History of Discovery

Concept of Vulnerable/Unstable Plaque

Aloke V. Finn, Masataka Nakano, Jagat Narula, Frank D. Kolodgie, Renu Virmani

Abstract—Today’s concept of vulnerable plaque has evolved primarily from the early pioneering work uncovering the
pivotal role of plaque rupture and coronary thrombosis as the major cause of acute myocardial infarction and sudden
cardiac death. Since the first historical description of plaque rupture in 1844, several key studies by leading researchers
and clinicians have lead to the current accepted views on lesion instability. Important to the complex paradigm of plaque
destabilization and thrombosis are many discoveries beginning with the earliest descriptions of advanced plaques,
reminiscent of abscesses encapsulated by fibrous tissue capable of rupture. It was not until the late 1980s that studies
of remodeling provided keen insight into the growth of advanced plaques, beyond the simple accumulation of lipid. The
emphasis in the next decade, however, was on a focused shift toward the mechanisms of lesion vulnerability based on
the contribution of tissue proteolysis by matrix metalloproteinases as an essential factor responsible for thinning and
rupture of the fibrous cap. In an attempt to unify the understanding of what constitutes a vulnerable plaque,
morphological studies, mostly from autopsy, suggest the importance of necrotic core size, inflammation, and fibrous cap
thickness. Definitive proof of the vulnerable plaque, however, remains elusive because animal or human data supporting
a cause-and-effect relationship are lacking. Although emerging imagining technologies involving optical coherence
tomography, high-resolution MRI, molecular biomarkers, and other techniques have far surpassed the limits of the early
days of angiography, advancing the field will require establishing relevant translational animal models that produce
vulnerable plaques at risk for rupture and further testing of these modalities in large prospective clinical trials. (Arterioscler
Thromb Vasc Biol. 2010;30:1282-1292.)
Key Words: acute coronary syndromes 䡲 coronary artery disease 䡲 pathology 䡲 thrombosis 䡲 vulnerable plaque

D espite recent advances in medical and interventional vulnerable patient, defined by high atherosclerotic burden,
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percutaneous or surgical therapies, coronary artery dis-
ease continues to be a major cause of morbidity and mortality
throughout the world. In the United States alone, coronary
artery disease is responsible for a majority of deaths, account-
ing for more than 400,000 (⬇1 of every 6 deaths) annually.1
The typical patient presents with acute coronary syndromes
(ACS) defined by acute myocardial infarction (AMI) or
unstable angina, where approximately 300,000 patients suc-
cumb to the initial coronary event. Modern cardiology is
focused on developing techniques designed to restore blood
flow in arteries possessing hemodynamically significant le-
sions causing cardiac ischemia and infarction. This reactive
strategy, however, does little to prevent future coronary
events. Although pharmacotherapy with agents such as aspi-
rin and statins has been proven to lower the risk of future
coronary events, it does not represent a panacea.
Major advances in coronary artery disease prevention will
require early detection of rupture-prone or so-called vulner-
able plaques. Therefore, it is essential to further identify
meaningful surrogates of lesion instability at the highest risk
of rupture. Moreover, vulnerable plaques tend to occur at
multiple sites, and some have advocated the concept of the
high-risk/vulnerable plaques, or thrombogenic blood. Para-
doxically, these patients might be recognized by biomarkers
other than those directed toward specifically identifying
vulnerable plaques.
History of the Vulnerable Plaque
An understanding of the pathophysiology of vulnerable
plaque would not have been possible without the pioneering
work that came before the elucidation of the pivotal role of
plaque rupture with superimposed coronary thrombosis as the
major cause of myocardial infarction (MI) (Figure 1).
The concept of plaque rupture was first reported at the
autopsy of the celebrated neoclassical Danish artist Bertel
Thorvaldsen, who died of sudden cardiac death in the Royal
Theater in Copenhagen in 1844.2,3 It was not until early in the
next century that researchers focused on pathological features
of culprit lesions responsible for sudden cardiac death.
Notable investigators such as Clark, Koch, Friedman, and
Constantinides were the first to describe fissures and erosions
on the intimal surface of coronary arteries as the causation of
thrombosis.4 – 6 Around the same time, Wartman and others,
such as Patterson and Winternitz, noted the importance of

From CVPath Institute, Inc, Gaithersburg, Md (F.D.K., M.N., R.V.); Department of Internal Medicine, Emory University School of Medicine, Atlanta,
Ga (A.V.F.); School of Medicine, University of California, Irvine (J.N.).
Correspondence to Renu Virmani, MD, CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878. E-mail rvirmani@cvpath.org
© 2010 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.108.179739

1282
 Finn et al
Figure 1. Timeline of important events related to the discovery of plaque rupture and its predecessor, the vulnerable plaque. SCD indi-
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cates sudden coronary death; AHA, American Heart Association.
intramural hemorrhage in the progression of coronary le-
sions.7–9 Using a systematic approach of serial sectioning,
Friedman made significant inroads describing many of the
findings that established today’s understanding of plaque
rupture. Adopting descriptive terms such as “intramural
atheromatous abscess” (first reported by Leary10), Friedman
demonstrated communication of necrotic material with the
occluding thrombus in 39 of 40 arteries, concluding that
rupture exposes the blood to highly thrombogenic contents of
the plaque, leading to clot formation.11 Another pioneering
pathologist, Michael J. Davies (1937–2002), devoted himself
to the study of plaque rupture and its associated features,
describing in detail the features of plaque disruption and the
role of inflammation in the development of plaque insta-
bility.12,13 Landmark reviews from a myriad of notable
investigators forwarding the more recent concepts of
lesion vulnerability became available in the mid-1990s, in
particular the classic article “Coronary Plaque Disruption”
by Erling Falk et al.14
As the understanding of the pathophysiology of lesion
instability began to expand, there was a necessity for consen-
sus terms regarding vulnerability; the adoption of a common
nomenclature would help support the study of acute coronary
events. To meet this need, a group of prominent investigators
convened in 2003 to resolve issues of terminology surround-
ing the identification of high-risk and vulnerable coronary
artery plaques.15 A unification of conceptual terms was
adopted to provide a fundamental basis for clinicians and
The Vulnerable/Unstable Plaque 1283
researchers whereby diagnostic methods of identifying vul-
nerable patients and the plaques that contribute to their
increased risk can be identified, in addition to defining the
critical lesions that may be amenable to treatment.
Although coronary thrombi were a frequent finding at
autopsy, the causative nature of thrombosis in the pathogen-
esis of AMI was contested for decades. Several researchers
emphasized the role of thrombosis in AMI; however, the
1960s and 1970s saw fierce debate over whether thrombus
formation followed or preceded AMI, fueled in part by the
inconsistent reporting of thrombi in fatal MIs. A negative
proponent, the noted pathologist William C. Roberts, be-
lieved that “the virtual absence of coronary thrombi in
patients dying suddenly of cardiac disease, and their presence
in only about one-half of those with myocardial necrosis,
supported the concept that coronary arterial thromboses were
consequence rather than cause of AMI.”16
It was not until 1980 that DeWood et al provided definitive
angiographic evidence that intracoronary thrombi have a
causal role in the pathogenesis of acute coronary occlusion in
AMI.17 An earlier study by Fulton and Sumner, using
premortem injection of 125I-labeled fibrinogen, gave rise to
the notion that thrombosis often preceded MI.18 The greater
understanding of the essential role of thrombosis in the
causation of MI led to the introduction of thrombolysis as a
means of treating infarction patients in the coronary care
units. This preceded the now well-accepted “open artery”
theory for all MI patients, where the current recommended
 1284 Arterioscler Thromb Vasc Biol July 2010
door-to-balloon time using primary percutenaous coronary
intervention is ⱕ90 minutes.19
Advancement in our understanding of the pathophysiology
of MI was an essential step in the definition of vulnerable
plaque. Retrospective angiographic studies of patients pres-
enting with AMI promoted the idea that MI frequently
develops in previously nonsevere lesions.20 In 1989, James E.
Muller et al named these hemodynamically insignificant
plaques vulnerable plaques, defined as lesions with a suscep-
tibility to rupture.21
More recently, our laboratory and others have defined
other etiologies of luminal thrombosis, namely plaque rup-
ture, erosion, and calcified nodules.22 Plaque rupture refers to
a lesion consisting of a necrotic core with an overlying thin
ruptured fibrous cap that leads to luminal thrombosis because
of contact of flowing blood with a highly thrombogenic
necrotic core.23 On the other hand, plaque erosion shows a
luminal thrombus with an underlying base rich in smooth
muscle cells and proteoglycans with mild inflammation.24
More than 50% of erosion lesions are devoid of a necrotic
core, but when present, the core does not communicate with
the lumen because of the thickened fibrous cap. The least
common of all lesions giving rise to acute coronary throm-
bosis is the calcified nodule, recognized by calcified plates
with superimposed calcified bony nodules that result in
discontinuity of the fibrous cap, with an irregular luminal
surface devoid of endothelial cells and overlying luminal
thrombus.22
From our examination of more than 800 cases of sudden
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coronary death at autopsy, 55% to 60% of subjects have
underlying plaque rupture as the etiology, whereas for 30% to
35% the etiology is erosion and for 2% to 7% it is thrombi
attributed to calcified nodules. Plaque rupture is also the
predominant cause of death at autopsy, occurring in 75% of
patients presenting with AMI (mean age, men⫽68⫾11,
women⫽70⫾9 years) diagnosed by ECG and enzyme eleva-
tion.25 In contrast, approximately 37% of women with AMI
had plaque erosion, whereas in men erosion was present in
only 18% (P⫽0.0004).25 Overall, plaque erosion appears to
be the primary cause of acute coronary thrombi in women
under the age of 50 years who present with sudden coronary
death.24 Thus, the etiology of the thrombus is dependent on
age and sex, where plaque rupture is a dominant mechanism
in men regardless of age and in older, postmenopausal
women older than 50.26
From a pathologist’s perspective, the understanding of
vulnerable plaque is mostly derived from comprehensive
examinations of plaque rupture simply because of the failure
to identify precursor lesions of erosions or the calcified
nodule. The lack of other precursor lesions besides rupture
represents a major shortcoming to the vulnerable plaque
paradigm, as discussed below.
Pathological Characterization of the Thin-Cap
Fibroatheroma or Vulnerable Plaque
The morphological criterion that supports the definition of
thin-cap fibroatheroma (TCFA) or vulnerable plaque results
from an astoundingly simple tenet that the preceding lesion
on the road to rupture bears a strong resemblance in mor-
phology to rupture itself (Figure 2). A necrotic core charac-
terizes plaque rupture with an overlying thin-ruptured cap
infiltrated by macrophages and lymphocytes. There are few
or no smooth muscle cells within the cap. The thickness of the
fibrous cap near the rupture site measures 23⫾19 ␮m, with
95% of caps measuring ⬍65 ␮m.27 It is precisely those
lesions with intact fibrous caps of ⬍65 ␮m observed at other
(oftentimes multiple) sites in the coronary vasculature, in
patients dying of acute plaque rupture, that are designated
vulnerable plaques or TCFAs. Therefore, the current defini-
tion of vulnerability is exclusive to plaque rupture.
Despite morphological similarities, TCFAs differ from
ruptures considering that they generally exhibit smaller ne-
crotic cores, fewer macrophages within the fibrous cap, and
less calcification.28,29 Although the vulnerable plaque was not
a recognized entity in the American Heart Association con-
sensus document, it was highlighted in our modified classi-
fication scheme published later in 2000.22 One of the major
limitations of the original American Heart Association clas-
sification was a lack of understanding that the fibrous cap
undergoes thinning before the onset of rupture, a concept
forwarded by Dr Peter Libby30 (Figure 3) and further defined
by our laboratory.27
Major Turning Points Toward an
Understanding of the Pathophysiology of
Lesion Instability
Lesion Growth in Advanced Plaques Differs
Significantly From Early Lesions
It gradually became apparent that 2 key processes are
involved in the growth of advanced plaques: (1) outward,
abluminal expansion of the arterial wall and (2) subclinical
plaque rupture of hemodynamically insignificant lesions,
where the thrombus is incorporated into the lesion, resulting
in greater luminal narrowing. Historically, these beliefs were
slow to evolve because the understanding of lesion progres-
sion in the clinic was, and still is, mostly based on angiog-
raphy, which cannot determine plaque morphology. The
prevailing notion surrounding lesion growth began to change,
however, following publication of a seminal study by Sey-
mour Glagov et al in 1987, reporting that progressive plaques
endure a lengthy phase of positive remodeling or arterial wall
expansion (occurring over years or decades) that is responsi-
ble for the preservation of lumen size.31 Luminal compromise
only occurs once the plaque advances beyond 40% narrow-
ing, ie, when positive remodeling stops. Davies forwarded the
concept that repeated silent plaque ruptures are the cause of
luminal compromise, which heal and lead to severe luminal
narrowing.32 Similarly, we reported in sudden death subjects
that plaques progress through repeated ruptures (ie, luminal
narrowing occurs through healed plaque ruptures) and that
only 11% of acute plaque ruptures are virgin ruptures.33
Rendering a Plaque Unstable: The Emergence of
Inflammation and Tissue Proteolysis as an
Underlying Mechanism of Plaque Vulnerability
A seminal article by Russell Ross et al described the presence
of macrophages within the fibrous cap in lesions from the
 Finn et al The Vulnerable/Unstable Plaque 1285

Figure 2. Morphological differ-

ences between TCFAs and
plaque rupture. A and B, Rep-
resentative images of a TCFA
and plaque rupture, stained by
hematoxylin and eosin, Movat
pentachrome, and antibody
against CD68 (recognition of
lesional macrophages). Both
lesion morphologies show
prominent necrotic cores and
overlying thin fibrous caps; the
boxed areas represent the cor-
responding high powers
below. In the Movat-stained
section in B, the site of plaque
rupture is identified (white
arrows) where the same areas
show numerous CD68-positive
macrophages. Although TCFAs
are reminiscent of ruptures,
they generally have smaller
necrotic cores and thicker
fibrous caps with less macro-
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phage infiltration; there is an

absence of a cap disruption
and luminal thrombosis.

superficial femoral artery collected at surgery.34 He noted that
the majority of fibrous caps overlying lipid cores from lesions
with superficial thrombi contained smooth muscle cells with
varying numbers of macrophages. What makes a plaque
stable is the intact and thick fibrous cap that is made up of
smooth muscle cells in a matrix rich in type I and III collagen.
Richardson and coworkers performed mechanical tests on
strips of fibrous caps with infiltrating macrophages from
human aortic samples with ulcerated or intact plaque caps and
showed a good correlation of increase in macrophage density
with greater extensibility and decreased maximum stress
(force per unit area).35
Key observations in the early to mid-1990s by Falk,14
Shah,36 and Moreno,37 implicating the significance of prote-
olyic enzymes released from macrophages in lesions respon-
sible for unstable angina, helped establish the paradigm of
matrix degradation and lesion instability. Around the same
time, Libby greatly expanded on this hypothesis, proposing
that collagen synthesis within the fibrous cap was impaired
and that matrix degrading enzymes, a main component of the
vast secretory repertoire of the macrophage, may ultimately
be responsible for degradation of the fibrous cap.38 Elegant in
vitro studies revealed the importance of interferon-␥, which is
secreted by activated T cell and is responsible for the
markedly decreased ability of human smooth muscle cells to
express interstitial collagen genes in both resting and stimu-
lated states.39 T cells synthesize interferon-␥, and in the
fibrous cap, they exhibit nonuniform patterns of type I
collagen gene expression, which is negatively associated with
the spatial presence of T cells.40
The perception of increased matrix degradation as a mech-
anism of lesion instability was mainly based on the early
 1286 Arterioscler Thromb Vasc Biol July 2010
tion of matrix-degrading enzymes produced by vascular smooth muscle cells and inflammatory macrophages. Activated macrophages
within the fibrous cap can secrete tissue proteases that support the breakdown of collagen and elastin to peptides and amino acids.
The loss of structural molecules provided by the extracellular matrix can thin and weaken the fibrous cap, rendering it particularly sus-
ceptible to rupture and acute coronary syndromes. Additional factors involved in the activation of macrophages include tumor necrosis
factor-␣ (TNF-␣), macrophage colony-stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1), among others.
Reproduced with permission from the American Heart Association (Circulation 1995;91:2844 –2850), with modifications by Peter Libby.
studies published by Henney et al demonstrating the presence
of stromelysin mainly in macrophages in coronary arteries.41
In the mid 1990s, Zorina Galis et al demonstrated 3 matrix
metalloproteinase (MMP) classes (interstitial collagenase,
MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin,
MMP-3) expressed primarily in the shoulder regions of
advanced plaques along with their endogenous inhibitors
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(tissue inhibitors of matrix metalloproteinases [TIMPs] 1 and
2).42– 44 MMP enzymatic activities were demonstrated by in
situ zymography (in vitro, lysis of a thin film of collagen
substrate) showing focal overexpression of activated MMP as
a potential mechanism that promotes destabilization. Further-
more, Shah et al showed that monocyte-derived macrophages
exposed in vitro to fibrous caps dissected from human aortic
or carotid plaques resulted in degradation of the fibrous cap.36
Incidence and Frequency of the TCFA
Burke et al, from our laboratory, not only defined vulnerable
plaques (as defined above) but also were among the first to
show that vulnerable plaques were commonly observed in
patients dying a sudden coronary death and were more
common in plaque ruptures than in stable plaques.27 The
number of vulnerable plaques correlated with both high total
cholesterol and the total cholesterol/high-density lipoprotein
cholesterol ratio.27 In subjects dying of plaque rupture,
additional lesion sites remote from the culprit plaque typi-
cally show TCFAs in 70% of cases. On the other hand,
TCFAs are less frequent (30%) in cases where death is
attributed to fibrocalcific plaques with flow-limiting stenosis,
regardless of MI status, or plaque erosion. Therefore, it must
be emphasized that not all TCFAs are likely to progress to
rupture; however, it is important to further define the essential
surrogates of lesion instability at the highest risk of rupture.29
In an additional 38 hearts from sudden coronary deaths
with severe luminal narrowing, in which the arteries had been
serially cut from coronary ostium to a distal intramyocardial
Figure 3. Illustration empha-
sizes the importance of colla-
gen synthesis and breakdown
in the maintenance of the
integrity of the fibrous cap.
Vascular smooth muscle cells
synthesize essential extracellu-
lar matrix proteins such as col-
lagen and elastin from amino
acids. This process may be
inhibited by interferon-␥ (IFN-␥)
secreted by activated T cells,
thereby disrupting collagen
synthesis, which may interfere
with the maintenance and
repair of collagen framework
supporting the fibrous cap.
Importantly, the expression of
CD40 ligand on T cells may
promote tissue proteolysis
through the release and activa-
location, mean luminal narrowing was least in sections with
TCFAs (59.6%), intermediate for lesions with hemorrhage
into a plaque (68.8%) and greatest in acute plaque ruptures
(73.3%) or healed plaque ruptures (72.8%). Overall, nearly
75% of lesions showed ⬍75% cross-sectional luminal-
narrowing or (⬍50% diameter stenosis), which may be a
useful indicator for the detection of vulnerable plaque.
Moreover, the location is also important, as approximately
50% of the TCFAs occur in the proximal portions of the
major coronary arteries (left anterior descending ⬎ left
circumflex ⬎ right coronary artery), with another one third in
the midportion and the remaining few in distal segments.28
A similar regional distribution of TCFAs is found for acute
and healed plaque ruptures. Clinical studies in AMI
patients also confirm that the proximal portions of all 3
major coronary arteries are the most common locations for
thrombotic occlusion.45
Remodeling, as mentioned above, can also be an impor-
tant sign of vulnerability. In this regard, plaque ruptures
had the highest remodeling index, followed by lesions with
hemorrhage ⬎ TCFAs ⬎ healed plaque ruptures ⬎ fibro-
atheromas.46 Conversely, lesions of total occlusion or
erosion exhibited negative remodeling.46 From this study,
it becomes evident that all lesions derived from or related
to plaque rupture show positive remodeling, which may
represent one important surrogate for detecting lesion
vulnerability.
Mechanical Stress, Lesion Vulnerability,
and Rupture
A limited number of biomechanical and imaging studies
started to emerge in the early 1990s addressing the role of
hemodynamic shear stress in the destabilization of vulnerable
plaques.47– 49 The underlying premise is based on observa-
tions that atherosclerosis is a focal point, where rupture
occurs more frequently at the proximal side of the stenosis
 Finn et al
near flow dividers, an area where secondary wall shear stress
is assumed to be the highest. Consistent with these observa-
tions, blood flow–induced shear stress may also present a
significant influence on processes that govern fibrous cap
morphology and composition,50 where increased peak cir-
cumferential stress is greater in thinner fibrous caps.49 There-
fore, regions of high shear stress typically exhibit high
strain,47 thus supporting the notion that mechanical stress
applied to a weakened fibrous cap may precipitate rupture,
particularly in the presence of microcalcification.51
Limitations to the Vulnerable
Plaque Paradigm
From the view of vulnerable plaque detection, morphological
studies should provide valuable insight regarding which
criteria are important for localizing high-risk lesions using
imaging modalities and assessing the potential risk for rup-
ture. Obvious important cause-and-effect data are missing
from the current paradigm because of our inability to accu-
rately detect vulnerable plaques in humans in vivo and
because of the lack of an animal model. In this regard,
representative lesions in current animal models rarely
progress beyond the stage of fibroatheroma; more often, they
consist of only masses of lipid-laden intimal macrophages
without a well-developed fibrous cap or necrosis. Lesions
with this histology rarely become clinically significant except
in examples of severe hyperlipidemia, in which the lumen can
become obstructed by the sheer plaque burden, a situation
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that is quite atypical in human disease.52 Therefore, a major
limitation today exists partly because the precise mechanisms
of progression from an asymptomatic stable to high-risk
plaque (TCFA or vulnerable plaque) that lead to rupture and
thrombosis are incompletely understood.
Although mouse models of atherosclerosis have provided
important insights into the genetic component of the disease,
major differences in the pathways directed toward lesion
composition between mice and humans remain apparent. For
example, inflammation is the most abundant plaque compo-
nent in mice, whereas in humans it constitutes only 2% to 5%
of total lesion volume.53 Moreover, intraplaque hemorrhage
from leaky vasa vasorum in human plaques is believed to be a
significant factor in necrotic core expansion,54 a phenomenon
rarely observed in mice. Perhaps more importantly, the mecha-
nisms of disease initiation and progression are quite distinct,
considering that mouse lesions are products of macrophages,
whereas in humans, early lesion progression arises from
smooth muscle cells enriched in an environment of proteo-
glycans and collagen with discreet pools of lipid, so-called
pathological intimal thickening.55,56 Although features of
fibrous cap formation, protease, activation, and cell death in
mice are reminiscent of human plaques, the applicability of
these to the natural progression of the disease has not yet been
tested.57 Therefore, we have proposed an alternative lesion
classification for mice in which early to intermediate lesions
are represented by varying degrees of macrophage infiltra-
tion.52 Rather than rupture per se, the pinnacle of advanced
plaques in mice appears to be the activated atheroma, character-
The Vulnerable/Unstable Plaque 1287
ized by focal medial degradation and extensive adventitial
inflammation, including mast cells with neovascularization.
Current Status of Vascular Imaging as an
Understanding Toward the Natural History of
the Vulnerable Plaque
To advance beyond the reactive clinical strategy that defines
modern cardiology, significant advances in our understanding
and natural history of TCFA (as well as other plaque morphol-
ogies) can only be achieved by improving our ability to accu-
rately define and locate these lesions in the clinic. Detection
based on morphology alone has been proposed using imaging
modalities such as intravascular ultrasound.58 Although some
articles have claimed to visualize ruptured plaques using this
technology, it is doubtful, considering the limited resolution (150
to 200 ␮m) of this modality. Perhaps more usefully, ultrasonog-
raphy has proven successful in the carotid circulation to predict
the future risk of stroke based on echolucency.59 Histologically,
echolucent plaques generally have higher lipid content, macro-
phage density, and hemorrhage.60
Among the current available modalities, MRI emerges as
most promising for assessing plaque morphology, in partic-
ular for assessing aortic and carotid plaques at risk for
embolic stroke. Its superior capability of determining plaque
size and composition with reasonable accuracy and reproduc-
ibility provides opportunities to study relationships between
plaque morphology and composition and subsequent cerebro-
vascular events. In this regard, Takaya et al tested the
hypothesis that the characteristics of carotid plaques assessed
by MRI are future predictors of ipsilateral cerebrovascular
events in 154 asymptomatic subjects with at least 12-month
follow-up with definitive stenosis (50% to 70%) by ultra-
sound.61 Correlates of lesion structure and composition with
associated cerebrovascular events included thinned or rup-
tured fibrous caps, presence of intraplaque hemorrhage,
larger maximum percentage of lipid-rich necrotic core, and
larger maximum wall thickness. Although current limitations
of MRI restrict its potential in the coronary vasculature, these
data support the contention that features of plaque composi-
tion alone may provide value in the assessment of risk of
future events.
Another noninvasive technology gaining clinical accep-
tance is computed tomography (CT) angiography, used pri-
marily for the detection of calcium; however, recently it has
been shown that it may be useful in detecting the plaques that
may be responsible for ACS. In a recent report, Motoyama
examined 2 important CT characteristics of culprit lesions,
plaque remodeling index and low attenuated plaques, pro-
spectively in 45 patients for 27⫾10 months.62 Of the 45
patients having combined features of plaque remodeling and
low attenuated plaque, 10 (22.2%) developed plaque rupture
during follow-up versus 1 patient (3.7%) in whom only a
single feature was detected. In contrast, of the 820 patients
who were negative for both features, only 4 (0.5%) developed
ACS. Therefore, patients with coronary lesions exhibiting
positive remodeling and low attenuation on CT angiography
were considered at higher risk for ACS compared with
patients having lesions without these characteristics.62 Con-
 1288 Arterioscler Thromb Vasc Biol July 2010
sidering the significant amount of radiation exposure to the
patient generated by this modality, before CT screening could
be advised, one would need to replicate these findings in a
much larger cohort to demonstrate their reproducibility in
predicting ACS.
More recently, intracoronary optical coherence tomogra-
phy (OCT), a technique that measures backscattered light, or
optical echoes, derived from an infrared light source directed
at the arterial wall, has been proposed as a high-resolution
analogue of intravascular ultrasound. The favorable resolu-
tion capabilities of 10 ␮m, validated ex vivo, allow superior
definition on the order necessary to resolve thin fibrous caps,
macrophages, and necrotic cores. One clinical study reported
the detection of TCFAs by OCT with frequencies of 72% for
acute MI, 50% for ACS, and 20% for ACS with stable
angina.63 Another interesting study by Tanaka examined 43
consecutive ACS patients who presented with ruptured
plaques diagnosed by OCT imaging.64 On the basis of the
level of physical activity at onset of ACS, patients were
stratified into a rest and exertion group. The data regarding
thickness of the ruptured fibrous cap in the exertion group
was significantly higher than that in the rest-onset group (rest
onset: 50 ␮m [interquartile median, 15 ␮m]; exertion: 90 ␮m
[interquartile median, 65 ␮m]; P⬍0.01). These results call
into question the paradigm that a standardized morphological
set of criteria will be able to identify vulnerable plaque in all
patients.
Although OCT is a promising technology, one major
limitation is the attenuation of signal intensity by blood
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necessitating prolonged, proximal occlusions to screen long
arterial segments. In light of this, further developments in
OCT technology have led to second-generation instruments
or optical frequency-domain imaging, a form of OCT
capable of acquiring images at much higher frame rates,
which enables rapid, 3-dimensional imaging of long cor-
onary segments.65,66
Another option that has recently emerged at the forefront
of the cardiovascular imaging field is the identification of
putative molecular and cellular targets to illuminate critical
processes in the transition from TCFA to rupture. In partic-
ular, fluorescence imaging using near-infrared fluorescence
has been used to detect proinflammatory and destructive
cysteine and serine proteases implicated in plaque rupture,
using activated reporter molecules.67 Putative targets have
included components of plaque neoangiogenesis, as well as
other elements associated with lesion instability, including
inflammation.
In addition, a variety of magnetic nanoparticles or super-
paramagnetic imaging agents have been developed to detect
inflammation in the atherosclerotic plaque. Nanoparticles are
engulfed by phagocytic cells and accumulate in resident
macrophages of the lesion. One advantage to magnetic
nanoparticles is that they are detectable by high-resolution
MRI or near-infrared fluorescence. Studies along these lines
have focused on imaging vascular cell adhesion molecule-1
in murine models68 and human plaques.68 Although proof-of-
concept experiments in animal models support the feasibility
of such technologies, the major question confronting the field
is which biomarkers are the best indicators in the transition
from TCFAs to rupture?
Proteolysis and Plaque Imaging
The release of matrix proteases, such as metalloproteinases
(MMPs) or cathepsin-associated proteases, may represent
another viable target for imaging, considering their role in
fibrous cap thinning and plaque destabilization.69 Typical
normal arteries do not possess active MMPs, although they
are expressed by macrophages in human atherosclerotic
plaques.43,70 One limitation to the approach of proteolytic
markers for imaging studies is low number of cells (predom-
inantly macrophages) expressing MMPs located in specific
regions of the plaque, such as shoulder areas. Therefore, the
localization of proteolytic factors would perhaps require
sensitive imaging technologies. Despite this potential limita-
tion, several studies have shown increased proteolytic activity
associated with macrophage infiltration of plaques using
noninvasive techniques, mostly involving radiolabeled mol-
ecules targeted at proteases developed for single-photon-
emission computed tomography and positron-emission
tomography.71–73
Alternative and perhaps more sensitive approaches have
also been explored involving the targeting of processes
responsible for upregulation of proteolytic activity or near-
infrared fluorescent molecular imaging using gelatinase-acti-
vated probes to detect the enzymatic activity of MMPs.74 The
first application of this technology was recently reported in
carotid plaques examined ex vivo with a MMP-sensitive
fluorescent probe, where hot spots corresponding to proteo-
lytic activity of MMP-9 were identified at the origin of the
internal carotid artery and at the level of the common carotid
bulb.75
Catheter-Based Near-Infrared Spectroscopy
and Assessment of Lipid Burden
In a recent study from the laboratory of Dr Muller, a novel
catheter-based near-infrared spectroscopy system was used
to identify lipid burden in human coronary plaques at
autopsy with correlative studies by histology.76 Using an
ex vivo model of human coronary segments under simu-
lated pressure, temperature, and flow, lipid core plaque
was identified in 115 of 2649 (4.3%) histological sections
from 51 validation hearts. The lipid core burden index
detected the presence or absence of any fibroatheroma with
an area under the curve of 0.86 (95% CI, 0.81 to 0.91)
based on receiver-operating characteristics analysis of
lipid core index values and histology truth. Moreover, a
retrospective analysis of lipid core burden index conducted
in extreme artery segments with either no or extensive
fibroatheroma yielded an area under the curve of 0.96
(95% CI, 0.92 to 1.00), thus confirming the accuracy of
spectroscopy in identifying plaques with diverse lipid
content, in an ideal setting. Thus, these preliminary data
suggest the potential of an invasive technology to assess
lipid core burden, which may be used as an adjunct to
 Finn et al The Vulnerable/Unstable Plaque 1289

Figure 4. Putative mecha-

nism(s) of necrotic core expan-
sion in human coronary
plaques. A to C, Illustration of
the concept of early, late, and
hemorrhagic necrosis, respec-
tively. A lipid pool rich in pro-
teoglycans and CD68-positive
macrophages characterizes
the early fibroatheroma; there
is a general absence of
smooth muscle cells (A). Infil-
trating macrophages capable
of engulfing apoptotic bodies
(ABs) are clearly recognized
within the necrotic core (NC).
As the lesion advances, late
necrosis is represented by
increased macrophage death
and cell lysis and by loss of
extracellular matrix (B). In this
case, free apoptotic bodies are
commonly seen, possibly indi-
cating the defective clearance
(efferocytosis) by resident
macrophages. In the third
example, hemorrhage may
promote the relatively rapid
expansion of necrotic core
where erythrocytes mem-
branes provide free cholesterol
(Free-Chol, arrow), which may
cause secondary inflammation (C). Resident macrophages are capable of removing hemoglobin/haptoglobin complexes via the CD163
receptor, although the efficiency of this mechanism is likely compromised as well. Modified and reproduced from Kolodgie et al, Patho-
genesis of atherosclerosis and the unstable plaque. In: PO Kwiterovich J, ed. The Johns Hopkins Textbook of Dyslipidemia. Baltimore:
Lippincott Williams & Wilkins; 2009.
Downloaded from http://ahajournals.org by on January 16, 2021

diagnostic angiography or intravascular ultrasound for risk
stratification and treatment of patients with ACS.
Involvement of Intraplaque Hemorrhage in
the Critical Transition From TCFA
to Rupture
Clearly, fibrous cap thickness, necrotic core size, and positive
remodeling are critical morphological features that distin-
guish TCFAs and ruptures from earlier progressive lesions,
defined as pathological intimal thickening or fibroatheromas.
During plaque development, the fibrous cap becomes a
functional structure distinct from underlying areas of necro-
sis, where it harbors the highly thrombogenic contents of the
necrotic core. Data from our laboratory provided evidence
that repeated intraplaque hemorrhage is a contributing factor
to necrotic core expansion, mainly considering that red blood
cell membranes serve as a potent source of free cholesterol.54
Based on the earlier work from studies by Katz et al in 197677
and later by Felton in 1977,78 there are significant differences
in lipid composition in different lesion types, where free
cholesterol is higher in disrupted plaques. In our study,
glycophorin-A, a highly expressed transport protein localized
to erythrocyte membranes, is commonly present within the
necrotic core of advanced coronary atheroma relative to
plaques in earlier phases of development.54 The source of
hemorrhage is likely leaky vasa vasorum that infiltrate the
plaque from the adventitia in response to a hypoxic environ-
ment created by increased lesion burden and inflammatory
macrophages. This, together with the death of macrophages
in the setting of defective phagocytic clearance of apoptotic
cells, is thought to contribute to the development of necrotic
core (Figure 4). MRI studies of carotid plaques over an
18-month period showed evidence of intraplaque hemorrhage
as a contributing factor to necrotic core volume and lesion
bulk.79
What to Look for When Imaging the
Vulnerable Plaque
Recent expanded morphometric examination of ruptures and
TCFAs in our laboratory was performed to further identify
relevant parameters of plaque rupture, besides cap thickness.
In this series of culprit plaques, 65% of ruptures exhibited
⬎75% cross-sectional luminal area narrowing, whereas 35%
showed stenosis of ⬍75%. The latter lesions were further
subdivided into those with luminal narrowing of 50% to 75%
(28% of lesions) and ⬍50% (7% of lesion) (Figure 5; R.
Virmani, unpublished data, 2010). For nonculprit vulnerable
plaques, 42% of TCFAs exhibited ⬎75% cross-sectional
luminal narrowing, and 57% showed stenosis ⬍75%. As for
ruptures, the latter lesions were similarly divided into those
with luminal narrowing of 50% to 75% (40% of lesions), and
17% showed ⬍50% diameter stenosis. In the clinic, a high
percentage of potential vulnerable plaques with ⬎75% ste-
nosis, irrespective of morphology, will likely be treated using
an invasive strategy, thereby removing the risk for rupture.80
Therefore, the majority of plaques at high risk for rupture
potentially amenable to noninvasive treatment are in the
target stenosis range of 50% to 70% (ruptures⫽28% versus
 1290 Arterioscler Thromb Vasc Biol July 2010
Figure 5. Bar graph shows the relative incidence of TCFAs and
ruptures (open bars) and necrotic core area (solid bars) stratified
by cross-sectional area luminal narrowing into tertiles of ⬍50%
(⬍25% diameter stenosis), 50% to 75% (25% to 50% diameter
stenosis), and ⬎75% (⬎50% diameter stenosis). Note that the
incidence of lesions with ⬍75% stenosis is greater for TCFAs
than for ruptures. Moreover, although the mean percentage area
of necrotic core in ruptures progressively increases with steno-
sis, this is not the case for TCFAs.
TCFAs⫽40%). Using lesions in this target range of stenosis,
area measurements of external elastic lamina (EEL), internal
elastic lamina (IEL), lumen, plaque, necrotic core, calcium,
and macrophages were performed together with other vari-
ables, including cap thickness, age and sex. In this select
group, multivariate analysis of culprit and nonculprit vulner-
able plaques of similar narrowing revealed only cap thickness
Downloaded from http://ahajournals.org by on January 16, 2021
(odds ratio 0.35, P⬍005), and necrotic core size (odds ratio
2.0, P⬍0.02), to be independent classifiers of rupture. Thus,
when interrogating patients presenting with ACS, it is impor-
tant not only to identify lesions with ⬍75% narrowing but
also to recognize those with relatively large necrotic cores, as
these plaques likely represent the highest risk for impending
rupture. This strategy needs to be pursued in the clinical
population based on the study of ACS patients with more
sensitive imaging modalities, such as optical frequency-
domain imaging or assessment of lipid core burden using
near-infrared spectroscopy.
Summary and Perspectives
Plaque rupture is a primary underlying cause of luminal
thrombosis responsible for provoking ACS. Although plaque
erosion and calcified nodules are also accountable for coro-
nary thrombi, unlike ruptures precursors to these lesions have
not been identified. The TCFA is considered an unstable
high-risk plaque with a propensity toward rupture. These
lesions, however, are morphologically different from rup-
tures, as they generally exhibit smaller necrotic cores and
intact thin fibrous caps less infiltrated by macrophages; the
degree of calcification is also less. The current paradigm
designating TCFAs as a prelude to ruptures is primarily
supported by autopsy findings, where definitive proof does
not exist because of a lack of prospective animal or human
data confirming a cause-and-effect relationship. Potential
morphological and biological processes that may be helpful
for the identification of TCFAs recognized by today’s imag-
ing modalities include necrotic core size, intraplaque hemor-
rhage, and positive remodeling. Advancing the field, how-
ever, will require establishing relevant translational animal
models that produce vulnerable plaques at risk for rupture and
furthering the development of novel imaging and therapeutic
modalities.
Sources of Funding
CVPath Institute provided the primary funding support for this work.
Disclosures
None.
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