed RCA from the aorta 0.15 11.2
to be mediated through complex signaling Small coronary 0.12 9.7
involving vascular endothelial growth factor fistulae
(VEGF) which is elaborated by the myocar- All other benign 0.03 1.6
dium. By the 25th day of embryonic develop- Potentially 0.26 19.4
ment, a non-contiguous vascular plexus can be malignant
found surrounding the fetal heart (Fig. 5.2). At Left main from the 0.008 0.059
pulmonary artery
6 weeks the vessels are continuous and con-
LAD from the 0.0008 0.06
nected to the aorta. Disruptions in this process pulmonary artery
are believed to underlie the development of cor- RCA from the 0.002 0.12
onary anomalies [10]. pulmonary artery
Left main from the 0.017 1.3
right sinus
LAD from the right 0.03 2.3
Incidence sinus
RCA from the left 0.107 8.1
sinus
While the incidence of coronary anomalies is
Single coronary artery 0.048 3.31
generally reported to be ~1 %, some series have
Large or multiple 0.05 3.7
reported a much higher incidence of ~5 % based fistulae
upon a stricter classification scheme [7]. In one
LAD Left anterior Descending, Cx Circumflex, LSV Left
series of 126,595 invasive angiograms, the over- sinus of valsalva, RSV right sinus of valsalva, RCA Right
all incidence was 1.33 % (Table 5.1) [11]. The coronary artery (Adapted from Yamanaka and Hobbs [11]
with permission)
78 B.T. Ebner and K.M. Chinnaiyan

rate of detection was similar in a coronary CT Table 5.2 (continued)

angiography (CTA) series [12]. 4. Anomalous location of coronary ostium at
improper sinus (which may involve joint
origination or “single” coronary pattern)
a. RCA that arises from left anterior sinus, with
Classification of Anomalies anomalous course
(1) Posterior atrioventricular groove or
Many classification schemes have been proposed retrocardiac
to describe the various configurations of coro- (2) Retroaortic
nary anomalies. The most thorough models (3) Between aorta and pulmonary artery
describe three aspects of an anomalous artery; (intramural)
the origin, course and termination (Table 5.2) [1]. (4) Intraseptal
While this method is sure to describe any type of (5) Anterior to pulmonary outflow
(6) Posteroanterior interventricular groove
(wraparound)
Table 5.2 A comprehensive coronary artery anomaly b. LAD that arises from right anterior sinus, with
classification scheme includes a description of origin, anomalous course
course and termination (1) Between aorta and pulmonary artery
A. Anomalies of origination and course (intramural)
1. Absent left main trunk (split origination of LCA) (2) Intraseptal
2. Anomalous location of coronary ostium within (3) Anterior to pulmonary flow
aortic root or near proper aortic sinus of Valsalva (4) Posteroanterior interventricular groove
(for each artery) (wraparound)
a. High c. Cx that arises from right anterior sinus, with
b. Low anomalous course
c. Commissural (1) Posterior atrioventricular groove
3. Anomalous location of coronary ostium outside (2) Retroaortic
normal “coronary” aortic sinuses d. LCA that arises from right anterior sinus, with
a. Right posterior aortic sinus anomalous course
b. Ascending aorta (1) Posterior atrioventricular groove
c. Left ventricle (2) Retroaortic
d. Right ventricle (3) Between aorta and pulmonary artery
e. Pulmonary artery (4) Intraseptal
(1) LCA that arises from posterior facing sinus (5) Anterior to pulmonary outflow
(2) Cx that arises from posterior facing sinus (6) Posteroanterior interventricular groove
(3) LAD that arises from posterior facing sinus 5. Single coronary artery (see A4)
(4) RCA that arises from anterior right facing B. Anomalies of intrinsic coronary arterial anatomy
sinus 1. Congenital ostial stenosis or atresia (LCA, LAD,
(5) Ectopic location (outside facing sinuses) RCA, Cx)
of any coronary artery from the pulmonary 2. Coronary ostial dimple
artery 3. Coronary ectasia or anyeurism
(a) From anterior left sinus 4. Absent coronary artery
(b) From pulmonary trunk 5. Coronary hypoplasia
(c) From pulmonary branch 6. Intramural coronary artery (muscular bridge)
f. Aortic arch 7. Subendocardial coronary course
g. Innominate artery 8. Coronary crossing
h. Right carotid artery 9. Anomalous origination of posterior descending
i. Internal mammary artery artery from the anterior descending branch or a
j. Bronchial artery septal penetrating branch
k. Subclavian artery (continued)
l. Descending thoracic aorta
5 Imaging of Coronary Artery Anomalies 79

Table 5.2 (continued) the basis for another type of classification of cor-
10. Split RCA onary anomalies depending on the outcome [11].
a. Proximal + distal PDs that both arise from The chapter will highlight the more common
RCA and/or significant in terms of coronary anomalies
b. Proximal PD that arises from RCA, distal PD encountered in clinical practice.
that arises from LAD
c. Parallel PDs ×2 (arising from RCA, Cx) or
“codominant”
11. Split LAD
Anomalous Coronary Artery
a. LAD = first large septal branch
from the Opposite Sinus (ACAOS)
b. LAD, double (parallel LADs)
12. Ectopic origination of first septal branch In ACAOS (Fig. 5.3), the coronary arteries arise
a. RCA from the non-coronary sinus or the opposite cor-
b. Right sinus onary sinuses [13].
c. Diagonal
d. Ramus 1. The RCA originates from the left coronary sinus
e. Cx as a separate vessel or as a branch of a common
C. Anomalies of coronary termination (single) coronary artery in 0.03–0.17 % of
1. Inadequate arteriolar/capillary ramifications patients undergoing angiography [8, 11],
2. Fistulas from RCA, LCA, or infundibular 2. The LM arises from the right coronary cusp in
artery to: 0.09–0.11 %, and
a. Right ventricle 3. The LCX can arise from the right coronary
b. Right atrium cusp in 0.32–0.67 % of patients undergoing
c. Coronary sinus angiography [8].
d. Superior vena cava
e. Pulmonary artery Autopsy studies suggest up to a 57 % mortal-
f. Pulmonary vein ity rate for ACAOS involving an anomalous left
g. Left atrium coronary system and 25 % mortality rate for
h. Left ventricle those involving the RCA [14]. There are limited
i. Multiple, right + left ventricles
natural history data available regarding the natu-
D. Anomalous anastomotic vessels
ral history of ACAOS. In one study, 24 of 72
From Angelini [1] with permission middle-aged adults with ACAOS identified on
LCA indicates left coronary artery, LAD left descending
coronary artery, RCA right coronary artery, Cx indicates coronary CTA, had an inter-arterial course. At a
circumflex, and PD posterior descending branch median follow-up of 15 months, two patients
underwent corrective surgery and there was one
death due to coronary disease (unrelated to the
anomaly, in clinical practice it is more practical ACAOS). Additionally, 73 % of patients had
to think in terms of common anomaly types. One improvement in the symptoms which led to the
of the most common groups encountered by adult initial CTA while the other 27 % had worsening
cardiologists is the anomalous coronary artery symptoms. Patients with anomalous RCA and
from the opposite sinus (ACAOS). These anoma- inter-arterial compression had more frequent
lies are further described by the course of the syncope and chest pain [15].
artery in relation to the great vessels, with an In a retrospective study of middle aged adults
inter-arterial course (traversing between the aorta in Japan, 56 patients with ACAOS were followed
and pulmonary artery) to be the most concerning. for a median of 5.6 years. Of these patients, 78 %
Additionally, the finding of an intramural course had anomalous RCA from the left coronary sinus
(traversing within the aortic wall) is worrisome. with an inter-arterial course and none had an
Finally, coronary anomalies may either be benign anomalous left main. All patients were managed
or malignant in terms of prognosis, which lends with negative chronotropes and activity restriction
80 B.T. Ebner and K.M. Chinnaiyan

a b

c d

Fig. 5.3 (Panel a) An anomalous left main coronary anterior descending (*) arising from the right coronary
artery arising from the right coronary artery; taking a low artery, coursing anterior to the right ventricular outflow
(inferior to the pulmonary valve) interarterial course (*). tract (RVOT). In (panel g) the right coronary artery is seen
Typically, an anomalous left main coursing between the giving rise to a large posterolateral branch (PLB), owing to
great arteries is recommended for surgical repair. A low congenital absence of the left circumflex artery. (Panels h,
interarterial course has been shown to be confer lower risk i) An anomalous left coronary artery arising from the right
of sudden death when the anomalous vessel is a right coro- sinus of Valsalva with a low interarterial course (*). The
nary [11]. In this variant, the low course has implications LAD is hypoplastic. Also seen in a large high obtuse mar-
for surgical management. (Panel b) A 3D rending of the ginal vessel which courses parallel to the LAD and sup-
anomaly from (panel a). The right ventricle and pulmonary plies much of the territory commonly supplied by the
artery have been removed. (Panels c, d). An anomalous LAD. (Panels j, k) Tomographic and 3D rendering of an
right coronary artery arising from the left anterior descend- anomalous left circumflex artery (*) arising from the right
ing taking a prepulmonic course (*). (Panels e, f, g) coronary cusp and coursing posterior to the aorta
Tomographic and 3D renderings of an anomalous left
5 Imaging of Coronary Artery Anomalies 81

e f

g h

i j

Fig. 5.3 (continued)

82 B.T. Ebner and K.M. Chinnaiyan

k disease, resolves with revascularization. A contin-

uous murmur may be related to mitral insuffi-
ciency with excess diastolic mitral flow from the
RCA to the anomalous left via collaterals [17].

Coronary Fistulas

A coronary fistula (Fig. 5.5) is an abnormal ter-

mination of a coronary artery into
1. A cardiac chamber (coronary cameral fistula) or
2. A low-pressure vessel as the pulmonary artery,
pulmonary vein, and coronary sinus (coronary
arteriovenous fistula).
Major sites of origin of fistula are the right cor-
onary artery (55 %), left coronary artery (35 %),
Fig. 5.3 (continued) and both coronary arteries (5 %). Major termina-
tion sites are the right ventricle (40 %), right atrium
(26 %), pulmonary arteries (17 %) and less fre-
despite symptoms attributable to ischemia and/or quently the superior vena cava or coronary sinus
a positive stress test. During the study period, and least often the left atrium and left ventricle.
there was only a single cardiac death, attributed This abnormality may lead to a coronary steal phe-
to aortic stenosis [16]. nomenon, arrhythmia and volume overloading the
chambers involved in the circuit. Presentation is
typically due to incidentally discovered continu-
Anomalous Coronary Artery ous murmur or symptoms of exertional dyspnea
from the Pulmonary Artery, and fatigue. They are readily identified a coronary
the Bland-White-Garland Syndrome angiography, CT or MR but may be seen on echo,
especially transesophageal echo. Unless they are
This syndrome (Fig. 5.4) constitutes the anoma- small and asymptomatic, coronary fistula should
lous origin of the left coronary artery from the be surgically treated since they rarely close on
pulmonary artery (ALCAPA). The identification their own and frequently become symptomatic and
of ALCAPA is most often encountered during the the worse outcomes of repair with advancing age.
first weeks of life when pulmonary artery pres- Options include surgical ligation and if possible
sure falls to a range no longer able to support catheter embolization [17].
anterograde flow in the anomalous vessel. If suf-
ficient collaterals are present, a coronary steal
phenomenon may result. Occasionally, the pat- Myocardial Bridging
tern of collaterals may be sufficient to sustain life
into adulthood. Over time, ventricular dilation, Typically coronary arteries are epicardial, but
dysfunction and significant fibrosis develop. autopsy series commonly demonstrate myocardial
Patients classically present in four ways; infant bridging, where a portion of the vessel traverses
syndrome, mitral insufficiency, continuous mur- the myocardium (Fig. 5.6). The proximal LAD is
mur or sudden death. Infant syndrome represents the most common site of bridging. During systole
90 % of cases, with failure to thrive, angina-like there is compression of the vessel with resultant
episodes or congestive heart failure in the first sev- retrograde flow, which is believed to accelerate
eral months of life. Mitral insufficiency tends to be atherosclerosis. The hemodynamic significance of
functional and in the absence of structural valve these lesions is likely related to the depth and
5 Imaging of Coronary Artery Anomalies 83

a b

c d

Fig. 5.4 A coronary CT angiogram from a 24 year old male (Panels d, e) Echocardiography demonstrating the LM
with abdominal pain and easy fatigability. A CT. (Panel a) coursing towards the pulmonary artery (white arrow) above
The coronary CT angiogram demonstrates an anomalous left the pulmonic valve (left). Doppler interrogation demonstrat-
coronary artery arising from the pulmonary trunk denoted ing abnormal diastolic flow within the main pulmonary
with an asterisk as well as left heart enlargement. (Panel b) A artery towards the transducer, which represents runoff from
3D rendering demonstrating enlarged right and left coronary the anomalous left coronary artery (large white arrowhead).
arteries, owing to a long standing high flow state. (Panel c) A There is normal systolic antegrade flow in the main pulmo-
short axis view showing robust epicardial and septal collat- nary artery (small white arrow). Ao aorta, PA pulmonary
eral network from the high-pressure right coronary artery artery, RCA right coronary artery (Panels d, e from Medscape
through the left coronary artery and into the pulmonary Drugs & Diseases (http://emedicine.medscape.com/), 2015,
artery. The patient underwent surgical reimplantation to the available at: http://emedicine.medscape.com/article/893290-
aorta with pericardial patch closure of the pulmonary trunk. overview with permission)
84 B.T. Ebner and K.M. Chinnaiyan

a b

Fig. 5.5 A gross specimen (a) (left) of a fistula between the left coronary artery (LCA) to the right ventricle (RV), on
the (b) right, echocardiographic demonstration of an LAD to RV fistula

a b

Fig. 5.6 (Panels a, b) A long axis and short axis view of myocardial bridging of a ramus intermedius. Note how the coro-
nary artery runs an intramyocardial course in the mid ventricle (a) and is circumferentially surrounded by myocardium (b)

length they traverse in the myocardium. Like other Symptoms

coronary abnormalities, they may cause ischemia,
infarction or sudden death, though with the fre- Very rarely does an anomalous coronary artery
quency at which they are found at autopsy this is result in impaired coronary blood flow at rest.
probably rare. Symptomatic lesions are treated Most anomalies in general do not impose limita-
with beta blockers or non-dihydropyridine cal- tions to blood flow at exercise either [7]. Some
cium channel blockers to prolong diastolic filling conditions like ALCAPA and coronary ostial
time. Nitroglycerin, which increases contractility atresia can cause resting ischemia [19]. While
may worsen compression and should not be used. most patients are asymptomatic, angina, dys-
When symptoms are refractory to medication, sur- pnea, palpitations, syncope, acute coronary syn-
gery to unroof the bridged segment may be appro- drome and sudden death have been attributed to
priate. Stenting has been used as well; though with the presence of underlying coronary anomalies,
higher than anticipated rates of restenosis and mostly on autopsy studies. In a post-mortem
coronary perforation [18]. series of sudden death amongst military recruits
5 Imaging of Coronary Artery Anomalies 85

a b

Fig. 5.7 High (a) (left) versus low (b) (right) inter arte- AO aorta, PA pulmonary artery, RVOT right ventricular
rial course of the RCA from the left coronary cusp. High outflow tract, asterisks origin of he RCA
and low are in relation to the level of the pulmonic valve.

symptoms of syncope, chest pain and dyspnea exercise. Some experts have observed a tangential
were reported more commonly in individuals suf- course of such anomalous arteries that exit the aor-
fering sudden cardiac death as compared to death tic lumen and traverse the aortic wall for a variable
from another cause [20]. In ACAOS, sudden distance [7]. The intramural segment of such an
death is usually associated with strenuous/ artery is found to comprise of thin inner and outer
extreme exercise in young adults, while the other aortic wall layers. Lateral luminal compression of
symptoms are more frequently seen in older such a segment is worse during systole. Additionally,
adults. Some experts note that these symptoms the section of the aortic root carrying the intramural
are associated with the onset of hypertension [1]. coronary segment becomes a localized weak spot,
Additionally, both the right and left coronary yielding more than the rest of the aortic wall during
arteries can be responsible for sudden death, systolic ejection and leading to worsened stenosis.
depending upon the severity of the baseline ste- Thus, other factors that affect the distensibility of
nosis, specific conditions at the time of the fatal the aortic wall such as cystic necrosis or ectasia may
crisis, as well as the extent of the myocardial ter- worsen the prognosis of such patients. Aging, which
ritory at risk [14]. However, in most patients, the stiffens the aorta appears to be protective against
exact pathophysiologic mechanisms of ischemia compression [7]. Dynamic obstruction to flow has
are yet to be determined, since these anomalies been demonstrated with intravascular ultrasound,
have not consistently demonstrated ischemia on which can be helpful in deciding on a surgical rec-
stress testing [7]. ommendation. Other high risk features include a slit
like orifice, acute angle take-off, and an inter-arte-
rial course, particularly when there is a high (above
Pathophysiology the pulmonic valve) inter-arterial course as opposed
to a low (at the right ventricular outflow level, below
Unlike atherosclerotic coronary artery disease, the pulmonic valve) as shown in Fig. 5.7 [14, 21].
obstruction to blood flow in ACAOS is dynamic. Other mechanisms include arrhythmic events pre-
Sudden death occurs most commonly during or cipitated by transient ischemia and reperfusion [22].
immediately following exercise [20], which is pos- The interarterial course (between the aorta
tulated due to aortic dilation and kinking of the and the pulmonary artery) of an anomalous
anomalous vessel with increased stroke volume in coronary artery is associated with a worse
86 B.T. Ebner and K.M. Chinnaiyan

prognosis [1, 23, 24]. On intravascular ultrasound Due to lack of large, longitudinal studies to
(IVUS) imaging, this interarterial course has guide current clinical practice, the scope of
been shown to consist of intramural proximal screening has not been determined. Specific
intussusception of the anomalous coronary artery screening protocols are recommended for ath-
at the wall of the aortic root [25]. While the letes and military personnel or those with symp-
“interarterial course” implied that the anomalous toms. Survivors of unexplained aborted sudden
artery was subject to compromise by virtue of cardiac death, life-threatening arrhythmias or left
lying between the aorta and the pulmonary artery ventricular dysfunction must undergo evaluation
through a scissors-like mechanism, particularly for coronary anomalies [28].
during exercise, some single-center IVUS studies Testing for patients with suspected ACAOS
have demonstrated other mechanisms of isch- may include electrocardiography, Holter moni-
emia in such patients. These include coronary toring to document symptoms of arrhythmias and
hypoplasia, lateral compression of the anomalous cardiac imaging.
artery and increased length of the stenotic seg-
ment. The intramural segment of the proximal
anomalous artery is found to be smaller in cir- Imaging for Coronary Anomalies
cumference compared to the extramural seg-
ments. It is postulated that arteries that arise Echocardiography
congenitally from within the aortic media are
unlikely to grow normally [25, 26]. Additionally, Focused expert transthoracic echocardiography
the cross section of the intramural segment is with Doppler interrogation can identify the origin
found to be ovoid in shape due to lateral com- of the coronary arteries as well as their proximal
pression. The smaller diameter vessel is further course [29–31]. For example, ALCAPA can be
compressed during systole, which is of particular identified on echocardiography in children and
importance during strenuous exercise [1]. adults by noting diastolic flow from the anoma-
Sudden death in ACAOS can occur immedi- lous vessel into the pulmonary, and often, a
ately after extreme exercise from low cardiac out- dilated right coronary ostium and abundant intra-
put, severe bradycardia or asystole, or terminal septal flow signal due to collaterals seen more
ventricular fibrillation as a result of critical isch- often in adults [32]. However, given the infre-
emia or reperfusion [22, 27]. quency of ALCAPA in the general population,
echocardiographic findings may be overlooked
or misinterpreted [33]. Due to its ready availabil-
Screening for Coronary Anomalies ity, short time needed for examination without
prior preparation, lack of exposure to ionizing
The primary challenges with most anomalies are radiation and relative lower cost of testing, echo-
identification and determination of clinical rele- cardiography is suitable as a first test, particularly
vance. Most often, the causative relationship in children.
between the anomaly and the presenting However, echocardiography becomes limited
symptom(s) is unclear. However, correct diagno- with increasing age and body mass [33, 34].
sis is imperative for assessment of prognostic Transesophageal echocardiography can be used
implications as well as for treatment options. In to identify some forms of anomalies like
various reports, it is noted that 55–93 % of patients ACAOS. However, because of its expense and
that die from coronary anomalies have no prior invasive nature, it is not considered to be a good
symptoms [7]. Thus, while cardiac symptoms screening tool.
may prompt work-up and identification of the Due to intrinsic limitations of echocardiogra-
anomaly, patients with no or mild symptoms are phy, it is not suitable as a stand-alone test for
diagnosed with this condition incidentally during screening, diagnosis or prognostication of coro-
work-up for other signs or symptoms. nary anomalies.
5 Imaging of Coronary Artery Anomalies 87

Coronary Magnetic Resonance Multiple studies comparing the accuracy of

Angiography CMRA to ICA have been published [39–41]. At
most centers skilled at this technique, 3-D CMRA
Multiple developments in coronary magnetic res- is preferentially used since it enables superior
onance angiography (CMRA) make it possible to reconstruction capabilities with excellent results.
achieve three-dimensional reconstruction and It is a particularly attractive modality in children
visualization of the origin and course of coronary and young adults because of lack of exposure to
anomalies. These include steady-state with free- ionizing radiation or to iodinated contrast. The
precession (SSFP) for CMRA, phase contrast MR limitations of ICA can be overcome with non-
imaging, parallel imaging for CMRA, 3 Tesla invasive techniques such as coronary computed
CMRA and whole heart CMRA [35]. The SSFP tomography (CT) angiography and magnetic
method enables obtaining high signal intensity resonance imaging (MRI). Although MRI is a
from the coronary arteries as well as high contrast useful tool to determine the origin of the coro-
between the ventricular blood pool and the myo- nary arteries from the aorta, its spatial resolution
cardium without the need for contrast agents [36]. can be inadequate for thorough analysis of the
It also permits CMRA during free-breathing with distal arterial course.
substantial improvements in signal-to-noise ratio,
contrast-to-noise ratio, and vessel sharpness as
compared with standard T2-prepared gradient- Coronary CT Angiography (CTA)
echo imaging [35]. The phase-contrast technique
measures blood-flow velocity along with arterial Computed tomography (CT) was first introduced
diameter to yield a quantitative measurement of as a non-invasive imaging technique in 1972 and
blood flow (in milliliters per minute) at rest and quickly revolutionized clinical medicine. Early
stress [34]. Parallel imaging reduces scanning CT scanners, however, were limited in their abil-
time by half or more [37]. However, the trade-off ity to visualize dynamic structures like the rap-
for reduced acquisition time is reduced signal-to- idly beating heart. Yet technical improvements in
noise ratio for visualization of the coronary arter- recent years, primarily due to faster speeds of the
ies. While most CMRA examinations are rotating gantry and thin (“sub-millimeter”) slice
performed on 1.5-Tesla MR systems, 3-Tesla sys- collimation, now permit multi-slice (or multi-
tems provide better signal and contrast values. detector) CT enough temporal and spatial resolu-
The increasing availability of 3-Tesla systems tion to produce 3-dimensional, motion-free
equipped with dedicated cardiac hardware (real- images of the heart and its coronary arteries [42].
time spectrometer, parallel receiver technology Published studies of the use of coronary CTA
with high bandwidth, body radiofrequency send for identification and characterization of coro-
coil, vector electrocardiography) and software nary anomalies have highlighted the benefits of
(parallel imaging, navigators, interactive inter- 3-dimensional imaging, similar to CMRA. The
face) may provide significant improvement in advantage of CTA over ICA is unambiguous
CMRA [35]. Whole-heart CMRA, which is anal- identification of the precise course of the anoma-
ogous to coronary CTA, allows for imaging of the lous vessels, particularly the proximal segments
entire coronary artery tree in an axially acquired [43, 44]. Additionally, CTA is superior for visual-
3D volume. Post-processing of the 3D images is ization of localized aneurysms of the coronary
performed in a manner similar to that for coronary arteries [45], coronary fistulae [46], and myocar-
CTA. The trade-off is a lower spatial resolution dial bridging [47]. It also readily identifies high-
(usually >1 mm in-plane and through-plane reso- risk features, like acute angle take off, slit like
lution) and lengthy scan times (10–15 min). orifice and inter-arterial course (Fig. 5.8). As a
Nevertheless, the whole-heart coronary MRA result of consistent demonstration of its ability to
approach has gained rapid acceptance on the basis identify and classify coronary artery variants,
of promising initial results [38]. anomalies and associated defects, coronary CTA
88 B.T. Ebner and K.M. Chinnaiyan

fistulas, myocardial bridging, and localized aneu-

rysms. However, ICA can be limited in detection
of the malignant forms of anomalies such as an
acute take-off angle from the aorta with a slit-like
orifice that can result in ischemia during exercise
[34]. Prior to the expanding role of CTA in iden-
tifying coronary anomalies, detection of the
course of the anomalous LM arising from the
right cusp was through identifying the “dot” and
“eye” signs (Fig. 5.9). The presence of an eye and
a posterior dot indicated a benign course, while
the presence of an anterior dot suggested the
more malignant interarterial course. However,
being two-dimensional, ICA may also not be reli-
able in detection of the relationship between the
anomalous vessels and underlying cardiac struc-
Fig. 5.8 A coronary CT angiogram from a 37-year old
tures [8]. Additionally, the costs and potential for
woman with atypical chest pain presenting to the emer- complications associated with the procedure
gency department. She had recently undergone an exer- limit its usefulness as a screening tool. Moreover,
cise treadmill test, which was stopped after 2.5 min due to the most clinically relevant anomalies are those
fatigue. The CT angiogram demonstrates an anomalous
left main coronary artery arising from the right sinus of
associated with potential catastrophic events;
valsalva with an interarterial course. Surgical marsupial- screening for every type of anomaly with ICA
ization was unsuccessful due to intraoperative finding of a may not be warranted in general practice.
course through the right ventricular outflow tract. Bypass In some studies, IVUS has resulted in high
grafting was then performed to the LAD and obtuse mar-
ginal with ligation of the proximal vessel
accuracy for noting the presence of the anoma-
lous origin as well as the specific anatomy of the
proximal trunk [33]. In addition, IVUS affords
with ECG gating is now considered the gold stan- excellent visualization of an intramural course
dard for the diagnosis of such conditions [48]. that is found to varying lengths of 5–35 mm in
However, CTA may not be as valuable as IVUS almost all cases of ACAOS [33]. IVUS has been
to accurately detail the anatomy of the intramural shown to also diagnose hypoplasia of the intra-
segment in ACAOS due to its lower spatial reso- mural segment (if present) as well the presence of
lution compared to IVUS (Fig. 5.9) [33]. lateral compression of the lumen of the intramu-
Moreover, CTA does involve exposure to ioniz- ral segment [33].
ing radiation as well as iodinated contrast and
therefore must be used cautiously in young
patients. These limitations also preclude its use Management of Coronary
as a screening test for populations at risk. Anomalies

Patients with symptoms attributed to coronary

Invasive Coronary Angiography anomalies have the options of observation and
medical management, percutaneous therapy with
Until recently, invasive coronary angiography stenting, or surgical repair [1]. Although data on
(ICA) was considered the gold standard for diag- the effect of various interventions are limited,
nosis and classification of coronary anomalies. they may be justified to prevent sudden death or
Traditionally, invasive coronary angiography has symptoms in certain cases. Medical therapy with
the ability of identifying, anomalous origins of beta-blockers is thought to be as effective as
the coronary vessel, separate ostia, coronary restriction of extreme strenuous activity [1, 49].
5 Imaging of Coronary Artery Anomalies 89

a
Left Main Coronary Artery Arising From the Right Sinus of Valsalva
Cross-sectional Representative RAO
Representation Angiographic Features C
“Eye”
Aortic Valve Septal Course M
s L
Circumflex
Anterior
Pulmonic Valve Descending

Septals

M = LM C = CIRC L = LAD

“Eye”
Aortic Valve
Anterior Course
Anterior M
Pulmonic Valve Descending C L

Circumflex

M = LM C = CIRC L = LAD

Aortic Valve Interarterial Course

“Dot”

Anterior M C L
Descending

Circumflex

Pulmonic Valve
M = LM C = CIRC L = LAD
Aortic Valve Retroaortic Course

Anterior L
M C
Descending

Circumflex
“Dot”

Pulmonic Valve
M = LM C = CIRC L = LAD

Fig. 5.9 Invasive evaluation of anomolous origin of the anterior dot indicated a malignant inerarterial course.
left main from the right coronary cusp. (Panel a) demon- (Panel b) demonstrates invasive angiography reveaing the
strates the “dot” and “eye” signs. The presenc of an anterior dot sign (From Serota et al. [56] with permission)
90 B.T. Ebner and K.M. Chinnaiyan

Fig. 5.10 Marsupialization of the tunneled segment (left through the proximal, intramural segment to identify the
panel). Disruption of the commissure during marsupial- appropriate position to create the new ostium (From
ization may result in aortic insufficiency. Creation of a Romp et al. [53] with permission)
neo-ostium (right panel). A surgical probe is passed

While percutaneous intervention with stenting options for ALCAPA include reimplantation of
sounds like an attractive option, the stenotic seg- the anomalous vessel to the aorta with pericardial
ment is typically intramural, making the proce- repair of the pulmonary artery and bypass graft-
dure technically challenging and coupled with ing with ligation of the proximal anomalous con-
the potential unknown interactions between the nection [51, 52]. When the artery course is
aorta and stented segment makes this a less intramural, the surgical approach may involve
attractive option. At present, there has been very marsupialization or unroofing the intramural seg-
limited experience with stenting, and most ment, which has potential for resultant aortic val-
involve anomalous right coronaries. vular insufficiency (Fig. 5.10). Perhaps the most
The need for surgical revascularization is appealing surgical approach is simply creating a
often the key decision point in managing neo-ostium after the intramural segment [53].
ACAOS. Surgical revascularization may be of Overall, surgical results tend to show favorable
benefit in the setting of documented vascular wall long-term outcomes [54].
hypoplasia, lateral compression or documented
obstruction to coronary flow [3]. Current guide- Conclusions
lines also suggest that surgical revascularization Coronary artery anomalies constitute a diverse
be considered in the setting of an anomalous LM group of congenital disorders with variable
or LAD with an interarterial course and also in pathophysiological mechanisms, with resul-
the presence of ALCAPA. tant variations in therapeutic options and long-
Depending on the patients anatomy different term prognosis. While many imaging
techniques for surgical correction have been modalities are available, the optimal screening
described. The most straightforward approach tool for these conditions remains elusive.
involves performing coronary bypass with or Larger, longer-term data are needed to under-
without proximal vessel ligation [50]. Surgical stand these entities with further clarity.
5 Imaging of Coronary Artery Anomalies 91

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 Coronary Flow Resistance
and Reserve 6
James L. Smith, Mark C. Pica, and Amr E. Abbas

Abstract
The coronary arteries are the initial vessels off of the aorta and eventually
end in a rich capillary bed that provides blood to the myocytes in a one to
one fashion (one capillary for each myocyte.) The myocardial oxygen con-
centration is at maximum such that any increase in myocardial blood flow
(MBF) can only be accomplished by increase in coronary blood flow
(CBF). As previously mentioned, the CBF is governed by local and sys-
temic factors that help regulate the high demands of the myocardium. The
final common pathway is the microvasculature that vasodilates or vaso-
constricts to adjust for changes in blood flow.
At resting condition, the CBF is known as the basal flow and resting
CBF under normal hemodynamic conditions averages 0.7–1.0 ml/min/g.
Regional CBF remains constant as coronary artery perfusion pressure is
reduced below aortic pressure over a wide range when the determinants of
myocardial oxygen consumption are kept constant, this is known as auto-
regulation. Earlier studies suggest the lower limit of autoregulation is
70 mmHg, however, canine studies suggest autoregulation may ensue up
to as low as a mean of 40 mmHg of coronary pressure.

J.L. Smith, MD
Department of Cardiovascular Disease,
Beaumont Health System, Royal Oak, MI, USA
e-mail: [email protected];
[email protected]
A.E. Abbas, MD, FACC, FSCAI, FSVM,
M.C. Pica, BS, CCRP FASE, RPVI (*)
Department of Cardiology/Research Institute, Department of Cardiovascular Medicine,
Beaumont Health System, Royal Oak, MI, USA Beaumont Health, Oakland University/William
e-mail: [email protected]; Beaumont School of Medicine, Royal Oak, MI, USA
[email protected] e-mail: [email protected]

© Springer-Verlag London 2015 95

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_6
96 J.L. Smith et al.

Keywords
Coronary blood flow (CBF) • Myocardial blood flow (MBF) • Basal
flow • Hyperemic coronary blood flow • Coronary flow reserve (CFR) •
Distal CFR • Relative CFR

Background and Physiology normal arteries it is a marker of microvascular

dysfunction [2].
The coronary arteries are the initial vessels off of In the presence of a coronary artery stenosis,
the aorta and eventually end in a rich capillary the perfusion pressure declines and when it falls
bed that provides blood to the myocytes in a one to the lower limit of autoregulation, the distal
to one fashion (one capillary for each myocyte.) microvasculature vasodilates in an attempt to
The myocardial oxygen concentration is at maxi- maintain distal perfusion. This leads to a decline
mum such that any increase in myocardial blood in the hyperemic reserve and a decrease in the
flow (MBF) can only be accomplished by increase CFR and flow becomes pressure-dependent,
in coronary blood flow (CBF). As previously resulting in the onset of subendocardial ischemia
mentioned, the CBF is governed by local and sys- [1, 3]. The following chapter will highlight the
temic factors that help regulate the high demands role of coronary artery resistance, CBF, and CFR
of the myocardium. The final common pathway in interventional cardiology.
is the microvasculature that vasodilates or vaso-
constricts to adjust for changes in blood flow [1].
At resting condition, the CBF is known as the  elationship of Coronary Artery
R
basal flow and resting CBF under normal hemo- Resistance and Basal Coronary
dynamic conditions averages 0.7–1.0 ml/min/g. Blood Flow
Regional CBF remains constant as coronary
artery perfusion pressure is reduced below aortic As in any vascular bed, the blood flow at a basal
pressure over a wide range when the determi- state is affected by the driving pressure and resis-
nants of myocardial oxygen consumption are tance throughout the system. Resistance in the
kept constant, this is known as autoregulation. coronary bed can be categorized into three vari-
Earlier studies suggest the lower limit of auto- ables: epicardial coronary vessels, microcircu-
regulation is 70 mmHg, however, canine studies lations, and the compressive forces [1, 4].
suggest autoregulation may ensue up to as low as 1. Epicardial coronary arteries R1: Normally,
a mean of 40 mmHg of coronary pressure [1]. there is no measurable drop in pressure
With exercise or with factors that vasodilate across the epicardial coronary arteries as
the distal microvasculature (hyperemia) either they do not offer significant resistance to
actively or passively, CBF can increase four to blood flow. In the presence of a significant
fivefold and is known as the hyperemic flow. The coronary artery stenosis (>50 %), epicardial
ratio between the hyperemic blood flow and the vessels begin to contribute to total coronary
basal flow is known as the coronary flow reserve artery resistance.
(CFR) and is highly dependent on the coronary 2. Microcirculatory arteries and arterioles
microvasculature. R2: This is dynamic and is offered by vessels
Factors that increase the basal flow or ranging in size from 20 to 400 μm in diameter.
decrease the hyperemic flow impair the CFR. In They are affected by flow mediated resistance
patients with CAD, the extent of the reduction in change (shear stress), intraluminal pressure
CFR is directly related to the severity of steno- mediated resistance change (myogenic); and
sis, whereas in persons with angiographically local metabolic factors such as PO2, pH,
6 Coronary Flow Resistance and Reserve 97

Fig. 6.1 Pressure, Conductive Prearterioles

Arterioles
resistance, and response to arteries (diameter
(diameter < 100 µm)
metabolites of epicardial (diameter >500 µm) 500–100 µm)
coronary arteries, arterioles,
and the microvasculature
(From Camici and Crea [2] Drop in pressure
with permission) from aorta
to capillaries

Response to
flow-dependent
dilatation

Response to
changes in
intravascular
pressure

Response to
metabolites

­ATP-­sensitive K+ channels, and adenosine. below a mean perfusion pressure of 40 mmHg.

They are illustrated in Fig. 6.1 and include: Conversely, subepicardial flow occurs
(a) Resistance arteries (100–400 μm) (pre-­ throughout systole and diastole and only
arterioles): these are primarily regulated by declines below a pressure of 25 mmHg.
shear and myogenic forces) Cardiac contraction raises the perivascular
(b) Arterioles (100 μm) connect the resistance pressure to that of LV systolic pressure at the
arteries to the microvascular bed, which in subendocardium layers impeding flow and to
turn feeds into the myocardial venous return. subpleural pressures in the subepicardium.
Arterioles contribute approximately 25–35 % This may also occur with elevated LV dia-
of total coronary resistance and are primarily stolic pressures that occur with heart failure.
regulated by myogenic and local forces; and Importantly, factors that may result in elevated
(c) The remainder of coronary R2 resistance is baseline flow may result in a decrease in flow
demonstrated in the capillary bed component reserve [1, 4]. These may be related to factors that:
and coronary venules of the microcirculation 1. Increase oxygen consumption, such as heart
[5]. Normally, there is minimal resistance rate, systolic blood pressure, increased con-
offered by these two components and remain tractility, age, or myocardial hypertrophy.
constant with changes in vasomotor tone. 2. Reduce arterial oxygen supply, such as ane-
They can contribute up to 20 % of the coro- mia and hypoxia will also increase baseline
nary resistance in the presence of maximum flow.
coronary vasodilatation. The capillary den- Finally, vasoactive drugs such as calcium
sity is 3,500/mm2 and is greater in the suben- channel blockers may decrease baseline vasomo-
docardium that the subepicardium. tor tone, resulting in baseline increase in flow.
3. Compressive resistance R3. Subendocardial Other contributing factors to CBF include the
flow primarily occurs in diastole and declines rheological composition of blood [1, 4].
98 J.L. Smith et al.

Fig. 6.2 Diagrammatic

representation of basal and
hyperemic coronary blood Hyperemic CBF
flow, fractional flow reserve
FFRS
(FFR), coronary flow reserve

Coronary blood flow

(CFR) in normal conditions
(CFRN), CFR in the CFRN
presence of a stenosis
(CFRS), as well as instanta-
neous wave free ratio (iFR)
CFRS
in the presence of stenosis
Basal CBF

iFRS
50 % 75 % 90 %
Coronary stenosis

Hyperemic Coronary Blood Flow Studies nearly 40 years ago demonstrated the
“threshold” that a 70 % stenosis results in reduc-
Coronary reserve is the ability of the coronary tion in coronary flow, and resultant myocardial
vascular bed to increased flow in response to ischemia [5]. Additionally, a stenosis greater than
stimuli. Such stimuli include reactive hyperemia 80–90 % result in reductions in resting blood
that results from vessel occlusion, active hyper- flow [5, 9] (Fig. 6.2). Yet, the simplification of
emia from exercise, or pharmacologic agents. worsening stenosis correlating to reduced coro-
Importantly, autoregulation results in intrinsic nary blood flow does not take into account the
vasoconstrictor tone of the arterioles, and neural three-dimensional anatomy of the coronary vas-
mechanisms though sympathetic or parasympa- cular bed, imprecisions in angiographic estima-
thetic drive contributes to the overall tone of the tion of coronary stenosis, and lesion length. In
coronary system. addition, the use of coronary stenosis severity as
Pharmacologic agents such as adenosine, guidance for percutaneous intervention is fraught
regadenoson, dipyridamole, and papaverine, are with pitfalls; including interobserver and intraob-
utilized to induce hyperemia in the coronary sys- server variability, diffuse disease, and reference
tem. This induction of hyperemia results in segment disease [10, 11].
removal of the intrinsic tone of the arterioles and
microvascularute, accentuating the contribution
of epicardial stenoses to resistance in the coro-  easures of Resistance and Flow
M
nary circuit. Impairment of endothelial-­dependent in the Cardiac Catheterization
vasodilatation, as with dyslipidemia, impairs Laboratory
hyperemic CBF and thus CFR.
Coronary flow reserve is the ratio of maximal 1. Coronary flow reserve (CFR): CFR assesses
hyperemic flow to resting coronary flow – usually a both epicardial vessel stenosis and micro-
ratio of 2–5 in humans [6, 7]. however, is typically cirulatory function and is assessed by a
only 2–3 when measured invasively in the cath lab. velocity wire, thermodilution, combined FFR
As epicardial coronary obstruction increases, resis- and CFR wire, and less accurately a pressure
tance increases in the coronary vessels resulting in wire. Values >3 are non-ischemic, values less
a reduction of coronary flow reserve. than 2 indicate either microcirculatory dys-
Importantly, stenosis severity first decreases funtion function and/or severe epicardial ves-
flow across a lesion during maximal hyperemia; sel stenosis [1, 4]. It is calculated as
only when that reduction in flow falls to below
Q h / Q b = Vh / Vb
resting levels does resting ischemia ensue [8].
6 Coronary Flow Resistance and Reserve 99

Where Qh = hyperemic CBF, Qb = Basal CBF, Pd = distal pressure Pv = central venous pressure,
Vh = hyperemic velocity, Vb = basal velocity Tmnh = hyperemic mean coronary thermodi-
2. Relative coronary flow reserve (rCFR): It is lution transit time.
the basis of non-invasive assessment of isch- A normal value is 8–25, >25 is abnormal, and a
emia. It can be performed in the cath lab by value <32 denotes greater LV recovery after an
calculating the ratio of CFR of a stenotic epi- MI. Usually it is calculated as the mean transit
cardial segment to the CFR in a normal remote hyperemic time of 3 ml of saline bolus and mea-
epicardial vessel allowing the assessment of sured simultaneously with the Pd. It may pro-
epicardial stenosis severity [1, 4]. vide a qualitative assessment of microvascular
3. Fractional flow reserve (FFR): It assesses epi- function at the time of primary PCI and s linked
cardial vessel stenosis and requires a pres- to microvascular obstruction as assessed by
sure wire. Its normal value is >0.8 [1, 4]. It contrast enhanced cardiac MRI. The coronary
will be discussed separately and is pressure/temperature-sensitive guidewire
calculated as (RADI Medical Systems, Uppsala, Sweeden is
used for obtaining this index.
Pd / Paorta
6. Hyperemic microvascular resistance (HMR):
Where Pd = distal coronary pressure and Paorta = it assesses the microcirculatory function and
aortic pressure is assessed by both a pressure and velocity
4. Hyperemic stenosis resistance (HSR): the- wire. It is similar to IMR, however, it uses
oretically assesses epicardial vessel ste- velocity rather than thermodilution as a cor-
nosis and requires both a pressure and relate of flow after NTG administration to
velocity wire it is the ratio of the hyper- maintain vessel cross sectional area [1, 4]. It is
emic stenosis pressure gradient to the calculated as
hyperemic flow (assessed by the hyper-
HMR = Pd / Vh
emic average peak velocity. Pressure mea-
surements may be obtained by the RADI HMR > 1.9 mmHg/cm/s is defined as high and
wire (RADI medical systems, Uppsala, its adequate assessment of actual microvas-
Sweden, and Doppler measurements by the cular resistance in the presence of epicardial
Doppler-tipped guidewire ( as Volcano stenosis is controversial due to its neglect of
wire, San Diego, CA). A normal value is 0 collateral flow
and a value ≥0.8 mmHg/cm/s is abnormal 7. Endothelial function assessment: These tests
[1, 4]. It is calculated as assess the change in coronary artery diameter
and Doppler wire velocity with acetylcholine
HSR = Paorta − Pd / Q h = Paorta − Pd / Vh injection. They demonstrate a decline or no
change in in epicardial coronary artery diameter
It was initially touted as more reliable and with epicardial endothelial dysfunction.
more comparable to non-invasive SPECT test- However, in the presence of microvascular endo-
ing than either CFR or FFR especially in the thelial dysfunction, there is a decline in CBF [1,
group of CFR/FFR mismatch. However, it is 4]. It requires a velocity wire and angiography.
currently reserved to research purposes
5. Index of microcirculatory resistance (IMR): it
assesses the microcirculatory function and is
assessed by a pressure wire [1, 4]. It is calcu-  ssessing Coronary Indices of Flow
A
lated as and Resistance: Technique
and Performance
IMR = Pd − Pv / Q h & Q h ∞ 1
/ Tmn h & Pv is negligible CFR measurements have been obtained with the
Then use of a Doppler wire to measure coronary blood
IMR = Pd × Tmn h flow velocity, thermodilution, combined FFR and
CFR wire measurements, and coronary pressure
100 J.L. Smith et al.

a Flow Wire
Flow Plug

J-Tip Models Torque

Unlock
Device
Flow Sensor 0.014′′ (0.36 mm) Diameter

3 cm Radiopaque Tip 3cm

Lock Connector
Radiopaque Tip
Flexible Length 30 cm

Working Length 175/300 cm SlyDx® Coating

501-0100.145/002

Combo Wire
b Flow Plug

0.0 cm Offset Pressure Plug

1.5 cm Offset
Model 9500
Model 9515
Flow Pressure Unlock
Flow Pressure Sensor Sensor
0.014′′ (0.36 mm) Diameter Torque Device
Sensor Sensor
1.5 cm Offset Radiopaque Tip 3cm
Connector
Radiopaque Tip Lock
Flexible Length 30 cm SlyDx® Coating PTFE Coating

Working Length 185 cm 501-0100.105/002

Fig. 6.3 (a) FloWire® Doppler guide wire – measures flow and provides CFR values; (b) ComboWire® pressure and
Doppler guide wire – measures both flow and pressure and provides CFR and FFR values (Courtesy of Volcano Corp)

wire stand alone measurements. Since flow = The velocity of red blood cells moving past
area × velocity, velocity maybe used as a corre- the ultrasound is then measured at rest, and dur-
late of flow when the cross sectional are of the ing peak hyperemia, and the ratio is calculated.
vessel remains constant. As such, nitroglycerin is Usually, in humans, this ratio is 2–5 [6, 7].
used to maintain constant vessel diameter. Thermodilution methods with injection of
Coronary flow reserve is traditionally mea- saline at proximal port and measurement of time
sured utilizing an angioplasty guidewire with a of transport as measurement of velocity over a
piezoelectric crystal at the tip to measure Doppler known distance have been utilized.
frequencies. The Volcano Flowire® (Fig. 6.3) is Novel mechanisms have been utilized recently
currently the only commercially available CFR with combined FFR and CFR wire, which has
wire using a piezoelectric crystal, which is avail- been well validated.
able in 0.014 × 175 cm and 0.014 and 300 cm In addition, pressure-derived CFR was calcu-
lengths. Coronary flow velocity is calculated uti- lated by the square root of the pressure gradient
lizing the principle of Doppler shift, using the across the stenosis during hyperemia divided by
magnitude of frequency shift to calculate velocity the square of the gradient at rest [12–16].
of red blood cells. However, the latter assumes that friction losses
across a coronary lesion are negligible. This
method has been shown to systemically underes-
( F 1- F 0 ) c timate CFR values suggesting that friction loss is
V=
2 F 0 ( cosq ) indeed an important determinant of pressure gra-
dient along a coronary artery stenosis. Different
Where V equals velocity of red cells, F1 is the agents that are used for hyperemia are include
frequency of returning Doppler signals, F0 is the adenosine either intravenous (140 mcg/kg/min)
transmitting frequency, c is the speed of sound in or ­intracoronary (30–60 mcg), intracoronary
blood, and cosθ is the angle of incidence of the papaverine (10–15 mg), and intracoronary nitro-
Doppler signals to flow of red blood cells (this prusside (50–100 mcg). The fastest acting and
value presumed to be 1). shortest duration is intracoronary adenosine. All
6 Coronary Flow Resistance and Reserve 101

these agents can cause hypotension, in addition, an epicardial vessel without significant stenosis.
adensoine can cause AV conduction disturbances, Essentially, this technique is akin to the stress por-
while papaverine can cause torsades [4]. tion of stress myocardial perfusion imaging in
nuclear medicine. Unlike coronary flow reserve
utilizing average peak velocities in the same ves-
Measurements Obtained sel, this technique takes basal flow out of the equa-
tion by utilizing two hyperemic flow quantities. In
Because of the relative speed and ease at which addition, abnormal microvascular function should
the measurements can be obtained, obtaining two not alter the final ratio – unless there is differential
sequential measurements is recommended for microvascular obstruction in the case of prior
reliable information. myocardial infarction of the coronary territory.
This ratio is unobtainable if there is no normal or
near normal coronary artery to use as a reference
Average Peak Velocity however [18]. The normal reference range for rela-
tive coronary flow reserve is 1.0 [17].
The blood flow velocity measured by either
Doppler flow wire or thermodilution techniques
is expressed as the average peak velocity (APV).
The APV is sampled at rest, then again during  oronary Flow Reserve in Different
C
hyperemia induced by intravenous vasodilatory Populations
therapy with medications such as adenosine,
papaverine, or dipyridamole. CFR is the ratio of When considering the utilization of CFR to assess
APV at hyperemia to resting APV. As noted, the coronary stenoses in a certain population, one must
normal value is generally 2.0–3.0, with values take into account the baseline disease processes’
less than 2 considered abnormal. contribution to microvascular dysfunction. Thus,
microvascular abnormalities in left ventricular
hypertrophy, diabetes mellitus, and prior myocar-
Distal CFR dial infarction will result in abnormally low CFR,
which may not be due to epicardial stenosis.
Initial doppler systems for measurement of intra-
coronary blood velocity were 3F systems. These
larger Doppler systems resulted in contributions Hypertension
to increased velocity themselves if crossed
through a lesion. Thus, proximal CFR was com- Reduced coronary flow reserve in hypertensive
monly used. With the advent of ­technology with patients with and without associated left ventric-
piezoelectric crystal location on the tip of an ular hypertrophy has been reported. The mecha-
0.014″ or 0.018″ guidewire, CFR was able to be nism of reduction in CFR is secondary to an
performed distal to epicardial stenosis, resulting elevation in baseline flow velocities, even if left
in better evaluation of epicardial coronary steno- ventricular mass is not elevated [19, 20]. It is pos-
sis physiology [17]. Obtaining the proximal/dis- tulated that the increased metabolic demands of
tal mean velocity ratio and the diastolic/systolic the hypertensive heart result in the elevation in
mean velocity ratio have also been utilized. baseline flow velocities. Reduced CFR was asso-
ciated with positive nuclear myocardial perfusion
imaging as well, despite normal or near normal
Relative CFR epicardial coronary arteries. Thus, myocardial
ischemia may occur in patients with hypertensive
Relative flow reserve describes the ratio of hyper- heart disease even in the absence of obstructive
emic flow in a stenotic artery to hyperemic flow in epicardial coronary artery disease [21].
102 J.L. Smith et al.

Diabetes Mellitus ents. Traditionally, intravascular ultrasound was

utilized to document progression of the endothe-
Impaired coronary flow reserve has been demon- lial changes. Physiologic assessment of trans-
strated in patients with type II diabetes mellitus, plant arteriopathy can provide additional
even with angiographically normal coronary diagnostic and prognostic information [29]. Yet,
arteries [22]. This suggests that atherosclerosis of measuring CFR in those with and without angio-
epicardial coronary arteries is not the only mech- graphically abnormal epicardial coronary arteries
anism of dysfunction in diabetic heart disease. In did not demonstrate significant differences with
addition, microcirculatory dysfunction with absolute CFRs. However, intrapatient variability
impairment of maximum vasodilation likely in CFR was demonstrated in those with evidence
plays a role. Altered cellular metabolism result- of transplant arteriopathy, suggesting early endo-
ing in higher basal flow rates may also contribute thelial dysfunction may predate the appearance
to abnormalities in coronary flow reserve [23]. of hemodynamically significant stenoses, dis-
rupting the endogenous tone and flow of the
transplanted allograft [29].
Tobacco Exposure Importantly, the effect of cellular rejection on
CFR levels is controversial, as some articles
Chronic tobacco abuse has been associated with describe significant correlations, while others do
reduction in coronary flow reserve, even in patients not [29–31].
with normal or near normal coronary arteries [24]. Further studies demonstrated that the stability of
Higher rates of cigarette smoking were correlated absolute CFR in transplant allograft coronary arter-
to worsened coronary flow reserve. Interaction ies is likely from a decrement in epicardial artery
between nicotine and the neurohormonal control of physiology due to transplant arteriopathy counter-
the coronary vasculature may explain the reduced balanced by improvements in microvascular circu-
CFR seen in smokers. Using Doppler echoacar- lation over time in the transplanted heart [32].
diography, even transient passive smoke exposure
by nonsmokers was found to reduce c­ oronary flow
reserve to the rates of chronic s­mokers [25]. Stenosis
Coronary microvascular dysfunction has been
demonstrated in asymptomatic smokers with no Improvement and normalization of coronary flow
evidence of CAD, in whom ­coronary flow reserve reserve has been demonstrated after percutane-
was reduced by 21 % as compared with the value in ous transluminal angioplasty (PTCA) [19]. In a
nonsmoking controls [26]. study of 42 patients, serial CFR measurements
demonstrated improvement in CFR in epicardial
coronary stenosis after PTCA and stent place-
Dyslipidemia ment. Measurements by CFR were the first to
suggest that physiologic assessment of coronary
Patients with hyperlipidemia and angiographi- stenosis should be considered, as residual reduc-
cally normal coronary arteries were demonstrated tions in CFR were seen at times with angioplasty,
to have reduced coronary flow reserve, thought to which were subsequently eliminated after stent-
be secondary to microvascular dysfunction [2]. ing of the coronary artery [33].
Studies have shown that statin therapy improves
coronary endothelium-dependent relaxation in
patients with hypercholesteremia [27, 28]. FFR Versus CFR

FFR measures the translesional pressure

Cardiac Transplant ­gradient – specifically the distal coronary pres-
sure over the aortic pressure as measured by the
Transplant arteriopathy is a major cause of mor- guiding catheter. It accurately measures the spe-
bidity and mortality in cardiac transplant recipi- cific contribution of epicardial stenosis severity.
6 Coronary Flow Resistance and Reserve 103

FFR is independent of loading conditions, micro- a 6

Group A
vascular disease, and not reliant on the presence
of other normal vascular beds. CFR on the other 5
hand, measures both epicardial and m­ icrovascular
disease. This is demonstrable in CFRs inverse 4
relationship to microvascular obstruction after

CFR
myocardial infarction [34]. 3
Importantly, trials of FFR guided percutane-
ous intervention compared with medical therapy 2
alone resulted in reduction in subsequent emer-
gent procedures following intervention [35, 36] 1
driving the current trend of physiologic assess-
ment of coronary stenosis above and beyond Group B
0
mere anatomic appearance. 0.0 0.2 0.4 0.6 0.8 1.0
In transplanted patients, 14 % of patients with FFR
normal FFR (>94 %) had abnormal CFRs (<2.0)
demonstrating microcirculatory dysfunction in FFR < 0.75 and CFR < 2.0
b 60 FFR < 0.75 and CFR ≥ 2.0 (Group A)
this population [37].
FFR ≥ 0.75 and CFR < 2.0 (Group B)
In a study of FFR and CFR assessed in 126 FFR ≥ 0.75 and CFR ≥ 2.0
consecutive patients with 150 intermediate coro- 50
Pressure gradient (mm Hg)

nary lesions (between 40 and 70 % diameter ste-

nosis by visual assessment), agreement between 40
FFR and CFR, categorized at cut-off values of
0.75 and 2.0, respectively, was observed in 109 30
coronary lesions (73 %), whereas discordant
­outcomes were present in 41 lesions (27 %). In 20
26 of these 41 lesions, FFR was <0.75 and CFR
≥2.0 (group A); in the remaining 15 lesions, FFR
10
was ≥0.75 and CFR <2.0 (group B). HMR,
defined as the ratio of mean distal pressure to
0
average peak blood flow velocity during maxi-
0 10 20 30 40
mum hyperemia, showed a large variability
Ditsal APV (cm/s)
(overall range, 0.65–4.64 mmHg · cm−1 · s−1) and
was significantly higher in group B than in group Fig. 6.4 (a) Relationship between FFR and CFR normal
A (2.42 ± 0.77 versus 1.91 ± 0.70 mmHg · cm−1 · s−1; and abnormal values. Groups A and B show discordant
FFR and CFR values and occurred in 27 % of the lesions
P = 0.034) [38] (Fig. 6.4). in this study. (b) pressure gradient-flow velocity data at
baseline and hyperemia for all groups. Line are quadratic
fits of form y = ax + bx2 (From Meuwissen et al. [39] with
Pitfalls and Challenges permission)

One must note, in assessing the physiologic tree, and pressure gradient across a plaque ste-
assessment of coronary plaque, that a low hyper- nosis [38].
emic pressure gradient as measured by FFR Technical factors in the assessment of CFR
does not necessarily correlate to flow related may also affect the resultant values. Specifically,
ischemia as determined by CFR. While coro- correct measurement of coronary flow velocities
nary flow and pressure gradient are related, they past the stenosis in question is critical. In addi-
are not interchangeable. Thus, it is important to tion, significant turbulence of coronary blood
have a basic understanding of the relationship flow will reduce the true velocity. As mentioned,
between stenosis severity, the coronary resis- rheologic factors such as altered blood viscosity
tance circuit, flow characteristics in the c­ oronary can change the blood flow profile.
104 J.L. Smith et al.

In addition, average peak velocity may vary 12. Marzilli M, Merz CNB, Boden W, et al. Obstructive
coronary atherosclerosis and ischemic heart disease:
depending on loading conditions and especially
an elusive link. J Am Coll Cardiol. 2012;60:951–6.
on heart rate. Thus, patients with arrhythmia may 13. MacCarthy P, Berger A, Manoharan G, Bartunek J,
have increased basal flow rates, giving false nor- Barbato E, Wijns W, Heyndrickx GR, Pijls NH, De
mal CFRs. Most importantly though, is that Bruyne B. Pressure-derived measurement of coronary
flow reserve. J Am Coll Cardiol. 2005;45:216–20.
abnormal CFR can be due to not only significant
14. Zhang ZD, Svendsen M, Choy JS, Sinha AK, Huo Y,
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in vasomotor tone, submaximal vasodilator dose,
Akiyama M, Watanabe N, Neishi Y, Takagi T, Shalman
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reserve. J Am Coll Cardiol. 2003;41(9):1554–60.
16. Pijls NH, De Bruyne B, Smith L, Aarnoudse W,
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 Fractional Flow Reserve
7
Ivan Hanson, Mazen Shoukfeh, and Amr E. Abbas

Abstract
Fractional flow reserve has been increasingly popular in assessing the
severity of coronary stenosis in indeterminate lesions. Moreover, it has
had an increasing role as a prognostic indicator and has been incorporated
in different angiographic scores to assess the appropriate revascularization
strategy. This chapter will review the current state of FFR.

Keywords
Fractional flow reserve (FFR) • Coronary flow reserve (CFR) • Relative
flow reserve • Coronary fractional flow reserve • Collateral fractional flow
reserve • FFR artifacts

Introduction has had an increasing role as a prognostic indi-

cator and has been incorporated in different
Fractional flow reserve has been increasingly angiographic scores to assess the appropriate
popular in assessing the severity of coronary revascularization strategy. This chapter will
stenosis in indeterminate lesions. Moreover, it review the current state of FFR.

I. Hanson, MD (*)
Department of Cardiovascular Medicine, Background and Physiology
William Beaumont Hospital, Royal Oak, MI, USA
e-mail: [email protected] The severity of coronary artery stenosis, as delin-
M. Shoukfeh, MD eated by coronary angiography, is a poor surro-
Department of Cardiovascular Medicine, gate for determination of myocardial blood flow
Beaumont Health System, Royal Oak, MI, USA
e-mail: [email protected] [1–3], which is closely linked to prognosis [4, 5].
This may be due to angiographic limitations,
A.E. Abbas, MD, FACC, FSCAI, FSVM,
FASE, RPVI such as foreshortening, bifurcation, and contrast
Department of Cardiovascular Medicine, streaming or lesion characteristics, such as
Beaumont Health, Oakland University/William ­calcium, tortuosity, branching vessels, and eccen-
Beaumont School of Medicine, Royal Oak, MI, USA tric lesions.
e-mail: [email protected]

© Springer-Verlag London 2015 107

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_7
108 I. Hanson et al.

Fig. 7.1 Diagrammatic

representation of basal and
hyperemic coronary blood
flow, fractional flow reserve Hyperemic CBF
(FFR), coronary flow reserve FFRS

Coronary Blood Flow

(CFR) in normal conditions
(CFRN), CFR in the presence
of a stenosis (CFRS), as well CFRN
as instantaneous wave free
ratio (iFR) in the presence of
stenosis
CFRS
Basal CBF

iFRS
50% 75% 90%
Coronary Stenosis

The effect of coronary artery stenosis on coro- determine the steepness of the stenosis-pressure-­
nary blood flow relates to the morphological fea- flow curve and become more ­important as flow
tures of a stenosis, where the resistance to flow increase or stenosis becomes more severe
varies exponentially with the luminal cross-­ 2. The pressure gradient is inversely related to
sectional area and linearly with lesion length as the square of the stenosis area and directly
outlined in Poiseuille’s law. related to the square of flow.
3. The lesion length, eccentricity, entrance and
8pm L
Poiseuille Law : Q = exit forces, and distal reference vessel all play
Aa2 a variable role
The gradient generated is exponentially pro-
Where Q=flow, μ = blood viscosity, L= length portionate to baseline stenosis and trans-lesion
stenosis, and Aa= cross-sectional area. flow in a curvilinear fashion such that a higher
Moreover, as blood flow converges towards a gradient is generated with a more severe stenosis
stenosis a trans-lesion pressure gradient is formed and at high flow levels.
as denoted in the Bernoulli equation. Several invasive techniques have been devel-
oped to ascertain myocardial blood flow and its
Bernoulli
change with coronary stenosis. These are high-
Equation : ∆P = f 1( 8pmL / As2 ) lighted below:
  1 1 
2
 Coronary flow reserve (CFR) is the ratio of
+ f 2 r / 2 −   blood flow in a coronary artery at rest to that dur-
  As An  
 ing maximal hyperemia, and is affected by resis-
∆P = Viscous Losses + Separation Losses tance to flow at any level (i.e. epicardial artery,
+ turbulence arterioles, capillaries and myocardium) and thus
lacks specificity to determine physiologic signifi-
Where ΔP=pressure gradient, As and νn are the cance of epicardial coronary stenoses (Fig. 7.1).
area at the stenosis and the normal reference ves- Relative flow reserve is the ratio of flow dur-
sel, respectively, ρ = mass density of blood, L is ing hyperemia in the coronary artery with a ste-
the length of the stenosis, μ=viscosity of blood, nosis to another coronary artery with no stenosis.
Accordingly, the pressure gradient occurs due However, due to the need for wiring two separate
to energy loss as a result of: vessels as well as the inherent limitation of mul-
1. Mainly viscous losses due to friction, turbulence tivessel disease, this has not been widely adopted
plays a minimum role, while separation losses clinically.
7 Fractional Flow Reserve 109

Fractional flow reserve (FFR) is a technique  haracteristics of Fractional Flow

C
that has been developed and validated [6–8] as a Reserve
means of specifically assessing the physiologic
significance of epicardial coronary stenoses. It is Certain characteristics render FFR attractive as a
defined as the ratio of hyperemic myocardial means of assessing the hemodynamic significant
blood flow beyond an epicardial stenosis (Qsmax) of a coronary stenosis. These are highlighted
to normal hyperemic myocardial flow in the below:
absence of stenosis (QNmax):
QSmax
FFRmyo =  he Theoretical Normal FFR Value Is 1
T
QNmax Regardless of the Patient, the Vessel,
and the Myocardial Bed
Flow (Q) is the ratio of pressure (P) decrease
across the microvasculature and myocardium This suggests the absence of epicardial vessel
divided by resistance (R), where Pd represents resistance to blood flow. The lowest recorded
pressure distal to stenosis, Pa represents pressure value for a normal coronary was reported at
in the central aorta, and Pv represents pressure in 0.94 [9].
the right atrium: Conversely in patients with detected athero-
sclerosis elsewhere, 50 % of the coronary arteries
( Pd - Pv ) / RSmax will have a lower than normal FFR, and on 10 %
FFRmyo =
( Pa - Pv ) / RNmax the FFR will be lower than the ischemic thresh-
old [9]. This suggests that in the absence of dis-
Peak hyperemia renders Rmax negligible, and crete coronary stenosis, but in the presence of
assuming right atrial pressure is relatively nor- atherosclerosis, the epicardial coronary arteries
mal, Pv also becomes negligible, and the ratio do contribute to the resistance to coronary blood
simplifies to the ratio of pressure distal to the ste- flow. Moreover, myocardial ischemia may be
nosis to that in the aorta: present in patients with atherosclerosis despite
the lack of a focal stenosis.
Pd
FFRmyo =
Pa
 bnormal FFR Has a Well-defined
A
On the other hand, Coronary FFR (FFRcor) Cutoff with a Narrow Grey Zone
represents the gradient across an epicardial coro- of 0.75–0.8
nary stenosis without collateral contribution and
is defined as FFR values <0.75 suggest inducible myocardial
ischemia, while values >0.8 may allow safe
( Pd - Pw ) deferral of revascularization. Intermediate values
FFRcor =
( Pa - Pw ) require sound clinical judgment prior to revascu-
larization or deferral; however, they constitute
Where Pw represents coronary wedge pres- <10 % of FFR values
sure or pressure in the coronary distal to an
inflated balloon.
Finally, Collateral FFR (FFRcol) is calculated  FR Is Not Influenced by Systemic
F
as (FFRmyo – FFRcor) and represents the FFR Hemodynamics
related to collateral circulation. FFRmyo is the
measure that is most frequently utilized clinically FFR is not affected by the response of the micro-
and thus will be referred to through the chapter as circulation the changes in heart rate, blood pres-
simply FFR. sure, and myocardial oxygen demand.
110 I. Hanson et al.

FFRmyo Accounts for Both Antegrade needle introducer has been backed out of the
and Retrograde (Collateral) hemostatic valve. Once the lesion is crossed, an
Blood Flow angiogram is obtained to confirm adequate distal
wire position. If the guide catheter is deep-seated,
As noted above, collateral flow is accounted for it is backed out to avoid pressure dampening (see
in the equation for FFRmyo. “Interpretation and Pitfalls” below). Usually,
adenosine infused at 140 μg/kg/min through an
intravenous catheter is used to induce hyperemia,
 FR Normalizes the Stenosis Severity
F which typically occurs within 3 min. Central
to Myocardial Mass Being Perfused venous catheters were used in the pivotal trials of
FFR, but peripheral administration is non-­inferior
This means that the larger the myocardial mass [10]. Other vaso-active agents, such as papaver-
being supplied by the coronary, the higher the ine, nitroprusside and ragenodoson, have also
hyperemic flow, the higher the gradient, and the been used, with variable results [11]. Flushing,
lower the FFR for a given stenosis. In addition, tachycardia, bradycardia, hypotension and tran-
when the perfusion territory is diminished sient heart block are common side effects of ade-
(as after a myocardial infarction), the FFR value nosine, while QT prolongation can occur with
would be higher for a given stenosis, reflecting papaverine, and hypotension routinely occurs
the decline in the myocardial territory at risk. with nitroprusside. Side effects are usually self-­
limiting upon cessation of the infusion.
After achieving steady state, the lowest ratio
 FR Has Unparalleled Special
F of mean Pd to Pa is recorded as the FFR for a
Resolution given lesion. The pressure loss due to diffuse ath-
erosclerosis is gradual, while that due to a severe
FFR reaches a spatial resolution of a few mm. It focal stenosis is abrupt. This difference can be
provides a per segment accuracy of stenosis sig- elucidated during wire pullback and preferably
nificance compared to per patient (exercise EKG) during IV administration. The setup for FFR and
and per vessel (stress test) assessment. a typical readout is displayed in Fig. 7.2.

Technique and Performance Artifacts, Pitfalls

and Troubleshooting
After canalization of the coronary artery, pres-
sure in the aorta is measured from the guide cath- Hyperemic Agents
eter and simultaneous distal pressure can be and Pharmacological Considerations
measured with a commercially available solid-­
state pressure transducer mounted on a 0.014″ Administration of the hyperemic agent as ade-
coronary guidewire, such as the FlowWire nosine should result in a measurable systemic
(St. Jude Medical). The transducer is located at hemodynamic response. If the patient does not
the transition of the radio-opaque distal portion experience symptoms and heart rate and blood
of the wire. Currently available wires are pressure remain unchanged, the adenosine may
­comparable in performance to standard coronary not have reached the systemic circulation. If a
workhorse wires. Prior to crossing the lesion, peripheral IV is being used, it should be checked
anticoagulation is achieved as for any percutane- for patency. If necessary, a central venous cathe-
ous coronary intervention. Intra-coronary ter can be placed to ensure reliable delivery of
­nitroglycerin 200 mcg is administered to amelio- vasodilator. If intra-coronary vasodilators are
rate any coronary vasospasm. The transducer is administered, the use of a guide catheter with
positioned at the tip of the guide catheter and side holes may result in delivery of some drug
­pressures are “equalized,” making certain that the into the aorta, rather than the distal coronary
7 Fractional Flow Reserve 111

Fig. 7.2 FFR In a patient with non-significant coronary decline in the gradient on pull back suggestive of diffuse
artery stenosis (Top left) (>0.8) and another with a signifi- atherosclerosis (red arrows). On the bottom right, there is
cant coronary lesion (Top right) (0.76). The bottom left a focal stenosis with an abrupt decline in the gradient on
image demonstrates a non-focal stenosis with a gradual pull back (red arrow)

microcirculation. Contrast should be cleared notch and overall appearance of waveform are
from the catheter using heparinized saline to preserved, both transducers should be re-zeroed
maximize fidelity of pressure recordings. In to atmospheric pressure and re-equalized at the
patients who have received adenosine antagonists tip of the guide catheter before proceeding.
as theophylline and caffeine, their effect can be Decreased pressure and flattening of the aortic
counteracted by intracoronary administration of diastolic tracing (“ventricularization”) usually
adenosine. occurs distal to a severe stenosis, but may also be
artifactually created with deep-seating of the
catheter into the coronary artery. In this case,
Hemodynamic Artifacts mean aortic pressure will be falsely underesti-
and Technical Considerations mated, which will lead to a false elevation in FFR
[12]. The mean decrease in FFR values for a
Careful assessment of pressure waveforms from proximal LAD stenosis between engaged and
both transducers is mandatory to obtain reliable disengaged catheters in the left main is 0.05
FFR data. If the appearance of either pressure +/- 0.04. If necessary, equalization of pressures
tracing is dampened (loss of dicrotic notch, can be done in the aorta before catheter engage-
reduction in pulse pressure), checking for air ment, then the catheter is engaged with advance-
bubbles or leak in transducer equipment is essen- ment of guide wire across lesion. The guide
tial. Small guide catheters (<5 French) and not catheter can then be disengaged from the coro-
removing the wire transducer will also cause nary artery with the wire still in place across the
abnormal pressure waveforms. lesion while FFR measurements are obtained.
If systolic and diastolic pressures “drift” This technique is particularly useful in the evalu-
downward in one or both transducers, but dicrotic ation of aorto-­ostial lesions.
112 I. Hanson et al.

Fig. 7.3 Hydrostatic pressure effect and FFR. In the left Fig. 7.4 Pressure recovery demonstrated during pull
figure, when the distal wire is placed in the PDA, the distal back. As the wire is pulled towards the lesion, the pressure
transducer is in a lower position than the guide catheter tip. gradient increases. Distal to the lesion, the gradient
The distal pressure increases due to increased hydrostatic decreases due to pressure recovery
pressure, while the pressure transduced from the guide
catheter remains unchanged. This results in a supernormal
ratio of distal to proximal pressure (FFR 1.1). The red Pressure Recovery
arrow indicates wire pullback to the ostium of the guide This manifests as an FFR that gradually decreases
catheter, at which point recorded pressures were identical during pullback from distally in the vessel to
proximal as the distal edge of the stenosis is
“Pseudolesions,” or kinks in the artery, may reached. It is similar to the pressure recovery
also lead to a falsely low FFR. Other factors that phenomenon that occurs across a stenotic aortic
may affect FFR measurements include, respira- valve and is related to recovery of pressure
tory variation, wirewip artifact, ectopy, and sin- upstream the valve as kinetic energy is recon-
ewave FFR. verted to potential energy and flow separates. It
Finally, failure to take into account elevated results in an overestimation of the FFR value. As
central venous pressure may lead to falsely such, it is recommended to place the wire trans-
elevated FFR. As an example, a lesion has
­ ducer 2–3 vessel diameters distal to the stenosis
Pa = 100 mmHg and Pd = 80 mmHg. Assuming (Fig. 7.4).
central venous pressure is negligible, FFR = 0.80.
However, if central venous pressure is 15 mmHg,  scillation of the FFR Waveform
O
assuming peak hyperemia is achieved (Rmax negli- This manifests as an oscillating pressure wave-
gible), FFR is actually (80–15)/(100–15) = 0.76. form secondary to a homeostatic mechanism to
maintain a stable blood pressure during vasodila-
tation. As blood pressure declines, a compensa-
 ess Common Physiological FFR
L tory mechanism ensues that overcorrects the drop
Artifacts in pressure and subsequently the pressure drops
again and the cycle continues. It is more manifest
 ydrostatic Pressure Effect
H during hyperemia and may interfere with accu-
This manifests as a Pd that is higher than Pa and rate FFR measurement (Fig. 7.5).
occurs downstream the site of equalization infer-
ring a possible artifact. It occurs due to a differ-  evere Hypotension, Low Flow/Low
S
ential plane of the distal vessel, which is higher Gradient Severe Stenosis,
than the proximal vessel (e.g.; PDA and proximal and Paradoxical Vasoconstrictive
RCA, respectively). This leads to an elevated dis- Response
tal pressure compared to aortic pressure and is This manifests as a hyperemic FFR that is higher
usually not greater than 5-mmHg difference. It is than baseline FFR and is more common in patients
more common in the resting condition and in the with multivessel disease. During hyperemia, sig-
presence of a stenosis (Fig. 7.3). nificant hypotension may render the myocardium
7 Fractional Flow Reserve 113

s­ tenosis despite its severity. This is similar to the

low flow/low gradient severe aortic stenosis
patients who generate a low gradient across the
aortic valve despite a severely narrowed area.
Finally, paradoxical vasoconstriction may
occur with adenosine in low flow states. A higher
than baseline hyperemic FFR may occur and it has
been estimated that this may occur in about 12 %
of patients in studies comparing iFFR and FFR.

Fig. 7.5 Oscillation of the FFR pressure waveform. Note

that as blood pressure declines (red arrow), oscillation of Specific Lesion and Patient Subsets
the waveform occurs as a compensatory mechanism that
ensues and overcorrects the drop in pressure and subse-  valuation of Indeterminate
E
quently the pressure drops again and the cycle continues
Coronary Stenosis
and Multivessel CAD

 afety and Efficacy Data

S
The FFR to Determine Appropriateness of
Angioplasty in Moderate Coronary Stenoses
(DEFER) trial [13] assessed 325 patients sched-
uled for percutaneous coronary intervention
(PCI) of an intermediate stenosis. Just before
planned intervention, FFR was performed. If
FFR was ≥0.75, patients were randomly assigned
to deferral or performance of PCI. If FFR was
<0.75, PCI was performed as planned. There was
no statistically significant difference in 5-year
survival of patients in the deferral or performance
groups, although survival was significantly worse
in the reference group (80 %, 73 % and 63 % for
Fig. 7.6 This patient developed hypotension during ade-
nosine infusion due to global LV ischemia, with a decrease deferral, performance and reference groups,
in the overall gradient from baseline (red arrows). This is respectively). This trial supports the safe deferral
thought to be due to a state of low flow from diminished of PCI for FFR ≥0.75.
cardiac output and/or paradoxical vasoconstriction effect
In the fractional flow reserve versus
caused by adenosine
Angiography for Multivessel Evaluation (FAME)
trial of over 1,000 patients with multi-vessel cor-
ischemic due to drop in coronary perfusion pres- onary artery disease [14], patients were random-
sure. There is a decline in LV contractility with ized to either PCI with drug-eluting stent using
decline in cardiac output and thus the trans-lesion angiography alone, or guided by FFR measure-
flow is decreased. The diastolic gradient also ments in addition to angiography (lesions with
decreases between Pd and Pa as a result of increased >50 % angiographic stenosis were treated if FFR
LV pressure. The net effect is an increase in hyper- <0.80). Significantly fewer stents were used in
emic FFR value compared to baseline FFR value patients with FFR guidance. The 1-year rate of
due to decreased trans-lesional flow (Fig. 7.6). the combination endpoint of death, non-fatal
In patients with severe decrease in LV func- myocardial infarction (MI) and repeat revascular-
tion and cardiac output, a low flow state may ization was 18.3 % in the group with angiography
result in a low gradient across an epicardial alone and 13.2 % in the group with FFR g­ uidance.
114 I. Hanson et al.

After 2 years of follow up, there was no signifi- Fearon et al. [15], three strategies for treating
cant difference between the groups for this end- patients with one or more intermediate stenosis
point, but rate of mortality or MI was significantly by angiography without prior non-invasive func-
lower when FFR was used versus angiography tional assessment were developed: (1) interven-
alone (8.4 % versus 12.9 %, respectively; tion was deferred and a stress test was done,
p = 0.02). In addition, for lesions deferred on the followed by PCI at a later time for flow-limiting
basis of FFR >0.80, the rate of MI was 0.2 % and lesions detected by the stress test, (2) FFR-guided
the rate of revascularization was 3.2 %. The PCI at the time of diagnostic angiography, (3)
results of this trial support routine use of FFR in stenting of all intermediate lesions without
patients with multi-vessel CAD in whom percu- ­evaluating their functional significance. The FFR
taneous revascularization is being considered, strategy saved $1,795 compared with stress test
and treatment of lesions with FFR <0.80. strategy and $3,830 compared with the indis-
Further evidence supporting FFR-guided PCI criminant stenting strategy.
in multivessel disease comes from the FAME-2
trial. This study enrolled patients with clinically  ombined Anatomic and Physiologic
C
stable, multivessel CAD for whom percutaneous Lesion Assessment
intervention was being considered, and evaluated The SYNTAX score is an angiographic scoring
all lesions with FFR. A total of 1,220 patients were system of coronary lesion complexity, which has
enrolled, 888 of whom had at least one stenosis been shown to predict outcome after PCI using
with FFR <0.80 and were randomized to either paclitaxel-eluting stents or coronary artery
optimal medical therapy or optimal medical ther- bypass surgery in patients with multivessel CAD
apy with PCI of the significant lesion(s). The [16]. Multicenter trial data support the practice of
remaining patients had no lesion with FFR <0.80 considering patients with medium or high risk
and were enrolled in a registry. It was halted pre- anatomy for surgery, and patients with low risk
maturely at the recommendation of data and safety anatomy for PCI [17]. In order for a lesion to be
monitoring board because of significant between- included in the SYNTAX score, it must cause
group difference in primary endpoint. The mean ≥50 % diameter stenosis of the angiographic
duration of follow up was ~7 months. For patients lumen. Nam et al. performed a post-hoc analysis
with at least one lesion with FFR <0.80, the inci- of 497 FAME patients who had FFR. By incorpo-
dence of the primary endpoint of composite of rating only lesions that were functionally signifi-
death, MI or urgent revascularization was 4.3 % in cant by FFR into the SYNTAX score, they
patients randomized to PCI and 12.7 % in patients calculated a “functional SYNTAX score” for
randomized to medical therapy (HR 0.32; each patient. Nearly a third of patients were
95 % CI, 0.19–0.53; P < 0.001), mainly driven by “reclassified” into a lower risk tertile. Major
urgent revascularization. The combined endpoint adverse cardiovascular events occurred in 9.0,
occurred in 3.0 % of patients in the registry. 11.3 and 26.7 % of patients in the low, medium
and high risk tertiles of functional SYNTAX
Cost Effectiveness scores. Functional SYNTAX score was a more
Economic evaluation of the FAME study reveals accurate predictor of MACE than traditional ana-
that FFR-guided PCI in patients with multivessel tomic SYNTAX score [18]. These findings have
disease is cost effective. Mean overall costs at major implications in the decisions regarding
1 year were significantly less in the FFR-guided method of revascularization.
versus the angiography-guided groups ($14,315
versus $16,700; p < 0.001). Bootstrap simulation
indicated that the FFR-guided strategy was cost-­ S
 erial Stenoses
saving in 90.74 % and cost-effective at a thresh-
old of $50,000 per quality-adjusted life-years in Coronary artery disease is a diffuse process [19].
99.96 %. In a unique decision model analysis by Not uncommonly, multiple stenoses coexist in
7 Fractional Flow Reserve 115

the same vessel being interrogated by FFR. One severity of remaining lesion(s) is still in question
method to assess the relative contribution of each after treatment of the most severe lesion, FFR can
lesion in series is to pull back the wire from distal be repeated to assess contribution of residual dis-
to proximal, noting the “step up” in FFR value ease to flow limitation.
across each lesion. The degree of step up in FFR
across a lesion is an estimate of its relative contri-
bution to flow impairment. While FFR measured Bifurcation Lesions
in the distal vessel accurately reflects the aggre-
gate hemodynamic significance of all lesions, a Not uncommonly, side branch ostia may be com-
distal lesion may limit flow through the vessel, promised when jailed by stent. Decisions regard-
which could interfere with accurate assessment ing management of jailed side branches can be
of a more proximal lesion. This hypothesis was difficult, since indiscriminant angioplasty may
tested by Pijls et al., who developed and experi- cause further injury to the side branch, and routine
mentally validated equations that predict the FFR side branch stenting increases likelihood of stent
of two individual lesions in series, as if the other restenosis and thrombosis [22]. Ideally, only ste-
lesion were absent [20] (A and B denote proxi- noses that are physiologically significant are
mal and distal lesion, respectively. Pa, Pm, Pd, treated. Anatomic assessment with either angiog-
and Pw denote mean aortic pressure, mean hyper- raphy or intravascular ultrasound (IVUS) corre-
emic coronary pressure between both lesions, lates poorly with functional significance of side
mean hyperemic distal coronary pressure distal branch stenosis as measured by FFR [23–25]. In a
to the most distal lesion, and coronary wedge decision tree study of 91 patients by Koo et al.,
pressure, respectively, measured before the treatment of residual side branch stenosis was
intervention): performed only for FFR <0.75. In all patients,
FFR of side branch was reassessed at 6-month
Pd - éë( Pm / Pa ) ´ Pw ùû
FFR ( A ) pred = angiographic follow up. In the patients in whom
( Pa - Pm ) + ( Pd - Pw ) angioplasty was performed, FFR ≥0.75 was
achieved in 92 %, despite mean angiographic
( Pm - Pd ) ´ ( Pa - Pw ) residual stenosis 69 %. During follow-up, there
FFR ( B ) pred = 1 -
Pa ´ ( Pm - Pw ) were no changes in side branch FFR in lesions
with (0.86 ± 0.05–0.84 ± 0.01, P = NS) and with-
These investigators then performed a study of out side branch angioplasty (0.87 ± 0.06–
32 patients with 2 serial stenoses in the same 0.89 ± 0.07, P = NS) [26]. An FFR-guided
coronary artery. Predicted FFR of each lesion sub-study of Nordic-Baltic Bifurcation Study III
before treatment using the respective equation enrolled 75 patients. There was higher post-­
(FFRpred) was close to FFR of each lesion after procedure FFR among patients who underwent
treatment of the other lesion (FFRtrue) in all final kissing balloon dilation (FKBD) versus no
patients (0.78 ± 0.12 versus 0.78 ± 0.11 mmHg; FKBD (0.92 vs. 0.85, respectively; p = 0.011).
r = 0.92; [DELTA]% = 4 ± 0 %). In contrast, FFR There was no significant decrease in FFR in either
of the proximal lesion using pressure measured group at 8-month angiographic follow up [27].
between stenoses (the “distal” pressure for the
proximal lesion) prior to treatment of either
lesion would have been significantly overesti- Left Main Coronary Artery
mated (0.85 ± 0.08;P < 0.01) [21].
For reasons of reliability and practicality, we Left main stenosis is almost always associated with
most often use pullback FFR to approximate the concomitant disease in other epicardial vessels
relative contribution of each lesion (Fig. 7.2). [28]. The presence of severe LAD or circumflex
The advantage of this approach is that it can be disease in addition to left main stenosis may limit
done before any intervention. If the stenosis achievement of peak hyperemia in myocardium
116 I. Hanson et al.

perfused by the left coronary artery, such that the noted that imaging is essential to guide the diag-
presence of severe disease in either branch may nosis of left main stenosis, assist with procedure
lead to a false negative FFR result in the left main. planning, and determine followup outcomes.
Yong et al. tested this hypothesis in a sheep experi-
ment. With an angioplasty balloon occluding the
LM simulating severe stenosis, the “true” LM FFR Bypass Grafts
was measured with a pressure wire in the circum-
flex. Then, a second balloon was inflated in LAD, The use of FFR to guide PCI of intermediate ste-
and FFR was re-measured in the circumflex noses in bypass grafts is safe and results in better
(“apparent” FFR, simulating coexistent LM and clinical outcomes as compared to the use of angi-
LAD disease). If the balloon in the LAD was ography alone. Di Serafino et al. performed a
inflated to near-occlusion, apparent LM FFR was study of 223 patients with stable or unstable
substantially higher than true FFR. The authors angina and intermediate stenosis involving an
concluded that severe “disease” in LAD reduced arterial or a venous graft. Percutaneous coronary
the overall flow in the left coronary artery, thereby intervention was performed in 23 patients (35 %)
decreasing the sensitivity of FFR across the LM of the FFR-guided group and 90 patients (57 %)
lesion [29]. of the angio-guided group (P < 0.01). In the FFR-­
The use of FFR to guide decision to perform guided group, PCI was more often performed in
coronary artery bypass grafting (CABG) in arterial grafts as compared with the angio-guided
patients with angiographically indeterminate left group (16 [70 %] vs 12 [13 %], respectively;
main (LM) stenosis is safe. In a study of 213 such P < 0.01). At median 3.8 years follow up, major
patients, those with LM FFR ≥0.80 were man- adverse cardiac and cerebrovascular event rate
aged either medically or with PCI of one or more was significantly lower in the FFR-guided group
non-left main stenoses. When FFR was <0.80, as compared with the angio-guided group
coronary artery bypass grafting was performed (18 [28 %] vs 77 [51 %], hazard ratio 0.33
(surgical group; n = 75). The 5-year survival esti- [0.11–0.96], P = 0.043]). Procedure costs were
mates were 89.8 % in the nonsurgical group and reduced in the FFR-guided group (€2240 ± €652
85.4 % in the surgical group (P = NS). The 5-year vs €2416 ± €522, P = 0.03) [32].
event-free survival estimates were 74.2 and
82.8 % in the nonsurgical and surgical groups,
respectively (P = NS) [30]. Acute Coronary Syndromes
As in non-left main bifurcations, FFR has
been studied in the context of LM bifurcation In ST-elevation myocardial infarction (STEMI),
stenting. Kang, et al. studied circumflex ostia that ECG and angiographic data are usually sufficient
were jailed by stent in LM extending into left to determine the culprit lesion, and FFR of
anterior descending (LAD) arteries. Pre-stenting infarct-related artery has little utility in the acute
and post-stenting angiography, IVUS and FFR setting. Even if a culprit lesion spontaneously
were performed. After stenting, diameter stenosis recanalizes, resulting in a non-severe stenosis,
in circumflex >50 % was observed in 18 (42 %) acute microvascular dysfunction that occurs in
patients, while only 3 (7 %) had FFR <0.80. Pre-­ the culprit vessel distribution precludes reliable
stenting minimum lumen area (MLA) <3.7 mm2 induction of peak hyperemia. In addition, partial
(sensitivity 100 %, specificity 71 %, a positive or complete-thickness infarction further limits
predictive value (PPV) 16 %, negative predictive ability to induce vasodilation. These factors will
value (NPV) 100 %, area under curve 0.80) and result in a higher FFR relative to a lesion of simi-
plaque burden >56 % (sensitivity 100 %, speci- lar stenosis severity under stable conditions. On
ficity 65 %, PPV 14 %, NPV 100 % (area under the other hand, FFR of non-culprit lesions is fea-
curve 0.80) were predictive of post-stenting FFR sible, even in the acute setting. Ntalianis et al.
<0.80 in circumflex ostium [31]. It should be performed FFR measurements in 112 nonculprit
7 Fractional Flow Reserve 117

stenoses in 101 STEMI patients immediately FFR Post Intervention

after PCI of culprit stenosis, and repeated FFR in
these lesions 35 ± 4 days later. The FFR value of The use of FFR to evaluate the success of PCI is
the nonculprit stenoses did not change between less well established and is surpassed by both
the acute setting and follow-up (0.77 ± 0.13 vs. OCT and IVUS. In the bare metal stent era,
0.77 ± 0.13, respectively, p = NS) [33]. a value <0.94 predicted worse outcomes and
In theory, FFR of culprit and non-culprit ­restenosis. After successful stenting, no hyper-
lesions should be reliable in the setting unstable emic gradient should remain. However, the
angina and non-ST elevation, as long as micro- reverse is not always true.
vascular function is minimal. Such patients are
under-represented in pivotal trials of FFR, yet
stand to gain substantial benefit from revascular-  alse Positive FFR and False
F
ization [34]. Both DEFER and FAME-2 excluded Negative FFR
unstable patients. In a subgroup analysis of the
original FAME trial [35], 328/1,005 patients with A negative FFR despite an apparent angiographic
unstable angina or non-ST segment elevation stenosis may be present with a small perfusion
myocardial infarction were evaluated with multi- territory (a stenosis in a vessel supplying an
vessel FFR. Importantly, patients with ST eleva- infarcted territory), abundant collaterals,
tion or total creatine kinase ≥1,000 U/l were advanced microvascular disease (uncommon),
excluded. As per the original FAME study design, diffuse rather than focal coronary disease, sub-
patients were randomized to either angiography maximal hyperemia, deep catheter engagement,
alone for PCI guidance, or FFR of all lesions with small ostium, catheter with side holes, electric
angiographic stenosis >50 % prior to PCI. The drift, equalization with introducer needle in place
use of FFR to guide PCI in ACS patients resulted and FFR estimation without it, severe ventricular
in similar reduction of risk of major adverse car- hypertrophy, exercise induced spasm, and acute
diac events as in patients with stable CAD (ARR ST segment elevation myocardial infarction.
5.1 % versus 3.7 % for ACS versus stable CAD Conversely, a positive FFR despite the lack of
patients, respectively; p = NS). an apparent stenosis could be noted in patients
with serial stenoses of intermediate severity in a
diffuse fashion, a large territory at risk, and poor
Ostial Lesions angiographic angles. A gradual decline versus an
abrupt decline the wave form helps distinguish
Ostial lesions in the major epicardial vessels focal versus diffuse disease as shown in Fig. 7.2.
maybe very difficult to assess angiographically
due to the inability to properly engage the vessel.
In addition, these lesions are usually heavily cal- Future Directions
cified. As such, angiographic determination of
stenosis severity is difficult in some cases. In Based on first principles, calculation of FFR has
addition, angiographic determination of ostial relied on the ability to induce peak hyperemia
side branches after main vessel stenting is also with vaso-active drugs. Instantaneous wave-free
common and has been discussed in bifurcation ratio (iFR) has been proposed as an alternative to
lesions. When performing FFR in epicardial ves- hyperemic FFR. It is defined as the resting trans-
sel stenosis, it is common to equalize in the lesional pressure gradient during a finite period
ascending aorta prior to catheter engagement. In in diastole (the wave-free period) and is based on
addition, after the vessel is wired, the catheter the assumption that mean myocardial resistance
should be disengaged from the coronary for short in the wave-free period is equivalent to peak
distance to avoid damping of the catheter and hyperemic resistance and therefore negligible.
inaccurate measurements. The VERIFY (VERification of Instantaneous
118 I. Hanson et al.

Wave-Free Ratio and Fractional Flow Reserve Conclusions

for the Assessment of Coronary Artery Stenosis In summary, FFR is the invasive criterion stan-
Severity in EverydaY Practice) study collected dard for assessing physiologic significance of
prospective and retrospective iFR and hyperemic epicardial coronary artery stenosis. A thorough
FFR in a total of 706 patients, and concluded that understanding of physiology underlying FFR
the overall diagnostic accuracy of iFR to predict measurement will increase reliability of data and
FFR ≤0.80 is 60 % overall and 51 % within the facilitate decision-making. Evaluation of multi-­
FFR range of 0.60–0.90. Other analyses have vessel CAD with FFR, including a spectrum of
shown mixed results [36, 37]. In summary, iFR clinical presentations and lesion subsets, is safe
requires further study before being adopted for and leads to improved clinical outcomes com-
routine clinical use [38]. pared to the use of angiography alone.
Applying computational fluid dynamics to ana-
tomic image data [39], investigators are now able
to predict FFR based on CT angiography (FFRCTA). References
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lent to fractional flow reserve and is not improved with Via Noninvasive Fractional Flow Reserve) study.
adenosine administration. Results of CLARIFY J Am Coll Cardiol. 2011;58:1989–97.
(Classification Accuracy of Pressure-Only Ratios 41. Taylor CA, Fonte TA, Min JK. Computational fluid
Against Indices Using Flow Study). J Am Coll Cardiol. dynamics applied to cardiac computed tomography
2013;61:1409–20. for noninvasive quantification of fractional flow
38. Samady H, Gogas BD. Does flow during rest and reserve: scientific basis. J Am Coll Cardiol.
relaxation suffice? J Am Coll Cardiol. 2013;61: 2013;61:2233–41.
1436–9. 42. Meuwissen M, Chamuleau SA, Siebes M,
39. Kim HJ, Vignon-Clementel IE, Coogan JS, Figueroa Schotborgh CE, Koch KT, de Winter RJ, Bax M, de
CA, Jansen KE, Taylor CA. Patient-specific modeling Jong A, Spaan JA, Piek JJ. Role of variability in
of blood flow and pressure in human coronary arter- microvascular resistance on fractional flow reserve
ies. Ann Biomed Eng. 2010;38:3195–209. and coronary blood flow velocity reserve in interme-
40. Koo BK, Erglis A, Doh JH, et al. Diagnosis of diate coronary lesions. Circulation. 2001;103(2):
ischemia-­causing coronary stenoses by noninvasive 184–7.
 Intravascular Ultrasound
8
Rolf Graning

Abstract
Despite being the gold standard for invasive assessment of coronary artery
disease (CAD), angiography provides a limited, planar evaluation of the
coronary vessels. While indispensable for assessment and treatment of
CAD significant limitations exist. Lesion assessment has been shown to be
unreliable with both significant intra- and inter-observer variability. The
addition of digital quantitative assessment is helpful, however still only
marginally improves overall reproducibility of coronary angiograms.
Extensively diseased coronary arteries with positive remodeling may
appear only minimally diseased or even angiographically normal, leading
to false reassurance of patient and provider alike. This is readily apparent
when patients who have undergone coronary CT angiograms demonstrat-
ing extensive three vessel disease are referred for catheterization and who
have minimal evidence of CAD angiographically. The use of intravascular
ultrasound (IVUS) allows excellent visualization of both the vessel lumen
as well as the surrounding vessel wall providing a more accurate assess-
ment of the extent of CAD. In addition measurements of the vessel size
and plaque characteristics can be indispensable for guidance of stent
placement. IVUS has been used for decades in clinical situations such as
ambiguous lesion and vessel assessment, evaluation of left main stenosis,
guidance of PCI, evaluation of restenosis and stent thrombosis and in sur-
veillance for transplant vasculopathy. Additionally, it has been invaluable
for research purposes, initially in the era of PTCA followed by use in all
of the major bare metal and drug eluting stent trials, providing the frame-
work for the currently accepted interventional practices.

R. Graning, MD
Department of Cardiology,
William Beaumont Hospital,
Royal Oak, MI, USA
e-mail: [email protected]

© Springer-Verlag London 2015 121

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_8
122 R. Graning

Keywords
Intravascular ultrasound (IVUS) • IVUS for coronary artery disease (CAD) •
IVUS catheter • Solid state IVUS catheter • Rotational IVUS catheter •
Proximal reference vessel • Distal reference vessel • Radiofrequency IVUS

Introduction Background

Despite being the gold standard for invasive The first coronary angiogram was an aggressive
assessment of coronary artery disease (CAD), step forward in identifying and treating patients
angiography provides a limited, planar evalua- with CAD. However, even today with the use of
tion of the coronary vessels. While indispensable digital quality imaging, angiography provides an
for assessment and treatment of CAD significant incomplete picture of the extent of coronary
limitations exist. Lesion assessment has been artery atherosclerosis. Because sound waves pen-
shown to be unreliable with both significant etrate through the vessel wall, IVUS allows a
intra- and inter-observer variability [1]. The more complete appreciation of this picture,
addition of digital quantitative assessment is allowing visualization of not only the lumen, but
helpful, however still only marginally improves the complete coronary vessel as well.
overall reproducibility of coronary angiograms. The first ultrasound imaging catheter for use
Extensively diseased coronary arteries with pos- in humans was developed by Bom and colleagues
itive remodeling may appear only minimally dis- in 1971 [2]. This was for use within the cardiac
eased or even angiographically normal, leading chambers and for assessment of the valves. In the
to false reassurance of patient and provider alike. early 1980s, work began on intracoronary IVUS
This is readily apparent when patients who have catheters and by 1988 the first coronary images
undergone coronary CT angiograms demonstrat- were recorded [3].
ing extensive three vessel disease are referred for IVUS has been used extensively since that time,
catheterization and who have minimal evidence reinforcing previous autopsy and pathology studies
of CAD angiographically. The use of intravascu- on the development and progression of CAD. In
lar ultrasound (IVUS) allows excellent visual- addition, it has been the cornerstone of many of the
ization of both the vessel lumen as well as the major interventional trials starting with PTCA and
surrounding vessel wall providing a more accu- continuing through bare metal (BMS), drug eluting
rate assessment of the extent of CAD. In addi- stents (DES) and now bio-absorbable platforms
tion measurements of the vessel size and plaque (BVS). Without the use of IVUS, current knowl-
characteristics can be indispensable for guidance edge on the progression of CAD, vessel reaction to
of stent placement. IVUS has been used for balloon and stent implantation, and long and short
decades in clinical situations such as ambiguous term remodeling of the coronaries after stent place-
lesion and vessel assessment, evaluation of left ment would not be known except through autopsy
main stenosis, guidance of PCI, evaluation of studies. In addition IVUS has been instrumental in
restenosis and stent thrombosis and in surveil- monitoring the coronary vascular bed following
lance for transplant vasculopathy. Additionally, initiation of medical therapy such as statins and for
it has been invaluable for research purposes, ini- monitoring for development and progression of
tially in the era of PTCA followed by use in all transplant vasculopathy in cardiac transplant
of the major bare metal and drug eluting stent patients. It is not an exaggeration to state that with-
trials, providing the framework for the currently out IVUS, the current practice of interventional
accepted interventional practices. cardiology would not be the same as it is today.
8 Intravascular Ultrasound 123

Rotating
Element

Mechanical

Fig. 8.1 Ultrasound waves are generated perpendicular

to the IVUS catheter (Courtesy of Boston Scientific) Multi-element array
Drive Shaft
Phased Array

Performance of IVUS is based upon the same

principles as used for ultrasound of any other Fig. 8.2 Top image is a rotating, or mechanical catheter.
organ in the body. Reflected sound waves gener- Bottom image is a solid state, or phased array catheter
(Courtesy of Boston Scientific)
ated by the imaging probe are used to visualize
the vessel and its surrounding structures which in
turn are used to generate a tomographic two information is then routed to a computer sys-
dimensional image, similar to a histologic cross tem, which in turn generates a cross sectional,
section. Due to different acoustic properties of real time image. The only commercially avail-
the intima, media, and adventitia one is able to able solid-state catheter currently available
readily identify these structures which in turn are (Volcano) has 64 separate transducer elements
used as landmarks for measurement and guid- arranged around the catheter tip and uses a
ance of procedures. 20 MHz scanning frequency. These catheters
are 3.5 French in size at the transducer and are
compatible with a 5 French guiding catheter
Technique and Instrumentation over a 0.014-in. guide-wire in a rapid exchange
design. Larger devices are also available for use
IVUS catheters use higher frequencies than non- over both 0.018 and 0.035-in. wires and are
invasive echocardiography in order to increase designed for use in the peripheral vessels and
radial resolution, however this comes at the aorta. Aside from conventional IVUS images,
expensive of tissue penetration. Depending on the Volcano solid-state catheters also perform
the manufacturer, current IVUS catheters use radiofrequency IVUS, also known as virtual
anywhere from 20 to 40 MHz for coronary imag- histology or VH-IVUS which will be discussed
ing and 10 to 20 MHz for peripheral imaging. in a later section.
With increasing frequency radial resolution is 2 Rotational (Mechcanical) IVUS.
improved, however tissue penetration decreases With rotational systems, a single transducer
(See Fig. 8.1). element is located at the tip of the catheter that
There are currently two different types of is rotated by an external motor drive attached
IVUS catheter designs; solid state and rotational to the proximal end of the catheter. As the
and both types of systems generate a circumfer- transducer rotates, echocardiographic infor-
ential, gray scale axial image (See Fig. 8.2) mation is gathered and generated into a cir-
1. Solid-state (Phased Array) IVUS: cumferential cross sectional image, identical
With solid-state catheters, there are multiple to that generated by solid-state systems. As
transducer elements that are mounted circum- the rotating transducer sits inside the catheter,
ferentially at the tip of the imaging catheter. there is a very short rapid exchange portion at
These are activated individually in a rotational the tip of the catheters for use with a 0.014 in.
fashion in order to generate a rotating ultra- guide-wire. Currently, rotational coronary
sound beam. The resulting echocardiographic imaging systems are available in three separate
124 R. Graning

Fig. 8.3 InfraRedX IVUS images. The yellow in the underlying longitudinal image represents lipid, which can be
quantified into a lipid core burden index (LCBI)

platforms (Boston Scientific, Volcano and grams of nitroglycerin intracoronary in order

Infraredx). The Boston Scientific coronary to have maximal epicardial vasodilation as
catheter has a 3.15 French crossing profile, is well as to minimize coronary spasm induced
compatible through a 5 French catheter, and by the imaging catheter which is a complica-
uses a 40 MHz scanning frequency. The tion in approximately 2 % [4]. The IVUS
Volcano rotational catheter has a 3.2 French catheter is then advanced over the guide-wire
crossing profile and is compatible through a 6 with the transducer beyond the area of inter-
French sheath and uses a scanning frequency est. After initiation of the IVUS catheter,
of 45 MHz. The Infraredx device has a 3.2 baseline circumferential images are obtained.
French crossing profile, is compatible through There are two different methods of then pro-
a 6 French sheath and uses a 40 MHz scanning ceeding with IVUS, which are manual pull back,
frequency. The main difference in the or motorized pullback, which can be done with
Infraredx catheter is that it also provides the any of the currently available catheters.
ability to perform near infrared spectroscopy In manual pull back, the operator will slowly
(NIRS) in addition to IVUS (See Fig. 8.3). withdraw the transducer across the area of inter-
For coronary imaging, both solid state and est. With solid-state catheters, the entire catheter
rotational systems are performed over a is slowly pulled back while with rotational cathe-
0.014 in. guide-wire which is placed by the ters the internal imaging catheter is slowly with-
operator across the area of interest and into drawn leaving the outer catheter in place beyond
the distal vessel after fully anticoagulating the the lesion. With motorized pull back, an external
patient. The majority of interventionalists will “sled” is attached to the proximal portion of the
then give a single dose of 100–200 micro- catheter which when activated will provide a
8 Intravascular Ultrasound 125

ogy the crossing profiles of both the solid-state

and rotational systems are essentially identical.
In addition, due to a longer monorail segment
there is less “buckling” of the catheter across
tight stenoses leading to improved crossibility.
Finally, one of the major disadvantages of the
solid-state systems is the use of 20 MHz frequen-
cies which allow imaging of larger vessels as
well as increased penetration, however has less
Fig. 8.4 Mechanical, or rotational, imaging system with axial resolution and are felt by many interven-
overlying catheter. Note the single transducer which is tionalists to provide less clear images. However,
rotated by an external drive shaft to create the cross- predominantly due to the simplified set-up and
sectional image (Courtesy of Boston Scientific)
use there is still a very strong role for these
catheters.
steady withdrawal of the catheter at a standard- With rotational catheters, axial resolution is
ized speed (See Fig. 8.4). The advantages of man- significantly better (38–50 μm compared to about
ual pullback are simplicity of operation and ability 150 μm with solid-state catheters) due to the use
to “fine tune” the catheter to the area of interest of 40–45 MHz frequencies. However, the set-up
for more detailed and prolonged investigations. for rotational systems is more cumbersome. The
The main advantage of motorized pullback is catheter is removed from its packaging and its
ability to provide information not only on vessel associated stop-cocks and lines are attached. The
diameter, but also provide longitudinal informa- motor drive is then handed over and placed in
tion as the length of the area visualized is reported sterile bagging as it is a re-usable part. The cath-
as well. This allows physicians to accurately eter is then connected to the motor drive followed
determine lesion length in order to tailor not only by flushing of the catheter in both the distal and
the diameter of stents, but the length as well. With proximal positions in order to remove all air from
manual pullback one is not able to determine between the inner and outer catheters. The cath-
length or gather longitudinal information. eter, which has a very short monorail at the distal
There are advantages and disadvantages of tip, is then placed on a 0.014 in. guide-wire and
both the solid-state and rotational systems. With advanced through the catheter beyond the area of
solid-state catheters setup is very simple: the interest. If manual pullback is to be performed, it
catheter system is removed from its packaging, is important to only pull back the inner catheter
the proximal end plug is passed off and con- during imaging leaving the stationary outer
nected to the computer system, and the catheter is sheath in place, as opposed to pulling back the
mounted on the 0.014 in. guide-wire over a rapid entire system as a unit. As the guide-wire runs
exchange segment followed by advancement to alongside the transducer (rather than through the
the area of interest. Because solid-state catheters catheter as with solid-state systems), an imaging
have a zone of “ring down” artifact around the artifact inherent to all rotational systems is
catheter, an additional step to mask this artifact is “guidewire artifact.” This is important to recog-
performed once the catheter is advanced into the nize in order to avoid misinterpretation of images.
coronary, which is done, on the computer con- Regardless of the type of system used, the gen-
sole. Other advantages of the solid-state catheters erated axial image is essentially the same and
include the lack of moving parts, lack of guide- interpretation and measurement relies upon the
wire artifact, and lack of “NURD” which is a ability to correctly identify the different portions
type of artifact with rotational systems which will of the blood vessel as well as identify diseased
be further explained in upcoming sections. and healthy appearing vessels. The three basic
Historically, the solid-state catheters were smaller histologic layers and composition of the blood
in size, however with further advances in technol- vessels provide the basis for image interpretation
126 R. Graning

Intima

Media

Adventitia

Fig. 8.5 Trilaminar structure of the blood vessels

(Courtesy of Boston Scientific)
Fig. 8.6 Healthy vessel. Note the trilaminar appearance
with a thin echogenic intima, echolucent media bounded
and result in the classic trilaminar appearance of by the internal and external elastic lamina, and echogenic
adventitia (Courtesy of Boston Scientific)
IVUS. These layers are the intima, media, and
adventitia (See Fig. 8.5). The innermost layer, the
intima, is in direct contact with the intraluminal As stated, the major strength of IVUS is its
space and is typically only one to two cell layers ability to see both the intraluminal as well as
thick in healthy arteries. Therefore, in truly nor- extra-luminal portions of the vascular bed in
mal coronaries, as seen in young individuals, the order to provide a more complete picture. It is
intima will not be able to be seen by IVUS because also a very useful tool for the accurate and
of the limits of the axial resolution. However, due reproducible measurement of many parts of the
to age as well as due to remodeling and deposition blood vessel. This provides many obvious uses
of atherosclerotic plaque from CAD, the majority such as comparison of vessel diameter across a
of adults evaluated in the cath lab have a much coronary stenosis and the reference vessel seg-
thicker intima allowing its visualization by IVUS ment and the ability to accurately determine the
which appears echogenic. The intima is separated size and length of coronary stents and balloons
from the media by the internal elastic membrane to be used during interventions. However, there
which is composed predominantly of homoge- are many other measurements which are com-
nous layers of smooth muscle cells in the coronar- monly used in major clinical trials as cut points
ies. As the smooth muscle cells do not reflect to guide interventions and therefore knowledge
sound waves well and there is less elastin and col- of how to determine these measurements is
lagen as compared to the intima and adventitia, important. The following is a brief list of many
the media appears as a thin echolucent strip sur- of the commonly used measurements and terms
rounding the vessel and separating the adventitia which are thought be important for the practic-
from the intima. The media is separated from the ing interventionalist. Later, discussions on clini-
adventitia by the external elastic membrane. It is cal utility of many of these measurements will
composed of fibrous connective tissue with a high be covered. While determination of measures
amount of elastin and collagen and therefore such as plaque burden and remodeling index are
appears echogenic. The imaged vessel wall there- not routinely performed in every day clinical
fore has, almost invariably, a classic trilaminar practice, the nomenclature is important as many
appearance (bright-dark-bright) providing impor- of these have been used in previous studies.
tant land marks for measurement (See Figs. 8.6 • Proximal Reference Vessel: The site with the
and 8.7). largest lumen proximal to a stenosis but within
8 Intravascular Ultrasound 127

Fig. 8.7 Cross-sectional and

longitudinal images
generated by IVUS. Note the
calcified stenosis in the
center of the longitudinal
image (Courtesy of Boston
Scientific)

the same segment, usually <10 mm from the • Atheroma or Plaque Area:
stenosis with no intervening branches. EEM CSA - Lumen CSA
• Distal Reference Vessel: The site with the • Atheroma or Plaque Burden:
largest lumen distal to a stenosis but within the
Atheroma CSA
same segment, usually <10 mm with no inter- ´100
EEM CSA
vening branches.
• Maximal Lumen Diameter: Maximal diam- • Remodeling Index (RI):
eter of the lumen, from leading edge of intima
Lesion EEM CSA
on each side of vessel ´100
Reference vessel EEM CSA
• Minimal Lumen Diameter: Minimal diame-
ter of the lumen, from leading edge of intima
on each side of vessel
• Lumen Eccentricity: Artifacts and Pitfalls
⎛ Maximum Lumen Diameter ⎞
⎜ − Minimum Lumen Diameter ⎟ Calcium
⎝ ⎠
Maximum Lumen Diameter
IVUS depends on differential absorption and
• Cross Sectional Area (CSA): Circumferential reflection of sound waves from tissues in order to
area bounded by the luminal border generate a grayscale image. Tissues that reflect
• Area Stenosis: large amounts of sound waves are termed echo-
⎛ Reference Vessel CSA ⎞ genic and appear brighter relative to tissues that
⎜ − Minimum Vessel CSA ⎟ do not reflect sound waves as well, which are
⎝ ⎠ × 100
termed echolucent and appear darker. Calcium is
Reference Lumen CSA
an exceptional reflector of sound waves and
• External Elastic Membrane Cross Sectional therefore appears very echogenic. In addition, as
Area (EEM CSA): Circumferential area the majority of sound waves are reflected and do
bounded by the leading edge of the external not penetrate to the underlying tissue; calcium
elastic membrane (EEM) has significant shadowing making it difficult or
128 R. Graning

Fig. 8.8 (a) Calcified vessel

a
with wire artifact in the
5 o’clock position (Courtesy
of Boston Scientific)
(b) Calcium artifact. Note the
echogenic signal with
acoustic shadowing beyond
the calcium

impossible to see beyond the calcium, this is also Wire Artifact

knows as shadowing (See Figs. 8.8 and 8.9).
Similar to calcium, guide wires are very echo-
genic resulting in shadowing and difficulty seeing
Non-uniform Rotational Distortion the vessel wall beyond the artifact. For those not
(NURD) familiar with this type of artifact misdiagnosis of
thrombus or dissection is possible (See Fig. 8.11).
This type of distortion is unique to rotational sys-
tems and results from mechanical binding of the
drive cable that rotates the transducer. This is typi- Motion
cally due to things which result in increased friction
on the drive cable such as tortuous vessels or guide Both mechanical and solid state catheters can move
catheters, excessive tightening of the hemostatic as much as 5 mm longitudinally between diastole
valve on the guide, kinking of the imaging sheath, and systole [5] which can preclude accurate assess-
or too small a guide catheter lumen (See Fig. 8.10). ment, especially with longitudinal measurements.
8 Intravascular Ultrasound 129

a b

Fig. 8.9 Calcium is described based upon its extent and located closer to the adventitia than the lumen (Courtesy of
location. (a) partially calcified vessel; (b) superficial calcium Boston Scientific)
located closer to the lumen than the adventitia; © deep calcium

Ringdown observed as bright halos of variable thickness

surrounding the catheter. They are produced by
This type of artifact refers to disorganization of acoustic oscillations in the transducer which
the image closet to the transducer or catheter. result in high-amplitude signals that obscure the
While present in all types of IVUS catheters it is area immediately adjacent to the catheter [4].
more common in solid state, or phased array
IVUS catheters which attempt to minimize these
artifacts by performing a “ringdown” on place- Blood Speckle
ment of the catheter into the vessel, which is sim-
ply a mask or digital subtraction over this area in Signals from blood cells can be imaged on
the center of the image. Ringdown artifacts are IVUS catheters. This “blood speckle” artifact
130 R. Graning

Fig. 8.10 Calcified vessel with wire artifact in the 5

o’clock position (Courtesy of Boston Scientific)
b

increases as transducer frequency increases and

as blood flow decreases. Therefore areas where
the catheter is across a tight stenosis with resul-
tant limitations in blood flow, blood speckle
artifact increases. This can result in decreased
ability to differentiate lumen from tissue, espe-
cially with soft plaque and thrombus. Flushing
the catheter with saline helps to clear the lumen
and reduce blood speckle, which in turn may
aid in identification of tissue borders (See
Fig. 8.12).

Patient Populations
Fig. 8.11 (a and b) NURD artifact which is unique to
Assessment of Intermediate Non-left rotational systems. Secondary to non-uniform rotation of
Main Coronary Lesions the transducer due to increased friction on the catheter.
Note the concentric ring artifacts that are generated
(Courtesy of Boston Scientific)
Because angiography is the planar 2D representa-
tion of a 3D structure, there are multiple potential
pitfalls in accurate interpretation. Diffuse refer-
ence vessel disease, foreshortening, tortuous ves- as angiographic stenosis of 40–80 % in most tri-
sels, overlapped segments, calcification, lesion als, and in fact has been shown to be more accu-
eccentricity, and poor contrast opacification all rate and reproducible than angiography and
can contribute to inaccurate assessment of lesion quantitative coronary angiography (See Fig. 8.13).
severity. Because of the tomographic representa- Currently, the gold standard for identification
tion of the vessel as well as the ability to evaluate of physiologically significant stenosis in the cath
the vessel wall it is not surprising that IVUS can lab is fractional flow reserve assessment (FFR).
be very useful in the assessment of the “interme- Much of the data done with FFR has demonstrated
diate” or “ambiguous” coronary stenosis, defined ischemic lesions that were angiographically
8 Intravascular Ultrasound 131

a a

b
b

Fig. 8.12 Blood speckle artifact noted in the image on

the (a) secondary to slow flow. This is improved in the
image on the (b) after flushing of the catheter (Courtesy of Fig. 8.13 Eccentric plaque which was estimated as 40 %
Boston Scientific) by angiography (a). IVUS evaluation demonstrates exten-
sive plaque with 95 % area stenosis (b) (Courtesy of
Boston Scientific)
assessed as only 50 % stenosis, and non-ischemic
lesions that appeared to be 80 % by angiography.
This clearly demonstrates that angiography alone stenosis is problematic, as represented by the
is not adequate in patients where the lesion is wide range of suggested values in the literature.
“intermediate.” In addition, there are multiple factors aside from
As with FFR, research with IVUS has been lesion severity which contribute to overall func-
done in an attempt to stratify intermediate lesions tional significance such as length, eccentricity,
as flow or non-flow limiting stenoses. However, and the myocardium which is subtended by the
as patients as well as coronary arteries come in vessel. This is represented in the ACC/AHA
all shapes and sizes the use of either MLA or 2011 PCI Guidelines in which FFR for evalua-
MLD as a cut-point for significant/non-significant tion of an intermediate stenosis receives an IIa
132 R. Graning

(LOE A) recommendation and IVUS receives an accuracy for functionally significant stenoses
IIb (LOE B) recommendation [6]. with an FFR <0.8. The best diagnostic accuracy
While FFR is currently considered by most was for the proximal LAD, where the best cutoff
the gold standard for invasive assessment of value to determine functional significance was an
intermediate coronary lesions, significant work MLA of <3.0 mm2. For the mid LAD, a MLA of
has been aimed at evaluating anatomic measure- <2.75 mm2 was also found to have a reasonable
ments by IVUS to predict significant coronary diagnostic accuracy for ischemic lesions by
lesions. Early work with IVUS suggested a MLA FFR. However, IVUS measurements of the right
cut point of ≥4.0 mm2 for prediction of hemody- coronary and circumflex arteries were not found
namically significant non-left main stenoses, in to correlate well with prediction of ischemic
particular of proximal epicardial vessels. A MLA lesions. In addition, the diagnostic accuracy for
≥4 mm2 had a diagnostic accuracy of 89 % in “large” (>3 mm) and small (<3 mm) vessels was
identifying a CFR of ≥2.0 [7]. In this same study also found to be poor indicating that lesion loca-
only the MLA by IVUS and the lesion length tion (proximal or mid LAD and not the circum-
were found to independently predict a CFR ≥2.0. flex or right coronary) may also be a determinant
In a study of 67 coronary lesions evaluated by of when to correctly use IVUS for evaluation of
both IVUS and stress myocardial perfusion imag- intermediate stenoses [11]. The diagnostic impact
ing, a MLA of ≤4.0 mm2 had a sensitivity of of the vessel being studied was also noted in a
91 % and a specificity of 95 % for detection of recent trial of 236 lesions evaluated by both
functionally significant coronary artery stenosis IVUS and FFR. The independent determinants of
[8]. Finally, in a study of 53 lesions with an angi- FFR <0.80 were MLA, plaque burden, and left
ographic stenosis of 40–70 % that were evaluated anterior descending artery location. In this study,
with both FFR and IVUS, a MLA of ≤4.0 mm2 the best cutoff value of the MLA to predict FFR
had a sensitivity of 92 % and a specificity of 56 % <0.80 was 2.4 mm2 however the diagnostic accu-
in identifying an FFR of ≤0.75. In addition an racy was only 68 %. In the 117 lesions with a
MLD of ≤1.8, lesion length of >10 mm, and area MLA ≥2.4 mm2, 96 % had a FFR ≥0.80. However
stenosis >70 % were all strong predictors of isch- only 37 % of lesions with a MLA <2.4 mm2 had
emic FFR values [9]. an FFR <0.80 [12] suggesting that vessels with
While a MLA of ≤4.0 mm2 for non-left main an MLA of ≥2.4 mm2 could be safely deferred
stenosis has been used by many as a potentially while those <2.4 mm2 may need further evalua-
reliable marker for determination of significance, tion with FFR.
there have been many other studies which have The majority of studies investigating use of
suggested different MLA values in addition to IVUS for intermediate non-left main stenoses
other vessel measurements in order to predict evaluated proximal “large” caliber vessels >3 mm
hemodynamically significant indeterminate in diameter. However, in patients with small body
lesions. In a group of 42 patients with 51 lesions habitus or diffuse coronary artery disease such as
that were evaluated by both FFR and IVUS the diabetics, many of the intermediate lesions occur
best determinant of an FFR <0.75 was an area in vessels with smaller luminal diameters. In the
stenosis of >60 % (sensitivity 92 %, specificity IDEAS (Intravascular Ultrasound-Derived
89 %). In addition, if a patient had both an area Anatomic Criteria for Defining Functionally
stenosis >60 % and a MLA of <3.0 mm2, there Significant Stenoses in Small Coronary Arteries)
was a 100 % agreement for the prediction of an trial, 94 intermediate coronary lesions were eval-
ischemic lesion as defined as an FFR of <0.75 uated by both IVUS and FFR. Definition of isch-
[10].In a more recent evaluation of IVUS to pre- emic lesions in this trial was an FFR of <0.75
dict ischemia, 267 intermediate lesions in proxi- using intracoronary adenosine. The average ref-
mal and mid epicardial vessels were assessed by erence vessel diameter was 2.72 mm and both
both IVUS and FFR with the goal of determining proximal and mid epicardial vessels in all three
the best IVUS parameters and their diagnostic major coronary arteries were evaluated. Over
8 Intravascular Ultrasound 133

40 % of lesions evaluated had a FFR <0.75. The lead to premature graft closure [15]. Angiographic
three most important determinants of the FFR assessment of the left main is historically very
were the MLA, plaque burden, and lesion length. difficult with high inter- and intra-observer vari-
The best cutoff values for these determinants to ability due to significant foreshortening, ostial
discriminate a FFR of <0.75 were a MLA of angulation, and streaming of contrast medium
≤2.0 mm2, plaque burden ≥80 %, and a lesion from the catheter tip in standard angiographic
length of ≥20 mm. Of the 22 lesions who were projections. Additionally, the typically diffuse
found to have all three IVUS determinants, 21 nature of coronary artery disease in the left main
had an FFR of <0.75. When all three of these fac- limits the comparison of a diseased-free refer-
tors were combined the receiver operating char- ence segment. With qualitative coronary angiog-
acteristic was 0.94 and significantly increased raphy, the left main has been shown to be the
compared with any of the IVUS characteristics least reproducible of any of the coronary seg-
alone. When using a FFR of <0.80 as the cutoff ments. In an analysis of 810 angiograms from the
value, only MLA and lesion length were found to Coronary Artery Surgery Study (CASS) of
be of value in predicting functionally significant patients with left main stenosis, one angiographer
lesions, however the receiver operating charac- reported a >50 % LMCA stenosis while a second
teristic curves remained high and similar to those angiographer reported no stenosis 19 % of the
for an FFR cutoff of <0.75 [13]. time in the same patients [16]. Further, multiple
When taken together, the above data demon- studies have noted that even with angiographi-
strate a large amount of variability in specific cally “normal” LMCA, up to 89 % of patients
cutoff values for determination of ischemic were found to have disease based upon IVUS
causing indeterminate coronary lesions. What evaluation [17].
is clear however is that measurements associated FFR evaluation of intermediate lesions has
with significant coronary stenoses are MLA, been shown to accurately stratify patients that
lesion length, plaque burden, and area stenosis. need revascularization from those that do not,
While absolute cutoffs for these measurements is with low event rates in those patients with non-
not feasible or reasonable for the vast majority of physiologically significant FFR that are medi-
patients evaluated in the catheterization lab pro- cally managed [18]. However, most patients with
gressive reduction in MLA, longer lesions, high left main disease have additional coronary artery
plaque burden, and increased area stenosis cor- disease in their left anterior descending and cir-
relate with reductions in FFR particularly in cumflex arteries that may make performance of
proximal epicardial vessels, and ideally the left FFR inaccurate due to “protection” of the distal
anterior descending. At this time FFR will likely circulation from induced hyperemia.
remain the de facto stratifying test for intermedi- The use of IVUS is uniquely suited for evalu-
ate lesions, however in patients where FFR is not ation of ambiguous left main lesions in order to
feasible due to significant distal disease or intol- stratify patients that may need revascularization
erance of adenosine, IVUS remains an option for from those that can be safely deferred to medical
the interventional operator. management.
Before proceeding, it is important to recognize
that angiographic evaluation of the left main is
Assessment of Left Main Stenosis poor, particularly when an intermediate lesion is
identified. Because of the poor prognosis associ-
Left main stenosis ≥50 % has been shown to ated with obstructive LMCA disease and the rela-
have a poor long term outcome [14] while tively normal survival of patient’s without
patients with mild or only moderate left main ste- obstructive LMCA disease, it is imperative that an
nosis have a low 1 year event rate with medical additional modality other than angiography be
management. In addition, premature bypass used to stratify patients prior to revascularization.
without physiologically significant stenosis can Because LMCA disease is most often encountered
134 R. Graning

in association with disease in the remaining was 16.25 mm2 with a standard deviation of
coronary tree, non-invasive stress tests may not 4.30 mm2. The “lower range of normal” was set
accurately discriminate ischemia caused by the at two standards deviations below the mean
left main versus other coronary disease. In a group which was defined as a MLA of 7.5 mm2. Using
of 51 patients with angiographic intermediate this value as the cut point, 214 patients with inter-
(40–80 %) LMCA stenoses that were evaluated by mediate angiographic left main lesions were then
FFR to determine functional significance (using evaluated by IVUS. Of these patients, 39 % had
cutoffs of both <0.75 and ≤0.80), 4 separate an MLA of <7.5 mm2. Left main coronary artery
“experienced” interventional cardiologists blinded revascularization was performed in 85.5 % (71 of
to FFR result were asked to classify the lesions as 83) of patients with an MLA of <7.5 mm2 and
‘significant,’ ‘not significant,’ or ‘unsure.’ The cor- deferred in 86.9 % (114 of 131) of patients with
relation with the FFR result for each reviewer was an MLA of ≥7.5 mm2. During long term follow-
less than 50 % regardless of the FFR cutoff, mean- up (mean of 3.3 ± 2.0 years) there was no signifi-
ing that over half the time the angiographic deter- cant difference in major adverse cardiac events
mination of significance was incorrect for each (target vessel revascularization, acute myocardial
blinded reviewer. Furthermore, interobserver vari- infarction, and death) [20]. This seminal investi-
ability was large resulting in unanimously correct gation leads to the conclusion that deferring
lesion classification in only 29 % of all cases [19]. revascularization for patients with a MLA
Therefore, when making management decisions ≥7.5 mm2 was safe.
regarding the left main, angiography is often not While the previous study determined an MLA
enough. cutoff based upon the Gaussian distribution of
The question however is what IVUS parame- the angiographically normal LMCA, the cutoff
ters should be used in order to determine func- for ischemic producing lesions was initially
tional significance? Because the left main is investigated using an FFR of <0.75 as the gold
typically a short vessel, presence of disease in a standard. In 55 patients with angiographically
single segment often predicts diffuse disease dur- ambiguous LMCA, FFR was initially obtained
ing IVUS interrogation. Because of this, it is dif- followed by performance of IVUS. The MLD
ficult, if not impossible, to determine a “normal” and MLA were both found to strongly correlate
vessel to use as a distal or proximal reference with FFR. Compared with FFR, an MLD of
segment. In addition, positive and negative 2.8 mm had the highest sensitivity and specificity
remodeling in the left main tends to be pro- (93 % and 98 % respectively) followed by an
nounced, again making identification of refer- MLA of 5.9 mm2 (93 % and 95 % respectively)
ence vessels difficult. For this reason, most of the [21]. In a retrospective review of 115 “real world”
studies evaluating IVUS parameters in compari- patients found to have de novo angiographically
son to FFR and SPECT have found MLA and intermediate LMCA stenosis evaluated by IVUS,
MLD to be the two most predictive measure- a significant stenosis was defined as an MLA
ments correlating to ischemia. ≤6.0 mm2 or a QCA diameter stenosis >50 % by
The initial investigation of IVUS for stratifica- angiography. A significant stenosis was seen in
tion of intermediate or ambiguous LMCA lesions 44 % of lesions by IVUS but in only 13 % of
initially looked at patients with angiographically lesions by QCA. In particular, only 36 % of ostial
normal or minimally diseased LMCA in order to lesions were found to be significant by IVUS
establish a “lower range of normal.” A total of while QCA analysis of ostial lesions was the least
121 patients underwent IVUS evaluation of their accurate [22]. This study again highlights the
LMCA and MLA were measured for all. These inherent inaccuracies of angiographic evaluation
values were then plotted and a standard bell alone. In addition, when using a MLA cut point
shaped, or Gaussian distribution, was plotted. of <6.0 mm2 to determine functional significance,
The mean MLA for these patients with angio- less than half of patients evaluated by IVUS in
graphically normal or minimally diseased LMCA this real world population were found to have
8 Intravascular Ultrasound 135

significant disease suggesting that the majority of a sensitivity of 89 % and a specificity of 83 %

patients with angiographic ambiguous LMCA [24]. Furthermore, very recent data suggests that
lesions were not severe by IVUS. an MLA of ≤4.5 mm2 may also be a reasonable
A prospective study to validate the use of a cutoff for prediction of physiologic stenosis as
MLA of 6 mm2 as the cutoff value for revascular- well [25].
ization was published in 2011. The LITRO It should not be surprising that there is no
(Prospective Application of Pre-Defined clear cutoff for IVUS derived LMCA cutoff val-
Intravascular Ultrasound Criteria for Assessment ues as vessels, like patients, come in a variety of
of Intermediate Left Main Coronary Artery shapes and sizes. What is clear based upon the
Lesions) Study remains the largest prospective current available data is that angiographic assess-
study evaluating an IVUS determined MLA to ment of the LMCA often does not provide an
guide revascularization. A total of 354 patients accurate or reproducible assessment of the true
were evaluated. Of the 168 patients with an MLA degree of disease and should not be relied upon
of <6 mm2, 90.5 % were revascularized, while when the operator is making decisions regarding
96 % of the 186 patients with MLA ≥6 mm2 were revascularization. When possible, FFR evalua-
deferred to medical management. In the 2 year tion should be the initial adjunct diagnostic
follow-up period survival free from cardiac was device for determination of physiologically sig-
97.7 % in the deferred group versus 94.5 % in the nificance. When this is not possible IVUS mea-
revascularized group (p = 0.5). Survival from surements, in particular the MLA and the MLD,
death, myocardial infarction, and any revascular- have been shown to correlate with FFR although
ization was 87.3 % in the deferred group and precise black and white cutoffs are not available
80.6 % in the revascularized group (p = 0.3). nor are they reasonable to expect. LMCA steno-
Importantly, in the 2 year follow-up period only 8 ses with a MLA >6.0 mm2 have been shown to be
(4.4 %) patients in the deferred group required safe for deferral to medical management in the
subsequent LMCA revascularization: in seven only randomized, prospective trial available [23].
because of stable angina and in one after unstable LMCA stenoses with an MLA of 4.8–6.0 mm2
angina [23]. Based upon this study, using a MLA represent a gray zone were some studies have
cut point of <6 mm2 is safe, with little adverse suggested correlation with physiologically sig-
events in patients deferred to medical nificant stenoses and others have not. Other fac-
management. tors to take into account in these situations would
While an MLA of <6 mm2 and an MLA be lesion length, plaque burden ≥70 % [24], and
<2.8 mm are currently the accepted, albeit heav- MLD <2.8 mm which have all also been associ-
ily debated, standards for IVUS evaluation of ated with significant FFR values although not to
functionally significant LMCA stenoses and are the degree as MLA.
recognized in the 2011 ACC/AHA guidelines
[6], a study published in 2011 challenged these
cutoffs as well. Using an FFR as the standard for IVUS Guided Bare Metal Stent
determining physiological significance of LM Placement
stenosis, 55 patients (31 with stable angina and
24 with unstable angina) found to have an iso- While the restenosis rates improved significantly
lated LM lesion of 30–80 % angiographic diam- with the advent of bare metal stents compared with
eter stenosis underwent IVUS and FFR. Using an PTCA alone, high in-stent restenosis rates con-
FFR of <0.80 as the cutoff, ischemic FFR’s had tinue to be an issue. In a retrospective cohort of
significant correlation with the MLA, plaque bur- 1,706 patients undergoing bare metal stent place-
den, and angiographic length of the lesion. ment the best predictors of binary restenosis dur-
However, the MLA was the only independent ing follow-up were longer stent length, smaller
determinant for FFR <0.80. The IVUS MLA that reference vessel MLD, and smaller stent CSA by
best predicted an FFR <0.80 was <4.8 mm2 with IVUS. For every 1 mm2 increase in stent CSA
136 R. Graning

there was a significant 19 % reduction in the risk balloon sizes and decreased subsequent revascu-
for binary restenosis during follow-up [26]. larization in follow-up due to less restenosis.
Malapposition as well as underexpansion of stents In a similar study using early generation BMS,
has also been shown to contribute to restenosis and 155 patients who had undergone successful stent
has led to the widespread adoption of the mantra implantation followed by IVUS were random-
of “bigger is better” and the adoption of high pres- ized into two groups: Group A in which no fur-
sure balloon inflations during stent deployment. ther dilations were performed and Group B in
The idea of IVUS guidance prior to interven- which further dilations were performed until
tion has many potential benefits to include ade- achievement of IVUS criteria for stent expansion
quate vessel sizing, assessment of degree of was obtained. The IVUS definition for full stent
calcification in consideration for rotational ather- expansion was a stent CSA ≥80 % of the average
ectomy and evaluation of lesion length. Use of of the proximal and distal reference CSA which
IVUS following intervention also has intuitive is a similar definition used by many other trials.
advantages, in particular allowing direct visual- At 6 months, all patients underwent angiographic
ization of the stent to ensure that there is adequate follow-up and there were no differences in binary
apposition and expansion and it allows better restenosis (28.8 % in Group A and 22.5 % in
assessment for complications such as distal and Group B, p = 0.25). However, the stent CSA was
proximal edge dissections. This has led to a Class larger in Group B (5.36 ± 2.81 mm2) versus Group
IIb recommendation for the use of IVUS for the A (4.47 ± 2.59 mm2, p = 0.03). Also, in multivari-
guidance of coronary stent placement in the 2011 ate analysis only the stent CSA was a predictor
ACC/AHA PCI guidelines [6]. IVUS guidance of for angiographic restenosis which was larger
PCI has been shown to increase balloon and stent both a baseline and at follow-up in Group B, sug-
size, increase the length and number of stents gesting that IVUS guidance to achieve adequate
used, and increase the MLD and stent CSA in stent expansion may lead to meaningful clinical
comparison to angiographic guidance. The ques- benefits, primarily reduced TLR secondary to
tion of whether these changes lead to improved reduced re-stenosis rates [28].
clinical outcomes however has resulted in mixed The OPTICUS (Optimization with
findings in many of the prospective studies evalu- Intracoronary Coronary Ultrasound to Reduce
ating IVUS guided versus angiographic guided Stent Restenosis) study evaluated 550 patients
bare metal stent implantation. with symptomatic coronary stenosis who were
The CRUISE (Can Routine Ultrasound randomized to undergo either ultrasound-guided
Influence Stent Expansion) study was a multi- or angiography-guided implantation of bare metal
center study which enrolled 525 patients into stents. The primary outcome was binary restenosis
either angiographically guided or IVUS guided at 6 months with a secondary outcome of 6 and
coronary intervention using Palmaz-Schatz 12 month major adverse cardiac events (death, MI
stents. Patients were followed for 9 months with and TVR). As opposed to the CRUISE study [27],
a primary outcome of major cardiac events there were no significant differences in balloon
(death, MI, or TVR). Despite no differences in size or inflation pressures between groups how-
baseline angiographic characteristics, patients in ever the IVUS guided group had a larger MLD and
the IVUS directed group had larger balloon sizes acute lumen gain following intervention (3.02 ver-
and balloon pressure during intervention. Further, sus 2.91 mm, P = 0.006; and 2.07 versus 1.93 mm,
following intervention the IVUS directed group P < 0.001 respectively). At the 6 month angio-
had a statistically significant larger minimal graphic follow-up, there were no significant differ-
lumen diameter and stent CSA. At 9 month fol- ences between the groups with respect to binary
low-up, target vessel revascularization occurred restenosis (24.5 % for IVUS guided and 22.8 %
less frequently in the IVUS-guided group (8.5 % for angiographically guided, P = 0.68). The MLD
versus 15.3 %, P < 0.05) [27], suggesting that use and percent diameter stenosis were also similar
of IVUS to guide BMS placement leads to larger between groups. At 12 months, both the individual
8 Intravascular Ultrasound 137

as well as combined secondary endpoints of major study may not have been able to adequately inter-
adverse cardiac events were similar in the entire pret the images. The TLR rates at 12 months
cohort as well as in all of the sub-groups [29]. between groups was not statistically significant
The TULIP (Thrombocyte activity evaluation (12.0 % in the angiography group and 8.1 % in the
and effects of Ultrasound guidance in Long IVUS group, p = 0.08). In patients with distal ref-
Intracoronary stent Placement) study was a erence MLD ≥2.5 mm, the 12 month TLR rates
smaller study which enrolled 144 patients with were less in the IVUS group (4.3 % versus 10.1 %,
stenoses >20 mm in length in large vessels per- p = 0.01). Further, patients with baseline angio-
mitting a stent diameter ≥3 mm, to either angio- graphic stenosis ≥70 % had reduced TLR rates at
graphic or IVUS guided BMS placement. Patients 12 months in the IVUS guided group (3.1 % ver-
in the IVUS group had longer total stent lengths sus 14.2 %, p = 0.002). The authors suggest that in
(42 ± 11 versus 35 ± 11, P = 0.001) as well as had larger vessels with severe angiographic stenosis,
the use of larger balloon sizes (3.5 ± 0.4 versus TLR rates can be reduced with the use of IVUS
3.3 ± 0.4, P < 0.001). At 6 month angiographic however many operators may not be able to ade-
follow-up, the IVUS group had a larger MLD quately interpret IVUS images to ensure adequate
(1.82 ± 0.53 versus 1.51 ± 0.71, P 0.042) and less stent expansion as was seen here [31].
binary restenosis (23 % versus 46 %, P = 0.008). Many of the prospective trials on IVUS use to
At 12 months, TLR was significantly less in the guide BMS had mixed results. Nearly all of these
IVUS group (10 %) compared to the angio- trials show improved baseline post-PCI MLD and
graphic group (23 %, P = 0.018) [30]. As men- stent CSA compared to angiographic guidance.
tioned previously, one of the best predictors of Further, nearly all trials with angiographic out-
restenosis following bare metal stent placement comes show reductions in binary angiographic
is lesion and stent length. Despite the use of lon- restenosis in IVUS guided cohorts however not all
ger stents, IVUS guided patients appeared to do of these have been statistically significant. Because
better in this trial, potentially secondary to the baseline post-PCI CSA has been strongly tied to
use of larger balloon sizes resulting in less malap- restenosis and subsequent TLR rates, many have
position and underexpansion. felt that use of IVUS to ensure adequate BMS
The AVID (Angiography Versus Intravascular expansion and apposition translates to improved
Ultrasound-Directed Bare Metal Coronary Stent clinical outcomes despite the mixed results from
Placement) trial looked at 12 month TLR rates in prospective studies. A meta-analysis on IVUS
patients randomized to either angiographic or guidance of BMS put to rest many of the lingering
IVUS guided BMS placement. Following optimal questions raised by these previous studies. Seven
angiographic stent placement with <10 % residual studies enrolling a total of 2,193 patients random-
stenosis, 800 patients were randomized to undergo ized to either IVUS guided or angiographic guided
either blinded IVUS or IVUS to guide optimal BMS implantation were analyzed. IVUS guidance
stent result (<10 % area stenosis or ≥90 % stent was associated with statistically significant larger
CSA compared to the reference vessel, full appo- post-procedure angiographic MLD (mean differ-
sition, and absence of a dissection). The final ence of 0.12 mm, p < 0.001) as well as reduced
minimum stent area was 6.90 ± 2.43 mm2 in the 6 month angiographic binary restenosis (22 % ver-
angiography group and 7.55 ± 2.82 mm2 in the sus 29 %, p = 0.02). In addition, IVUS guidance
IVUS group (p = 0.001), again demonstrating that resulted in a significant reduction in revasculariza-
IVUS guidance results in larger post-procedure tion rate (13 % versus 18 %, p = 0.004) and overall
stent CSA which has been shown to reduce rates major adverse cardiac events (19 % versus 23 %,
of restenosis. Interestingly, only 37 % of patients p = 0.03) although there was no difference in myo-
in the IVUS guided arm who had IVUS criteria cardial infarction or mortality during the follow-up
for inadequate stent expansion (<90 % stent CSA period of 6 months to 2.5 years [32]. Table 8.1
compared to the reference vessel) received further highlights two major recent metaanalysis of the
therapy demonstrating that many operators in this use of IVUS in the BMS era.
138 R. Graning

Table 8.1 Major meta-analysis of the use of IVUS to guide BMS and DES implantation
Number
Meta analysis Number of studies of patients Population Outcomes
Parise 7 randomized 2,193 BMS (larger MLD IVUS with lower risk of:
AJC 2011 with IVUS) 6 m restenosis: (OR 0.64, 95 % CI
0.42–0.96, p = 0.004)
TVR: (OR 0.66, 95 % CI
0.48–0.91, p = 0.046)
MACE: (OR 0.69, 95 % CI
0.49–0.97, p = 0.03)
Death: (NS)
MI: (NS)
Junqueira 5 randomized 1,754 BMS MACE: (NS)
Syst Rev 2012 Death: (NS)
MI: (NS)
Zhang 1 randomized 19,619 DES IVUS with lower risk of:
Euro Int 2012 10 registries TLR: (NS)
TVR: (NS)
Death: (OR 0.59, 95 % CI
0.48–0.73, p < 0.001)
MI: (NS)
Stent thrombosis: (OR 0.58, 95 %
CI 0.44–0.77, p < 0.001)
MACE: (OR 0.87, 95 % CI
0.78–0.96, p = 0.008)
Ahn 3 randomized 26,503 DES (more, longer, IVUS with lower risk of:
AJC 2014 14 observational and larger stents TLR: (OR 0.81, 95 % CI 0.66–1,
used with IVUS) p = 0.046)
Death: (OR 0.61, 95 % CI
0.48–0.79, p < 0.001)
MI: (OR 0.57, 95 % CI 0.44–0.75,
p < 0.001)
Stent thrombosis: (OR 0.59, 95 %
CI 0.47–0.75, p < 0.001)
Jang 3 randomized 24,849 DES IVUS with lower risk of:
JACC Int 2014 12 Observational TVR: (OR 0.81, 95 % CI
0.68–0.95, p = 0.01)
Death: (OR 0.64, 95 % CI
0.51–0.81, p < 0.001)
MI: (OR 0.57, 95 % CI 0.42–0.78,
p < 0.001)
Stent thrombosis: (OR 0.59, 95 %
CI 0.42–0.82, p = 0.002)
MACE: (OR 0.79, 95 % CI
0.69–0.91, p = 0.001)

IVUS Guided Drug Eluting Stent reduced revascularization rates. Therefore, much
Placement of the data on IVUS guidance for DES comes
from retrospective registries or non-randomized
While much of the data for IVUS guided BMS studies which mirror much of the data from BMS
came from prospective trials, by the time drug studies. Because stent thrombosis has been linked
eluting stents arrived it was accepted that IVUS to stent malapposition and underexpansion, many
guided coronary interventions resulted in larger have questioned whether IVUS guidance of DES
balloons/stents with resultant improved stent will result in decreased late and very late stent
apposition, decreased restenosis rates, and thrombosis rates and potentially improve cardiac
8 Intravascular Ultrasound 139

mortality. Contrary to this line of thinking is that While the study was not powered for clinical
DES in comparison to BMS have significantly endpoints, there was no difference at 30 days or
reduced rates of restenosis which has been the 24 months in myocardial infarctions, target
major advantage of IVUS guided BMS implanta- lesions/vessel revascularization, or cardiac death.
tion, causing many to doubt the added time and Interestingly, despite the fact that the AVIO study
cost of IVUS guidance in the DES era. proposed a new set of “optimal stent deploy-
The AVIO (Angiography Versus IVUS ment” criteria, only 48 % of lesions in the IVUS
Optimization) [33] trial was the first major ran- group met these criteria. Not surprisingly, the
domized prospective trial comparing IVUS patients with the largest MLD post-procedure
guided DES to angiographic guidance. One of were those that met the AVIO criteria.
the problems with many of the studies on IVUS The ADAPT-DES (Assessment of Dual
guided BMS placement was the lack of consen- Antiplatelet Therapy With Drug-Eluting Stents)
sus regarding the definition of optimal stent [35] study was a large-scale, prospective, multi-
placement. The majority of studies utilized the center study designed to assess the relationship
MUSIC (Multicenter Ultrasound Stenting in between platelet reactivity and other clinical and
Coronaries) criteria [34]. While over 80 % of procedural variables with subsequent stent
patients in the MUSIC study fulfilled criteria for thrombosis. A pre-specified sub-study was per-
optimal stent placement this threshold has been formed comparing the outcomes of IVUS guid-
difficult to replicate in subsequent IVUS guided ance versus angiographic guidance of DES
studies with only 48 % meeting criteria in the implantation. This was an “all comers” study in
AVID study and 56 % in the OPTICUS study. patients treated with ≥1 DES at 11 US and
The AVIO trial proposed a new set of criteria German sites. Eight thousand five hundred
(Table 8.2) for optimal stent deployment using eighty-three patients were enrolled, 39 % (3,349)
IVUS guidance. Optimal stent expansion was of which underwent IVUS guided DES place-
defined as 70 ± 10 % of the cross sectional area of ment and 61 % (5,234) who underwent angio-
the inflated balloon used to post dilate the stent. graphic guided DES at the primary operator’s
The size is the non-compliant balloon selected discretion. The primary outcome was definite or
was the average of the media to media diameters probably stent thrombosis according to the
of the stented area measured proximally, medi- Academic Research Consortium definitions at
ally, and distally inside the stent and rounded to 1 year. Solely on the basis of the IVUS evalua-
the closest 0.0 or 0.5. With this definition, 284 tion, the operator changed the PCI strategy in
patients with “complex coronary lesions,” 74 % of patients, most often in order to use a
(lesions >28 mm, chronic total occlusions, bifur- larger stent or balloon or to perform additional
cation lesions, vessels ≤2.5 mm, and patients post-dilation due to incomplete expansion or
requiring four or more stents) were randomized apposition. At 1 year, the rate of definite/proba-
to either IVUS guided or angiographic guided ble stent thrombosis was significantly lower in
stenting. Patients in the IVUS arm underwent the IVUS-guided group compared with the
IVUS following pre-dilation and stent implanta- angiography-guided group (0.6 % versus 1.0 %,
tion and choice of post-dilation balloon was HR 0.53, p = 0.017). This difference was present
determined by averaging the media-to-media within 1 month and there was continued diver-
diameters of the distal and proximal stent seg- gence of the curves between 1 and 12 months. As
ments as well as at the sites of maximal narrow- this was a non-randomized trial, patients in the
ing within the stent. The primary outcome of angiography guided group had a small but sig-
post-procedure MLD was significantly higher in nificant increased use of first generation DES
the IVUS guided group. In addition, patients in which may have contributed to the difference.
the IVUS arm had use of larger post-dilation bal- However, even after adjustment there was still a
loons although there was no difference in stent significant benefit with IVUS. Patients in the
length, diameter, or inflation times/pressures. IVUS group received larger diameter and longer
Table 8.2 Comparison of studies with IVUS optimization of PTCA with or without BMS or DES implantation
140

Results
Balloon sizing (BS) IVUS criteria Angiographic IVUS Study design
CLOUT 1997 (MLD + If PTCA balloon size was already MLA 2.21 ± 0.47 MLA 4.52 ± 1.14, p < 0.001 155 pts; observational study;
MVD)*0.5 in the equal to BS obtained according to Acute gain 0.20 Acute gain 0.26, p < 0.001 only postprocedural endpoints
proximal and distal the formula, no further dilatation
segment performed (27 % lesions)
MUSIC 1998 IVUS used for 1. Complete apposition against the MLD 2.90 ± 0.36; MLD 3.10 ± 0.40 161 pts; observational
evaluation of vessel wall of the entire stent. Acute gain 1.79 ± 0.39
appropriate stent (a) MLA ≥90 % of the average 7 months TLR: 5.7 %
apposition reference lumen area or
SIPS 2000 (MLD+MVD)*0.5 in ≥100 % of lumen area of the MLD 2.38 ± 0.67; MLD 2.49 ± 0.66, p = 0.12; 269 pts, randomized
the proximal and reference segment with the Acute gain 1.67 ± 0.76 Acute gain 1.85 ± 0.72; prospective; 6 months
distal segments lowest lumen area. p = 0.02 angiographic and 2 years
(b) MLA >9.0 mm2. clinical FU
2 years clinical FU: clinically driven TLR
(c) MLA ≥80 % of the average
reference lumen area or 43 % 21 %, p = 0.02
≥90 % of lumen area of the
reference segment with the
lowest lumen area.
2. Symmetric stent expansion
CRUISE 2000 No detailed IVUS Post procedure IVUS analysis in MLD 2.59 ± 0.43 MLD, 2.96 ± 0.55, 525 pts, multicenter
criteria the core lab MLA 7.06 ± 2.13 p < 0.001 prospective observational
MLA 7.78 ± 1.72 IVUS substudy
9-month FU
TLR 15.3 % TLR 8.5 %, p < 0.05
BEST 2003 Balloon diameter IVUS criteria for crossover to IVUS-guided PTCA Stent 254 pts, multicenter,
closest to the vessel stent: >30 % stenosis or MLA MLD 2.55 ± 0.49 MLD 2.75 ± 0.49, p = 0.013 randomized
diameter (EEM mean <6 mm2 MLA 6.60 ± 2.05 MLA 7.28 ± 2.22, p = 0.02
diameter)
6-months FU: no significant angiographic and MACE
differences
R. Graning
 8

RESIST 1998 Stent CSA >80 % of the mean MLD 2.46 ± 0.46 MLD 2.57 ± 0.41 155 pts; multicenter,
proximal and distal reference Acute gain 1.45 ± 0.53 Acute gain 1.62 ± 0.43, randomized, single-blinded
vessel CSA MLA 7.16 ± 2.48 p = 0.04
Only 77 % of pts with adequate MLA 7.95 ± 2.21, p = 0.04
angiographic result satisfied IVUS 6-months FU
criteria
Restenosis 28.8 % Restenosis 22.5 %, p = 0.25
MLA 4.47 ± 2.59 MLA 5.36 ± 2.81, p = 0.03
OPTICUS 2001 MUSIC criteria for optimal stent MLD 2.91 ± 0.41 MLD 3.02 ± 0.49; p = 0.01 550 pts; multicenter,
Intravascular Ultrasound

implantation achieved in only Acute gain 1.91 ± 0.66 Acute gain 2.07 ± 0.50; randomized
56 % of patients p < 0.0001
MLA 8.10 ± 2.30
6-months FU
Binary restenosis 22.8 % Binary restenosis 24.5 %,
Late loss 1.00 ± 0.58 p = 0.68
Late loss 1.07 ± 0.62;
p = 0.20
TULIP 2002 1. Complete stent apposition; MLD 2.80 ± 0.31 MLD 3.01 ± 0.40, p = 0.008 150 pts, multicenter,
2. MLD ≥80 % of the mean of Acute gain 1.81 ± 0.45 Acute gain 2.04 ± 0.62, randomized
prox and distal reference p = 0.045
diameters; MLA 6.00 ± 3.30
3. MLA ≥ distal reference lumen 6-months FU
area. Criteria accomplished in
Binary restenosis 46 % Binary restenosis 23 %,
89 % of patients
Late loss 1.33 ± 0.55 p = 0.008
TLR 10 % Late loss 1.20 ± 0.51,
p = NS
TLR 3 %, p = 0.037
AVID 2000 1. MLA ≥90 % of distal minimal MLD 2.89 ± 0.51 MLD 2.95 ± 0.49, p = 0.15 800 pts, multicenter
vessel lumen CSA; MLA 6.90 ± 2.43 MLA 7.55 ± 2.82, p = 0.001 randomized
2. Stent fully apposed; Dissections 12 months FU
covered by stent Criteria
TLR 10.1 % TLR 4.3 %, p = 0.01
accomplished only in 48 %
patients
(continued)
141
Table 8.2 (continued)
142

Results
Balloon sizing (BS) IVUS criteria Angiographic IVUS Study design
AVIO 2012 Median vessel The diameter of the NC post MLD angiography 2.51 ± 0.46 284 pts, multicenter
media-to-media dilatation balloon is chosen on the MLD IVUS 2.7 ± 0.46, p = 0.0002 randomized, complex lesions
diameters at different basis of the average media-to- 24 months FU (bifurcations, long lesions,
sites in the stent media diameters of the vessel at MACE, cardiac death, MI, TLR, TVR NS between CTO, or small vessels)
segment different points of the stented area groups
NC balloon: 2.25, Criteria for optimal stent
2.5, 3, 3.5, 4, 4.5 mm implantation achieved in only
AOR: 3.5, 4, 6, 8, 10, 48 % of patients
12 mm2, respectively
ADAPT DES No detailed IVUS IVUS use was associated with 12 months FU 8,583 pts, multicenter
2014 criteria larger diameter devices, longer Stent thrombosis: 0.6 % IVUS 1 % angiography (AHR randomized, unrestricted
stents, and/or higher inflation 0.4, 95 % CI 0.21–0.73; p 0.003) population
pressures in 74 % of IVUS cases MI: 2.5 % IVUS 3.7 % angiography (AHR 0.66, 95% CI
0.49–0.88; p 0.004)
MACE: 3.1 % IVUS 4.7 % angiography (AHR 0.7, 95%
CI 0.55–0.88; p 0.002)
Modified and updated from Rogacka et al. [57] with permission
IVUS intravascular ultrasound, MLD minimal lumen diameter (mm), MLA in stent minimal lumen area (mm2), TLR target lesion revascularization, FU follow-up, EEM external
elastic membrane, AOR achievable optimal result, NC non compliant
R. Graning
8 Intravascular Ultrasound 143

length stents and despite this had a significantly

reduced incidence of peri-procedural myocardial
infarction. In addition, spontaneous target vessel
myocardial infarction was significantly reduced
by IVUS guidance as was the combined endpoint
of MACE (cardiac death, stent thrombosis, or
myocardial infarction), and ischemic driven
TLR/TVR with the greatest benefit in patients
with complex lesions (left main, bifurcation,
multivessel, and acute coronary syndromes),
although all IVUS subgroups had better event-
free survival during follow-up. On multivariate
propensity adjusted analysis, IVUS was a strong
independent predictor for stent thrombosis, sub-
sequent myocardial infarction, and MACE with
significant decreased rates compared with angi- Fig. 8.14 Stented vessel. The stent is well opposed and
ography alone. fully expanded in this image (Courtesy of Boston Scientific)
A recent meta-analysis [36] evaluated 3 ran-
domized trials and 12 observational studies com-
paring IVUS guided to angiographic guided
DES. A total of 24,849 patients (11,793 IVUS
guided and 13,056 angiography guided) were
included. IVUS guided DES was associated with
a 21 % reduction in the risk of MACE and a 36 %
reduction in the risk of mortality compared with
angiography guided DES. This is similar to a pre-
vious meta-analysis [37] which showed a 41 %
reduction in mortality with IVUS guidance. In
addition, IVUS guided PCI was associated with a
significant reduction in MI, TVR, TLR, and stent
thrombosis compared with angiography guided
PCI. Table 8.1 highlights the major recent meta-
analysis of the use of Ivus in the DES era.
Overall, the data demonstrates that IVUS guid-
ance results in the use of larger balloons/stents
without any increased risk of peri-procedural Fig. 8.15 In-stent restenosis. Note the concentric layers
echogenic fibrotic tissue within the stent (Courtesy of
MI. In addition, IVUS use tends to change an
Boston Scientific)
operators planned procedure the majority of the
time, typically resulting in the use of larger post-
dilation balloons and longer stents. During fol- and 8.20 demonstrate the role of IVUS in guiding
low-up, IVUS use is associated with a significant stent implementation.
reduction in spontaneous myocardial infarction,
target vessel and lesion revascularization, and
reduced stent thrombosis. Much of these benefits IVUS Guided PCI in Unprotected LM
are likely derived from a reduction in malapposi- Lesions
tion and under-deployment of stents as well as
recognition of distal and proximal edge dissec- Percutaneous revascularization of unprotected left
tions. Figures 8.14, 8.15, 8.16, 8.17, 8.18, 8.19, main coronary stenosis is becoming more frequent
144 R. Graning

Fig. 8.18 Chromaflow feature on Volcano IVUS catheter

showing a well apposed stent (Courtesy of Volcano
Fig. 8.16 Multiple layers of stent (Courtesy of Boston
Corporation)
Scientific)

Fig. 8.17 Unopposed stent. Note the significant malappo-

sition from 12 to 7 o’clock (Courtesy of Boston Scientific)
Fig. 8.19 Chromaflow feature on a Volcano IVUS cath-
eter showing an unopposed stent (Courtesy of Volcano
particularly in high risk surgical patients, in a Corporation)
large part due to many of the registries demon-
strating favorable outcomes. Randomized studies can understandably be devastating, optimization
as well as a meta-analysis comparing surgical of procedural results with IVUS has been advo-
revascularization with drug eluting stents have cated by many with the hope of improving both
demonstrated comparable rates of major adverse short and long term outcomes. While many regis-
cardiac and cerebrovascular events, a lower risk tries have shown potential benefit [39–41] there is
of stroke, and a higher risk of target vessel revas- a lack of randomized studies. Therefore, recom-
cularization [38]. Because the complications mendations are mostly supported by expert opin-
associated with stent placement in LMCA lesions ion. The 2011 ACC/AHA PCI guidelines [6] give
8 Intravascular Ultrasound 145

Fig. 8.20 Angiograms show the vessel prior to (left) and following stent placement (right). Follow-up IVUS demon-
strates a small proximal edge dissection which was not seen on angiography (Courtesy of Boston Scientific)

a Class IIb recommendation to IVUS guidance percutaneous revascularization of the

in left main lesions. LMCA. Five hundred five of these patients
The MAIN-COMPARE (Revascularization (30.2 %) underwent IVUS guidance and using a
Unprotected Left Main Coronary Artery Stenosis: propensity score-matching method 505 patients
Comparison of Percutaneous Coronary without IVUS guidance were compared over
Angioplasty Versus Surgical Revascularization) 3 years of follow-up. Similar to studies of IVUS
registry is the largest study to date looking at guidance of non-LMCA lesions, patients in this
IVUS guidance compared with angiographic registry with IVUS guidance had use of larger
guidance of LMCA lesions. In the 201 propensity balloons and stents. Importantly, of those patients
score matched patients during the 3 years of fol- undergoing a two stent technique, the side branch
low-up, there was a trend toward a reduction in balloon and stent were also larger in the IVUS
mortality with the use of IVUS (6.0 % versus group. Overall mortality was significantly
13.6 %, HR 0.54, p = 0.063). Of the 145 patients reduced in the IVUS group (7.4 % versus 13.0 %,
who received a DES, there was a significant p = 0.01) as was the combined endpoint of death
reduction in mortality with IVUS guidance (4.7 % + MI + TLR (14.4 % versus 22.2 %, p = 0.006)
versus 16.0 %, HR = 0.39, p = 0.048) however no which was driven primarily by mortality. Stent
benefit in the BMS IVUS guided group. When the thrombosis was also significantly reduced in the
outcomes were rigorously adjusted by propensity IVUS group (0.6 % versus 2.2 %, p = 0.04).
score, the conclusions of the trial were that the Importantly, the combined endpoint of death +
risk of 3-year mortality for IVUS guidance was MI + TLR was also significantly reduced in the
about 60 % lower than that for angiography- sub-group of patients with distal LMCA lesions
guidance in the matched population [40]. and in the sub-group who were treated with a two
A recently published pooled analysis of four stent technique despite the smaller overall num-
national registries of LM revascularization ber of patients in these groups, again driven pri-
showed similar results to the MAIN-COMPARE marily by a reduction in mortality [42].
study. A total of 1,670 patients were included in While the mechanism of improved mortality in
this analysis of patients who had undergone IVUS guided LMCA DES is not specified, a leading
146 R. Graning

hypothesis is that improved stent apposition and another registry, 758 patients with non-left main
reduced under-expansion lead to reductions in stent coronary bifurcation lesions with propensity
thrombosis. While there are currently no random- score matching were analyzed. IVUS guided
ized prospective trials on IVUS guided LMCA stenting significantly reduced the long term all-
revascularization, the available data strongly sug- cause mortality (HR 0.31, p = 0.008) in the total
gest a clinical benefit in its use. As opposed to IVUS population and in patients receiving DES (HR
guided non-LMCA interventions for BMS and 0.24, p = 0.03) but not in patients receiving
DES where the benefit is greatest for a reduction in BMS. Very late stent thrombosis was also reduced
target lesion revascularization, restenosis, and myo- in patients receiving DES with IVUS guidance
cardial infarction the benefit in IVUS guided LMCA compared with angiographic guidance (0.4 %
PCI comes predominantly from a reduction in mor- versus 2.8 %, p = 0.03) [48].
tality and likely stent thrombosis. Prior to undergoing intervention, IVUS has
also been evaluated as a potential tool to predict
side branch occlusion. Two hundred eighty-eight
IVUS Guided PCI in Bifurcation patients with a bifurcation stenosis undergoing
Lesions DES placement using a single stent provisional
side branch technique were evaluated by IVUS
Bifurcation lesions represent a challenging sub- prior to intervention. Independent IVUS predic-
set of patients treated in the catheterization lab. In tors for an ischemic FFR of the side branch
a large registry of bifurcation lesions treated per- (<0.80) after stenting were MLA of the side
cutaneously side branch occlusion (TIMI flow branch ostium before PCI, MLA within the main
<3) occurred 8.4 % of the time. Angiographic branch just distal to the carina, and plaque burden
predictors of occlusion were pre-procedural per- at the side branch ostium before PCI. The best
cent diameter stenosis ≥50 % of the side branch cutoff of MLA within the side branch ostium
and proximal main vessel, side branch lesion before PCI was 2.4 mm2 (sensitivity 94 %, speci-
length, and acute coronary syndrome [43]. Based ficity 69 %) [49]. Using a pre-PCI side branch
on multiple, large, prospective trials a single- MLA of ≥2.4 mm2 provisional side branch inter-
stent strategy with provisional side branch inter- vention can usually be deferred. However if the
vention has become the favored approach for MLA is <2.4 mm2 clinical judgment or additional
most bifurcation lesions [44–46]. evaluation, such as with FFR, should be used to
There have been a handful of registries which guide side branch intervention.
have looked at IVUS to either predict side branch
closure or assess its clinical impact to guide stent
placement in non-left main bifurcation lesions. Radiofrequency IVUS
From a registry of 1,668 patients who had under-
gone bifurcation stenting, 487 patients with While traditional gray scale IVUS uses the return-
IVUS guidance and 487 patients with angio- ing ultrasound waveform to generate an axial
graphic guidance were matched using propensity image, radiofrequency IVUS uses backscatter sig-
scoring. Patients with IVUS guidance more often nal analysis as well as amplitude data from the
underwent a two stent technique despite similar intravascular ultrasonograpic signal in order to
angiographic characteristics. Maximal stent characterize plaque composition (See Figs. 8.21
diameters at both the main vessel and the side and 8.22). These tissue types have been correlated
branch were larger in the IVUS-guided group. with data from histologic samples [50, 51]. In
The incidence of death or myocardial infarction addition, pathological studies have shown that
was significantly lower in the IVUS-guided thrombotic coronary occlusion after rupture of a
group (3.8 % versus 7.8 %, p = 0.03) as was the lipid-rich atheroma with only a thin fibrous layer
peri-procedural creatine kinase-MB elevation of intimal tissue covering the necrotic/lipid laden
>5× UNL (7.9 % versus 13.0 %, p = 0.02) [47]. In core (thin cap fibroatheroma, or TCFA) is the
8 Intravascular Ultrasound 147

rupture, the so called “vulnerable plaque” is a

potential way to reduce the incidence of myocar-
dial infarction and cardiac death. Radiofrequency
IVUS is one of the modalities that have been eval-
uated for the detection of TCFA. Major limita-
tions of the current radiofrequency-based IVUS
imaging technologies included the inability to
accurately detect thrombus, to characterize plaque
behind calcium due to shadowing, and the limited
resolution which makes accurate detection of a
thin fibrous cap <65 um not possible [55].
The PROSPECT (Providing Regional
Observations to Study Predictors of Events in the
Coronary Tree) study was a prospective trial that
evaluated both gray scale and radio frequency
backscatter analysis to predict future coronary
Fig. 8.21 Virtual Histology (VH) IVUS. Using backscat- events. Six hundred ninety-seven patients present-
ter signal analysis, plaque is characterized into four differ- ing with acute coronary syndrome underwent PCI
ent categories which have been correlated with histologic of all of the culprit lesions. Following this, gray
samples [50, 51]. These plaque types are fibrotic (dark
scale and radiofrequency intravascular ultraso-
green), fibrofatty (light green), necrotic core (red) and
dense calcium (white). This plaque is predominantly nography was performed on the left main and the
fibrotic and fibrofatty with very little necrotic core and proximal 6–8 cm of each of the major epicardial
dense calcium (Courtesy of Volcano Corporation) coronary arteries in addition to standard angiogra-
phy. Patients were followed for a median of
3.4 years with a primary composite endpoint of
cardiac death, cardiac arrest, myocardial infarc-
tion, or re-hospitalization due to unstable angina.
During follow-up, the cumulative rate of the pri-
mary end point was 20.4 %. Events were second-
ary to culprit lesions (i.e. those originally treated
at study entry) in 12.9 % of patients and to
non-culprit lesions in 11.6 % of patients. Most
non-culprit lesions were angiographically mild at
baseline (mean diameter stenosis 32.3 ± 20.6 %).
On multivariate analysis, independent predictors
of future coronary events in non-culprit lesions
were plaque burden ≥70 % (HR 5.03, p = <0.001),
MLA ≤4.0 mm2 (HR 3.21, p = 0.001), or presence
of thing-cap fibroatheroma as defined by radiofre-
quency analysis (HR 3.35, p < 0.001). In patients
with the presence of all three findings event rates
were 18.2 % during follow-up as opposed to
Fig. 8.22 VH-IVUS showing a plaque composed of pre-
1.9 % in patients without any of these features.
dominantly necrotic core and dense calcium (Courtesy of
Volcano Corporation) While this is a significant difference, the authors
were quick to point out that the overall specificity
most common cause of myocardial infarction and of these findings was insufficient as a means of
death from cardiac causes [52–54]. Therefore, identifying sites in the coronary vasculature
identification of and treatment of TCFA prior to for potential intervention. Of the 595 TCFAs
148 R. Graning

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 Optical Coherence Tomography
9
Amr E. Abbas and Justin E. Trivax

Abstract
Coronary angiography alone is often insufficient in the evaluation of coro-
nary artery disease (CAD). In certain scenarios, more information is
required before and after percutaneous coronary revascularization (PCI).
Determination of degree of calcification may be important to determine if
further vessel modification is required with either higher pressure non-
compliant balloons and/or mechanical rotablation atherectomy. Longer
stent length may be necessary if there is lipid rich plaque at the margins of
the lesion being treated. Ambiguities of angiography may need to be fur-
ther delineated prior to committing to PCI. After PCI, determination of
stent results maybe suboptimal with angiography alone with significant
limitations involving stent malapposition or underexpansion, proximal or
distal dissections, and angiographic haziness due to clot or tissue prolapse.
This chapter will highlight the role of OCT in coronary artery disease and
intervention.

Keywords
Optical coherence tomography (OCT) • Optical coherence technology •
OCT and image display • OCT and percutaneous coronary intervention
(PCI) • OCT and intravascular ultrasound (IVUS)

A.E. Abbas, MD, FACC, FSCAI,

Introduction
FSVM, FASE, RPVI (*)
Department of Cardiovascular Medicine, Coronary angiography alone is often insufficient
Beaumont Health, Oakland University/William in the evaluation of coronary artery disease
Beaumont School of Medicine, Royal Oak, MI, USA
(CAD). In certain scenarios, more information is
e-mail: [email protected]
required before and after percutaneous coronary
J.E. Trivax, MD, FACC, FSCAI
revascularization (PCI). Determination of degree
Department of Cardiovascular Medicine,
Beaumont Health System, Birmingham, MI, USA of calcification may be important to determine if
e-mail: [email protected] further vessel modification is required with either

© Springer-Verlag London 2015 153

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_9
154 A.E. Abbas and J.E. Trivax

higher pressure non-compliant balloons and/or travelling to the patient (sample arm) and another
mechanical rotablation atherectomy. Longer stent travelling a predefined distance (reference arm).
length may be necessary if there is lipid rich After leaving the tissue, the two arms are col-
plaque at the margins of the lesion being treated. lected and combined by a detector. Interference
Ambiguities of angiography may need to be fur- occurs when the distance travelled by both arms
ther delineated prior to committing to PCI. After are roughly equivalent generating a pattern of
PCI, determination of stent results maybe subop- high and low intensities that are analyzed by the
timal with angiography alone with significant OCT system to determine the amount of back-
limitations involving stent malapposition or scatter in relation to the delay time (and thus
underexpansion, proximal or distal dissections, depth of tissue) and known as A lines. The axial
and angiographic haziness due to clot or tissue range over which an OCT image can be obtained
prolapse. This chapter will highlight the role of is termed ranging depth and ranges between 4
OCT in coronary artery disease and intervention. and 6 mm and for circular images, the total width
of the image is twice that value (8–12 mm).
Prior to this technique, intravascular ultra-
Optical Coherence Technology sound (IVUS) was readily available to assess
coronary arteries. The superior resolution of
Optical coherence tomography (OCT) provides OCT is limited by its tissue penetration and is
high resolution imaging of tissue microstructure dependent on the spatial resolution. This includes
by recording backscatter and light reflections the axial resolution, which is approximately
from a fiber optic wire while simultaneously 10–20 μm for OCT and is dependent on the
being pulled back and rotating. This technology spectral bandwidth and the lateral resolution that
was originally developed for retinal imaging, is best at the focal point, which is 1–3 mm from
but the clinical applications soon included coro- the catheter and is approximately between 20 and
nary artery imaging. Initial time-domain (TD) 40 μm. Conversely, the axial resolution of IVUS
OCT systems made way for newer, more is typically between 100 and 200 μm. The higher
advanced frequency-domain (FD) OCT with resolution of OCT compared to IVUS provides a
faster frame rates, pullback and acquisition powerful tool in assessment of the intimal layer
times [1–3]. The first commercially available of the coronary vessel in exchange for lower pen-
TD-OCT systems required and a low-pressure etration. Additionally, the use of ultrasound
occlusion balloon with distal flush ports to dis- waves also has the advantage of transmitting
place blood with saline and the acquisition through blood cells without attenuation artifact
phase. Optimal imaging was limited by pro- seen with OCT.
longed occlusion times [4–6]. Currently avail- Refractive index is a property of a material
able FD-OCT systems eliminate the need for that governs the speed of light through the mate-
balloon occlusion and use an injected contrast rial. Because the speed of light is slower in flush-
medium to displace blood. The underlying tech- ing media and tissue than it is in air, the distances
nology is similar to ultrasound where measuring in the images need to be corrected for this delay.
the delay time of optical echoes reflected or OCT manufacturers provide a correction for
backscattered from subsurface structures in bio- refractive index by dividing the distance in the
logical tissues relay structural information as a axial direction in the OCT image by the estimated
function of depth [1]. refractive index of the flushing media and tissue.
The infrared light source emits wavelengths Once corrected, the images may be used to obtain
up to 1250–1350 nm [6, 7] within the near infra- area and length measurements.
red (NIR) range. This higher wavelength limits As a light beam encounters a boundary
tissue penetration to 1–3 mm for OCT versus between two tissues with different refractive indi-
4–10 mm for IVUS. Interferometry refers to the ces (optical impedances), a portion of the light is
collection of light or backscatter by the OCT scattered, and a portion is transmitted. OCT mea-
catheter. The light emitted splits to a portion sures light that is reflected or backscattered from
9 Optical Coherence Tomography 155

the interface and is collected by the catheter. The Image Display Techniques
amount of backscattered light, and therefore the
intensity of the OCT image, is dependent on the As the lens pulls back to map a vessel segment, a
magnitude of the difference in refractive indi- 5 cm long spiral scan is created within less than
ces of the tissues. For larger planar structures 3 s where one pull back creates approximately
with dimensions that are large compared with 270 frames. Each image consists of pixels
the wavelength of light, such as stent struts, the (5 × 19 μm) and lines (each frame consists of 500
reflected light is higher when the object is per- rotational lines. The more lines/frame, the finer
pendicular to the direction of the optical beam. the texture of the image and the higher the frame
Contrast affects the quality of the image and is rate (number of frames/time) the higher the reso-
related to the difference in backscattered intensi- lution. As noted above, the optical resolution of
ties that distinguish an object from other objects OCT is 15 μm axial × 20–40 μm lateral.
and the background. Dynamic range is the differ- Displaying the OCT images can be performed by
ence between the minimal and maximal reflected one of the methods below. Currently, FFR and
signals that can be detected or visualized by the OCT technologies are combined in the
OCT system. The typical dynamic range of OCT ILUMIEN™ OPTIS PCI optimization system (St
systems ranges from 30 to 50 dB (103 –105). OCT Jude Medical, Westford, MA) (Fig. 9.1). The fol-
instruments are often characterized by sensitivity, lowing are the different OCT displays (Fig. 9.2):
which is a parameter describing how faint a back-
scattered signal can be detected, and is typically
in the range of −90 to −110 dB (10−9–10−11). Intensity Scaling
Penetration depth is a term that defines how
deeply within tissue one can obtain OCT image The dynamic range of the OCT signal is too large
data that are higher background noise. As the light to be displayed by conventional display monitors
passes through the tissue, it is attenuated by scat- and as such, are commonly shown as the loga-
tering and absorption. The predominant form of rithm of the OCT signal, which compresses the
attenuation encountered by OCT systems is scat- data range for display.
tering. Highly attenuating tissue, such as lipid,
has a low penetration depth, and therefore, OCT
does not see as deeply within some Color Mapping
lipid-containing plaques. Other tissues, such as
collagen and calcium, have lower attenuation, The OCT signal intensity is mapped to a color
and as a result, OCT can see deeper into these scale that can be displayed on a monitor. The
tissues. For this reason, the penetration depth in common color maps are grayscale (low is black,
arteries depends on tissue type and usually ranges high is white), inverted grayscale, and the sepia
from 0.1 to 2.0 mm using typical OCT NIR light. scale, ranging from black (low OCT signal)
OCT cannot image through blood because blood through brown, gold, yellow and white (high
attenuates the OCT light before it reaches the OCT signal). Less commonly used are color
artery wall. As a result, OCT images are acquired mappings (e.g. rainbow-like) that can bring out
as blood is flushed from the field of view. Image faint details in an image, but also strongly influ-
processing of the OCT image requires manual ence the shape-perception and measurements of
calibration of the OCT system is require prior to the visualized data (Fig. 9.2).
image acquisition. The Z-offset refers to the man-
ually adjustable image calibration of the OCT
system. Adjustment is often dependent on using L-mode Display
the catheter diameter as a reference. A simple 1 %
change in magnitude of the Z-offset can result in An L-mode view is a longitudinal reconstruction
a 12–14 % error in area measurements [5]. These of an OCT pullback dataset at a particular rota-
definitions were obtained from reference [1]. tional angle. As with IVUS, the plane through
156 A.E. Abbas and J.E. Trivax

standards for 3D OCT visualization diagnosis or

measurements (Fig. 9.2).

Co-registration of Three-dimensional
OCT and Cineangiography

Co-registration of cine angiography and 3D OCT

is available by the QAngio® OCT RE system by
Medis Specials (Netherlands) (Fig. 9.2).

Image Acquisition Protocols Using

the FD OCT Catheter

After the catheter (Dragonfly catheter (DUO C7,

and OPTIS), St Jude Medical, Westford, MA) is
removed from the packaging, a 3 cc syringe that
is provided is used to flush with non-diluted con-
trast the side arm of the catheter. The catheter is
then connected to the console and then advanced
over the wire. At least a 6Fr-guiding catheter is
required for FD-OCT imaging. The OCT imag-
ing catheter is advanced distally into the coronary
artery via a standard angioplasty guide wire.
Correct guide catheter position can be confirmed
by manual injection of a small flush bolus through
the guide catheter prior to imaging, if needed.
Automated OCT pullback is performed during
manual contrast injection through the guide cath-
eter using the manifold syringe. Automated OCT
pullback speeds for FD-OCT systems typical
ranges from 10 to 40 mm/s.
Fig. 9.1 OCT ILUMIEN PCI Optimization System
(Courtesy of St. Jude Medical)
Lesion and Stent Morphology
which the longitudinal section is taken should by OCT
intersect the center of mass of the artery or the
lumen. Distance measurements can be made OCT can identify a variety of vascular morpholo-
using the L-mode images when the frame rate gies before or after PCI based on the following
and pullback speeds are known (Fig. 9.2). criteria:
1. Back scatter (high or low) and signal
intensity (rich or poor): Backscattering
Three-dimensional Visualization refers to the signal intensity and the higher
the backscattering, the brighter (signal rich)
3D visualization including cutaway or flythrough the image will appear. Lesion characteristics
views of volume renderings have been utilized to with low backscattering will appear dark
display OCT datasets. At present, there are no (signal poor and vice versa).
9 Optical Coherence Tomography 157

Fig. 9.2 OCT Grey scale, inverted grey scale, Sepia, colored scale (a), L-display (b), 3D display (c), and co-registered
3D OCT and angiographic images (d). The asterisk (*) is wire artifact (From Tearney et al. [1] with permission)
158 A.E. Abbas and J.E. Trivax

Fig. 9.2 (continued)

2. Attenuation (high or low): Attenuation refers characteristics of high attenuation, luminal

to penetration beyond the lumen. In the (and wall) evaluation would be more difficult.
catheterization laboratory, when there is a ves- 3. Borders (sharply or poorly delineated):
sel with a lesion in the wall with low attenua- 4. Shape (focal, linear, layered):
tion, one can evaluate the lumen (and wall) 5. Consistency (homogenous or heterogeneous):
beyond the lesion; whereas if the lesion had 6. Location:
9 Optical Coherence Tomography 159

OCT Coronary Evaluation Prior confined within a higher superficial cap. Thin-
to Percutaneous Coronary capped fibrous atheromas and thicker-capped
Intervention fibrous atheroma can be differentiated by the
thickness of the bright superficial layer, which
Interventional cardiologists who have been using may have implications in plaque vulnerability.
intracoronary imaging were undoubtedly initially Calcific plaques or calcified nodules within
trained using intravascular ultrasound techniques. the vessel wall have low backscatter with low
Because cardiologists have become well versed attenuation therefore appearing dark. Due to the
in traditional cardiovascular imaging such as nature of calcific nodules within the vessel wall,
transthoracic echocardiography, transesophageal the borders of calcium are sharp and
echocardiography, and intravascular ultrasound well-demarcated.
imaging, all of which require understanding of Optical coherence tomography can help dif-
ultrasound physics, many have difficulty with ferentiate if thrombotic burden is platelet rich
image interpretation of light technology. As men- (white thrombus) or red blood cell rich (red
tioned above, the basics of image interpretation thrombus) and is superior to IVUS in thrombus
require understanding two basic concepts of detection [14, 15]. Light does not penetrate
backscatter and attenuation. beyond red blood cells, which is the reason con-
The normal coronary artery has three layers of trast is required to displace the blood. Therefore,
intima, muscular media, and adventitia. Different red blood cell rich thrombus has high attenuation
from intravascular ultrasound, the media is low and high backscatter. If there is a thrombus in the
signal with low attenuation. The intima and lumen, which makes the lumen difficult to evalu-
adventitia are brighter with higher backscatter. ate beyond the thrombus, it is likely to be rich in
Three of the most common vessel features RBC. If there is a platelet rich thrombus, light is
encountered in the catheterization laboratory, able to penetrated beyond the thrombus.
other than the normal vessel, include fibrotic Conversely, white thrombus has lower attenua-
plaque, calcified plaques, and lipid rich plaque. tion and high backscatter.
Fibrotic plaques or fibrotic caps are com- OCT definitions for aneurysms, pseudoan-
monly encountered in the catheterization lab. eurysms, and true vs. false lumen only apply
Fibrotic plaques have high backscatter with low when the EEM can be identified and are as
attenuation therefore appearing diffusely and follows:
homogenously bright with the ability to see True aneurysm: A lesion that includes all layers
clearly beyond the lumen. It has been suggested of the vessel wall with an EEM and lumen
from post-mortem studies [8] that thin fibrous area >50 % larger than the proximal reference
caps (<65 um) are vulnerable for rupture. segment.
However, a plaque thickness ranging anywhere Pseudoaneurysm: Disruption of the EEM, usu-
from 50 to 90 um has potential for rupture at the ally observed after intervention.
shoulder [9, 10]. OCT has demonstrated that True versus false lumen: A true lumen is sur-
statins have the ability to thicken and stabilized rounded by all three layers of the vessel;
fibrous caps [11]. intima, media, and adventitia. Side branches
Inflammation of the intimal lining may pro- communicate with the true, but not with the
duce strong optical signals through a lipid rich false lumen. A false lumen is a channel, usu-
layer of macrophages [12, 13]. Densely infil- ally parallel to the true lumen that does not
trated macrophages on the surface of plaque may communicate with the true lumen over a por-
scatter light signal and appear as dark shadow tion of its length.
and be misinterpreted as a thin-cap fibroather- Table 9.1 delineates the most common lesions
mona creating a superficial optical artifact. Lipid identified by OCT as outlined in the consensus
rich plaques within the vessel wall have low document. Figures 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,
backscatter with low attenuation and typically 9.10, 9.11, and 9.12 reveal different native vessel
appear as if there is a pool of darkness, which is pathologies on OCT.
160 A.E. Abbas and J.E. Trivax

Table 9.1 Lesion morphology by OCT

Lesion OCT characterization
Normal vessel wall or Intima: high backscatter, signal-rich, Media: low backscatter, signal poor,
intimal thickening Adventitia: heterogonous high backscatter, signal rich, Periadventitial: large clear
(Fig. 9.3) structures (adipocytes)
Internal (intima and media boundary) and External (medial and adventitia boundary)
elastic lamina: appear as highly back scattering thin structures
Atheroma Mass-like (focal) lesion, or less of a layered structure of a vessel wall, IEL and EEL
may or may not be visualized
Fibrous plaque (Fig. 9.4a) High backscattering and a relatively homogenous signal
Fibrocalcific plaque Evidence of fibrous tissue (defined previously), along with calcium that appears as a
(Fig. 9.4c) signal-poor or heterogeneous region with a sharply delineated border (leading,
trailing, and/or lateral edges). Microcalcifications are not well defined
Necrotic core/lipid core Signal-poor region within an atherosclerotic plaque, with poorly delineated
borders, a fast signal drop-off, and little or no OCT signal backscattering, within a
lesion that is covered by a fibrous cap. It may also contain OCT evidence of
cholesterol crystals. Certain plaque components such as macrophages, which have a
high attenuation, may reside at the surface of a plaque and generate the appearance
of a signal- poor region below
Fibrous cap A tissue layer, which is often signal-rich, overlying a signal-poor region
Fibroatheroma OCT-delineated fibrous cap and a necrotic core
OCT-thin capped OCT- delineated necrotic core with an overlying fibrous cap where the minimum
fibroatheroma (TCFA) thickness of the fibrous cap is less than a predetermined threshold (65 μm). Some
(Fig. 9.5) studies have used an additional parameter that the necrotic core should subtend an
arc that is greater than 90° or comprise more than 1 quadrant of an image displayed
in Cartesian coordinates
Macrophage accumulation Signal-rich, distinct, or confluent punctate regions that exceed the intensity of
(Fig. 9.6) background speckle noise. Macrophages should only be evaluated in the context of a
fibroatheroma and may often be seen at the boundary between the bottom of the cap
and the top of a necrotic core. Macrophages attenuate the IVOCT light significantly,
and as a result, superficial macrophages can shadow underlying tissue, giving it the
appearance of a necrotic core. Macrophage accumulations may also be confused on
occasion with microcalcifications, cholesterol crystals, or IEM and EEM
Intimal vasculature Signal-poor voids that are sharply delineated and can usually be followed in multiple
(Fig. 9.7a) contiguous frames
Cholesterol crystals Thin, linear regions of high intensity, usually associated with a fibrous cap or
(Fig. 9.7b) necrotic core
Thrombus A mass attached to luminal surface or floating within the lumen of 2 types
Red (red blood cell–rich) thrombus: which is highly backscattering and has a
high attenuation (resembles blood) (Fig. 9.8a),
White (platelet-rich) thrombus: which is less backscattering, homogeneous,
and has low attenuation (Fig. 9.8b)
Dissections (Fig. 9.11) Tissue flap, which may be intimal, medial, adventitial, intramural hematoma, or intra
stent
Plaque rupture (Fig. 9.9a) Intimal tearing, disruption, or dissection of the cap
Plaque ulceration (Fig. 9.10) A recess in the plaque beginning at the luminal-intimal border
OCT erosion (Fig. 9.9b) OCT evidence of thrombus, an irregular luminal surface, and no evidence of cap
rupture evaluated in multiple adjacent frames
Calcified nodule A single or multiple regions of calcium that protrudes into the lumen, frequently
forming sharp, jutting angles
Aneurysms Cavity-like appearance, may be true or false depending on disruption of EEM with a
true and false lumen
9 Optical Coherence Tomography 161

well established. It is more commonly identified

in patients with acute coronary syndromes. In a
study of 73 patients (80 vessels) with tissue pro-
lapse identified with OCT had no clinical events
during the index hospitalization. Based on this
small subset of patients, it appears that non-flow
limiting tissue prolapse appears to be a benign
phenomenon and might not require further treat-
ment [17].

Malapposition

Because light physically cannot penetrate metal-

lic structures, OCT only shows the endoluminal
aspect of the stent strut. To be classified as malap-
Fig. 9.3 Normal vessel architecture on grey scale OCT posed, the strut must not be in contact with the
(From Tearney et al. [1] with permission) vessel wall. Malapposition is present if the strut
center reflection to vessel wall distance was
greater than the sum of stent strut thickness, the
Coronary Evaluation After polymer thickness, and the axial resolution of
Percutaneous Coronary OCT (varying from 10 to 20 mm). There is now
Intervention data to support that leaving the catheterization
laboratory with malapposition is a predictor for
While coronary evaluation prior to percutaneous late and very late stent thrombosis [18]. Stent
coronary intervention is helpful for vessel sizing, malapposition was diagnosed 39 % versus 14 %
determination of degree of calcium, and plaque (p < 0.001) when using OCT versus IVUS,
vulnerability, optical coherence tomography is respectively [16].
superior to all other available imaging modalities
evaluation after stenting. Due to the high axial
resolution of optical coherence tomography, the Dissections
ability to identify pathology after stenting that
was previously invisible, is now possible. Certain Plaque fracture is essential for vessel modification
pathologies can be identified as follows. during angioplasty for lumen enlargement. During
stent implantation, dissection may occur at the
transition of the rigid stent strut and the adjacent
Plaque Protrusion vessel wall. Dissection has been associated with
early stent thrombosis and adverse cardiac events
In a study evaluating post-stent lesions with both and are almost never seen with angiography
intravascular ultrasound and intravascular optical unless dramatic. Reported incidences of stent
coherence tomography, tissue protrusion, defined edge dissection range from 5 % to 23 % of the
as plaque protruding through stent struts into percutaneous coronary intervention (PCI) proce-
the lumen was identified 95 % versus 18 % dures as detected by IVUS. The superior resolu-
(p < 0.001) when using OCT versus IVUS, tion of OCT compared with IVUS results in more
respectively [16]. With the utilization of OCT, we frequent recognition of vascular injury during
have identified many more cases of plaque pro- PCI. Many feel that coronary dissections are
trusion, and the clinical impact of tissue prolapse exceedingly difficult to identify and are often
after stenting, when identified by OCT, is not missed. In one study, dissections were identified
162 A.E. Abbas and J.E. Trivax

a b

c d

Fig. 9.4 Different Plaque Compositions on OCT: Mixed plaque with both calcified plaque (red arrows) and
(a) Fibrous Plaque with intact IEM (green arrow) and signal poor plaque with poorly defined margins (yellow
EEM (yellow arrow). (b) Plaque without IEM or IEM arrows). The asterisk (*) is wire artifact(From Tearney
(white arrow). (c) Fibrocalcific plaque with signal poor et al. [1] with permission)
heterogonous lesions with well-demarcated margins. (d)

13 % versus 0 % (p < 0.013) when using OCT ver- Opening distance is the distance from the tip of
sus IVUS, respectively [16]. Dissection severity the flap to the lumen contour along a line pro-
has been defined using several measurements jected through the gravitational center of the
including: depth, length, area, and opening dis- lumen [19]. The severity of a dissection can be
tance. Depth has been defined as the distance also be quantified according to: (1) circumferen-
from the luminal surface to the joint point with the tial extent (in degrees of arc) using a protractor
vessel wall at the base of the flap. Length is the centered on the lumen; (3) length using motorized
distance from the tip of flap to the joint point of transducer pullback; and (4) size of residual
the flap with the vessel wall. Area is identified lumen (CSA). Additional descriptors of a dissec-
with planimetry of a region outlined by lumen tion may include the presence of a false lumen,
contours incorporating and interpolating the flap. the identification of mobile flap(s), the presence
9 Optical Coherence Tomography 163

Fig. 9.5 OCT-TCFA a signal poor plaque with poorly

defined margins (yellow arrows) and a thin fibrous cap
(red arrow) (From Tearney et al. [1] with permission)

of calcium at the dissection border, and dissec-

tions in close proximity to stent edges. Dissections
can be classified into five categories [1]:

Intimal: Limited to the intima or atheroma, and

not extending to the media.
Medial: Extending into the media.
Adventitial: Extending through the EEM.
Intramural hematoma: An accumulation of [blood
Fig. 9.6 Inverted grey scale OCT with punctuate high
or] flushing media within the medial space, backscattering focal area consistent with macrophages
displacing the internal elastic membrane (red arrows). The asterisk (*) is wire artifact (From
inward and EEM outward. Entry and/or exit Tearney et al. [1] with permission)
points may or may not be observed.
Intra-stent: Separation of intima or neointimal ter, red blood cell rich thrombus has high attenua-
hyperplasia from stent struts. tion and high backscatter; platelet rich thrombus has
lower attenuation and high backscatter and light is
Because of the 10-μm resolution of OCT, able to penetrated beyond the thrombus. Due to the
small intimal dissections, also termed small inti- spatial resolution of IVUS, small thrombus cannot
mal disruptions, are frequently seen by OCT. The be identified as 13 % versus 0 % were identified
clinical significance of these smaller intimal using both OCT and IVUS, respectively [15].
defects is not known.

Strut Coverage, Restenosis,

Stent Thrombosis and Neoatherosclerosis

In patients presenting with acute stent thrombosis Optical coherence tomography is useful in delin-
(AST), intra-coronary imaging is almost always eating stent strut coverage as well as restenosis
indicated to more clearly delineate the cause of the [1]. We have long theorized the restenosis was
complication. As previously discussed in this chap- exclusively due to dense fibrotic “scar” tissue
164 A.E. Abbas and J.E. Trivax

a b

Fig. 9.7 (a) OCT revealing intimal vasculature (yellow with high backscatter. The asterisk (*) is wire artifact
arrows) with well-defined areas with low backscatter. (From Tearney et al. [1] with permission)
(b) Cholesterol crystals (yellow arrows) with linear areas

a b

Fig. 9.8 Thrombus characterization by OCT. (a) Red and low attenuation (white arrow). The asterisk (*) is wire
thrombus with high backscatter and attenuation (yellow artifact (From Tearney et al. [1] with permission)
arrow). (b) White thrombus with homogenous backscatter

growing on the endoluminal surface of the capped fibroatheromas between the previously
previously placed stents. With the utilization of placed struts and the lumen, and even ruptured
OCT, restenosis is seen not only as fibrous thick- caps with platelet rich thrombus within stents
ening (signal rich band without attenuation), but [20]. These OCT findings have broadened our
there is also evidence of neoatherosclerosis knowledge regarding late stent thrombosis,
within this fibrous plaque seen as lipid plaque which is not exclusively due to exposed stent
with signal-poor region and invisible struts, thin- struts without endothelialization, but also due to
9 Optical Coherence Tomography 165

a b

Fig. 9.9 (a) Plaque rupture with a broken cap (yellow (white arrow). The asterisk (*) is wire artifact (From
arrow) and a cavity (white arrow). (b) Plaque erosion Tearney et al. [1] with permission)
with a white thrombus on an irregular luminal surface

Fig. 9.10 Atherosclerotic

ulcer demonstrated on OCT
sepia axial view and
longitudinal view

vulnerable plaques located within restenotic and fibroatheromas were more common than
fibrous tissue. In one study, neoatherosclerosis fibrocalcific lesions. There were more frequent
was noted in 15 % of lesions, more common in macrophage accumulations but rare microvessels
Paclitaxel versus Sirolimus drug eluting stents, and surface erosions and no plaque ruptures [20].
166 A.E. Abbas and J.E. Trivax

Table 9.2 identifies the variable stent findings OCT for Vessel Sizing
that can be evaluated with the use of and Determination of Ischemia
OCT. Figures 9.13, 9.14, 9.15, 9.16, 9.17, and
9.18 reveal different stent pathologies on OCT. One of the most important decisions prior to
angioplasty and stenting is determination of
appropriate vessel diameter for selection of
appropriate stent and balloon size selection. OCT
utilizes the size of the catheter as a reference. In
the current technologies, the integrated consoles
“auto-calibrate” with the four fiduciaries aligning
to the outermost border of the catheter—a known
size. Using the size of the catheter, the size of the
vessel can then be inferred. For vessel sizing with
OCT, ensuring that the markers are correctly
positioning is crucial as Bezerra et al. have
observed 1 % change in magnitude can result in
up to a 14 % error in area measurements [4].
Therefore, in our lab, a minimum of three cali-
brations, with the catheter in the center of the
Fig. 9.11 OCT demonstration of a dissection flap vessel, is performed to reassess measurements. If

Fig. 9.12 OCT/angiographic demonstration of reference (left red arrow) and stenotic segments (right red arrow)
9 Optical Coherence Tomography 167

Table 9.2 Stent assessment by OCT

Stent abnormality OCT characterization
Tissue prolapse The projection of tissue into the
(Fig. 9.16) lumen between stent struts after
implantation
Malapposition Malapposition is present when
(Fig. 9.13) the axial distance between the
strut’s surface to the luminal
surface is greater than the strut
thickness. Two forms of
apposition have been described
in the literature:
1. Protruding, where the
endoluminal strut boundary
is located above the level
of the luminal surface,
2. Embedded, where the
endoluminal strut boundary
is below the level of the
luminal surface; however, Fig. 9.13 Post-stenting with stent malposition noted
the clinical significance of
this classification is unclear
Stent thrombosis As above
Dissection As above
Strut coverage Struts are termed covered by
(Fig. 9.17a, b) OCT if tissue can be identified
above the struts. Struts are
dubbed uncovered by IVOCT if
no evidence of tissue can be
visualized above the struts
Restenosis Signal-poor, layered, or
(Fig. 9.17c, d) signal-rich tissue overlying stent
struts
Bioabsorbable The amount of backscattering
scaffolds detected from the struts and the
underlying vessel wall will vary.
One classification includes
(preserved box, open box,
dissolved bright box, and
dissolved black box) for one
type of bioabsorbable scaffold
Neoatherosclerosis In stent OCT-TCFA with Fig. 9.14 Following post dilatation with a larger non-
variable cap thickness, thrombi, compliant balloon revealing well apposed stent
intimal disruption

intravascular OCT measured a catheter size of

the catheter is touching the endoluminal surface 3.06 mm. Furthermore, in this study, intraobserver
of the vessel it is difficult to determine the outer variability is much improved with OCT when
edge and measurements may be under or compared to IVUS.
overestimated. With the safety and feasibility of FFR to assess
When compared with intravascular ultra- hemodynamic significance of a stenosis, ana-
sound, OCT provides vessel sizing more accu- tomic measurements should not be used for
rately [16]. In an in-vitro phantom model of a assessment of ischemia. However, studies over
known catheter measuring 3.08 mm, IVUS the past two decades have suggested that a mean
measured a catheter size of 3.27 mm, whereas luminal area of less than 4 mm2 correlated well
168 A.E. Abbas and J.E. Trivax

Fig. 9.15 Overlapping stents

noted on OCT (From Tearney
et al. [1] with permission)

are trying to determine the “OCT-equivalent” of

the IVUS data. Despite several limitations of this
technique including the difference of proximal
versus distal vessels, vessels supplying infarcted
myocardium, vessels supplying more than on
coronary territory (collaterals), and different size
vessels in patients of varying body habitus,
Shiono et al. studied 62 intermediate stenoses
with fractional flow reserve and OCT [21]. An
OCT derived mean luminal area of 1.91 mm2 had
the best cut-off values for fractional flow reserve
of less than 0.75.
To date, unlike IVUS, there have been no
definitive studies using an OCT-determined MLA
of the left main coronary artery to determine
hemodynamic significance. However, without
definitive data and increasing use of this technol-
Fig. 9.16 Tissue prolapse at proximal edge of stent
(From Tearney et al. [1] with permission) ogy in the catheterization lab, could surmise that
the currently accepted IVUS value of 4.0 mm2
would be lower with OCT and therefore, if an
with both coronary flow reserve of less than 2.0, OCT-derived value of the left main is 4.0 mm2 or
FFR < 0.75, and ischemia on a single-photon greater, PCI could safely be deferred at this time.
emission CT. Many interventional cardiologists Future studies are required to confirm this notion.
9 Optical Coherence Tomography 169

a b

c d

Fig. 9.17 (a) OCT demonstrating stent strut coverage. intensity in-stent restenosis. (d) OCT with in-stent reste-
(b) OCT demonstrating covered (yellow box) and uncov- nosis and high back scattering neointima. The asterisk (*)
ered (green box) stent struts. (c) OCT with low signal is wire artifact (From Tearney et al. [1] with permission)

OCT Versus IVUS Assessment better depiction of neointimal hyperplasia. In

of Coronary Artery Disease addition, OCT Malapposition and tissue pro-
and Percutaneous Coronary lapse were more frequently identified by OCT
Intervention Results [22].

OCT appears to depict more severe native coro-

nary artery disease compared to IVUS with Artifacts
smaller minimal lumen area (MLA)
(2.33 ± 1.56 mm2 versus 3.32 ± 1.92 mm2, respec- Several artifacts may be encountered with
tively p < 0.001) with similar reference vessel OCT and knowledge of their characteristic
diameter. Immediately post-PCI, FD-OCT and appearance may help further guide image
IVUS had similar MLAs, however, at follow up interpretation. Artifacts are highlighted in
MLA was smaller with OCT versus VUS due to Table 9.3.
170 A.E. Abbas and J.E. Trivax

a b

Fig. 9.18 3D OCT demonstrating stent fracture (yellow arrows) (From Kim et al. [28] with permission)

Fig. 9.19 Suboptimal flushing with blood in lumen

(From Tearney et al. [1] with permission)
Fig. 9.20 OCT NURD artifact (arrows). The asterisk (*)
is wire artifact (From Tearney et al. [1] with permission)
Limitations
renal insufficiency, although the average amount
TD-OCT left a concern that balloon occlusion for of contrast was found to be around 30 mL in
prolonged periods of time may result in ischemia. recent trials [23, 24].
Manufacturers recommended inflation times less
than 30 s. Some studies suggested that scans per-
formed with occlusive and non-occlusive tech- Future Technology
niques did not result in clinically significant
ischemia or myocardial damage. Non-occlusive Newer versions of OCT have incorporated three-
scanning performed with FD-OCT may be lim- dimensional imaging rendering of coronary ves-
ited by contrast load in patients with baseline sels which can be helpful in ambiguous traditional
9 Optical Coherence Tomography 171

Fig. 9.22 Tangential tissue dropout (white arrows). The

Fig. 9.21 Multiple reflections artifact asterisk (*) is wire artifact (From Tearney et al. [1] with
permission)

a b

Fig. 9.23 (a, b) Wire shadowing artifact, (arrows). The asterisk (*) is wire artifact (From Tearney et al. [1] with
permission)

OCT imaging to determine stent types, stent been used as a tool to assess the severity of mitral
fracture, and longitudinal stent deformation. The stenosis by characterizing pulmonary vasculature
evidence based use of three-dimensional OCT [25]. Evaluation of a patent ductus arteriosus in a
imaging in the catheterization lab has not been patient with congenital heart disease has been
established to date. reported [26]. OCT even provides provide insight
As the scope of endovascular procedures for the evaluation of pulmonary vein stenosis
broadens, so will the use of OCT imaging. It has after radiofrequency ablation [27].
172 A.E. Abbas and J.E. Trivax

Fig. 9.26 Sew up artifact (yellow arrow). The asterisk

(*) is wire artifact (From Tearney et al. [1] with
permission)

Fig. 9.24 Blooming artifact (yellow arrows). The

asterisk (*) is wire artifact (From Tearney et al. [1] with
permission)

Fig. 9.27 Saturation artifact (yellow arrows). The

asterisk (*) is wire artifact (From Tearney et al. [1] with
permission)

Fig. 9.25 Fold over artifact (yellow arrows). The

asterisk (*) is wire artifact (From Tearney et al. [1] with
permission)
9 Optical Coherence Tomography 173

Fig. 9.28 Strut orientation artifact (From Tearney et al.

[1] with permission)

Table 9.3 Artifacts noted on OCT

Artifact OCT characterization
Suboptimal If concentration of red blood cells (RBCs) is high, this may results in scatter and unfocused
flushing with imaged. Blood may be misinterpreted as thrombus (Fig. 9.19)
blood in the lumen
Non-uniform Smearing of the OCT signal in the circumferential direction. It arises from binding of the
rotational drive cable or rotating optical components because of a defective catheter or increased friction
distortion (NURD) on the rotating components from a tortuous vessel, constriction or crimping of the imaging
sheath by a tight hemostatic valve, severe stenosis (Fig. 9.20)
Multiple Reflections may bounce of multiple facets of the catheter, creating circular lines within the
reflections image (Fig. 9.21)
Wire and catheter Eccentric position (closer) to lumen wall may result in increased distance light travels to
positioning with opposite wall–decreasing resolution (scattering). If the catheter is not parallel to the
eccentricity, longitudinal axis of the vessel or the optical beam perpendicular to the vessel wall, elliptical
scattering and/or distortion may occur interfering with accurate measurements
vessel curvature.
Proximity artifact When the catheter is near or touching vessel wall, the grey scale values maybe higher
Tangential signal When the catheter is near or touching vessel wall, the optical beam may be parallel to the
drop out tissue surface and as such, is attenuated as it passes along the wall, which may appear signal
poor (Fig. 9.22)
Shadowing Drops in signal intensity on the abluminal side of the objects by opaque objects as wire, strut,
blood, thrombus, and macrophages. Densely infiltrated macrophages on the surface of plaque
may scatter light signal and appear as dark shadow and be misinterpreted as a thin-cap
fibroatheroma (Fig. 9.23)
Blooming Excess intensity as stent struts creates a bright reflector that is enlarged and smeared along the
axial direction (Fig. 9.24)
Fold over When the vessel is larger than the ranging depth, a portion of the vessel may appear to fold
over in the image (Fig. 9.25)
Speckle Grainy noise within image
Motion/sew-up Rapid movement of the vessel, wire, or catheter may misalign intimal border (Fig. 9.26)
Saturation Reflection of light source off a reflective surface (metal, wire or stent strut) with too high a
back scatter for the detector results in streaking scan lines of different intensity along the axial
direction (Fig. 9.27)
Strut orientation When the catheter is near a stented wall, the struts form a pinwheel pattern appearing to face
artifact the catheter and as been termed “sunflower” or “merry-go-around” artifact (Fig. 9.28)
Data from Tearney et al. [1] and Bezerra et al. [4]
174 A.E. Abbas and J.E. Trivax

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 Intracoronary Imaging for Plaque
Characterization 10
Ryan D. Madder

Abstract
Decades of post-mortem evaluations have demonstrated that the plaques
triggering fatal myocardial infarction have certain distinct morphologic
characteristics. As various intracoronary imaging techniques have been
developed and brought to market, there has been a growing interest to
apply these imaging modalities to detect specific plaque morphologic fea-
tures that may indicate lesion vulnerability. The focus of this chapter will
be to discuss plaque characterization using each of the intracoronary
imaging modalities that are currently available for clinical use in the
United States. These intracoronary imaging modalities include intravascu-
lar ultrasound (IVUS), optical coherence tomography (OCT), and near-
infrared spectroscopy (NIRS). This chapter will provide an overview of
these modalities in plaque characterization.

Keywords
Intravascular ultrasound (IVUS) • Optical coherence tomography (OCT) •
Near-infrared spectroscopy (NIRS) • Imaging for plaque characterization
• IVUS and coronary plaque • OCT and coronary plaque • NIRS and
coronary plaque

Introduction characteristics. As various intracoronary imaging

techniques have been developed and brought to
Decades of post-mortem evaluations have demon- market, there has been a growing interest to apply
strated that the plaques triggering fatal myocar- these imaging modalities to detect specific plaque
dial infarction have certain distinct morphologic morphologic features that may indicate lesion
vulnerability. The focus of this chapter will be to
discuss plaque characterization using each of the
R.D. Madder, MD, FACC intracoronary imaging modalities that are cur-
Department of Cardiovascular Medicine,
Frederik Meijer Heart and Vascular Institute,
rently available for clinical use in the United
Spectrum Health, Grand Rapids, MI, USA States. These intracoronary imaging modalities
e-mail: [email protected] include intravascular ultrasound (IVUS), optical
© Springer-Verlag London 2015 175
A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_10
176 R.D. Madder

coherence tomography (OCT), and near-infrared in length [2]. When imaging a vessel with IVUS,
spectroscopy (NIRS). spotty calcification may be important to recog-
nize, as it has been associated with accelerated
atheroma progression [2] and is found in roughly
Plaque Characterization by IVUS half of culprit lesions in acute myocardial infarc-
tion [4]. Consequently, spotty calcification has
Coronary plaque has traditionally been differen- been proposed as a possible marker of plaque
tiated into several distinct types by grey-scale vulnerability [2, 4].
IVUS. These plaque types include calcified Calcified nodules are evident by IVUS as cal-
plaque, attenuated plaque, fibrous plaque and cium protruding into the lumen and having an
mixed plaque. Of these, calcified plaque and irregular and convex luminal surface [3, 5].
attenuated plaque will be discussed in this chap- Calcified nodules are associated with older age,
ter, due to their association with certain clinical and perhaps surprisingly have been found to be
implications. In addition to these plaque types, associated with severe calcification of the
IVUS may also be used to measure the plaque corresponding angiogram in only 1 % of cases
burden of any given lesion, which has predictive [5]. Rather, calcified nodules are associated with
value for future coronary events and lesion pro- a normal angiogram in over 80 % of cases [5].
gression. Virtual-histology IVUS (VH-IVUS) is Although pathologic studies have identified
another IVUS-based technique capable of differ- calcified nodules as a rare trigger of coronary
entiating plaque into different sub-types and will thrombosis [6], a recent analysis of the
also be discussed in this section. PROSPECT data demonstrated that the presence
of a calcified nodule by IVUS represented an
independent predictor of freedom from future
Calcified Plaque by IVUS coronary events [5].

Calcified plaque by IVUS is evident as highly

echogenic material (bright white) that casts a Attenuated Plaque by IVUS
shadow of attenuation owing to the inability of
the ultrasound signal to penetrate calcium. Attenuated plaque by IVUS is characterized as
Although the thickness of calcium within a attenuation of the ultrasound signal in the absence
plaque cannot be determined by IVUS, calci- of overlying calcification (Fig. 10.2) [7–9]. When
fied plaque can be described by its circumferen- visualized with IVUS, attenuated plaque may in
tial arc of deposition, by the number of some cases represent lipid-rich plaque, as histo-
quadrants in which it is found, by its length on logic analyses have demonstrated attenuated
a longitudinal image of the vessel, by whether plaques by IVUS to contain greater amounts of
its pattern of deposition is consistent with lipid, cholesterol clefts, and necrotic core com-
spotty calcification or a calcified nodule, and by pared to non-attenuated plaques [8, 10]. Although
the depth of deposition within the atheroma attenuated plaque is frequently present at culprit
[1–3]. The depth of calcium deposition is lesions in acute coronary syndromes [11], the
defined as superficial or deep depending on concept that attenuated plaque is a marker of
whether the leading edge of the attenuated sig- plaque vulnerability has been challenged by data
nal is within the shallowest or deepest 50 % of demonstrating the stability of such lesions over
the plaque plus media thickness [1]. The vari- time [12].
ous patterns of calcified plaque by IVUS are Perhaps the most important reason to recog-
shown in Fig. 10.1. nize attenuated plaque by IVUS is that the pres-
The term spotty calcification is defined as an ence of attenuated plaque at the target site prior to
arc of calcification that is <90° and only 1–4 mm percutaneous coronary intervention (PCI) is an
10 Intracoronary Imaging for Plaque Characterization 177

a b

c d

Fig. 10.1 Patterns of coronary calcification by defined as an arc of calcification that is <90° and only
IVUS. Calcification is defined as superficial (a) or deep 1–4 mm in length (c). Calcified nodules defined as cal-
(b) when the leading edge of the attenuated signal is cium protruding into the lumen and having an irregular
within the shallowest or deepest 50 % of the plaque plus and convex luminal surface (d). IVUS intravascular ultra-
media thickness, respectively. Spotty calcification is sound (arrows point to the abnormalities described)

independent predictor of both angiographic no- Plaque Burden by IVUS

reflow and peri-procedural myocardial infarction
[8, 9]. Importantly, the association between atten- Defined as the plaque plus media cross-sectional
uated plaque and these acute PCI-related compli- area divided by the external elastic membrane
cations has been demonstrated in both ACS cross-sectional area [1], plaque burden has been
patients and those with stable angina [8, 9]. demonstrated to be an independent predictor of
Finally, the circumferential extent of attenuation adverse cardiovascular events [14, 15]. More spe-
may also be important in determining the risk of cifically, the presence of a plaque burden ≥70 %
PCI-related complications [7, 13]. was associated with a 9.6 % lesion-specific event
178 R.D. Madder

over 3 years and was the strongest independent

predictor of future events in the PROSPECT trial
[14]. More recently, large plaque burden has been
demonstrated to be an independent predictor of
lesion progression in the PREDICTION study
[16]. A description of how to measure plaque
burden is provided in Fig. 10.3.

Plaque Characterization by VH-IVUS

VH-IVUS, which uses radiofrequency analysis

of backscattered IVUS signals to identify plaque
composition, classifies intracoronary plaque as
fibrotic, fibrofatty, densely calcified, or necrotic
core (Fig. 10.4). These various VH-IVUS plaque
Fig. 10.2 Attenuated plaque by IVUS. Attenuated plaque components are each represented on the image
by IVUS is characterized as attenuation of the ultrasound display by a different color, wherein green repre-
signal (asterisks) in the absence of overlying calcification.
Histologic analyses have demonstrated attenuated plaques sents fibrotic plaque, light green represents fibro-
to contain greater amounts of lipid, cholesterol clefts, and fatty plaque, white represents densely calcified
necrotic core compared to non-attenuated plaques. IVUS plaque, and red represents necrotic core plaque
intravascular ultrasound [17] (Fig. 10.4). A VH-fibroatheroma is defined

Plaque Burden = 66%

Fig. 10.3 Measuring plaque burden by IVUS. An IVUS then calculated as the plaque plus media area divided by
image of an intracoronary plaque is shown (left). In order the EEM area. The presence of a plaque burden ≥70 % is
to measure the plaque burden of this lesion, the EEM associated with a 9.6 % lesion-specific event rate during
(blue line, right) and the lumen (orange line, right) are follow-up and is an independent predictor of both site-
traced. The difference between the EEM cross-sectional specific future events and lesion progression. EEM exter-
area and the lumen cross-sectional area is equal to the nal elastic membrane, IVUS intravascular ultrasound
plaque plus media cross-sectional area. Plaque burden is
10 Intracoronary Imaging for Plaque Characterization 179

Fig. 10.4 VH IVUS plaque characterization: VH IVUS plaques (From Murray [39]. J Am Coll Cardiol Intvn
revealing Fibrous (top left), Fibrofatty (top right), 2013;6:838–846 with permission
Fibrocalcified (bottom left), and necrotic (bottom right)

as a lesion having >10 % necrotic core. If a Prior to performing PCI, plaque characteriza-
VH-fibroatheroma has >30° of the necrotic core tion using VH-IVUS may be useful to assess the
abutting the lumen in three consecutive frames risk of peri-procedural complications during
(approximately 1.5 mm in length) it is considered PCI. The presence of VH-IVUS necrotic core at
a VH-thin cap fibroatheroma (VH-TCFA) [14, the PCI target site has been associated with the
15]. Alternatively, if the necrotic core is not adja- occurrence of angiographic no-reflow, peri-
cent to the lumen, the lesion is considered a procedural myocardial infarction, and distal
VH-thick capped fibroatheroma [14, 15] embolization [18–22]. The concept that necrotic
(Fig. 10.5). VH-IVUS can be used to define sev- core plaque by VH-IVUS is associated with acute
eral additional lesion types, including pathologic PCI-related complications has been further dem-
intimal thickening, fibrotic plaque, and fibrocal- onstrated in a recent meta-analysis [23].
cific plaque, the definitions of which are summa- Apart from its use to assess the risk of peri-
rized in Table 10.1. procedural complications, VH-IVUS has also
180 R.D. Madder

FT
IMT PIT FC

FA Ca FA TCFA CaTCFA

Fig. 10.5 Types of atherosclerotic plaque identified by fibroatheroma, Ca FA calcified thick cap fibroatheroma,
VH. IMT intimal medial thickness, PIT pathological inti- TCFA thin cap fibroatheroma, CaTCFA calcified thin cap
mal thickness, FT fibrotic, FA non calcified thick cap fibroatheroma (From Cheng et al. [40] with permission)

Table 10.1 Lesion classification by VH-IVUS been studied to identify lesions at risk of causing
future coronary events. In the PROSPECT trial,
Lesion type Definition
nearly 700 patients with acute coronary syn-
Pathologic intimal ≥15 % fibrofatty tissue
thickening dromes underwent multi-vessel VH-IVUS
<10 % confluent necrotic
core imaging to identify lesion characteristics predic-
<10 % confluent dense tive of future coronary events [14]. Approximately
calcium half of all patients in PROSPECT were found to
Fibrotic plaque Mainly fibrous tissue have at least one non-culprit VH-TCFA at base-
<10 % confluent necrotic line. Over approximately 3 years of follow-up,
core the presence of a VH-TCFA at baseline was an
<10 % confluent dense independent predictor of subsequent major
calcium
adverse cardiovascular events, most of which
Fibrocalcific plaque Mainly fibrous tissue
were rehospitalizations for unstable or progres-
<10 % confluent necrotic
core sive angina. Despite this finding, the identifica-
>10 % confluent dense tion of a VH-TCFA was associated with a limited
calcium positive predictive value for future events, as only
Thin-cap >10 % confluent necrotic 26 of the 595 VH-TCFAs identified at baseline
fibroatheroma core triggered a recurrent cardiovascular event during
>30 % of necrotic core abuts the 3 years of follow-up. A similarly low lesion-
the lumen in ≥3 consecutive
frames
specific event rate for VH-TCFA was demon-
Thick-cap >10 % confluent necrotic
strated in the VIVA study [15]. This low event
fibroatheroma core associated with a VH-TCFA can be partially
Necrotic core does not abut overcome in the presence of additional plaque
the lumen in ≥3 consecutive characteristics, as lesions characterized as
frames VH-TCFA that also had a minimal luminal area
Data from Bose et al. [21] and Kawamoto et al. [22] of 4.0 mm2 or less and a plaque burden of at least
10 Intracoronary Imaging for Plaque Characterization 181

Fig. 10.6 Plaque rupture by OCT. Shown is an example Fig. 10.7 Calcification by OCT. Calcified plaque by
of plaque rupture of a lipid-rich plaque by OCT. At pres- OCT is defined as the presence a signal-poor region hav-
ent, OCT is the only available intracoronary imaging ing well-defined margins (asterisks). When using OCT, it
modality with sufficient spatial resolution to visualize the is important to recognize that calcification may in some
fibrous cap covering coronary atheroma. Owing to this cases be difficult to differentiate from lipid-rich plaque, as
superb spatial resolution, disruption of the fibrous cap can both plaque types are defined by the presence of signal-
detected by OCT, similar to the example depicted here. poor regions. Calcification and lipid-rich plaque are dif-
OCT optical coherence tomography ferentiated by their margins, which are well-defined in
calcification and are poorly-defined in lipid-rich plaque.
70 % had a lesion specific event rate was 18 % OCT optical coherence tomography
during follow-up [14].
Calcification and Fibrous Plaque
by OCT
Plaque Characterization by OCT
Calcified plaque by OCT is defined as the pres-
Plaque Morphology by OCT ence a signal-poor region having well-defined
margins (Fig. 10.7). It is important to recognize
The unique plaque characterization abilities of that by OCT calcification may in some cases be
intracoronary OCT imaging are attributable to its difficult to differentiate from lipid-rich plaque, as
superb spatial resolution, which is approximately both plaque types are defined by the presence of
tenfold higher than the resolution of IVUS. With signal-poor regions [25]. In contrast to these sig-
an axial resolution of 10–20 μm [24, 25], OCT is nal poor lesions, fibrous plaque by OCT is defined
the only intracoronary imaging modality capable by relatively homogenous signal-rich plaque [24,
of assessing the fibrous cap covering coronary 25]. An example of fibrous plaque visualized by
atheroma [24, 25]. Visualization of the fibrous OCT is demonstrated in Fig. 10.8.
cap allows for detection of plaque rupture
(Fig. 10.6) and for the measurement of fibrous
cap thickness. Although its spatial resolution is Lipid-Rich Plaque and OCT-Derived
superior to that of IVUS, OCT is not able to Thin Cap Fibroatheroma
assess plaque burden in many cases due to a lim-
ited depth of signal penetration. Despite this limi- Lipid-rich plaque is characterized by OCT as
tation, OCT can identify several plaque types signal-poor region with poorly-defined borders
including calcification, fibrous plaque, lipid-rich [24, 25]. In order for a plaque to be considered
plaque, and OCT-derived TCFA. lipid-rich, some studies have required the signal
182 R.D. Madder

Fig. 10.8 Fibrous plaque by OCT. Fibrous plaque by

OCT is defined by relatively homogenous signal-rich Fig. 10.9 TCFA as detected by OCT. Lipid-rich plaque
plaque (asterisks). Unlike lipid-rich plaque and calcifica- is characterized by OCT as signal-poor region with
tion, which can sometimes be difficult to differentiate, poorly-defined borders (asterisks). In order for a plaque to
fibrous plaque is easily recognized by OCT imaging. OCT be considered lipid-rich, some studies have required the
optical coherence tomography signal poor region to extend >90°. In this example the
signal-poor region extends through an angle of nearly
180°. If the fibrous cap overlying the lipid-rich plaque
poor region to extend >90° [26–28]. If the fibrous measures <65 or 70 μm, the plaque is defined by OCT as
a TCFA. The above example is consistent with a TCFA, as
cap overlying the lipid rich plaque measures <65 the fibrous cap, which has ruptured on the right side of the
or 70 μm, the plaque is defined by OCT as a image, is <65 μm in thickness (arrow). OCT optical
TCFA [26–28]. An OCT-derived TCFA is coherence tomography, TCFA thin cap fibroathermoa
depicted in Fig. 10.9.
Consistent with the concept from histopatho- seems to be associated with an increased risk of
logic studies that TCFA are responsible for the peri-procedural myocardial infarction in both
majority of ACS events, OCT studies have ACS and stable angina [26, 27].
detected TCFA at culprit sites in most acute myo-
cardial infarctions [29, 30]. Furthermore, OCT
has identified rupture of the fibrous cap at the cul- Plaque Characterization by NIRS
prit lesion in more than two-thirds of myocardial
infarctions, which is significantly more frequent NIRS Detects Lipid-Core Plaque
that identified by IVUS [31]. Whether the identi-
fication of OCT-derived TCFA at non-culprit Intracoronary NIRS is a catheter-based imaging
sites will allow for the prediction of future coro- technique that has been developed and vali-
nary events has not yet been determined. dated to detect lipid-core plaque in the coronary
Apart from its role in acute coronary syn- arteries [32, 33]. The image produced after per-
dromes, TCFA may be important to identify prior forming a NIRS pullback within an artery is
to PCI. When present at the target lesion prior to termed a chemogram. Oriented with the x-axis
PCI, OCT-derived TCFA is associated with peri- representing longitudinal position in millime-
procedural myocardial infarction in one-half to ters and the y-axis representing circumferential
three-quarters of cases and has been shown to be position in degrees, a chemogram is essentially
the strongest independent predictor of peri- a map of the artery wherein yellow indicates the
procedural myocardial infarction by OCT imag- presence of lipid and red indicates the absence
ing [26, 27]. Furthermore, OCT-derived TCFA of lipid at any given location (Fig. 10.10). In
10 Intracoronary Imaging for Plaque Characterization 183

360°

Circumferential position

0°

Position along the vessel in mm

Fig. 10.10 A NIRS chemogram. An example of a NIRS indicates the absence of lipid and yellow indicates the
chemogram is shown. The chemogram is oriented with presence of lipid at any given location in the artery. In this
the x-axis representing longitudinal position along the example, NIRS has detected large lipid cores located at
vessel in millimeters and the y-axis representing circum- positions of 20–30 mm and at 75–105 mm along the
ferential position around the vessel in degrees. The distal x-axis. NIRS near-infrared spectroscopy
aspect of the vessel is towards the right of the x-axis. Red

addition to generating a chemogram, the NIRS and Peri-procedural Myocardial

currently available NIRS imaging system pro- Infarction
vides simultaneous greyscale IVUS images that
are automatically co-registered with the NIRS The quantity of lipid detected by NIRS at a target
findings, thereby providing information regard- lesion prior to percutaneous coronary interven-
ing both plaque structure and composition tion has been associated with the risk of peri-
(Fig. 10.11) [34]. procedural myocardial infarction. Goldstein et al.
found target lesions that resulted in a peri-
procedural infarct to have a significantly greater
Quantifying Lipid-Core Plaque lipid content as measured by maxLCBI4mm than
by NIRS lesions that did not result in a peri-procedural
infarct [35]. Furthermore, a maxLCBI4mm ≥500 at
Not only can NIRS detect the presence or the target lesion was associated with a 50 % risk
absence of coronary lipid, but NIRS can also of peri-procedural myocardial infarction. In con-
provide an estimate of lipid quantity at any trast, only 4 % of those with a maxLCBI4mm <500
given site within the coronary arteries. Lipid at the target lesion experienced a periprocedural
quantity is reported as the lipid core burden myocardial infarction [35].
index (LCBI), defined as the fraction of pixels
within a region of interest indicating lipid multi-
plied by 1,000 [32, 33]. An additional metric NIRS Findings at Culprit Sites in ACS
describing focal lipid quantity is the maximum
LCBI in a 4-mm sub-segment of the artery In addition to its potential role in assessing the
(maxLCBI4mm) [35, 36]. risk of peri-procedural myocardial infarction,
184 R.D. Madder

Fig. 10.11 Combined NIRS-IVUS imaging. In addition to location of the IVUS image on the NIRS chemogram is dem-
generating a chemogram (right), the currently available onstrated by the vertical green line on the chemogram
NIRS imaging system provides simultaneous greyscale (right). The chemogram at this location is wrapped circum-
IVUS images that are automatically co-registered with the ferentially around the IVUS image (left). The center of the
NIRS findings, thereby providing information regarding both IVUS image contains a color corresponding to the color of
plaque structure and composition. An example of a com- the block chemogram at this location. IVUS intravascular
bined NIRS-IVUS image is shown (left). The corresponding ultrasound, NIRS near-infrared spectroscopy

NIRS has been used to study the lipid content [37]. Future studies will likely test the maxL-
of culprit lesions across the ACS spectrum. CBI4mm ≥400 threshold as a site-specific pre-
Consistent with autopsy findings supporting dictor of future coronary events [38].
the role of lipid core plaque in the pathogenesis
of ACS, NIRS studies have identified lipid-rich Conclusions
lesions at culprit sites in the majority of Different types of plaque morphologies have
patients with unstable angina, non-ST-segment been shown to correlate with variable out-
elevation myocardial infarction, and comes. A multitude of invasive imaging
ST-segment elevation myocardial infarction modalities are currently available for athero-
(STEMI) [36, 37]. In patients with STEMI, sclerotic plaque characterization and are sum-
culprit lesions are frequently characterized by marized in Table 10.2. Whether or not
a maxLCBI4mm ≥400, which is a NIRS thresh- identifying plaque morphology will guide
old that identified the culprit segment in treatment has not been delineated and is a sub-
STEMI with a high sensitivity and specificity ject of current research studies.
 10
Table 10.2 Differentiating the role of various invasive imaging modalities in plaque characterization as evaluated in different studies
Clinical problem FFR IVUS VH-IVUS OCT NIRS
Assessing lesion severity
Non-LMCA + MLA PROSPECT
DEFER 0.75 Cut-off
FAME-I 0.8 2–4 mm2
FAME-II 0.8 MLA
Mean
MLA
2.1–4 mm2
LMCA + +
0.8 4.8 mm2
6.0 mm2
Identifying the culprit lesion ± PROSPECT + ±
Plaque rupture/erosion Plaque rupture/erosion LCBI >400
Calcified nodule Red and white thrombus
Positive remodeling
Identifying vulnerable plaque Large eccentric plaque with + ± ±
Intracoronary Imaging for Plaque Characterization

echolucency PROSEPCT Fibrous cap <65 μm,

Plaque burden >70 % VH-TCFA macrophages in cap, underling
MLA < 4 mm2 lipid core
Extremes of remodelling
VIVA
ATHEROMA-IVUS
Predicting distal embolization + + + ±
Large echolucent plaque Necrotic core OCT-TCFA Large lipid rich
Plaque rupture VH-TCFA Plaque rupture plaque
Optimizing stent implantation + ±
Under-expanded stent (but not ? unknown
malapposition)
Inflow/outflow disease
Assessing stent failure + +
Neoatherosclerosis Similar to IVUS
Underexpansion Lack of stent strut tissue
Inflow and outflow coverage
Data from Mintz [41]
185
186 R.D. Madder

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 Intracoronary Imaging for PCI
Planning and Stent Optimization 11
Ryan D. Madder

Abstract
The currently available intracoronary imaging techniques in the US,
including intravascular ultrasound (IVUS), optical coherence tomography
(OCT), and near-infrared spectroscopy (NIRS), play an important role in
percutaneous coronary interventions (PCI). The applications of intracoro-
nary imaging in PCI include its use for PCI planning, in which imaging is
performed prior to PCI, and its use for stent optimization, in which imag-
ing is performed after PCI. With respect to PCI planning, intracoronary
imaging is useful in assessing lesions of intermediate stenosis severity, in
sizing the target vessel for stent selection, and in providing risk assessment
for peri-procedural myocardial infarction and angiographic no-reflow
prior to PCI. With respect to stent optimization, the utilization of intra-
coronary imaging to assess the adequacy of the PCI result has been associ-
ated with improved clinical outcomes. Given the current litigious medical
environment and the advent of public reporting of outcomes, the use of
intracoronary imaging for PCI optimization is likely to gain increasing
importance.

Keywords
Imaging for percutaneous coronary intervention (PCI) • Intravascular
ultrasound (IVUS) • Optical coherence tomography (OCT) • Near-infrared
spectroscopy (NIRS) • Intracoronary imaging for PCI planning •
Intracoronary imaging for stent optimization • Benefit of OCT imaging

R.D. Madder, MD, FACC

Department of Cardiovascular Medicine,
Frederik Meijer Heart & Vascular Institute,
Spectrum Health, Grand Rapids, MI, USA
e-mail: [email protected]

© Springer-Verlag London 2015 189

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_11
190 R.D. Madder

Introduction whether to apply additional techniques to con-

firm lesion significance.
The currently available intracoronary imaging
techniques in the US, including intravascular Measuring Target Lesion MLA
ultrasound (IVUS), optical coherence tomogra- The first step in obtaining an MLA measurement,
phy (OCT), and near-infrared spectroscopy regardless of whether using IVUS or OCT, is to
(NIRS), play an important role in percutaneous identify the appropriate frame(s) upon which to
coronary interventions (PCI). The applications of make the measurement. In order to locate the
intracoronary imaging in PCI include its use for frame to use for an MLA measurement, operators
PCI planning, in which imaging is performed can either scroll through the cross-sectional
prior to PCI, and its use for stent optimization, in images or utilize the longitudinal view of the ves-
which imaging is performed after PCI. With sel to find the site of most severe stenosis. Once
respect to PCI planning, intracoronary imaging is the frame depicting the most severe stenosis is
useful in assessing lesions of intermediate steno- identified, the MLA is measured by tracing the
sis severity, in sizing the target vessel for stent interface between the blood and leading intimal
selection, and in providing risk assessment for edge [5, 6]. Although MLA measurements by
peri-procedural myocardial infarction and angio- both IVUS and OCT have been shown to be
graphic no-reflow prior to PCI. With respect to highly reproducible [7, 8], the MLA values
stent optimization, the utilization of intracoro- obtained by these two modalities are not inter-
nary imaging to assess the adequacy of the PCI changeable, as IVUS generates MLA measure-
result has been associated with improved clinical ments that are 5–10 % larger than OCT [9, 10].
outcomes. Given the current litigious medical
environment and the advent of public reporting Clinical Application of IVUS MLA
of outcomes, the use of intracoronary imaging for in Non-left Main Locations
PCI optimization is likely to gain increasing The use of IVUS MLA measurements to evaluate
importance. lesions of intermediate stenosis severity is sup-
ported by studies directly comparing MLA mea-
surements to FFR results [11–14] and also by
Intracoronary Imaging for PCI evidence supporting the clinical safety of this
Planning approach [15, 16]. It is important to recognize
however that the correlation between IVUS MLA
Assessing Lesions of Intermediate values and FFR values is only modest, the corre-
Stenosis Severity lation varies according to the reference vessel
size, and that the correlation is weakest in vessels
Given the limitations of invasive angiography in of smaller diameter [11, 13, 14].
determining the hemodynamic significance of The optimal MLA thresholds for identifying
coronary lesions [1], lesions of intermediate ste- an FFR <0.80 as reported recently by the pro-
nosis severity should routinely be evaluated with spective FIRST registry are presented in
techniques other than angiography prior to per- Table 11.1. Due to their poor sensitivities and
forming PCI. Although fractional flow reserve modest specificities, the clinical application of
(FFR) remains the gold standard for determining these “optimal” MLA thresholds as a sole crite-
the hemodynamic significance of a coronary rion to make decisions regarding PCI should be
lesion [2–4], IVUS and OCT can also be applied undertaken with caution. It has been suggested
to assess lesions of intermediate stenosis severity. that application of an MLA threshold of 4.0 mm2
Using either IVUS or OCT, lesions can be scruti- may be more clinically useful for several reasons
nized for their minimal luminal area (MLA). [17]. First, an MLA ≥4.0 mm2 is associated with
Once measured, the operator can use the MLA a high sensitivity for identification of a hemody-
value to determine whether to defer PCI or namically significant lesion by FFR [13]. Thus
11 Intracoronary Imaging for PCI Planning and Stent Optimization 191

Table 11.1 IVUS and OCT optimal MLA thresholds mediate severity stenoses in the left main coro-
that are associated with an fraction flow reserve of <0.80
nary artery [18, 19]. Although a left main MLA
according to reference vessel diameter
of 7.5 mm2 has been established as the lower
Reference range of normal [20], this threshold should not be
vessel diameter MLA Sensitivity Specificity
(mm) (mm2) (%) (%) used as a surrogate for hemodynamic signifi-
IVUS cance. The optimal MLA threshold in the left
<3.0 <2.4 63 67 main to identify a hemodynamically significant
3.0–3.5 <2.7 58 75 lesion by FFR analysis was <5.9 mm2 in one
>3.5 <3.6 57 71 study [18] and was <4.8 mm2 in another [19].
OCT Unlike the optimal thresholds in non-left main
≥3.0 1.95 82 63 locations, these MLA thresholds in the left main
<3.0 1.62 80 83 are characterized by higher sensitivities and spec-
IVUS MLA thresholds and their respective sensitivities ificities for hemodynamic significance [18].
and specificities are those reported in the FIRST trial Lending further support to an IVUS-based
(Data from Waksman et al. [11]. OCT MLA thresholds approach to assess intermediate stenoses in the
and their respective sensitivities and specificities are those
reported by Gonzalo et al. (Data from Gonzalo et al. [12])
left main, a prospective multicenter study has
IVUS intravascular ultrasound, MLA minimal luminal demonstrated that deferring PCI on left main
area, OCT optical coherence tomography lesions with a MLA ≥6.0 mm2 is associated with
a favorable clinical outcome [21]. A detailed
review of IVUS use to assess intermediate left
intermediate severity lesions in non-left main main lesions has been recently published [22].
locations having a MLA ≥4.0 mm2 are rarely
associated with a FFR <0.80 [11]. Second, defer- Clinical Application of OCT MLA
ring PCI on non-left main lesions characterize by Analogous to studies comparing IVUS with
an MLA ≥4.0 mm2 is associated with a low rate FFR, OCT has also been directly compared with
of adverse clinical events [15, 16]. For these rea- FFR for the assessment of lesions intermediate
sons, it is generally considered appropriate to stenosis severity [12, 23]. In a study by Gonzalo
defer PCI on intermediate stenosis severity et al. [12], the optimal OCT-derived MLA to
lesions with a MLA ≥4.0 [17]. Importantly and identify an FFR ≤0.80 was 1.95 mm2, character-
owing to the poor specificity of the MLA 4.0 mm2 ized by a sensitivity of 82 % and specificity of
threshold for identifying an FFR <0.80, a MLA 63 % (Table 11.1). Due to this limited specificity,
<4.0 mm2 does not imply hemodynamic signifi- the presence of an MLA less than 1.95 mm2 by
cance and should not be used to justify PCI per- OCT does not justify performance of PCI. Rather,
formance [13, 17]. In fact, the performance of such lesions should be further evaluated with
PCI on intermediate lesions based upon an MLA FFR to determine hemodynamic significance.
<4.0 mm2 results in a higher rate of PCI than in When using OCT to evaluate lesions of interme-
an FFR-based approach [16]. When using IVUS diate stenosis severity in vessels having a refer-
MLA to assess intermediate lesions in non-left ence diameter <3.0 mm, a threshold MLA of
main locations, finding an MLA <4.0 mm2 should 1.62 mm2 has been found to be the optimal
prompt further evaluation with FFR to determine threshold for identifying lesions having an FFR
hemodynamic significance prior to performing ≤0.80 [12].
PCI [17] (Fig. 11.1). There are several important considerations
regarding the use of OCT to evaluate lesions of
Clinical Application of IVUS MLA intermediate stenosis severity. The fact that
in the Left Main these OCT-derived MLA thresholds are smaller
Analogous to studies performed in non-left main than those of IVUS is consistent with the con-
locations, several studies have compared IVUS cept that OCT generates smaller vessel mea-
MLA and FFR values in the assessment of inter- surements than IVUS [9, 10]. Although the
192 R.D. Madder

b c

Fig. 11.1 IVUS evaluation of a lesion having an interme- site was found to be 3.05 mm2 (c). Owing to the poor
diate stenosis severity. A 68 year-old male underwent specificity of an MLA <4.0 mm2 to identify lesions that
catheterization for the evaluation of acute chest pain. are hemodynamically significant, an MLA <4.0 mm2
Angiography of the right coronary artery demonstrated an should not be used to justify PCI. Consequently, FFR was
intermediate stenosis in the mid-RCA (a). IVUS was used performed to further evaluate the hemodynamic signifi-
to further interrogate the lesion with the intent to defer cance of the lesion and generated an FFR value of 0.85
PCI if the MLA was >4.0 mm2. Such a strategy is support (d). As a result, PCI was not performed and the patient
by the concept that lesions having an MLA >4.0 mm2 are was treated with medical therapy. FFR fractional flow
rarely associated with a significant FFR result and are reserve, IVUS intravascular ultrasound, MLA minimal
associated with a low rate of future cardiac events. The luminal area, PCI percutaneous coronary intervention,
IVUS frame having the most severe stenosis within the RCA right coronary artery
lesion is shown (b). The MLA at the most severe stenosis

sensitivities of the OCT-derived MLA thresh- Intracoronary Imaging for Stent

olds are higher than those reported by many Selection
IVUS studies [12], longitudinal prospective
OCT studies have not been performed to dem- Once the decision has been made to perform PCI on
onstrate the safety of deferring PCI in the set- a target lesion, IVUS and OCT can be utilized in a
ting of a particular MLA. Finally, due to the similar fashion to guide stent selection. Because
limited ability of OCT to evaluate ostial lesions, stent selection requires both stent diameter and a
assessment of left main lesions with OCT may stent length, measurements of the proximal and dis-
be difficult, especially in the case of ostial and tal reference vessel diameters and the lesion length
proximal left main lesions. To date, no OCT are the most useful imaging parameters to aid with
studies comparing MLA and FFR values for left stent selection. Whether using IVUS or OCT, these
main lesions have yet been performed. linear measurements are highly reproducible.
11 Intracoronary Imaging for PCI Planning and Stent Optimization 193

Intracoronary Imaging to Assess IVUS Predictors of Acute PCI-Related

the Risk of Peri-Procedural Complications
Myocardial Infarction Several morphologic characteristics, when iden-
and Angiographic No-Reflow tified by greyscale IVUS at the target lesion prior
to PCI, have been shown to be associated with an
Periprocedural Infarction increased risk of peri-procedural myocardial
and No-Reflow infarction or angiographic no-reflow. These
Associated with both short- and long-term IVUS findings include include attenuated plaque,
mortality, peri-procedural myocardial infarc- larger plaque burden, positive remodeling, a lipid
tion and angiographic no-reflow remain com- pool-like image, and intracoronary thrombus
mon complications in contemporary PCI [30]. Of these, attenuated plaque, which is
[24–29]. In many cases, these complications defined by the presence of attenuation of the
are triggered by the embolization of plaque ultrasound signal in the absence of overlying cal-
contents that are liberated from the target cification (Fig. 11.2), has been shown to be the
lesion during PCI [24–29]. Thus, the underly- strongest independent predictor of no-reflow [31]
ing morphology and composition of the under- and in another study to be the only independent
lying target plaque plays a role in determining IVUS predictor of peri-procedural myocardial
PCI risk. Importantly, the risk of angiographic infarction [32]. Furthermore, it has been demon-
no-reflow and peri-procedural myocardial strated that the extent of attenuated plaque by
infarction can be assessed prior to PCI by using IVUS, rather than just its mere presence, predicts
intracoronary imaging with IVUS, OCT, or procedural complications during PCI [33, 34].
NIRS in order to scrutinize the target lesion for Similar to greyscale IVUS, virtual histology
certain high risk features [30]. (VH)-IVUS is also capable of assessing the risk

a b

Fig. 11.2 Attenuated plaque by IVUS. Attenuated plaque procedural myocardial infarction during PCI. Attenuated
by IVUS is defined as attenuation of the ultrasound signal plaque should not be confused with attenuation of the
in the absence of overlying calcification (asterisks, a). The ultrasound signal (asterisks) secondary to overlying calci-
presence of attenuated plaque at the culprit site is an inde- fication (red arrows, b). IVUS intravascular ultrasound,
pendent predictor of angiographic no-reflow and peri- PCI percutaneous coronary intervention
194 R.D. Madder

of acute PCI-related complications. When found fraction of pixels within a region of interest indi-
at the target lesion prior to PCI, VH-IVUS cating lipid multiplied by 1,000 [43, 44]. Another
necrotic core, which is color-coded as red on the commonly used metric to describe focal lipid
VH-IVUS images, has been associated with an quantity by NIRS is maxLCBI4mm, defined as the
increased risk of angiographic no-reflow, peri- maximum LCBI in any contiguous 4-mm seg-
procedural myocardial infarction, and distal ment of vessel [45].
embolization during PCI [35–39]. Among patients with ACS and stable angina,
the maxLCBI4mm by NIRS of the target lesion is
OCT Predictors of Acute PCI-Related associated with the risk of peri-procedural myo-
Complications cardial infarction during PCI [45]. In fact, the
Due to its superb spatial resolution, OCT is the presence of a maxLCBI4mm ≥500 at the culprit
only currently available intracoronary imaging site (Fig. 11.4) is associated with a 50 % rate of
modality capable of visualizing the thickness of peri-procedural myocardial infarction [45]. In
the fibrous cap overlying a coronary atheroma. A contrast, the rate of peri-procedural myocardial
fibrous cap is considered “thin” by OCT if its infarction among those with a maxLCBI4mm <500
thickness is <65–70 μm [40–42]. Using this defi- was demonstrated to be only 4 % [45]. The notion
nition, an OCT-derived thin-cap fibroatheroma that the quantity of lipid detected by NIRS at the
(TCFA) is defined by the presence of a thin-
fibrous cap overlying a lipid-rich plaque
(Fig. 11.3), which in turn is defined as lipid span-
ning at least two quadrants on a cross-sectional
image [40–42].
When using OCT to image the target lesion
prior to PCI, the presence of TCFA at the target
site has been identified as the strongest OCT pre-
dictor of PCI-related complications and has been
associated with a 50–75 % risk of peri-procedural
myocardial infarction during PCI [40, 41]. Even
without consideration of the fibrous cap thick-
ness, the underlying lipid arc is another important
morphologic feature by OCT that predicts acute
PCI-related complications. Accordingly, the lipid
arc by OCT is an independent predictor of angio-
Fig. 11.3 OCT-defined thin-capped fibroatheroma at a
graphic no-reflow during PCI, with no-reflow
culprit site in a patient presenting with an acute coronary
occurring in up to 75 % of cases when PCI is per- syndrome. OCT imaging was performed for PCI planning
formed on a target lesion having a lipid arc >180° within the culprit vessel of a patient who presented with
[42]. Further emphasizing the importance of lipid an acute coronary syndrome. A representative frame from
within the culprit lesion is shown. Lipid, evident by OCT
in the target lesion, angiographic no-reflow was
as low-attenuation regions with poorly defined borders
shown not to occur in the absence of a lipid-rich (asterisks), is present and involves greater than two quad-
plaque in one study [42]. rants of the image. The fibrous cap overlying the lipid
measures less than 65 μm in the region highlighted by the
white circle. The concomitant presence of these features is
NIRS Predictors of Acute PCI-Related consistent with an OCT-defined TCFA. Identification of a
Complications TCFA has been shown to be the strongest OCT predictor
Intracoronary NIRS has been validated to detect of periprocedural myocardial infarction. Furthermore, a
the presence of lipid core plaque within coronary lipid arc spanning >180°, as shown in this image, is a
strong predictor of the occurrence of angiographic no-
arteries and to quantify the amount of lipid pres-
reflow during PCI. OCT optical coherence tomography,
ent [43, 44]. By NIRS, lipid is quantified as the PCI percutaneous coronary intervention, TCFA thin-
lipid core burden index (LCBI), defined as the capped fibroatheroma
11 Intracoronary Imaging for PCI Planning and Stent Optimization 195

maxLCBI4mm=745
360°

0°

Fig. 11.4 NIRS identifies a large lipid core plaque within and distal [2] angiographic culprit margins have been
the angiographic culprit margins prior to stenting. Routine marked. Upon placing these bookmarks the NIRS console
combined NIRS-IVUS imaging was performed within the automatically generates a maxLCBI4mm value, which in
culprit vessel for PCI planning and to assess the risk of this case was 745. The presence of a maxLCBI4mm ≥500 at
peri-procedural complications during stenting. The NIRS the culprit site is associated with a 50 % rate of peri-
chemogram of the culprit vessel is shown on the left. The procedural myocardial infarction during PCI. A represen-
standard orientation of the chemogram has the distal ves- tative combined NIRS-IVUS frame from within the
sel on the right and the proximal vessel on the left. The culprit lesion is shown on the right and depicts the pres-
x-axis represents position along the vessel in mm and the ence a large, bulky, eccentric, lipid core plaque. IVUS
y-axis represent circumferential position around the ves- intravascular ultrasound, maxLCBI4mm maximum lipid
sel in degrees. Red on the chemogram is indicative of the core burden index in a 4-mm segment, NIRS near-infrared
absence of lipid whereas yellow indicates the presence of spectroscopy, PCI percutaneous coronary intervention
lipid core plaque. In the example above, the proximal [1]

culprit site is an important predictor of peri- Intracoronary Imaging for Stent

procedural myocardial infarction is consistent Optimization
with observations by IVUS and OCT wherein the
quantity of attenuated plaque and the degree of Stent Optimization with IVUS or OCT
lipid, respectively, are associated with the risk of
acute PCI-related complications [30]. When applied after stent implantation, intra-
coronary imaging can be used to optimize the
Limitation of Using Intracoronary stent result. Although the application of OCT
Imaging to Assess PCI Risk for PCI guidance has not yet been addressed by
Based on the findings of multiple studies, it is contemporary guidelines, use of IVUS for stent
clear that intracoronary imaging can identify tar- optimization is supported by a IIb recommen-
get lesions at risk of inducing no-reflow and peri- dation in the 2011 guidelines [47]. The pres-
procedural myocardial infarction during ence of guideline support for IVUS and the lack
PCI. However at present, there are no studies of similar support for OCT is likely attributable
demonstrating that identification of such high-risk to the shorter duration that OCT has been avail-
lesions, whether by IVUS, OCT or NIRS, should able to generate an evidence base supportive of
alter the clinical approach to PCI. Importantly, the its routine use in PCI. When utilized after stent
routine use of distal embolic protection devices implantation, IVUS or OCT should focus on
during PCI without consideration of underlying detecting edge dissections, strut malapposition,
plaque morphology is not beneficial [46]. Until stent under-expansion, incomplete lesion cov-
studies evaluating the clinical benefit of pre-PCI erage, thrombus, and tissue protrusion. Many of
risk assessment are performed, widespread adop- these findings have been associated with
tion of pre-PCI intracoronary imaging to assess adverse clinical events when identified by
procedural risk is unlikely. IVUS [17, 48, 49], although studies linking
196 R.D. Madder

these findings by OCT with adverse clinical has been associated with a higher rate of stent
events clinical events have not yet been thrombosis [51]. Stent underexpansion has sim-
reported. ilarly been associated with an increased risk of
stent thrombosis [48] and has also been pro-
posed as the most important determinant of
Stent Strut Malapposition restenosis risk after bare-metal stent placement
and Underexpansion in IVUS studies [52].
Regardless of whether detected by IVUS or
Whereas stent strut malapposition (Fig. 11.5) is OCT, the identification of malapposition or
defined as the presence of struts that are not in underexpansion after stent placement should
contact with the vessel wall [5, 17], stent under- likely prompt further post-dilation to optimize
expansion (Fig. 11.6) is often defined as a mini- the stent result. When using OCT to evaluate a
mal stent area <80 % of the smallest reference recently placed stent, there are several impor-
segment luminal area [50]. Stent strut malappo- tant caveats to consider. First, studies have not
sition, when identified by IVUS at follow up, yet linked malapposition and underexpansion

a b c

Fig. 11.5 Stent strut malapposition. Tandem stenoses are were well-apposed to the vessel wall (white arrows, c).
evident by invasive angiography in the mid-RCA (a). Stent However, OCT also identified stent strut malapposition
placement (proximal and distal stent margins are marked (red arrows, d), which was completely unapparent by
by green lines) and post-dilation with a non-compliant bal- angiography. Further post-dilation with a larger non-com-
loon yielded an adequate angiographic result (b). OCT was pliant balloon was subsequently performed. OCT optical
performed after initial post-dilation to ensure an optimal coherence tomography, PCI percutaneous coronary inter-
PCI result and demonstrated that most of the stent struts vention, RCA right coronary artery
11 Intracoronary Imaging for PCI Planning and Stent Optimization 197

Mid stent Distal stent Adjacent reference

MLA = 7.4 mm2 MLA = 4.7 mm2 MLA = 7.9 mm2

Expansion = 94 % Expansion = 59 %

Fig. 11.6 Intracoronary imaging for stent optimization: had an MLA that was 94 % of the reference segment area.
identifying stent under-expansion. After stent placement Stent underexpansion, often defined as an in-stent MLA
and post-dilation with a non-compliant balloon, routine <80 % of the reference segment lumen area, was evident
performance of IVUS was performed to ensure an optimal in the distal stent, as the distal stent MLA was only 59 %
PCI result. Whereas the mid-stent appeared to be ade- of the adjacent reference segment lumen area. Stent
quately expanded (left), the mid stent appeared underex- underexpansion has been linked to an increased risk of
panded (middle) compared to the adjacent reference stent thrombosis and restenosis. Consequently, the distal
segment (right, top row). Lumen areas were quantitatively stent in this case was further post-dilated after IVUS
measured for the mid-stent, distal-stent, and adjacent ref- imaging. IVUS intravascular ultrasound, MLA minimal
erence segment. Compared to the reference segment lumen area, PCI percutaneous coronary intervention
lumen area, the mid-stent was adequately expanded as it

identified by OCT to adverse clinical out- Stent Edge Dissections

comes. Second, owing to its superior spatial
resolution, OCT identifies malapposition sig- After stent placement, edge dissections are iden-
nificantly more often that IVUS [53]. However, tified by IVUS in 5–23 % of cases and by OCT in
further study is needed to determine whether up to one-third of cases (Fig. 11.7). Whereas sev-
this higher identification rate of malapposition eral IVUS studies have demonstrated edge dis-
will result in improved clinical outcomes. sections to be associated with stent thrombosis
Third, because OCT imaging can only visual- after bare-metal stent placement [48, 49], edge
ize the leading edge of the stent strut, the iden- dissections detected by OCT have not been asso-
tification of malapposition by OCT requires ciated with an increased cardiac event rate [55].
information about the strut thickness of the Once visualized after stent placement, the opti-
implanted stent [54]. mal approach to stent edge dissections has not yet
198 R.D. Madder

a b

Fig. 11.7 Stent edge dissections by IVUS and treated. After stent placement, edge dissections are identi-
OCT. Examples of stent edge dissections detected by fied by IVUS in 5–23 % of cases and by OCT in up to
IVUS (a) and OCT (b) are shown. In each case the dissec- one-third of cases. IVUS intravascular ultrasound, OCT
tion was not flow-limiting and was unapparent by angiog- optical coherence tomography
raphy. As a result, the stent edge dissections were not

been defined. It has been suggested that edge

dissections do not require treatment if they are
not flow-limiting, if the MLA is >4.0 mm2, and if
the dissection is not evident by angiography [55].

Tissue Protrusion

Postmortem evaluation of implanted stents has

demonstrated plaque compression by stent struts
in 94 % of cases [56]. It is thus not surprising that
OCT, with its excellent spatial resolution, was
shown to detect tissue prolapse between adjacent
stent struts in >95 % of cases after stent place-
ment [57]. Likely owing to a lower spatial resolu-
tion than OCT, IVUS detects tissue protrusion Fig. 11.8 OCT evidence of tissue protrusion between
after stent placement in less than half of cases struts after stent placement. The above image was captured
[58]. Although the protrusion of tissue between by OCT performed immediately after stent placement in
stent struts may often appear ominous by intra- order to ensure an optimal PCI result. Whereas there is no
significant tissue protrusion on the left side of the image,
coronary imaging (Fig. 11.8), tissue protrusion
the right side of the image demonstrates considerable tis-
has not been associated with adverse clinical sue protrusion (arrows) between the stent struts. Two of
events in several studies [57, 59]. Consequently the stent struts are circled and produce a characteristic
in the absence of flow-limiting tissue protrusion, attenuation pattern (asterisks). Tissue protrusion, which is
identified by OCT in >95 % of cases after stent placement,
further intervention is likely not necessary when
has not been associated with adverse outcomes in several
tissue protrusion is visualized after stent studies [57, 59]. OCT optical coherence tomography, PCI
placement. percutaneous coronary intervention
11 Intracoronary Imaging for PCI Planning and Stent Optimization 199

Clinical Benefit Associated bosis [60]. In further support of IVUS-guidance

with Intracoronary Imaging during drug-eluting stent placement the recently
published prospective multicenter ADAPT-DES
Longitudinal studies demonstrating a clinical study, which included over 8,000 patients, dem-
benefit of OCT imaging to guide stent implanta- onstrated that IVUS-guidance is associated with
tion have not yet been published. The clinical a 60 % reduction in rate of drug-eluting stent
benefit derived by using IVUS to guide stent thrombosis [61]. In addition, ADAPT-DES
implantation is dependent upon whether a bare- showed that IVUS-guidance during drug-eluting
metal or drug-eluting stent is being deployed. stent placement was associated with a reduction
in myocardial infarction, target lesion revascular-
ization, and target vessel revascularization at
Benefit of IVUS-Guided Bare-Metal 1 year [61]. Furthermore, IVUS-guidance was
Stent Placement demonstrated to be beneficial in both complex
and non-complex lesion subsets [61].
Compared to an angiographic-guided strategy, Interestingly, the clinical benefits associated with
using IVUS to guide bare-metal stent placement IVUS guidance were evident 1 month after PCI
results in improved clinical outcomes and leads but continued to accrue over the first year. Finally,
to a reduction in restenosis and in target vessel in the setting of elective PCI of unprotected left
revascularization [52]. The reductions in resteno- main lesions, IVUS-guidance during drug-
sis and target vessel revascularization associated eluting stent placement has been associated with
with IVUS-guidance during bare-metal stent a reduction in mortality [62].
placement have been attributed to the application
of a more aggressive post-dilation strategy when Conclusion
IVUS-guidance is used during PCI [17]. It is thus Intracoronary imaging with IVUS, OCT, and
not surprising that compared to angiographic- NIRS can currently be applied independently
guidance, an IVUS-guided strategy is associated or in combination for PCI planning and for
with a larger minimal luminal diameter after stent stent optimization. Whereas the use of IVUS
placement [52]. Although IVUS-guidance during during stent placement has been associated
bare-metal stent placement reduces the risk of with improved clinical outcomes, studies to
restenosis and target vessel revascularization, it evaluate the benefit of OCT and NIRS on clin-
does not reduce the incidence of stent thrombosis ical outcomes are currently underway. While
or myocardial infarction after bare-metal stent ongoing improvement in the image acquisi-
placement [52]. tion and resolution of these imaging tech-
niques are being sought, these imaging
modalities are likely to continue to play an
Benefit of IVUS-Guided Drug-Eluting important role in contemporary PCI for the
Stent Placement foreseeable future.

Unlike IVUS-guided bare-metal stent placement,

IVUS-guidance during drug-eluting stent place-
ment is not associated with a reduction in reste-
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 Non-invasive Correlation
of Invasive Imaging 12
A. Neil Bilolikar, Amr E. Abbas,
and James A. Goldstein

Abstract
Performance of non-invasive cardiac testing to help detect patients with sig-
nificant coronary artery disease has helped reduce the incidence of myocar-
dial infarction by an estimated 47 % in the past 50 years. In generations past,
exercise stress testing was the traditional means by which hemodynamically
significant coronary artery stenoses could be identified and treated. In recent
decades, the addition of imaging modalities to this examination has led to a
higher sensitivity and specificity of the overall examination, spurring a
marked rise in the number and frequency of stress tests performed. Currently,
there are nearly ten million stress tests performed annually in the US, a figure
that has doubled from the 1990s into the 2000s. Testing has clearly impacted
the incidence and prevalence of disease in our population, and though it has
come under scrutiny of late for its perhaps too widespread use, it remains a
valid and appropriate test for the diagnosis of coronary artery disease and
coronary ischemia. Coronary computed tomographic angiography (CTA) has
continued the trend of non-invasive testing used to help complete the assess-
ment of the patient with chest pain; however, in the wrong hands, this tech-
nology can be simultaneously over utilized and undervalued.

A.N. Bilolikar, MD • J.A. Goldstein, MD

Department of Cardiovascular Medicine,
William Beaumont Hospital, Royal Oak, MI, USA
e-mail: [email protected];
[email protected]
A.E. Abbas, MD, FACC, FSCAI, FSVM,
FASE, RPVI (*)
Department of Cardiovascular Medicine,
Beaumont Health, Oakland University/William
Beaumont School of Medicine, Royal Oak, MI, USA
e-mail: [email protected]

© Springer-Verlag London 2015 203

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_12
204 A.N. Bilolikar et al.

Keywords
Non-invasive cardiac testing • Detection of coronary artery disease •
Detection of myocardial infarction • Coronary computed tomographic
angiography • Coronary calcium scoring CT • Fractional flow reserve
CTA (FFRct)

Background ideal plaque characterization tool would provide

a complete roadmap of atherosclerotic burden
Performance of non-invasive cardiac testing to throughout the coronary tree and provide per-
help detect patients with significant coronary plaque lesion specific data outlining the architec-
artery disease has helped reduce the incidence of ture, composition and dynamic biology of each
myocardial infarction by an estimated 47 % in plaque. Comprehensive plaque analysis should
the past 50 years [1, 2]. In generations past, exer- include the following parameters:
cise stress testing was the traditional means by
which hemodynamically significant coronary 1. Architecture: Plaque volume, length, eccen-
artery stenoses could be identified and treated. In tricity, remodeling, and impact on lumen area.
recent decades, the addition of imaging modali- 2. Physiology: Impact on basal coronary flow
ties to this examination has led to a higher sensi- and coronary flow reserve.
tivity and specificity of the overall examination, 3. Composition: Lipid, fibrous tissue, calcium.
spurring a marked rise in the number and fre- 4. Patho-biology: Presence of inflammation,
quency of stress tests performed [1–7]. Currently, neovascularization, fibrous cap metabolism,
there are nearly ten million stress tests performed apoptosis, etc.
annually in the US, a figure that has doubled from
the 1990s into the 2000s [1, 2]. Testing has A coronary calcium scoring CT is a non-
clearly impacted the incidence and prevalence of invasive, low radiation dose, non-contrast CT of
disease in our population, and though it has come the chest which detects calcium in the coronary
under scrutiny of late for its perhaps too wide- artery walls. Levels of such calcium have been
spread use, it remains a valid and appropriate test directly linked to coronary atherosclerosis, over-
for the diagnosis of coronary artery disease and all cardiac events and patient outcomes [8–11].
coronary ischemia. Coronary computed tomo- For this reason, calcium scoring has become an
graphic angiography (CTA) has continued the effective screening tool for coronary artery dis-
trend of non-invasive testing used to help com- ease and is well validated among asymptomatic
plete the assessment of the patient with chest patients presenting for risk stratification [8–13].
pain; however, in the wrong hands, this technol- When the calcium score is 0, it is a strong predic-
ogy can be simultaneously over utilized and tor of very low risk for cardiac events, and the
undervalued. patient has been given a ‘warranty period’ of
4 years wherein the chances of any hard cardiac
event to occur is quite low [11, 12]. Conversely,
The Ideal Coronary Plaque when calcium scores are elevated (>100) discuss-
Characterization Tool ing the score and its implications with the patient
was an independent factor which improved patient
To have a better understanding of what underlies medication compliance and recommended life-
true coronary ischemia, an appreciation of the style changes [13]. The test typically utilizes
information necessary to precisely characterize 0.1 mSv of radiation, is non-contrast, and is gen-
plaques and the fundamental data provided by erally widely available with low cost, making it an
plaque imaging technologies is essential. The ideal screening tool for coronary atherosclerosis.
12 Non-invasive Correlation of Invasive Imaging 205

However, this test cannot give accurate coronary give FFR –like data to the user to be able to delin-
luminal information and has no plaque character- eate the functional significance of a plaque or ste-
ization ability outside of coronary calcium den- nosis [28, 29]. Angiographic stenosis may or
sity, and currently should only be used among may not be flow limiting, and even today, the best
those patients who are asymptomatic and for risk methods clinicians have to assess this signifi-
stratification purposes only. cance is via functional testing at a patient or coro-
Cardiac Computed Tomographic nary level. The implications of a non-invasive test
Angiography (CTA) is a non-invasive diagnos- to provide the user with degree of coronary artery
tic cardiac test used for the detection and assess- stenosis and functional significance without a
ment of coronary artery stenosis [14–20]. As stress exam or an invasive catheterization are
technological advances have allowed for higher self-evident. The greatest issues working against
quality images with improved spatial and tempo- FFRct currently are time and cost. Currently, the
ral resolution, use of CTA has risen as well, pro- test can only be done in the imaging core lab of
viding clinicians with invaluable information the company with proprietary rights to the soft-
about the patient’s atherosclerotic disease bur- ware, and thus, the scan must be sent away for
den. The advantages CTA has over traditional review at out of pocket expense. As this takes on
invasive coronary angiography (ICA) is: the order of days, real time information cannot be
obtained from this technique at this time. Another
1. Avoidance of the risks of a catheter based pro- interesting modality, which has been developed
cedure, and and currently being studies in research, is CT
2. Detailed depiction of the coronary artery wall perfusion (CTP) imaging. CTP takes the stan-
lending to comprehensive plaque analysis. dard CTA and turns it into a ‘CTA stress test’.
First, the patient undergoes a CTA with tradi-
This technology gives insight into a disease tional coronary imaging. This is followed by
process, which was not possible in the past save infusion of a pharmacologic stress agent, fol-
for implementation of advanced invasive tech- lowed by repeat myocardial imaging to deter-
niques such as intravascular ultrasound (IVUS) mine relative uptake of contrast into the
or a post-mortem examination [21–27]. The use myocardial pool. This imaging is then able to
of advanced coronary imaging techniques such as determine if stenoses are causing decreased myo-
IVUS, as well as optical coherence tomography cardial perfusion [30]. The concepts are similar
(OCT) near infrared spectroscopy (NIRS) and to a nuclear myocardial perfusion imaging (MPI)
virtual histology (VH) in the past decade has study; however it combines the anatomic infor-
allowed for detailed depiction of the coronary mation of a CTA with the functional information
lumen and wall and has propelled forward the of a stress MPI. Both FFRct and CTP are promis-
field of plaque imaging. Numerous studies have ing tools which will become more widely
shown good correlation between CTA and the available to the general public in the coming
more invasive catheter based techniques. years, but as yet are not available as part of our
Importantly, each of these modalities is used in a workup of patients with chest pain.
complementary fashion, furthering the knowl- In aggregate, non-invasive cardiac testing is
edge base in the search for the elusive ‘vulnerable the backbone by which coronary artery disease as
plaque’. a cause of cardiac symptoms is diagnosed and
More recently, CT techniques have been treated. Over time, we have learned to better risk
developed which have targeted CT to become not stratify patients through use of these non-invasive
only an anatomical test, but a functional test as imaging techniques and have refined our practice
well. Fractional flow reserve CTA, or FFRct, patterns to know which patients do and do not
takes advantage of mathematical modeling of the need to be tested and treated. This chapter will
heart and coronary flow to allow for accurate highlight information attained from the direct
evaluation of coronary stenosis, and in addition, comparison of non-invasive cardiac testing to
206 A.N. Bilolikar et al.

that of invasive coronary angiography and a male who is 56 years old, which places him at
advanced coronary imaging techniques, to give elevated risk for CAD, but he has no other traditional
the reader insight as to the true utility of these risk factors. His symptoms could be consistent with
non-invasive tests in current practice. a slow, progressive development of coronary athero-
sclerosis. Your pre-test probability for CAD as the
cause of his symptoms is in the intermediate based
Case 1. Stress Testing: Validity upon this information, and you review Fig. 12.1 for
and Correlation help selecting the best diagnostic test for the patient.
You decide to have him undergo an exercise stress
Case Presentation echocardiogram, as his ECG is interpretable, he is
able to exercise and the imaging modality will
Mr. M is a 56 year old male with no medical his- increase the sensitivity and specificity of the test in
tory who presents to your office for evaluation of this intermediate risk patient.
recent onset dyspnea on exertion. He has no pre- Several studies have been published over the
vious history of such symptoms, but has noted a past 40 years correlating stress testing to
progressive increase in shortness of breath over ICA. The various modalities, their overall diag-
the past 6 months, particularly when doing heavy nostic accuracies are summarized in Table 12.1.
lifting at work. He denies any overt chest pain but In general, the more sensitive the test the more
has had progressive fatigue for over 2 years. He likely one is able to detect the outcome in ques-
denies orthopnea, but admits to mild leg swelling tion. Most of the validation studies for stress test-
at times over this period, which is unusual for ing from the past 40 years have used angiographic
him. He is a former one pack per day smoker for stenosis of 50 or 70 % as the ‘gold standard’ for
20 years, having quit 15 years ago. He takes no significance. Thus, if a stress echocardiogram
medications and has no surgical history. He does showed a wall motion abnormality in the inferior
not see doctors regularly; however given his wall, and the ICA demonstrated a 50 % or greater
symptoms he did see his primary care physician a stenosis in the right coronary, then this was a cor-
few weeks ago for evaluation. The primary care relative study. By this reasoning, a test with 80 %
physician performed an ECG which showed nor- sensitivity is ‘right’ 80 % of the time when there
mal sinus rhythm with no ischemic changes, was a 50 % or greater lesion in the coronary tree
heart rate of 90 BPM and was normal, and in the correct anatomic distribution. The specific-
referred him to our office for further care. ity of the test relates to the number of times the
In your office, his physical examination test was negative in the absence of disease. It is
reveals a blood pressure of 140/80 mmHg, a heart calculated as the number of true negative results
rate of 80 and regular, and he has a room air oxy- (normal stress echo, and stenosis by ICA <50 %),
gen saturation of 98 %. He appears anxious about divided by the true negatives added to the total
being in the office today, but in no acute distress. number of false positive results (positive stress
His cardiovascular exam reveals a normal S1, S2 echo, coupled with a stenosis by ICA <50 % in
without S3, a regular rate and rhythm with no that distribution). This calculated value is
murmurs or gallops. His precordial exam reveals adversely affected when evaluating patients on a
a normal PMI with no RV heave or lift. He has per-segment assessment, as opposed to a per-
mildly elevated jugular venous pressure to 8 cm patient assessment. On a per-segment assess-
H2O, and he has trace bilateral lower extremity ment, the specificity will always be higher, as the
edema. His pulmonary exam reveals normal patient is unlikely to have wall motion abnormal-
breath sounds without wheezes, rhonchi or rales. ities in the majority of segments which are angio-
Among the items included in your differential graphically normal. Reporting the per-segment
diagnosis for his dyspnea on exertion is coronary specificity is a method of increasing the total
ischemia resulting in heart failure. However, select- number of true negatives and thus raising the
ing the best test for this patient can be difficult. He is specificity. Thus, in the reporting, it is common to
12 Non-invasive Correlation of Invasive Imaging 207

Acute chest pain initial testing algorithm based upon pre-test proability of CAD

Low risk (<10 %) Intermediate risk (10−90 %) High risk (>90 %)

N (pursue functional testing)

Interpretable ECG? Interpretable ECG? Symptoms compatible with
previous angina or MI, or
Y N Y N other high risk features?***

Able to exercise?
Able to exercise? High risk for radiation Y
Y N
exposure? ‡
Y N
GXT CTA N Cardiac catheterization
Y

Morbid Obesity? (BMI>40 kg/m2)

-Pharmacologic
Y N
High risk for radiation Echocardiography -CTA†
exposure? ‡ -Stres perfusion -Pharmacologic MPI or
-Stree perfusion MRI** MRI** echocardiography*
N -Dobutamine Stree Echo
Y with contrast
-Stress PET MPI** ‡; Women <40 years of age, or
-Pharmacologic MPI or
thouse with previous chest
Echocardiography*
radiation reaching their maximal
-CTA†
radiation dose limit
Morbid Obesity? (BMI>40 kg/m2) *; Based upon local expertise
N Morbid Obesity? (BMI>40 kg/m2) **;where available, if not
Y available, alternate options as
Y N listed
***; features include (but not
-Exercise stress limited to) multiple coronary risk
-Exercise stress
echocardiography -Stress PET MPI** -CTA† factors, high TIMI risk score >3,
echocardiography with -Exercise MPI or exercise
-Stress perfusion presence of exam findings of new
contrast Stress echocardiography
MRI** heart failure or shock,
-Stress perfusion MRI**
†; Where available; CTA can be
performed in the morbidly obese,
but specific parameters must be
used in scanning

Fig. 12.1 Acute chest pain initial testing algorithm based upon pre-test probability of CAD

Table 12.1 Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of various non-
invasive cardiac diagnostic testing procedures for the detection of significant coronary artery disease (ICA at least 50 %
stenosis)
Diagnostic test Sensitivity (%) Specificity (%) PPV (%) NPV (%) DA (%)
Exercise stress (GXT) 67 72 71 69 70
Exercise echocardiography 88 74 77 86 81
Dobutamine stress 81 80 80 81 81
echocardiography
SPECT MPI (exercise) 82 80 80 82 81
SPECT MPI (dipyridamole) 61 90 85 69 75
SPECT MPI (adenosine) 83 87 86 84 85
PET perfusion MPI 93 81 83 92 87
Coronary CTA (64-slice) 98 91 92 98 95
Coronary CT Perfusion (CTP) 91 74 83 85 83
Coronary CT FFR (FFRCT) 85 79 63 92 80
Stress perfusion MRI 87 85 85 86 86
Percent stenosis of 50 % was the cutoff used most commonly among studies. Few studies utilized a cutoff of >70 % steno-
sis by ICA. Data is pooled from several studies and meta-analyses where both cutoffs were used. In cases where diagnostic
accuracy was not given, this value was calculated from sensitivity and specificity. MPI performed with technetium
NPV negative predictive value, PPV positive predictive value, DA diagnostic accuracy, GXT gated exercise treadmill
test, SPECT single photon emission computed tomography, MPI myocardial perfusion imaging, PET positron emission
tomography, CTA coronary tomographic angiography
208 A.N. Bilolikar et al.

report a per-segment as well as a per-patient sen- (Maximal ST depression or elevation before,

sitivity and specificity. The per-patient assess- during or after exercise; angina score calculated
ment will be more generalizable when utilizing as 0=no angina, 1=non-limiting angina, 2=angina
the test among many patients. during exercise limits exercise).
In this patient’s case, there is concomitant dys- Thus Mr. M’s Treadmill score is calculated at
pnea and exam evidence of mild heart failure, thus −12, which places him at ‘high risk’ for long term
the imaging portion of the exam also gives insight events (Table 12.3). He was a reasonable candi-
into the patient’s left ventricular systolic function date for imaging as well given his pre-test risk
adding valuable information to the clinical picture. and alternative diagnoses being considered; how-
He undergoes his exercise stress echocardiogram ever, on the basis of his exercise test alone he
per your request. His ECG at baseline is normal, would be a very reasonable candidate for percu-
and he is able to perform a Bruce protocol for 7 min taneous intervention without the need for con-
with significant worsening of his dyspnea during comitant imaging. His treadmill score gives him
exercise, now eliciting chest pain and significant a 74 % chance of having significant three vessel
2–3 mm of ST depression in multiple leads on ECG CAD, or left main coronary artery disease [36,
(Fig. 12.2). His echocardiogram showed an EF of 37]. As it stands, the patient did have wall motion
60 % at rest, however this dropped to 45 % at stress abnormalities on echocardiography which local-
with anterior wall motion abnormalities (Fig. 12.3). ized his coronary disease to the anterior wall, cor-
He was referred for cardiac catheterization. relating angiographically to the 99 % stenosis
His catheterization showed a normal right sys- found in the LAD. Of important note, ECG
tem, with minimal disease throughout, however testing cannot localize level or extent of disease
showed a significant 99 % stenosis of the mid based upon the location of ST deviation [37].
LAD (Fig. 12.4). He underwent successful angio- Conversely, if there is diffuse ST segment depres-
plasty and stent placement in the mid LAD with a sion, this is a very specific sign for severe multi-
drug eluting stent, and did well post procedurally. vessel disease or left main coronary artery disease
Stress testing performed with an imaging [36]. Thus, this patient’s ECG at peak stress
modality has a sensitivity of ~75–80 % and speci- would also qualify him as having a significant
ficity on the per-patient level of ~80 % burden of disease, once again obviating the need
(Table 12.1). Thus it is a reasonable test to help for concomitant imaging in this case.
rule in disease among patients in whom you sus- Other features of the treadmill exam have valu-
pect a significant atherosclerotic burden [31]. able importance to predict overall mortality. The
The modality chosen will depend upon numerous ‘one minute heart rate recovery’- which examines
patient issues, including contraindications to var- the rate of the patient’s heart rate decline after
ious stress agents, and chemical tracers [7, 32, reaching peak exercise – has been studied among
33]. The ability to exercise should lead all patients patients referred for exercise treadmill testing,
to proceed directly with an exercise stress exam and was found to be an independent predictor of
[31, 34–36], as invaluable information is gath- mortality [38, 39]. When the one minute post
ered from the ECG portion of the examination, exercise heart rate did not drop by greater than 12
including the Duke treadmill score, one-minute beats per minute there was a two to fourfold
heart rate recovery, and reproduction of symp- increase in mortality at 5 year follow up. The
toms with exercise, as was the case for this 1 min heart rate recovery in this patient showed a
patient. The Duke treadmill score has been well drop in heart rate by ten beats per minute, a strong
validated to predict both morbidity and mortality predictor of mortality. Mr. M was seen back in the
in 4 year follow up [34, 35] (Table 12.2). This office 2 weeks after his intervention and was
patient’s Duke treadmill score was calculated as: doing well. His dyspnea completely resolved, and
Treadmill score = Duration of exercise (min- he was able to perform all of his activities of daily
utes) – (5xmaximal ST segment deviation) – (4x living without symptoms of dyspnea or chest
angina score pain, and his fatigue had also resolved.
12 Non-invasive Correlation of Invasive Imaging 209

Fig. 12.2 (Top, a) Resting ECG from patient with symp- from Bruce protocol, peak stress showing ST depression
toms of dyspnea on exertion. Mild ECG changes at base- of 3 mm in the infero-lateral leads. Stress ECG does not
line in inferior ST segments (bottom, b). Resulting ECG localize the site of injury

The use of echocardiography or nuclear critical information, particularly among those

imaging in conjunction with stress testing can patients with known coronary artery disease, as
accurately localize the area of ischemia, which it may help to guide revascularization. Take for
the ECG exam alone cannot [7, 32, 33]. This is example a patient with moderate CAD on last
210 A.N. Bilolikar et al.

Fig. 12.3 Stress echocardiogram from patient in case 1. arrows show the anterior wall, thickening at rest and not
Resting end-diastolic frames (left), resting end-systolic thickening or contracting at peak stress (right). Red lines
frames (center) and peak stress end-systolic frames (right) indicate area of endocardium showing mid-distal anterior
of the parasternal long axis (top), mid-chamber short axis wall motion abnormality
(center) and apical two chamber views (bottom). The red

a b

Fig. 12.4 Cardiac catheterization from patient in case 1. angioplasty and stenting, and the result is seen in the panel
(Top left, a) The Left system shows a 90 % stenosis in the to the right (b), showing 0 % residual stenosis in the area
mid LAD, with the circumflex and RCA showing mild of stenting. The vessel itself has continued disease distal
disease (not shown). The LAD was treated with balloon to the placed stent
12 Non-invasive Correlation of Invasive Imaging 211

cath 6 years ago in the LAD and circumflex for detecting ischemic heart disease is one that
arteries, with stenosis in the 50–60 % range in employs more than visualization of the coronary
both arteries who now presents with chest pain. lumen. Soon, we will have exciting new technol-
At re-cath, the vessels continue to show 60 % ogies which can combine the functional nature of
stenoses. A stress examination would reveal the a stress examination with the imaging needed to
area of ischemia (possibly both), thus allowing confirm disease, thus lowering the false positive
for the proper revascularization avenue. This is rate. The best example of this is CT perfusion
certainly an area which has improved in recent imaging. The first large study to document the
years in the cath lab with the advent, and now efficacy of CT perfusion imaging was the Core
widespread use, of fractional flow reserve 320 study [30], which showed that a protocol of
(FFR). For more information on FFR, please see stress imaging combined into a CT scan can give
Chap. 8. (1) coronary information, (2) perfusion informa-
tion beyond areas of stenosis, (3) myocardial
function and regional myocardial dysfunction
Future Use and (4) delayed enhancement to suggest areas of
infarction. This broad information is invaluable
Diagnostic testing for the presence of coronary as it combines several key components into one
atherosclerosis has been challenging for years, as picture. If the coronary CTA shows a 60 % steno-
the reference standard of luminal stenosis by sis, and the patient has chest pain, they are likely
invasive coronary angiography is perilous. going to undergo a cardiac catheterization to
Various studies show that the hemodynamic sig- determine the functional significance of that
nificance of an invasively proven 50 % stenosis lesion. Fractional flow reserve testing in the cath
varies from patient to patient and an arbitrary cut lab has been used for just such intermediate
point of 70 % stenosis is more sensitive for lesions and is well validated for determining the
‘hemodynamically significant’ disease, but function significance of these lesions (see Chap.
unfortunately makes the test less sensitive for the 8). With the perfusion information gleaned from
detection of disease. In truth, the best modality the CTP exam, one would know at the comple-
tion of the scan if a lesion was causing perfusion
Table 12.2 Duke treadmill score and impact on long deficits by way of analyzing regional myocardial
term survival contrast uptake along with a wall motion abnor-
4 year survival Annual mortality mality in that area on functional testing. This
Duke score (%) rate added layer of information may change the way
Low (≥5) 99 0.25 in which patients with chest pain are triaged and
Moderate (−10 to 4) 95 1.25 treated, with traditional stress testing perhaps
High (≤10) 79 5 becoming obsolete.

Table 12.3 Pre-test probability of CAD based upon Diamond and Forrester criteria, and ACC/AHA guidelines
Age Gender Non-cardiac chest pain Atypical chest pain Typical chest pain
<39 M Low Intermediate Intermediate
F Very low Very low Intermediate
40–49 M Intermediate Intermediate High
F Very low Low Intermediate
50–59 M Intermediate Intermediate High
F Low Intermediate Intermediate
>60 M Intermediate Intermediate High
F Intermediate Intermediate High
M male, F female
212 A.N. Bilolikar et al.

Case 2. Coronary Computed has no findings on her pulmonary examination,

Tomographic Angiography: and she has no evidence of lower extremity
Accuracy of Disease Detection swelling.
In her family history, she notes her mother had
Case Presentation an MI at age 60, and she has two sisters in their
50s, the eldest, currently 59 with a myocardial
Mrs. T is a 55 year old female who presents to the infarction (MI) 1 year ago. Further, given her
emergency department for symptoms of short- family history she underwent a coronary calcium
ness of breath and recent chest pain. She is previ- score CT (non-contrast CT of the chest at 3 mm
ously known to be healthy, however has noticed slice thickness) at age 50 which returned a total
progressive symptoms over the past 6–9 months calcium score of 0 Agatston units. She was
of shortness of breath, fatigue and in the past asymptomatic at that time.
3 days has noted mild chest discomfort. She has a You understand her symptoms are largely
medical history significant for hypertension and non-exertional, but are sub-sternal and are
takes chlorthalidone 25 mg daily with reasonable relieved with nitroglycerine. Her pain is atypical
blood pressure control. She saw her primary care by definition, but with a calcium score of zero
physician who obtained an ECG which was unre- 5 years ago, you decide to obtain a contrast CTA
markable (Fig. 12.5). She mentions she has never for acute chest pain (see Table 12.1, Algorithm-
been hospitalized, and has never had symptoms Intermediate Risk). Mrs. T undergoes a CTA with
similar to this prior to 9 months ago. Her primary the images shown in Fig. 12.6. She has evidence
care doctor worked her up for typical causes of of severe disease in the left anterior descending
fatigue, including a complete blood count and artery. Of note, collateral blood vessels cannot
thyroid panel, which all returned normal. usually be seen by CTA given their small
In the emergency department, her blood pres- diameter.
sure is 136/76 mmHg, her heart rate is 80 beats In this case, the patient had a calcium score of
per minute and her body mass index is 27 kg/m2. 0 with her presentation 5 years ago. This is not
She appears well, and in no acute distress. Her surprising, as her CTA and cardiac catheteriza-
cardiac examination reveals a normal S1 and S2, tion did not document any vessel calcification. It
with no murmurs or rubs. She has a normal is established that patients with a zero calcium
carotid upstroke and normal jugular venous pres- score have a 4-year “warranty” period for very
sures. Her precordial examination reveals no RV low risk of cardiac events [11, 12]. The
heaves or lifts, and the PMI is non-displaced. She likely explanation for a 4 year – and not a

Fig. 12.5 ECG from patient in case 2. Normal sinus coronary ischemia, and the evaluation must continue past
rhythm and normal ST segments/T waves. A resting ECG a resting ECG for disease detection among patients at
may or may not be helpful in the detection of ongoing intermediate to high risk for CAD
12 Non-invasive Correlation of Invasive Imaging 213

a b

Fig. 12.6 CTA image (left, a) and corresponding ICA stenosis in the mid vessel. The patient had a calcium score
image (right, b) of the LAD for the patient in case 3, pre- of 0 5 years ago, and now there is still no calcium in the
senting with progressive dyspnea. The LAD shows a 99 % coronary tree, however significant disease in the artery

longer – warranty is twofold: (1) the presence of plaque is higher than that for calcified plaque
non-calcified disease which cannot be accounted [42–45]. These calcified plaques cause a ‘bloom-
for by non-contrast studies alone and (2) the ing effect’ in the artery, making the plaque appear
development of new coronary plaques not previ- larger and giving the appearance of a higher
ously seen. Thus, a calcium score, while very degree of stenosis than is truly present. This is
helpful for risk stratification and detection of dis- typically the case when viewing an image in a
ease, only detects disease which is currently clin- maximum intensity projection (MIP), as the pix-
ically quiescent, and scans which are older than els will appear the color of the highest Hounsfield
4 years must be considered with caution in the units which resides within it border; a problem
decision making process. Moreover, the conver- which can largely be overcome with multi-planar
sion from a “Zero calcium score” state to a reformatting (MPR) viewing. Thus with MIP, a
“positive calcium score” state is non linear, small amount of calcium may cause the appear-
bringing into question the benefit of repeating the ance of a significant stenosis depending upon its
coronary calcium score. location within the vessel. In general however,
CTA has a high diagnostic accuracy for the the more calcium that is present within a given
detection of ICA confirmed stenosis [14–20]. plaque, the more difficult the lumen of the artery
Among the testing modalities listed in Table 12.1, is to interpret in that area. In Fig. 12.7, separate
CTA has the highest sensitivity and negative pre- CTA MIP examples are shown of calcified
dictive value, making it a very reliable test for plaques which make luminal interpretation diffi-
both ruling in and ruling out disease among cult. In the first case with a moderate amount of
patients presenting to the ED with acute chest calcium, the CTA called a high degree of stenosis
pain [40, 41]. The limitation of CTA is its inabil- (>70 %) in the ostial LAD, and the invasive
ity to inform the physician about the hemody- angiogram confirmed this. However, in the sec-
namic significance of disease once that disease is ond example, with more severe calcium present,
discovered. Various studies have shown that the the CTA was read as having critical disease in the
accuracy of CTA stenosis in cases of non-calcified LAD, however the invasive angiogram showed a
214 A.N. Bilolikar et al.

a b

c d

Fig. 12.7 Examples of calcified plaques seen by CTA. patient’s LAD, with CTA showing a heavily calcified
(Above, a, b) CTA showing a moderately calcified plaque LAD and critical stenosis, and ICA showing a moderate
which does not affect the ability to diagnose the severe level of stenosis. As the degree of calcification increases
degree of underlying stenosis. ICA done the following on CTA, the ability to predict the angiographic stenosis
day confirms severe proximal/ostial LAD stenosis. becomes more difficult
(Below, c, d) CTA and corresponding ICA depicting the

moderate stenosis in that area. In general, the less their study, the largest predictor of a false positive
calcium which is present to fill pixels in the coro- CTA was patient calcium score (OR 5.2) and seg-
nary wall, the less blooming will occur, and the mental calcium (OR 10.2). Interestingly, the
more accurate the CTA will be for detection of same paper discusses that the absence of calcium
coronary stenosis [42–45]. was also a predictor of a false negative test; say-
Factors other than coronary calcium will ing in essence that non-calcified plaques are not
affect the diagnostic accuracy of a CTA. In a infrequently present and the lack of calcium may
study by Yan et al. [46], 291 patients were evalu- skew the interpretation by the CTA reader into
ated by CTA and quantitative coronary angiogra- ‘missing’ non-calcified plaques. Important pre-
phy for determination of predictors of inaccurate dictors of inaccurate coronary artery stenosis
coronary artery segments. Not surprisingly in severity found by multivariate analysis were the
12 Non-invasive Correlation of Invasive Imaging 215

presence of intracoronary stents (OR 4.2), seg- presents to the emergency department for symp-
ment tortuosity (OR 3.5), venous contamination toms of recent onset chest pain. He describes the
(OR 3.5), and small vessel size (OR 0.48). pain as a vague, non-radiating pain in the left
Naturally, improved luminal contrast was found chest which comes and goes. He notes it is pres-
to improve overall accuracy by decreasing the ent more with exertion, but at times it has
false negative rate (OR 0.96). It is important to occurred without exertional symptoms, then last-
note CTA has limitations, and should only be ing only a few minutes and stopping. He is a quiet
used in select patient populations, with caution man, with little else to offer in terms of history.
employed among cases of previously placed He notes no previous symptoms similar to this,
intracoronary stents, significant coronary cal- and has had no previous cardiac examinations.
cium, significant vessel tortuosity, and/or poor His physical examination reveals a blood pres-
scan quality and poor coronary opacification. In sure of 146/92 mmHg, a resting heart rate of 84
general, a CTA, which is interpreted by a reader beats per minute, and a BMI of 31 kg/m2. The
who does not maintain a high volume of CTA patient’s cardiovascular exam shows a normal S1
reading, has a higher likelihood of either false and S2, no murmurs are auscultated. There is no
positive or false negative results [47, 48]. evidence of a precordial heave or lift, and PMI is
CTA has a high degree of reliability with non-displaced. The pulmonary exam reveals no
regard to plaque and coronary lumen visualiza- rales or wheezes. There is no evidence of elevated
tion. In a meta-analysis by Voros et al. [26], jugular venous pressure and the lower extremities
Coronary CTA had excellent diagnostic accuracy are free of edema.
for the detection of coronary plaques using IVUS Given his recent onset symptoms, an ECG is
as the reference standard, with an area under the obtained, which is normal with no ischemic
curve for receiver operating characteristic analy- changes. His blood work includes standard test-
sis of 0.94 (95 % confidence intervals [CI]: 0.92– ing, with a complete blood count, and chemistry
0.96), a sensitivity of 0.90 (95 % CI: 0.83–0.94) panels, all of which reveal values within normal
and a specificity of 0.92 (95 % CI: 0.90–0.93). ranges. His cardiac biomarkers are normal, with a
This meta-analysis confirmed that coronary CTA Troponin I <0.03 μg/L at outset, and a CK of
may slightly overestimate luminal area, presum- 94 mg/dl. He is admitted to the chest pain obser-
ably because of partial volume averaging effects vation unit to rule out MI. He is kept overnight
which can lead to overestimation of the size of and in the AM, diagnostic testing is performed.
very bright structures (such as the contrast- His symptoms are acute, but atypical, with no
enhanced lumen), whereas plaque area, volume, suggestion of elevated biomarkers thus a coro-
and area stenosis measurements are similar nary CTA is obtained. The pertinent coronary
between CT and IVUS. Thus, when viewing a CTA images are reviewed in Fig. 12.8. There is
coronary CTA, luminal size and area can be used evidence of mild disease with calcific plaques
fairly accurately for stent sizing and lesion length, throughout the three epicardial vessels; however
with the caveat that a slightly smaller lumen size there is evidence of a disrupted plaque seen in the
may actually be present. first obtuse marginal (OM1) branch of the left
circumflex artery. The OM1 is diffusely diseased
in the ostial and proximal segments with a calci-
Case 3. Unstable Coronary Plaque fied plaque followed by a long non-calcified
Detection by CTA plaque in the proximal portion, with areas of
plaque disruption in the form of intra-plaque dye
Case Presentation penetration seen within the non-calcified plaque.
The patient was felt to have an unstable plaque
Mr. H is a 59 year old male with a history of with significant arterial narrowing and underwent
hypertension and a former one pack per day a cardiac catheterization as a result. The pertinent
smoker for 30 years who quit 10 years ago, who cath images are also shown in Fig. 12.8. The
216 A.N. Bilolikar et al.

Fig. 12.8 Comparative CTA (left) and ICA (center) in dye penetration, yellow arrows) seen by CTA in an area of
the OM branch of the circumflex from the patient in case non-calcified, lipid plaque, and haziness seen on ICA (yel-
3. The white arrows delineate areas of calcified plaque on low arrows). The non-calcified plaque (yellow bracketed
CTA and ICA. By CTA the degree of stenosis appears area) can be seen localized on CTA and corresponding
slightly larger due to blooming artifact; on ICA the steno- ICA. Post PCI (right), the OM stenosis improves to 0 %,
sis appears less severe. (Left) After a small side branch, and the area of ruptured plaque is now fully covered
there is evidence of frank plaque disruption (intraplaque

proximal OM1 shows a smooth tapering with a plaque, also appear to indicate a higher risk
slight haziness with a stenosis severity of 70 %. plaque [54, 55].
He underwent successful revascularization of the Coronary CTA has the ability to detect fea-
proximal OM1 with placement of a drug eluting tures of frankly disrupted plaques, indicated on
stent. CTA by intra-plaque dye penetration and ulcer-
The invasive angiographic hallmark of ACS is ation [56, 57]. Intra-plaque dye penetration refers
a complex culprit plaque characterized by lesion to the presence of contrast dye within the plaque
irregularity, haziness, ulceration, contrast dye itself possibly from a disrupted thin cap fibroath-
persistence within the plaque, intra-luminal fill- eroma, or a leaky or disrupted vaso-vasorum
ing defect and impaired flow seen by ICA [49– leading to intra-plaque hemorrhage, as was seen
52]. These angiographic features correlate with in this case. Plaque ulceration refers to disruption
plaque rupture and thrombus at pathological of the thin cap fibroatheroma with loss of integ-
examination and by direct coronary imaging with rity of the plaque contrast interface, which allows
IVUS, which reveals such plaque to be bulky, for pooling of contrast within this ‘fissure’ con-
eccentric, positively remodeled, ulcerated and tiguous with the lumen (Fig. 12.9). Although pro-
ruptured [49–52]. Unstable coronary plaques are spective evidence from natural history studies is
thought to arise from “vulnerable” lesions at high lacking, retrospective autopsy studies suggest
risk for disruption. CTA plaque features have several histological types of suspected vulnerable
been identified which may predict future plaque, the most common of which is an inflamed
ACS. The presence of positive remodeling, and thin cap fibroatheroma, thought to account for
the presence of low attenuation plaque by CTA, 60–70 % of coronary events; another 30–40 % of
or the so-called ‘2-feature positive’ plaque has a events are felt attributable to plaque erosions.
strong statistical correlation with an ‘at risk’ When present, these findings correlate well with
plaque [53]. Such plaques would be at a greater complex plaque features seen on ICA and IVUS
than 20-fold higher risk (HR 22.8, CI: 6.9–75.2) studies among patients presenting with acute cor-
of inciting an ACS event than plaques without onary syndrome [58–60].
such features present. CTA findings of “signet- In summary, CTA evidence of bulky low
ring” or “napkin ring” signs, demonstrating an attenuation plaque and positive remodeling may
eccentric bulky low attenuation intramural indicate lesions at higher risk for acute coronary
12 Non-invasive Correlation of Invasive Imaging 217

Fig. 12.9 CTA evidence of plaque disruption, as seen in example of an ulcerated plaque in a patient with ACS,
the patient in case 3. (left) Evidence of intraplaque dye with the contrast sitting in the fissure of the plaque (red
penetration (red arrows) which has Hounsfield Unit atten- arrow) and the plaque of low attenuation, likely lipid core
uation as the contrast pool, and not calcium as depicted (yellow arrows). Both features correlate well to invasive
more proximally in the vessel (white arrow). (Right) angiographic features of plaque complexity

syndromes, whereas less bulky higher attenua- Given his relative stable presentation, you are
tion lesions may be of lesser concern. Clearly, the about to have him undergo a stress echocardio-
proximal location of a given lesion, percentage gram, however his ECG is obtained (Fig. 12.10)
diameter stenosis, patient vulnerability and other and shows inferior q waves, and anterolateral Q
factors undoubtedly influence the behavior of a waves. On questioning, he notes having been told
given plaque over time. since he was a teen that he had an ‘abnormal’
ECG and he is adamant that he has not had a pre-
vious MI. However, given his resting ECG abnor-
Case 4. CTA: Correlation malities, you elect to proceed with a coronary
to Advanced Coronary Imaging CTA for evaluation.
The CTA shows a lesion in the distal RCA just
Case Presentation proximal to the PDA and PLB branches. The
artery tapers smoothly there, and there is slight
Mr. S is a 50 year old male who presents to your haziness in this location with a non-calcified
offices for evaluation of recent onset chest dis- plaque, but the stenosis is interpreted as 50 %. He
comfort. He notes the discomfort coming and is still having symptoms of chest discomfort, but
going for the past 2 months, and there is little no other significant artery disease is found. Given
correlation with exertion. He denies symptoms his ECG changes and his continued symptoms,
similar to this previously. He has a history of he undergoes a cardiac catheterization for possi-
hypertension which is well controlled and is a ble IVUS and fractional flow reserve interroga-
former smoker, having quit 15 years ago. He is tion of this lesion.
active and notes regular exercise running In the cath lab, images are obtained. The
2–3 miles daily, along with light weight training patient has no significant stenosis of the left
daily and previously noted no symptoms with system (not shown). The distal RCA is interro-
exercise 2 weeks ago prior to his discomfort. He gated, and is felt to have a hazy appearance.
was reluctant to exercise for the past 2 weeks The stenosis severity is felt to be 60 %, similar
given his discomfort, and it was at that time that to the CTA, and the CTA and ICA images are
he made the appointment to see you. In the office represented in Fig. 12.11. The patient then
he appears well, in no acute distress. He is chest undergoes NIRS-IVUS of the plaque to deter-
pain free. On examination, he has a blood pres- mine the nature of this haziness. The NIRS-
sure of 128/70 mmHg, his heart rate is 68 beats IVUS images (Fig. 12.12) confirm that the
per minute, and his BMI is 27 kg2/m2. vessel in this location houses critical plaque
218 A.N. Bilolikar et al.

Fig. 12.10 ECG for the patient in case 4. Inferior Q tion. This is not an absolute contraindication for exercise
waves and anteroseptal Q waves will make detection of testing as an uniterpretable ECG is defined as the presence
peri-infarct ischemia difficult by exercise ECG examina- of a left bundle branch block or ventricular pacing

Fig. 12.11 Curved planar CTA (left) with luminal axial area of lipid core plaque, green arrows show reference
slices depicted (center), and corresponding ICA (right) of vessel. On ICA, the area appears hazy and the stenosis in
the distal right coronary artery. Yellow arrows demarcate the moderate to severe range
12 Non-invasive Correlation of Invasive Imaging 219

Fig. 12.12 Coregistration of ICA (left), NIRS-IVUS with selected frames from the IVUS (top right) and the
exam (center and top right) and curved planar axial view CTA (bottom right) showing the area of dense lipid core
of coronary lumen (right bottom). The block chemogram plaque. The lipid core burden index (LCBI) from this scan
delineates the area of dense, lipid core plaque, seen in the was 292 over 4 mm of artery length, placing it at extremely
longitudinal IVUS view. The black arrow shows the lipid high burden of lipid core plaque
burden area as it is seen on the longitudinal IVUS views,

with a large volume of lipid core plaque and Several studies have pointed to lipid core
plaque which is “hugging” the IVUS catheter plaque as the proximate cause of acute coronary
(lipid core burden index of 292). Despite this, syndrome [49–52]. Recent investigations show
FFR is done which confirms the hemodynamic that CTA can correlate to intracoronary and path-
significance of this lesion: a 2 min adenosine ological investigations with respect to the detec-
infusion caused the FFR value to dip from 0.98 tion of non-calcified, lipid core plaque [21–27,
to 0.74. The patient was treated with a drug 53–55]. Interestingly, the VH evaluation of such
eluting stent extending from the proximal edge plaques find those with the most lipid core, and
of the lipid core seen by NIRS extending into thus highly rupture prone, are the APO-B and
the proximal PDA where the plaque was felt to small HDL particle containing plaques [25]. This
terminate (Fig. 12.13). is notable as the plaques with the lipid rich large
The patient’s CTA in this case showed cause HDL particles were more likely to be calcified,
for concern; there was clearly a stenosis caused and again by principle more stable. This has
by low attenuation plaque, which correlated to implications beyond mere imaging, and delves
the ICA. The severity of the plaque was felt to be into the realm of cholesterol management. CTA
moderate by CTA, confirmed by ICA. The hemo- studies have shown plaque regression with use of
dynamic significance of this lesion was tested by high dose statin medications [61], lending sup-
FFR which was positive (0.74), supporting this port to the idea that the lipid core may be altered
plaque as the cause of the patient’s ongoing in these plaques with appropriate medical
symptoms. The patient followed up in the office therapy. Thus, the clinical impact of finding such
post procedure and was now asymptomatic, con- plaques is implicit.
firming this lipid core plaque and resulting coro- The strongest evidence thus far for invasive
nary stenosis as the cause of his symptoms. detection of vulnerable plaque is that of necrotic,
220 A.N. Bilolikar et al.

Fig. 12.13 Angiographic result pre (left) and post (right) guided the length of lesion coverage extending into the
intervention in the distal RCA in patient from Case 4. Post PDA (yellow arrow)
PCI NIRS-IVUS revealed no lipid burden remaining and

Table 12.4 Relative strengths and weaknesses of ICA, CTA, IVUS, OCT, NIRS and VH in coronary and plaque
imaging
ICA CTA IVUS OCT NIRS VH
Coronary lumen imaging ++++ ++++ ++++ ++++ 0 0
Coronary wall imaging 0 +++ ++++ + +++ ++++
Plaque volume 0 ++++ ++++ 0 +++ ++++
Remodeling + ++++ ++++ 0 + ++
Plaque density 0 +++ ++ + +++ ++++
Calcification +++ ++++ +++ ++ ++ ++++
Plaque composition/lipid 0 +++ +++ + ++++ +++
ICA invasive coronary angiography, CTA coronary computed tomographic angiography, IVUS intravascular ultrasound,
OCT optical coherence tomography, NIRS near infrared spectroscopy, VH virtual histology

lipid core plaque [62–64]. The volume of litera- detect low attenuation plaque, via low (<50) HU
ture correlating non-invasive and invasive plaque values [53]. Further, comparative studies have
detection is growing daily, and the evidence is shown that plaques with more than 10 % compo-
mounting supporting the ability of CTA to detect sition of necrotic core by IVUS and VH, have
lipid core plaque and its correlation to more inva- significantly lower CTA HU values [25]. In con-
sive techniques, such as IVUS, OCT, VH and junction with this, IVUS/VH has been correlated
NIRS [21–27, 53–55, 60, 62–66]. A summary of with NIRS for localization and detection of non-
the relative strengths and weaknesses of CTA and calcified plaque composition, and the two can
the advanced imaging modalities with respect to show similar data when co-registered [25, 26].
coronary imaging is presented in Table 12.4. Clinical implications of finding low attenua-
Recent studies of CTA have shown the ability tion, lipid rich plaques are evident [62–65]. Lipid
to detect differences in fibrous, calcified and rich necrotic core plaques are at higher risk for
lipid-rich plaque [25, 26, 53–57] and similar pre- becoming a culprit lesion [63, 64], and CTA
viously done studies have shown CTAs ability to proven low attenuation plaque has been associated
12 Non-invasive Correlation of Invasive Imaging 221

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 Intra-cardiac Echocardiography-
Guided Interventional Imaging 13
Frances O. Wood and George S. Hanzel

Abstract
Intra-cardiac Echocardiography (ICE) is a widely used tool in the inter-
ventional and electrophysiology laboratories because of its safety profile,
ease of use and imaging to provide anatomical positioning of veins, septa,
ridges and chambers of the heart. Its application overcomes some of the
limitations of TTE: need for a separate operator and potential interference
with the interventionalist, limited acoustic windows, and prolonged proce-
dure using general anesthesia.
Ultrasound to image the heart was first described by Cieszynksi in
1960. Rotating single crystal probes preceded the mechanical 4-element
probe followed by a 32-element phased array coil. Pandian et al. described
atheterosclerosis and coronary remodeling with higher frequency rota-
tional catheters. Transvascular passage of a phased-array probe to the
heart to close experimental atrial septal defects in piglets was first
described by Valdez-Cruz et al. In the early 1990s, ICE was being devel-
oped for visual guidance during electrophysiologic ablation and human
ASD closure. The high-resolution imaging has evolved to deliver both far-
field and near-field views to provide perspective, orientation and anatomi-
cal detail. 3D ICE is currently available and its role and incremental value
compared to 2D ICE is yet to be determined.

Keywords
Intra-cardiac echocardiography (ICE) • 2D ICE • 3D ICE • Phased-array
catheter • For ICE for Atrial Septal Defect (ASD) evaluation • Secundum
atrial septal defect closure • Patent foramen ovale closure • Percutaneous
balloon mitral valvuloplasty • Lead thrombus

F.O. Wood, MD G.S. Hanzel, MD (*)

Department of Cardiovascular Medicine, Beaumont Department of Cardiovascular Medicine, William
Health System, Royal Oak, MI, USA Beaumont Hospital, Royal Oak, MI, USA
e-mail: [email protected] e-mail: [email protected]

© Springer-Verlag London 2015 225

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2_13
226 F.O. Wood and G.S. Hanzel

Introduction depiction of both atrial chambers and atrio-

ventricular valves.
Intra-cardiac Echocardiography (ICE) is a widely • Can be used as IVUS for great vessels.
used tool in the interventional and electrophysi- • Needs a dedicated console.
ology laboratories because of its safety profile, • Mostly used for electrophysiology EP procedure.
ease of use and imaging to provide anatomical
positioning of veins, septa, ridges and chambers
of the heart. Its application overcomes some of AcuNav/Viewflex Fixed or Phased
the limitations of TEE: need for a separate opera- Array Echo Catheter
tor and potential interference with the interven- (AcuNav® phased-array 10 Fr, 5.5–10 MHz
tionalist, limited acoustic windows, and catheter with 90° sectorial sector image and
prolonged procedure using general anesthesia. Doppler capability (Acuson, a Siemens
Ultrasound to image the heart was first Corporation, Mountain View, California)
described by Cieszynksi in 1960 [1]. Rotating
single crystal probes [2, 3] preceded the mechan- • Similar to TEE images
ical 4-element probe [4] followed by a 32-element • Electronically controlled multiple transducers
phased array coil [5, 6]. Pandian et al. described affixed to one side of the catheter shaft,
atheterosclerosis and coronary remodeling [7, 8] • A wedge-shaped image sector
with higher frequency rotational catheters. • Large depth of field, good frequency range
Transvascular passage of a phased-array probe to and steerability.
the heart to close experimental atrial septal • Doppler imaging color and spectrum
defects in piglets was first described by Valdez- • Better image resolution and definition.
Cruz et al. [9]. In the early 1990s, ICE was being • Can be coupled with multiple and different
developed for visual guidance during electro- consoles.
physiologic ablation and human atrial septal • Usually used in structural heart disease
defect ASD closure [10]. The high-resolution procedures.
imaging has evolved to deliver both far-field and
near-field views to provide perspective, orienta- The phased array catheters are mostly used in
tion and anatomical detail. 3D ICE is currently structural cases, while the mechanical type is uti-
available and its role and incremental value com- lized primarily in EP procedures. There are pri-
pared to 2D ICE is yet to be determined. marily two commercially available Phased-array
ICE catheters with varying features, Table 13.1.
The catheters are expensive, $2,000–$2,500, and
Types of ICE are for single use only. Currently, the most com-
monly used catheter is produced by AcuNav.
Ultra ICE Mechanical Echo Catheter
(Ultra ICE mechanical, 9 Fr, 9 MHz catheter,
with 360° radial image) (Boston Scientific, Phased-Array Catheter
Natick, Massachusetts)
A phased array probe has multiple small ele-
• Similar to IVUS catheters imaging ments at the probe tip that emit a beam, which
• Rotating ultrasound transducer driven by a can be pulsed individually at a computer-
motor unit at the opposite end of a braided calculated timing. This allows for a wide volume
drive shaft region to be swept at a high speed. The pulsed
• A 360-degree view perpendicular to the elements emit pressure waves which add up to a
catheter. single wave front traveling at a set angle. The
• Better near-field resolution, larger field of data from multiple beams is combined as the
view and allows for a more comprehensive probe is swept through the examined tissue creat-
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 227

Table 13.1 Comparison of the two commercially available phased-array ICE catheters
Ultrasound Catheter Frequency Depth of
Catheter method size (F) range (MHz) field (cm) Steerability Doppler/color
ViewFlex Phased-array 9 4.5–8.5 Up to 21 Anterior/posterior, 120° Yes
PLUSa
AcuNav# Phased-array 8 or 10 5.0–10 Up to 1 Anterior/posterior Yes
Left/right, 160°
Data from Kim et al. [11]
a
Boston Scientific, Natick, Massachusetts; #St. Jude Medical, St. Paul, Minnesota

ing a visual image showing a slice through the Home View

object. The AcuNav catheter contains a
64-element phased-array transducer which can The home view is obtained by advancing the
penetrate up to 15 cm in the heart. Resolution and probe into the mid right atrium without any flex-
depth penetration are inversely related. There is ion and the transducer facing the tricuspid valve.
four way directional steering in two bidirectional Counter clockwise rotation of the catheter may be
planes (1) anterior-posterior and (2) right-left. needed. The right atrium, tricuspid valve, right
These two knobs allow the operator two steer ventricle, right ventricle outflow tract, aortic
while the third knob locks the catheter position in valve, anterior part of the atrial septum, pulmo-
a desired position. In addition, the catheter itself nary valve and the proximal part of the pulmonary
can be rotated clockwise or counterclockwise. artery can be visualized in the home view.
Tricuspid and pulmonic insufficiencies are best
seen in this view. If the catheter is rotated clock-
Main Views for ICE wise, the beam is swung posteriorly allowing you
to visualize the left atrium, left atrial appendage,
Venous access can be obtained either internal mitral valve, pulmonary veins, and proximal
jugular or femoral approach. The 90–100 cm descending aorta.
catheters advanced through an 8F or 10F venous
sheath. ICE access site can be either the ipsilat-
eral or contralateral to the working venous access Septal View (Also Called Atrial View)
side. If using the ipsilateral approach, a long
30 cm venous sheath is recommended to reduce From the home view, rotate the catheter counter-
entanglement with other devices. Others have clockwise until the atrial septum is seen. At this
recommended contralateral access if the patient point, the catheter is locked and a posterior tilt
weighs less than 35 kg. Closure can be a figure of performed to point the beam cephalad. Both atria
eight or manual pressure. Infusion of 500 cc are visualized and this is the only view to see the
saline prior to the procedure dilates the veins and superior rim of the atrial septum. If the beam is
chambers; thus assisting with probe advancement moved cephalad with a right tilt, the superior cava
and later device placement. The rigid ICE probe is seen on the right side of the screen. The inferior
without any flexion should be advanced under vena cava is seen by moving the probe caudal.
fluoroscopic guidance as the probe tip is blunt Pulmonary venous return to the left atrium and
and can puncture or dissect the vein. There are the coronary sinus can be seen in the view.
four traditional views (home, septal, long axis,
short axis) used during intracardiac interventions
(Fig. 13.1). The chamber closest to the beam and Long Axis View (Also Caval View)
at the top of the display screen is always the
chamber where the probe is positioned, usually The long axis view is the locked septal view
the right atrium. but the posterior flexed catheter is more
228 F.O. Wood and G.S. Hanzel

cephalad to see the superior vena cava (SVC) Short Axis View
or caudal to visualize the Inferior vena cava
(IVC). The cephalad position allows better The short axis view is obtained by moving the
visualization of the SVC, superior aspect of the catheter cephalad below the aortic valve and
atrial septum and posterior superior rim. The towards the tricuspid valve. The posterior-
caudal positioning views the IVC, inferior anterior knob is adjusted to have less flexion
aspect of the atrial septum and the posterior while the left-right knob is rotated more leftward.
inferior rim. Clockwise or counterclockwise This allows visualization of the aortic and pulmo-
rotation or posterior-anterior flexion shows nary valves and the superior anterior rim (closest
right and left pulmonary veins. to aortic valve) and inferior-posterior rim.

a b

Fig. 13.1 ICE standard views. (a) Schematic diagram of anteroposterior fluoroscopy and corresponding ICE
heart. LA left atrium, LV left ventricle, A aorta, PA pulmo- images (c, e, g, i). (b, c) Home view; (d, e) Septal view; (f,
nary artery. (b, d, f, h) show ICE beam projection using g) Long axis view; (h, i) Short axis view
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 229

e f

g h

Fig. 13.1 (continued)

230 F.O. Wood and G.S. Hanzel

ICE Guidance for Intracardiac Examples Using Intracardiac

Interventions Echocardiography

ASD Evaluation Secundum Atrial Septal Defect

Closure
Figure 13.2 shows the best views to visualize
the atrial septals rims for Atrial Septal Defect The patient shown in Fig. 13.2 was a 74 year old
(ASD) evaluation. The septal view shows the gentleman with tachy-brady syndrome requiring
inferior-posterior rim and superior anterior a permanent pacemaker, remote surgical ventric-
rim. The long axis view allows for visualiza- ular septal defect repair with NHYA Class III
tion of the inferior and superior rims while the dyspnea. Echocardiography revealed severe bi-
long axis view lays out the posterior and ante- atrial enlargement, mitral valve prolapse with
rior rims. moderate mitral regurgitation, and atrial septal

a b

Fig. 13.2 Secundum ASD closure. (a) ICE catheter in width. (g) Deployment left atrial side 18 mm Amplatzer
septal view position. (b) Septal view. (c) Color Doppler. ASO. (h) Tug test. (i) Deployed Amplatzer. J. Deployed
(d) Rosewire across interatrial septum (e) 30 mm sizing Amplatzer in LAO cran
balloon. (f) LAO cran view to measure tunnel length and
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 231

e f

g
h

Fig. 13.2 (continued)

232 F.O. Wood and G.S. Hanzel

defect with predominately left to right shunting. sizing balloon was advanced over the Rosen wire
The secundum ASD measured 1.6 cm with the to determine length and width of the PFO tunnel.
following rims measurements: aortic 26 mm, Balloon sizing was utilized more often with PFO
superior 40 mm, retroaortic 24 mm, posterior closure when the ASD occluder devices were
40 mm, inferior vena cava 51 mm and superior used rather than the cribriform device. More
vena cava 42 mm. often, no balloon sizing is performed with the lat-
10.5F and 12F short sheaths were placed in the ter. However, the distance from the wire across
right femoral vein. A 5F sheath was placed in the the PFO to the septum edge is measured and
left femoral artery. Baseline right and left heart accordingly the size of the Cribriform device is
evaluation revealed cardiac index 4.6 L/min/m2 chosen. This is also true when implanting an
and QP:QS 1.9. Intracardiac echocardiography Amplatzer PFO device. There was a 10 mm waist
(ICE) was performed with the 10F AcuNav cath- across the PFO (Fig. 13.3d). A 25 mm Amplatzer
eter (Fig. 13.2a–c). The ASD was crossed with a cribiform PFO closure device was advance into
Rosen wire (Fig. 13.2d) and 7F Goodale-Lubin the left atrium. The left atrial wing was deployed,
catheter. The Rosen was exchanged for an extra pulled to the septum followed by right atrial wing
stiff Amplatz wire which was positioned in the deployment (Fig. 13.3e). ICE confirmed a seal of
left upper pulmonary vein. The secundum defect the occlusion with no Doppler color flow around
was measured at 1.5–1.6 mm by ICE and fluoros- the waist of the device. The device was released
copy (Fig. 13.2e–f). The left atrial wing of the from the delivery catheter after the tug test. The
18 mm Amplatzer ASO device was deployed sheaths were removed and a figure-of-eight stitch
(Fig. 13.2g) and pulled against the interatrial sep- was placed for hemostasis.
tum prior to deploying the right atrial wing.
Positioning and color Doppler were performed
and there was no color flow around the device. Percutaneous Balloon Mitral
The Amplatzer ASO device was released after the Valvuloplasty
push-pull test, also known as tug test, confirmed
adequate defect coverage and stability The patient shown in Fig. 13.4 was a 73 year old
(Fig. 13.2h). The right femoral venous sheaths female with rheumatic heart disease and NYHA
were closed with a single figure-of-eight stitch. class III dyspnea. Baseline hemodynamic evalua-
tion at heart rate 85 beats per minute and blood
pressure 140/60 showed a direct left atrial pressure
Patent Foramen Ovale Closure of 24 mmHg with a V wave of 44 mg and left ven-
tricular pressure of 140/18 mmHg. Mitral valve
The patient shown in Fig. 13.3 is a 39 year old area was 1.08 cm2 with a mean mitral gradient was
female with a cryptogenic stroke and heterozy- 11 mg. Echocardiography revealed mild mitral
gous methylenetetrahydrofolate reductase regurgitation and a Wilkins-Block score of 6.
(MTHFR) genetic mutation. Transesophogeal The 10F AcuNav catheter was advanced
echocardiography showed a patent foramen ovale under fluoroscopy through a 11 × 30 cm left
(PFO) by color Doppler and agitated saline con- femoral venous sheath. An extreme short axis
trast. The inter-atrial septum was not ICE view crossing the tricuspid valve
aneurysmal. (Fig. 13.1a) was used to view the mitral valve
As with ASD closure, 10.5F and 12F short (Fig. 13.1b). The 7F Mullins sheath was
sheaths were placed in the right femoral vein. The advanced via the 7F right femoral venous sheath
10F ICE catheter was advanced to the right atrium to the left atrium. Transeptal pucture with a
to visualize the PFO and a positive agitated saline Brockenbrough needle was performed using
study (Fig. 13.3a, b). A 6F multipurpose catheter standard anterioposterior fluoroscopy and septal
and 038 × 260 cm Rosen wire was used to cross view by ICE (Fig. 13.1c). The Toray coiled-
the PFO (Fig. 13.3c). The Rosen wire was posi- tiped wire was looped into the left atrium
tioned in the left upper pulmonary vein. A 25 mm (Fig. 13.1e) in order to provide support to dilate
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 233

a b

c
d

Fig. 13.3 PFO closure. (a) Interatrial septum in modified septal view. (b) Positive right to left agitated saline study.
(c) Rosen wire across PFO. (d) 25 mm balloon sizing of PFO. (e) 25 mm Amplatzer cribiform PFO closure device
234 F.O. Wood and G.S. Hanzel

the transeptal puncture with the Inoue dilator. 1.8 cm2. In addition, severity of mitral regurgita-
Multiple dilatations were performed using a tion was assessed using by advancing the ICE
28 mm Inoue balloon inflated to 24, 26 and catheter in the right ventricle and imaging the
28 mm (Fig. 13.1e, f). Simultaneous left atrial mitral valve and left ventriculography
and left ventricular pressures were obtained (Fig. 13.1g, h). There was moderate mitral
after each inflation. Final hemodynamic evalua- regurgitation with an anteriorly directed jet.
tion showed a mean transmitral gradient of Figure-of-eight sutures were placed to obtain
7 mmHg and a calculated mitral valve area of hemostasis after removal of the venous sheaths.

a b

Fig. 13.4 ICE and fluoroscopy guided percutaneous bal- 28 mm Inoue balloon. (f) 28 mm Inoue balloon inflated to
loon mitral valvuloplasty. (a) Fluoroscopy extreme short 28 mm in RAO. (g) ICE assessment of mitral regurgita-
axis view. (b) ICE extreme short axis view. (c) Transeptal tion post mitral valvuloplasty. (h) Left ventriculography
puncture. (d) Coiled tip wire in left atrium. (e) Inflation of to assess mitral regurgitation
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 235

e f

g
h

Fig. 13.4 (continued)

Lead Thrombus was aborted given the risk of thrombus dislodge-

ment. This case exemplifies why it is important to
A 62 year old patient presented to the laboratory assess all structures visualized by ICE as the lead
for direct pressure assessment across the mitral thrombus changed our management.
valve. She underwent percutaneous mitral valvu-
loplasty 4 years previously for rheumatic heart dis-
ease. Warfarin for persistent atrial fibrillation after Figure-of-Eight Stitch
multiple ablations was held 3 days prior to cathe-
terization and INR was 1.2. Arterial and femoral The figure-of-eight stitch utilizes the skin to obtain
accesses were obtained and the venous sheath was venous stasis for large venous or multiple venous
upsized to a 10.5F sheath. A deep short axis view sheaths. Electrophysiologists routinely use these
with the catheter across the tricuspid valve showed stitches to maintain hemostasis. Figure 13.6 shows
the rheumatic mitral valve (Fig. 13.5a). During the the step by step approach. We tend to place the
evaluation of the mitral valve and interatrial sep- larger sheath for the ICE inferiorly and the smaller
tum, a thrombus was visualized on the right ven- venous sheath 1 cm superiorly. Figure 13.6g sche-
tricular pacing lead (Fig. 13.5b). The procedure matically demonstrates entry points of the needle. It
236 F.O. Wood and G.S. Hanzel

a b

Fig. 13.5 Lead thrombus. (a) Deep septal view for mitral assessment. (b) Thrombus on atrial pacemaker lead

a b

c d

Fig. 13.6 Figure-of-eight stitch. 8F venous (blue), 10.5F as sheaths removed. (f) Final figure-of-eight stitch. (g)
venous (white) (a). (b, c) Suture medial to lateral inferi- Schematic approach for stitch
orly. (d) Suture medial to lateral superiorly. (e) Tie suture
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 237

e f

g 4 3

2 1

Fig. 13.6 (continued)

is important to make the entry points outside the Advantages/Limitations

diameter of the largest sheath. Two people are
needed for the final step to tie the suture ends, 1 and Compared to TEE, ICE does not require anesthesia
4, tightly. One person ties the knot while the other and requires less man power and allows the inter-
person removes the sheaths. The suture is cut at 4 h vention cardiologist to control his views during
and manual pressure is held if needed. There is a structural heart interventions. However, has less
risk of skin and tissue damage if the suture remains septal delineation in complex ASD anatomy.
in place longer than 4 h. Phased-array equipment is more versatile, with
Doppler capability, and has a better image resolu-
tion and definition than the mechanical equivalent.
Mechanical Versus Phase Array The cost is higher than the mechanical probe but
Imaging and 3D Imaging can be coupled with multiple and different con-
soles. The mechanical probe doesn’t have Doppler
Comparative images of both ICE modalities are capability and image definition is not as good, nev-
demonstrated in Fig. 13.7 as well as 3D ICE ertheless, has a larger field of view and allows for a
images. The incremental role of 3D ICE is yet to more comprehensive depiction of both atrial cham-
be determined. bers and atrioventricular valves with their relation-
238 F.O. Wood and G.S. Hanzel

a b c

d e

Fig. 13.7 Mechanical versus phased array ICE and 3D vs. Phased array (g); 2D ICE imaging of the atrial septum
ICE. Intra-atrial septum: mechanical (a) vs. Phased array (h) and ASD (j); 3D ICE imaging of the atrial septum (i)
(b) ICE catheters (c); Atrial septal defect: mechanical (d) and ASD (k) (c From Kim et al. [11] with permission)
vs. Phased array (e); Amplatzer occluder: mechanical (f)
13 Intra-cardiac Echocardiography-Guided Interventional Imaging 239

f g

h i j k

Fig. 13.7 (continued)

ships and it also can be used as IVUS for great 7. Pandian NG, Kreis A, Brockway B, Isner JM,
Sacharoff A, Boleza E, Caro R, Muller D. Ultrasound
vessels. However, it needs a dedicated console. angioscopy: real-time, two-dimensional, intraluminal
ultrasound imaging of blood vessels. Am J Cardiol.
1988;62:493–4.
References 8. Pandian NG, Kreis A, Weintraub A, Motarjeme A,
Desnoyers M, Isner JM, Konstam M, Salem DN,
Millen V. Real-time intravascular ultrasound imaging
1. Cieszynski T. Intracardiac method for the investiga-
in humans. Am J Cardiol. 1990;65:1392–6.
tion of structure of the heart with the aid of ultrason-
9. Valdes-Cruz LM, Sideris E, Sahn DJ, Murillo-Olivas
ics. Arch Immunol Ther Exp. 1960;8:551–7.
A, Knudson O, Omoto R, Kyo S, Gulde
2. Kimoto S, Omoto R, Tsunemoto M. Ultrasonic
R. Transvascular intracardiac applications of a minia-
tomography of the liver and detection of heart atrial
turized phased-array ultrasonic endoscope: initial
septal defect with the aid of ultrasonic intravenous
experience with intracardiac imaging in piglets.
probes. Ultrasonics. 1964;2:82.
Circulation. 1991;83:1023–7.
3. Kossoff G. Diagnostic application of ultrasound in
10. Seward JB, Khandheria BK, McGregor CG, Locke
cardiology. Aust Radiol. 1966;10:101–6.
TJ, Tajik AJ. Transvascular and intracardiac two-
4. Eggleton RC, Townsend C, Kossoff G. Computerized
dimensional echocardiography. Echocardiography.
ultrasonic visualization of dynamic ventricular con-
1990;7:457–64.
figuration. 8th ICMBE; July 1969; Session 10–3.
11. Kim SS, Hijazi ZM, Lang RM, Knight BP. The use of
5. Bom N, Lancée CT, Van Egmond FC. An ultrasonic
intracardiac echocardiography and other intracardiac
intracardiac scanner. Ultrasonics. 1972;10:72–6.
imaging tools to guide noncoronary cardiac interven-
6. Bom N, ten Hoff H, Lancée CT, Gussenhoven WJ,
tions. J Am Coll Cardiol. 2009;53(23):2117–28.
Bosch JG. Early and recent intraluminal ultrasound
devices. Int J Card Imaging. 1989;4:79–88.
 Index

A Atherosclerosis
Acetylcholine, 22, 23, 99 atherogenesis theories
AcuNav® phased-array echo catheter, 226 encrustation, 33
Acute coronary syndromes (ACS), 29, 116–117 insudation, 33
Adenosine, 19, 100, 110 reaction to injury, 34
American College of Cardiology/American Heart atherosclerotic lesion, development
Association (ACC/AHA) classification, 72 macroscopic description, 35–36
Amplatz left (AL) catheter, 51, 52 microscopic description, 34–35
Amplatz right (AR) catheter, 52, 53 CAD, cause of, 32
Angiography versus intravascular ultrasound-directed evolution and progression of, 36, 37
bare metal coronary stent placement lesion morphology/types
(AVID) trial, 137 type I, 37–38
Angiography versus IVUS optimization (AVIO) trial, 139 type II, 38
Anomalous coronary artery from the opposite sinus type III, intermediate lesion, 38–39
(ACAOS), 79–82 type IV, 39
Anomalous origin of the left coronary artery from the type V, 39–40
pulmonary artery (ALCAPA), 82 type VI, 40
Arrhythmias, 70, 86 Attenuated plaque, 176–178
Arteriovenous (AV) fistula, 68 Average peak velocity (APV), 101, 103
Artifacts
blood speckle, 129–131
calcium, 127–129 B
guidewire, 125 Bifurcation lesions
OCT FFR, 115
blooming, 172 PCI, 146
characterization, 169, 173 Bland-White-Garland syndrome. See Anomalous origin
fold over, 172 of the left coronary artery from the pulmonary
multiple reflections, 171 artery (ALCAPA)
NURD, 170 Blood speckle artifact, 129–131
saturation, 172 Bypass grafts
sew up, 172 coronary angiography, 60–61
shadowing, 171 FFR, 116
strut orientation, 173
suboptimal flushing, 170
tangential tissue dropout, 171 C
ringdown, 129 CABG. See Coronary artery bypass grafting (CABG)
wire, 128, 130 CAD. See Coronary artery disease (CAD)
Assessment of dual antiplatelet therapy with drug-eluting Calcified aortic valve, 66, 67
stents (ADAPT-DES) study, 139 Calcified coronary artery plaque, 66
Atherogenesis theory Calcified plaque, 176, 177
encrustation, 33 Calcium artifact, 127–129
insudation, 33 Can routine ultrasound influence stent expansion
reaction to injury, 34 (CRUISE) study, 136

© Springer-Verlag London 2015 241

A.E. Abbas (ed.), Interventional Cardiology Imaging: An Essential Guide,
DOI 10.1007/978-1-4471-5239-2
242 Index

Cardiac catheterization, 23, 48, 210 procedural complications, 66–67

Cardiac computed tomographic angiography (CTA), pseudoaneurysm, 67
205, 212–215 quantitative (QCA), 70–71
Cardiac parenchyma, 2 radial catheters, 53–54
Cardiac transplant, 102 radiation dose measurement, 54
CBF. See Coronary blood flow (CBF) RCA, 60
CFR. See Coronary flow reserve (CFR) retroperitoneal hematoma, 67–68
Cineangiographic imaging right coronary bypass graft angiography, 61, 62
coronary angiography, 54, 56 RIMA graft catheterization, 63
OCT, 156 routes of access, 48
Circumflex bifurcation, 59 segments, 57, 58
Collateral FFR (FFRcol), 109 stroke, 70
Combined NIRS-IVUS imaging, 183, 184 thrombus, 65–66
Contrast induced nephropathy (CIN), 68 TIMI flow grades, 70, 71
Coronary angiogram, 122 ventriculography
Coronary angiography LV ejection fraction, calculation, 64–65
angiographic projections, 55–57 mitral regurgitation, 64
arrhythmias, 70 technique, 63, 64
AV fistula, 68 ventricular septal defect (VSD), 64, 65
bypass graft angiography, 60–61 wall motion abnormalities, 63, 64
CAA, 65 Coronary artery
calcified aortic valve, 66, 67 anatomy, 2, 32
calcified coronary artery plaque, 66 aneurysm, 42
cardiac catheterization, 48 aneurysms (CAA), 65
CIN, 68 definition, LAD artery, 2, 6–7
cineangiographic imaging, 54, 56 dissection, 41–42, 66, 68, 69
circumflex and marginal branches, 59 distal-segment anatomy, 8
complications, 68 dominance, 8
considerations, 54, 55 histological structure
contrast types, 54–56 tunica adventitia, 9–11
coronary artery tunica media, 10
dissection, 66, 68, 69 tunic intima, 8–10
perforation, 69 vessel wall, 8, 9
spasm, 68 left circumflex artery, 7
tortuosity, 66 left main artery, 6
death, 69 mid-segment anatomy, 8
equipment selection, 49, 50 myocardial bridging, 5
heart failure, 70 origin
hematoma, 67 perforation, 69
JL catheter proximal-segment anatomy, 8
Amplatz left (AL), 51, 52 RCA, 5–6
femoral approach, left coronary artery, 50 restenosis, 43–44
principle, 49, 51 spasm, 68
JR catheter tortuosity, 66
Amplatz right (AR), 52, 53 Coronary artery anomalies
femoral approach, right coronary artery, 50–51 ACAOS, 79–82
principle, 49, 51 ALCAPA, 82
LAD classification of, 78–79
circumflex bifurcation, 59 coronary fistula, 82
diagonal branches, 59 embryologic development, 77
spider view, 59, 60 imaging for
left coronary artery bypass graft angiography, 61–62 CMRA, 87
left main artery, 58, 59 CTA, 87–88
LIMA graft catheterization, 62, 63 echocardiography, 86
limitations, 73 ICA, 88
local complications, 67 incidence, 77–78
MP catheter, 52–53 LAD, 76
PCI LCX, 76
ACC/AHA classification, 72 management of
SCAI classification, 72 beta-blockers, 88
SYNTAX score, 72, 73 surgical revascularization, 90
Index 243

myocardial bridging, 82, 84 neurohormonal factors, 21–22

normal anatomy, 76 tachycardia effects, 22–23
pathophysiology, 85–86 Coronary calcium scoring CT, 204
RCA, 76 Coronary CT angiography (CTA), 87–88
screening for, 86 Coronary FFR (FFRcor), 109
sudden death, cause of, 76 Coronary fistula, 82
symptoms, 84–85 Coronary flow reserve (CFR)
Coronary artery bypass grafting (CABG) APV, 101
coronary angiography, 72 assessment, technical factors, 103
myocardial infarction related to, 32 autoregulation, 96
Coronary artery disease (CAD) basal flow, 96
angina, 30 cardiac catheterization laboratory, 98–99
arterial remodeling, 36–37 cardiac transplant, 102
and arterial remodeling, 36–37 CBF, 96
by atherosclerosis (see Atherosclerosis) compressive resistance, 97
causes, 29 coronary artery stenosis, 24–25
IVUS, 122 coronary indices assessment, 99–101
Coronary artery disease (CAD) diabetes mellitus, 102
angina, 30 distal, 101
arterial remodeling, 36–37 dyslipidemia, 102
and arterial remodeling, 36–37 epicardial coronary arteries, 96
by atherosclerosis (see Atherosclerosis) FFR, 108, 118
causes, 29 hyperemic coronary blood flow, 98
indeterminate coronary stenosis and multivessel hyperemic flow, 96
acute coronary syndromes, 116–117 hypertension, 101
bifurcation lesions, 115 MBF, 96
bypass grafts, 116 microcirculatory arteries and arterioles, 96–97
combined anatomic and physiologic lesion relative flow reserve, 101
assessment, 114 stenosis, 102
cost effectiveness, 114 tobacco exposure, 102
left main coronary artery, 115–116 vasoactive drugs, 97
ostial lesions, 117 vs. FFR, 102–103
post intervention, 117 Coronary magnetic resonance angiography (CMRA), 87
safety and efficacy data, 113–114 Coronary plaque
serial stenoses, 114–115 IVUS
IVUS, 122 attenuated plaque, 176–178
Coronary artery stenosis calcified plaque, 176, 177
CFR, 24–25 plaque burden, 177–178
FFR, 107–108 NIRS
hemodynamic significance, 23–24 chemogram, 182–183
significance assessment, 25–26 findings at Culprit Sites, ACS, 183, 184
Coronary blood flow (CBF) lipid quantification, 183
artery resistance, 15–17 peri-procedural myocardial infarction, 183
bradycardia effects, 23 OCT
CFR, 96 calcification, 181
control and autoregulation, 18–19 fibrous plaque, 181, 182
endothelial factors lipid-rich plaque, 181, 182
EDHF, 21 OCT-derived TCFA, 181, 182
endothelins, 21 plaque rupture, 181
nitric oxide, 20–21 VH-IVUS
prostacyclin, 21 atherosclerotic plaques, 179, 180
future directions, 26 calcified plaque, 178, 179
hyperemic, 98 fibrocalcific plaque, 179, 180
mechanical determinant, 13–15 fibrofatty plaque, 178, 179
metabolic factors fibrotic plaque, 178, 179
adenosine, 19 necrotic core plaque, 178–180
ATP, 19 pathologic intimal thickening, 178, 179
carbon dioxide, 20 thick-cap fibroatheroma, 178, 179
oxygen and pH levels, 19 thin-cap fibroatheroma, 179, 180
mycardial oxygen demand and VH-fibroatheroma, 178, 179
supply, 17–18 Coronary thrombus, 65–66
244 Index

Coronary vasculitis, 43 safety and efficacy data, 113–114

Coronary vasospasm, 23 serial stenoses, 114–115
CT angiography FFR (FFRCTA), 118 intermediate non-left main coronary lesions, 130–133
CT perfusion (CTP) imaging, 205 left main stenosis, 133, 134
low flow/low gradient severe stenosis, 112–113
oscillating pressure waveform, 112, 113
D paradoxical vasoconstrictive response, 112–113
Diabetes mellitus, 102 Poiseuille’s law, 108
Dissections, OCT pressure gradient, 108
classification, 163 pressure recovery, 112
plaque fracture, 161 relative flow reserve, 108
severity measurements, 162 severe hypotension, 112–113
Distal CFR, 101 stenosis severity, 110
Distal reference vessel, 108, 127 systemic hemodynamics, 109
Duke treadmill score, 208, 211 technique and performance, 110, 111
Dyslipidemia, 98, 102 theoretical normal value, 109
unparalleled spatial resolution, 110
vessel sizing and ischemia determination, 167–168
E vs. CFR, 102–103
Echocardiogram (ECG), 86, 208–210 Fractional flow reserve CTA (FFRct), 205
Elastic arteries, 10 Frequency-domain (FD) OCT, 154
Endothelins, 9, 21
Endothelium derived hyperpolarizing factor
(EDHF), 20, 21 G
Epicardial coronary arteries, 96 Graft failure, 44–45
Guidewire artifact, 125

F
FAME study, 114 H
FFRmyo, 110 Hematoma, 67
Figure-of-eight stitch, 235–237 Hyperemic coronary blood flow, 25, 98
Fractional flow reserve (FFR) Hyperemic flow, 96, 101
abnormal value, 109 Hypertension, 18, 101
angiographic limitations, 107
Bernoulli equation, 108
CFR, 108, 118 I
characteristics, 109 Image display and OCT, 155, 157–158
coronary artery stenosis, 107–108 Indeterminate coronary stenosis and multivessel CAD
CT angiography (FFRCTA), 118 acute coronary syndromes, 116–117
definition, 109 bifurcation lesions, 115
false positive and false negative, 117 bypass grafts, 116
FFRcol, 109 combined anatomic and physiologic lesion
FFRcor, 109 assessment, 114
FFRmyo, 110 cost effectiveness, 114
hemodynamic artifacts and technical considerations, left main coronary artery, 115–116
111–112 ostial lesions, 117
hydrostatic pressure effect, 112 post intervention, 117
hyperemic agents and pharmacological safety and efficacy data, 113–114
considerations, 110–111 serial stenoses, 114–115
iFR, 117–118 Instantaneous wave-free ratio (iFR), 117–118
indeterminate coronary stenosis and multivessel CAD Intermediate non-left main coronary lesions
acute coronary syndromes, 116–117 angiographic stenosis, 130, 131
bifurcation lesions, 115 FFR, 130–133
bypass grafts, 116 MLA, 132, 133
combined anatomic and physiologic lesion Intra-cardiac echocardiography (ICE)
assessment, 114 AcuNav® phased-array echo catheter, 226
cost effectiveness, 114 advantages, 237, 239
left main coronary artery, 115–116 ASD evaluation, 230
ostial lesions, 117 discovery, 226
post intervention, 117 figure-of-eight stitch, 235–237
Index 245

home view, 227, 228 manual pull back, 124–125

lead thrombus, 235–237 maximal lumen diameter, 127
long axis view, 227–229 minimal lumen diameter, 127
mechanical vs. phased array, 237–239 motorized pull back, 124–125
patent foramen ovale closure, 232, 233 proximal reference vessel, 126–127
percutaneous balloon mitral valvuloplasty, 232, 234–235 remodeling index (RI), 127
phased array catheter, 226–227 trilaminar structure, 126
secundum atrial septal defect closure, 230–232 solid-state (phased array), 123
septal view, 227, 228 ultrasound imaging catheter, 122
short axis view, 228, 229 unprotected LM lesions, PCI
ultra ICE mechanical echo catheter, 226 LMCA, 144–146
Intracoronary acetylcholine, 21 revascularization, 145
Intravascular ultrasound (IVUS) vessel sizing and ischemia determination, 167, 168
bare metal stent placement wire artifact, 128, 130
AVID trial, 137 Invasive coronary angiography (ICA), 88, 220
BMS and DES implantation, 137, 138 Invasive imaging modalities, 184–185
Class IIb recommendation, 136 IVUS. See Intravascular ultrasound (IVUS)
CRUISE study, 136
OPTICUS study, 136–137
restenosis rates, 135–136 J
stent optimization, 199 Judkins left (JL) catheter
TULIP study, 137 Amplatz left (AL), 51, 52
bifurcation lesions, PCI, 146 femoral approach, left coronary artery, 50
blood speckle artifact, 129–131 principle, 49, 51
CAD, 122 Judkins right (JR) catheter
calcium artifact, 127–129 Amplatz right (AR), 52, 53
coronary angiogram, 122 femoral approach, right coronary artery, 50–51
drawbacks, 148 principle, 49, 51
drug eluting stent placement
ADAPT-DES study, 139
AVIO trial, 139 L
meta-analysis, 143 Left anterior descending (LAD) artery
optimal stent expansion, 139 circumflex bifurcation, 59
stent optimization, 199 coronary artery anomalies, 76
intermediate non-left main coronary lesions definition, 2, 6–7
angiographic stenosis, 130, 131 diagonal branches, 59
FFR, 130–133 FFR, 115–116
MLA, 132, 133 spider view, 59, 60
interventional trials, 122 Left circumflex artery (LCX)
left main stenosis coronary artery, 7
FFR, 133, 134 coronary artery anomalies, 76
LMCA, 133–135 Left coronary artery bypass graft angiography, 61–62
MLA, 134, 135 Left internal mammary artery (LIMA) graft
motion, 128 catheterization, 62, 63
NURD, 128, 130 Left main (LM) artery, 6
OCT, 148, 154, 169 Left main stenosis
principles, 123 FFR, 133, 134
radiofrequency, 146–148 LMCA, 133–135
ringdown artifact, 129 MLA, 134, 135
rotational (mechcanical) Lipid core burden index (LCBI), 124, 183, 194, 219
advantages and disadvantages, 125 L-mode display, OCT, 155–156
area stenosis, 127
atheroma/plaque area/plaque burden, 127
cross sectional area (CSA), 127 M
distal reference vessel, 127 Minimum lumen area (MLA)
external elastic membrane cross sectional area intermediate non-left main coronary lesions, 132, 133
(EEM CSA), 127 left main stenosis, 134, 135
guidewire artifact, 125 measurement and clinical applications
InfraRedX images, 124 IVUS MLA, 190–192
lumen eccentricity, 127 OCT MLA, 191, 192
246 Index

Mitral regurgitation, 64, 230, 231, 234 saturation, 172

Multipurpose (MP) catheter, 52–53 sew up, 172
Muscular arteries, 10 shadowing, 171
Myocardial blood flow (MBF), 96, 108, 109 strut orientation, 173
Myocardial bridging, 5, 82, 84 suboptimal flushing, 170
Myocardial infarction, 31 tangential tissue dropout, 171
cine angiography and 3D, co-registration, 156
color mapping, 155
N coronary evaluation
Near-infrared spectroscopy (NIRS) after PCI, 161
chemogram, 182–183 definitions, 159
predictors, 194–195 lesion morphology, 159, 160
Neoatherosclerosis, 164, 165 dissections
Nitric oxide (NO), 20–21 classification, 163
Non-invasive cardiac testing plaque fracture, 161
cardiac computed tomographic angiography, severity measurements, 162
205–206, 212–215 3D visualization, 156
comprehensive plaque analysis, 204 dynamic range, 155
coronary calcium scoring, 204 endovascular procedures, 171
correlation to advanced coronary imaging, 217–221 frequency-domain (FD), 154
ideal plaque characterization tool, 204 future technology, 170–173
performance, 204 image acquisition protocols, 156
stress testing, 206–211 image display techniques, 155, 157–158
catheterization, 208, 210 intensity scaling, 155
diagnostic accuracies, 206, 207 interference, 154
Duke treadmill score, 208, 211 interferometry, 154
echocardiogram, 208–210 IVUS, 148, 154, 169
future aspects, 211 lesion and stent morphology
M’s Treadmill score, 208, 211 attenuation, 158
pre-test probability, CAD, 206, 207 back scatter, 156
unstable coronary plaque detection, CTA, 215–217 limitations, 170
Non–ST-segment elevation myocardial infarction L-mode display, 155–156
(NSTEMI), 30 malapposition, 161
Non-uniform rotational distortion (NURD) neoatherosclerosis, 164, 165
artifacts, 170 optical impedances, 154
IVUS, 128, 130 penetration depth, 155
plaque protrusion, 161
refractive index, 154
O resolution, 154
OCT. See Optical coherence tomography (OCT) restenosis, 163, 164
OCT-defined thin-capped fibroatheroma, 194 stent assessment, 167
Optical coherence technology stent thrombosis, 163
dynamic range, 155 strut coverage, 163, 169
FD, 154 time-domain (TD), 154
interference, 154 vessel sizing and ischemia determination
interferometry, 154 catheter, 166–167
IVUS, 154 FFR, 167–168
optical impedances, 154 IVUS, 167, 168
penetration depth, 155 Optimization with intracoronary coronary ultrasound
refractive index, 154 to reduce stent restenosis (OPTICUS) study,
resolution, 154 136–137
TD, 154 Oscillating pressure waveform, 112, 113
Z-offset, 155 Ostial lesions, 117, 134
Optical coherence tomography (OCT)
artifacts
blooming, 172 P
characterization, 169, 173 Patent foramen ovale closure, 232, 233
fold over, 172 PCI. See Percutaneous coronary interventions (PCI)
multiple reflections, 171 Percutaneous balloon mitral valvuloplasty, 232, 234–235
NURD, 170 Percutaneous coronary interventions (PCI)
Index 247

ACC/AHA classification, 72 guidewire artifact, 125

acute PCI-related complications InfraRedX images, 124
IVUS predictor, 193 lumen eccentricity, 127
NIRS predictor, 194, 195 manual pull back, 124–125
OCT predictor, 194 maximal lumen diameter, 127
angiographic no-reflow, 193 minimal lumen diameter, 127
bifurcation lesions, 146 motorized pull back, 124–125
FFR, 113, 114 proximal reference vessel, 126–127
IVUS MLA measurement remodeling index (RI), 127
left main, 191 trilaminar structure, 126
non-left main location, 190–192
lesion assessment, 190
limitations, 195 S
myocardial infarction related to, 31 Secundum atrial septal defect closure
OCT, 161 AcuNav catheter, 230, 232
OCT-derived MLA, 191, 192 Amplatzer ASO device, 231, 232
peri-procedural myocardial infarction, 193 Rosen wire, 230, 232
SCAI classification, 72 Society of Cardiovascular Imaging and Interventions
stent selection, 192 (SCAI) classification, 72
SYNTAX score, 72, 73 Solid-state (phased array) IVUS, 123
unprotected LM lesions, 144–146 Spider view, 59, 60
Percutaneous transluminal angioplasty (PTCA), 102 Spontaneous myocardial infarction, 31
Phased array catheter, 226–227 Stable angina, 30
Plaque Steady-state with freeprecession (SSFP), 87
burden, 177–178 ST-elevation myocardial infarction (STEMI),
erosion, 40–41 29, 116–117, 184
protrusion, 161 Stenosis, 102
rupture, 40 Stent optimization
Prinzmetal variant angina, 30 clinical benefits
Prostacyclin pathway, 21 IVUS-guided bare-metal stent placement, 199
Proximal reference vessel, 126–127 IVUS-guided drug-eluting stent placement, 199
Pseudoaneurysm, 67 edge dissections, 197–198
with IVUS/OCT, 195–196
stent strut malapposition, 196
Q stent underexpansion, 196, 197
Quantitative coronary angiography (QCA), 70–71 tissue protrusion, 198
Stent thrombosis
definition, 43–44
R myocardial infarction related to, 31
Radial catheters, 53–54 OCT, 163
Relative CFR, 101 risk factors, 44
Relative flow reserve, 101, 108 Stress echocardiogram, 208, 210
Restenosis, 43, 163, 164 Stress testing
Retroperitoneal hematoma, 67–68 catheterization, 208, 210
Right coronary artery (RCA) diagnostic accuracies, 206, 207
coronary angiography, 60 Duke treadmill score, 208, 211
coronary artery anomalies, 76 echocardiogram, 208–210
dominant, 5–6 future aspects, 211
Right coronary bypass graft angiography, 61, 62 M’s Treadmill score, 208, 211
Right internal mammary artery (RIMA) graft pre-test probability, CAD, 206, 207
catheterization, 63 Stroke, 70, 85, 144
Ringdown artifact, 129 Strut coverage, 163, 169
Rotational (mechcanical) IVUS SYNTAX score
advantages and disadvantages, 125 coronary angiography, 72, 73
area stenosis, 127 fractional flow reserve (FFR), 114
atheroma/plaque area/plaque burden, 127
cross sectional area (CSA), 127
distal reference vessel, 127 T
external elastic membrane cross sectional area Thick-cap fibroatheroma, 178, 179
(EEM CSA), 127 Thin-cap fibroatheroma, 179, 180
248 Index

Three dimensional visualization, OCT, 156 V

Thrombocyte activity evaluation and effects Vasoactive drugs, 97
of ultrasound guidance in long Ventricular septal defect (VSD), 64, 65
intracoronary stent placement Ventriculography
(TULIP) study, 137 LV ejection fraction, calculation, 64–65
Thrombolysis in myocardial infarction (TIMI) flow mitral regurgitation, 64
grades, 70, 71 technique, 63, 64
Time-domain (TD) OCT, 154 ventricular septal defect (VSD), 64, 65
Tobacco exposure, 102 wall motion abnormalities, 63, 64
Typical angina. See Stable angina VH-fibroatheroma, 178, 179
Vulnerable plaque, 40, 147, 148

U
Ultra ICE mechanical echo catheter, 226 W
Unstable angina (USA), 30 White thrombus, 40, 159, 164, 165
Unstable coronary plaque detection, CTA, 215–217 Wire artifact, 128, 130