Vulnerable Atherosclerotic Plaque: A Multifocal Disease

Ward Casscells, Morteza Naghavi and James T. Willerson

Circulation. 2003;107:2072-2075
doi: 10.1161/01.CIR.0000069329.70061.68
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 MINI-REVIEW:
EXPERT OPINIONS

Vulnerable Atherosclerotic Plaque

A Multifocal Disease
Ward Casscells, MD; Morteza Naghavi, MD; James T. Willerson, MD

T
he recent proliferation of invasive and noninvasive
techniques to locate vulnerable atherosclerotic
plaques raises important questions. Will such tech-
niques add useful prognostic information? If so, will the
information prevent myocardial infarction, stroke, or death in
at least some patients at risk? Will it lead to new research
advances? Will the benefits justify the costs?
Plaque Progression: Often Abrupt,
Rarely Predictable
Some facts are now certain. First, plaque progression and
clinical outcome are not always closely related, and each is
poorly predicted by clinical and angiographic variables.1– 4
Second, many plaques progress episodically because of
episodes of thrombosis triggered by rupture, erosion (denu-
dation), or occasionally endothelial activation or inflamma-
tion.5,6 Unless there is a relatively hypercoagulable state, at
least some thrombi remain mural rather than occlusive and
produce few if any symptoms unless they embolize7; and if
lysis is incomplete and followed by re-endothelialization, the
result is a plaque growth. Another mechanism of rapid plaque
growth is hemorrhage into the plaque, which is particularly
important in the pathogenesis of carotid artery rupture.8,9 Still
other plaques develop foci of rapidly proliferating smooth
muscle cells.10
Independent Progression of Individual Plaques:
Third, plaques within a given patient often progress largely
independently.11 This frustrating unpredictability of patient
outcomes— even in patients without heart failure or arrhyth-
mias (whose prognosis reflects variables outside the scope of
this review)—is probably due in part to fluctuation of risk
factors and “triggers,” eg, day-to-day changes in diet, activ-
ity, stress, cold weather, pollution, smoking, infection, hydra-
tion, and blood pressure. Nevertheless, independent plaque
behavior in a given patient must be due in large measure to
the marked heterogeneity of plaque histology and to differ-
ences in the physical forces to which plaques are
subjected.12,13
Vulnerable Plaque Versus Stenotic Plaque
In the past decade, it has become clear that most plaques that
underlie a fatal or nonfatal myocardial infarction are, as
shown by angiography, less than 70% stenosed. Approxi-
mately 60% are caused by rupture of plaques with a large,
thrombogenic core of lipid and necrotic debris (including foci
of macrophages, T cells, old hemorrhage, angiogenesis, and
calcium). The ruptured cap is thin, presumably because
macrophages digest it as they cross into and out of the plaque,
and because smooth muscle cells (which synthesize the cap)
have become sparse because of senescence or apoptosis
caused by inflammatory cytokines.
Plaque Inflammation
Another 30% to 40% of coronary thrombi overlie plaques
denuded of endothelium, and many if not most of these have
luminal inflammation.14,15 Activated T cells in the non-culprit
arteries and systemic circulation of patients with unstable

From the Division of Cardiology, Department of Internal Medicine, Medical School, The University of Texas Health Science Center at Houston; The
Texas Heart Institute at St. Luke’s Episcopal Hospital; and President Bush Center for Cardiovascular Health at Memorial Hermann Hospital, Houston,
Tex.
Drs Casscells, Willerson, and Naghavi are shareholders in Volcano Therapeutics, Inc, a company developing diagnostic and therapeutic modalities for
vulnerable plaques.
Correspondence to Ward Casscells, MD, The University of Texas Medical School at Houston, 6431 Fannin St, MSB 1.252, Houston, TX 77030. E-mail
s.ward.casscells@uth.tmc.edu
(Circulation. 2003;107:2072-2075.)
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000069329.70061.68

2072
Downloaded from http://circ.ahajournals.org/ by guest on January 26, 2014
 Casscells et al
angina,16,17 together with recent demonstrations that serum
levels of C-reactive protein (CRP) predicts the risk of
myocardial infarction (MI) or stroke better than total and
low-density lipoprotein cholesterol levels,18 help explain why
techniques such as thermography to detect foci of plaque
inflammation before the development of thrombosis have
been developed.19,20
However, the lack of data on the natural history of such
plaques poses problems. Does everyone with coronary artery
disease have vulnerable plaques, or just a subset, such as
those with unstable angina and/or elevated serum CRP
levels? Do all of these plaques rupture, erode, or thrombose?
Do some quiesce or heal? Can these plaques be localized
noninvasively or will catheterization be required? Although
an elevated serum CRP does not distinguish coronary from
aortic, carotid, or peripheral disease (or from infection,
malignancy, trauma, or other causes of inflammation), would
it be sufficient for screening purposes to combine serum CRP
values with some noninvasive techniques such as electron
beam computed tomography (EBCT) coronary calcium
score?
Multifocal Nature of Vulnerable Plaques
Recent studies21,22 have emphasized that, by some criteria,
many unstable patients have a second or even a third
vulnerable plaque, and have called for an emphasis on proven
systemic therapies, such as a Mediterranean diet, statins,
angiotensin-converting enzyme (ACE) inhibitors, and clopi-
dogrel, rather than unproven approaches, such as stenting.
Another promising approach is vaccination against influenza.
In hypercholesterolemic mice, the influenza infection exac-
erbated plaque inflammation and caused thrombosis.23 Clin-
ical studies suggest that many MIs, strokes, and deaths may
be avoided by influenza vaccination.24
Clinico-Pathological Correlation
Nevertheless, we believe that finding and treating individual
vulnerable plaques may also prove useful. Our rationale
begins with the fact that, in autopsy studies of victims of fatal
MI, a second occlusive thrombus is found in 6% to 16% of
victims, though most of these individuals have a second
vulnerable plaque (rarely three).25,26 Approximately half of
these have rupture or erosion with a mural (non–infarct-
related) thrombus. In patients with stable symptoms, arterial
inflammation is not diffuse, and in these patients most
plaques are predominantly fibrotic. Even a study that reported
diffuse vascular inflammation in these patients reveals, in its
table, that only 2.5% of plaques had moderate or marked
infiltration by both macrophages and T cells.14
Angiographic Studies
By coronary angiography, progression of stenoses over 2
years was noted in only 22% of patients with angina pectoris,
even in the pre-statin era. Patients with progression averaged
only 1.1 progressing lesion, which suggests that simultaneous
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Vulnerable Atherosclerotic Plaque 2073
progression of 2 plaques must be rare.27 Ge et al28 found no
instances of a second vulnerable plaque in an angiographic
and ultrasound study of angina patients. Another group found
a second suspicious lesion in 14% of patients.29 In a series of
patients medically stabilized after presenting with unstable
angina, Kaski et al30 found 22% of stenoses progressed over
8 months, but no patient had progression in 2 lesions.
However, in a series of unstable angina patients, the same
researchers described an average of 2.6 vulnerable lesions per
patient, using the single criterion of angiographic thrombus or
irregularity. In patients who had experienced a fatal MI and in
whom plaque rupture and thrombus were correlated with
post-mortem angiography, no second thrombi or ruptures
were described.31 Subsequently, Goldstein et al32 found that
40% of patients with MI had a second vulnerable plaque
designed by angiographic evidence for at least 2 of the
following 4 criteria: slow flow, ulceration, irregular surface,
or mobile filling defect.
IVUS Studies
The finding of more than 1 ruptured or vulnerable plaque in
patients with MI or unstable angina is also supported by a
recent intravascular ultrasound study by Riofoul et al,33 who
found 2 or more plaque ruptures in 79% of patients with acute
coronary syndromes. However, another study described a
single plaque rupture in half of patients who presented with
unstable angina.28
Angioscopic Studies
Angioscopy almost always reveals only 1 thrombus in pa-
tients with an MI. However, yellow plaques, which have a
high risk of progression to rupture, are found in some patients
with stable angina, most patients with unstable angina, and
nearly all patients with an acute MI.34 –39
Thermography Studies
The recent finding that plaques with superficial inflammation
are warmer than other plaques whereas normal arteries are
uniform in temperature40 has led to the development of
thermography catheters. Thermal heterogeneity is found in
some patients with stable angina and in almost all patients
with unstable angina, with 2 or even 3 hot plaques being
present in patients with an acute MI.21 Interestingly, levels of
serum CRP were not well correlated with the number of hot
plaques, and most patients with stable angina and 1 hot
plaque had a normal serum CRP level. In the only follow-up
study reported to date, thermal heterogeneity was a strong
independent predictor of adverse events.41
Needed: Clinical Trials of New Techniques
For Detecting Vulnerable Plaques
Because not all ruptured or eroded plaques are yellow, warm,
calcified, etc, it is logical to ask what combination of new
techniques might be optimal for risk stratification. The ideal
approach would provide both anatomic and functional data.
2074 Circulation April 29, 2003
Plaques at greatest risk for rupture should have an inflamed,
thin (or fissured) cap, a large lipid core, and high wall stress
(ie, large lumen). Those at risk of erosive thrombosis would
have an irregular or denuded inflamed lumen, and thrombo-
genic slow flow due to a stenosis upstream or downstream.
Patients with either of these types of plaque would be at
higher risk if they are in a hypercoagulable state or if the
lesion is in the proximal left anterior descending coronary
artery, particularly if collaterals are inadequate.
Clinical trials are likely to demonstrate that such plaques
can be detected with some combination of MRI or computed
tomography (CT) with contrast, angiography, thermography,
ultrasound or optical coherence tomography (OCT) (either of
which could incorporate elastography or integrated backscat-
ter), near-infrared spectroscopy, and/or angioscopy.42,43
Such an approach would be expensive, but could prove
useful. For example, if a patient is found to be at greater risk
than predicted by office or bedside techniques, including
serum CRP level, this information may lead the patient to
reschedule a physically or mentally stressful task in lieu of
rest, or of a critical family meeting or reconciliation. Aware-
ness of vulnerability may also improve adherence to diet and
medications, as well as influencing the physician’s treatment
goals as to weight, blood pressure, lipids, glucose, and even
frequency of office visits. In particular, the presence of
vulnerability may merit multiple therapies, such as various
combinations of aspirin with warfarin or clopidogrel, ACE
inhibitors with ␤-adrenergic blockers, statins with niacin,
fibrates, resins, etc. Finally, as statins may not reduce
mortality significantly until 1 year after initiation of therapy,
the most vulnerable plaques may merit stenting or some other
form of local therapy to “buy time.”
Conclusion
Trials to answer these questions are now being planned. We
predict that these trials will lead to a graded, individualized
approach to each patient. Because atherosclerosis is a sys-
temic, multi-genic, and multi-focal disease, optimal care is
likely to require systemic and multi-focal diagnosis and
therapy, including local plaque therapy in some patients. This
more complicated approach will likely be more expensive in
the short-term, but could be offset by substantial reductions in
morbidity and mortality.
Acknowledgments
This work was supported in part by Department of Defense grant
#DAMD 17– 01–2-0047. The authors wish to thank Mohammed
Madjid, MD, for his advice and suggestions.
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