© 1997 American Heart Association, Inc.
Articles |
The Unstable Atheroma
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Richard T. Lee, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail rtlee{at}bics.bwh.harvard.edu
Key Words: • unstable lesions • fibrous cap • plaque rupture
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Introduction |
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For several decades, our understanding of the pathogenesis of unstable atherosclerotic lesions has continued to grow. A consistent picture of unstable plaque structure, inflammation, matrix degradation, and prothrombotic activity is emerging. Meanwhile, the mortality rates for coronary artery disease in the United States have steadily declined.1 Changes in the American life style likely account for much of this decline,2 and we can expect further improvements through the beneficial use of aspirin and cholesterol-lowering therapy in subsets of the population.3 4 5 Many of these improvements were based on careful epidemiological studies, with fundamental vascular biology serving a largely supportive role.
In light of this major clinical progress, it is reasonable to consider whether further basic understanding of the unstable atherosclerotic lesion will be translated into a clinical benefit beyond these recent advances.6 We propose that the basic biology of the unstable lesion will now assume even greater importance for two fundamental reasons. First, even with aspirin and cholesterol-lowering therapy, acute vascular events will continue to be a major cause of morbidity and mortality in developed countries. Performing clinical trials and epidemiological studies in the United States and other developed countries will become more difficult and expensive as the number of patients needed for each study increases. Thus, developing new successful approaches to the prevention of acute vascular syndromes will require a sound understanding of the pathogenesis of lesion destabilization, and proceeding to clinical breakthroughs will require strong justification from vascular biology before clinical trials are undertaken. Second, even as the age-adjusted incidence of ischemic heart disease falls in the United States, the worldwide importance of ischemic heart disease is increasing. In fact, a recent comprehensive survey of the global patterns of disease has projected that by the year 2020, ischemic heart disease (currently the fifth leading cause of global disease burden) will surpass communicable diseases to become the leading cause of disability in the world.7
This review will discuss our current understanding of the unstable lesion as well as the important gaps in that understanding. The difficult process of filling in these gaps will be critical to translating vascular biology into the prevention of clinical plaque rupture. However, the stakes are high, because the benefits of successful lesion stabilization may be enormous. These benefits potentially include the prevention not only of acute myocardial infarction but also of many or most cases of unstable angina, peripheral vascular disease,8 stroke, and aortic aneurysm formation. Indeed, prevention of myocardial ischemic injury by plaque stabilization is an excellent way to reduce the incidence of congestive heart failure.
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The Unstable Lesion and the Biology of Fibrous Cap Strength |
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Two major mechanisms of plaque disruption may lead to coronary thrombosis: frank rupture of a plaque's fibrous cap and superficial erosion of the endothelium. As early as 1934, plaque rupture was proposed as a mechanism for acute arterial thrombosis.9 In the past 15 years, careful pathological examinations of human lesions have refocused attention on plaque rupture as the cause of the majority of acute coronary events. These studies, which have recently been reviewed in depth,10 11 have consistently identified several morphological features that characterize the unstable atheroma, including a thin, eccentric fibrous cap and a large necrotic core of lipid and cellular debris. Analyses of human lesions by modern computer methods and biomechanical testing have established the probable link between this characteristic morphology and the actual rupture event. This plaque configuration is particularly unstable because large mechanical stresses develop in the thinnest portions of the fibrous cap.12 13 The soft lipid core is unable to bear these mechanical forces, and excess stresses are thus "concentrated" in the fibrous cap, particularly at the junction with the normal vessel (the "shoulder" region). Like the Achilles' tendon of an athlete, under some circumstances the collagenous extracellular matrix of the fibrous cap cannot withstand these stresses, and the fibrous cap ruptures.
However, numerous recent observations tell us that other critical factors contribute to the ultimate fracture of a fibrous cap. First, many plaques with the typical geometric features of an unstable atheroma do not rupture and are only incidentally found at autopsy.14 Second, the mechanical strength of human fibrous caps varies considerably.15 16 This variability may explain why some atheromas with similar geometric features rupture and others do not. Third, a body of consistent evidence supports the view that the extracellular matrix of the fibrous cap is a dynamic, biologically active environment. Together, these three observations suggest that there is potential for modulating the biological activity of the fibrous cap to increase its strength, possibly by converting the unstable plaque that is highly prone to rupture to a more stable lesion. In this approach, we can consider the intact fibrous cap a "healed wound" and plaque rupture a "wound failure." Because most of the mass of the fibrous cap is extracellular matrix, particularly fibrillar collagen, understanding how cells of the atheroma secrete, organize, and degrade the collagenous matrix is a central theme of plaque stabilization.
Molecular Regulation of Matrix Synthesis
Extracellular matrix accumulation is characteristic of
atherosclerotic as well as hypertensive arteries. Vascular smooth
muscle cells are the primary source of this matrix, which primarily
comprises collagens, elastin, proteoglycans, and microfibrillar
proteins. In the normal artery, both the synthesis and degradation of
extracellular matrix proteins are remarkably slow; for example,
collagen turnover in the normal artery has been estimated to be in
years.17 Atherosclerosis and injury to the
artery lead to increased synthesis of many matrix components, including
elastin, collagen types I and III, and several proteoglycans. In the
later stages of atherosclerosis, nonfibrillar collagen
types IV (usually a basement membrane collagen) and V can be found in
the fibrous cap.18 Cytokines and growth factors in
the atheroma regulate the synthesis of matrix components;
for example, transforming growth factor-ß (TGF-ß) potently
stimulates collagen synthesis whereas interferon-
suppresses
expression of collagen.19 For atherosclerotic lesions
causing chronic stable ischemia, excess matrix accumulation is
the primary mechanism of occlusion of the atherosclerotic artery lumen.
In contrast, unstable lesions may fail to synthesize a sufficient mass
of matrix to provide strength to the fibrous cap.
Matrix Organization
Once extracellular matrix constituents are secreted, they must
organize into a functional three-dimensional structure. The smooth
muscle cell probably participates in this process, particularly with
respect to collagen organization. Smooth muscle cells (as well as
fibroblasts and other cells) not only secrete collagen but also have
ß1 integrins that serve as receptors for collagen. Cultured vascular
smooth muscle cells use ß1 integrins to organize type I collagen in a
three-dimensional culture as shown by experiments using monoclonal
antibodies specific to integrin subunits.20 In addition,
we have found that promoting excess adhesion with anti-integrin
monoclonal antibodies also inhibits collagen organization, suggesting
that collagen organization is a dynamic process that requires both
adhesion and release of adhesion to collagen. This process may be
analogous to cellular migration, which may be inhibited by either
insufficient or excess adhesion to matrix components.
Many extracellular matrix proteins interact with other matrix molecules, growth factors, and cell surface receptors in complex ways. For example, decorin, a proteoglycan abundant in the artery wall, binds to collagen as well as TGF-ß, a growth factor that regulates both collagen synthesis and degradation.21 Another well described example is the binding of basic fibroblast growth factor (FGF-2) to heparan sulfate proteoglycans in the extracellular space or on the cell surface, thereby regulating the presentation of FGF-2 to the high-affinity FGF receptor.22 The extent and physiological relevance of these extracellular matrix molecule interactions are incompletely understood, but these interactions likely influence the ultimate strength of fibrous atherosclerotic tissue.
Matrix Degradation
Let us suppose that the cells of the atheroma
construct a structurally stable, healed wound so that any increased
mechanical stress in the fibrous cap is adequately balanced by the
strength of the fibrous cap collagenous matrix. There are two possible
ways this structure could become unstable. First, the stresses in the
fibrous cap could increase, perhaps by further lipid accumulation or a
surge in blood pressure.23 Second, the matrix could be
weakened somehow, such as through enzymatic degradation. In the past
decade, knowledge of the mechanism of matrix degradation has rapidly
expanded, and it is now clear that some degree of ongoing matrix
degradation is a highly controlled and essential component of normal
tissue homeostasis. It is also clear that increased matrix-degrading
activity is a common finding in unstable atherosclerotic lesions, thus
presenting a potential therapeutic target. There are three major
pathways of extracellular matrix degradation: the serine proteases,
which include urokinase-type plasminogen
activator and plasmin; the cysteine proteases; and the
matrix metalloproteinases (MMPs; see the
Table
). Membrane-associated serine
proteases participate in cellular migration and metastasis and can
digest proteoglycans, fibronectin, and laminin.24
Noda-Heiny et al25 reported augmented urokinase receptor
expression in human atherosclerotic lesions; excess serine protease
activity has not been demonstrated in unstable lesions. The cysteine
proteases, such as cathepsins S, B, and L, usually localize in the cell
within lysosomes and function under acidic conditions. However,
cathepsin S retains substantial proteolytic activity at the neutral pH
of the extracellular space and can digest elastin, an important
constituent of arterial matrix. Sukhova et
al26 found that both macrophages and
nonmacrophage cells express cathepsin S in advanced fibrous
lesions near the shoulder region of the lesion, suggesting that this
elastolytic enzyme may participate in fibrous cap degradation
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The MMPs are members of a family of related enzymes that function at neutral pH in the extracellular space.27 To date, 12 members of the MMP family have been identified and numbered from 1 to 15 (numbers 4, 5, and 6 were initially thought to be members of the MMP family but were later removed). Each of the MMPs depends on zinc and calcium ions for enzymatic activity. Most MMPs are secreted as proenzymes into the extracellular space. In 1994 Sato et al28 described a new membrane-type metalloproteinase (MT-MMP, or MMP-14) that had a transmembrane domain and was cell-surface associated. Specific MMPs have preferential substrates, but often more than one MMP can digest a given substrate. For example, collagen type I, a prominent component of the atheroma's fibrous cap, can be digested by either MMP-1 or MMP-8.
Given the ability of MMPs to digest all of the major extracellular
matrix components, it is not surprising that the activity of these
enzymes is controlled at multiple levels. First, MMPs are under
transcriptional regulation. For example, both MMP-1 and MMP-3 have
consensus sequences for phorbol ester–responsive elements and
activator protein-1 sites, and in a broad variety of cells,
cytokines induce synthesis of these enzymes.29
Second, after synthesis and secretion into the extracellular space, the
enzymes must be activated.30 This activation step
is generally associated with cleavage of 
10 kDa of the
N-terminus from the proenzyme, allowing the enzyme to obtain
full activity. In vitro, the activation step can be achieved by a
variety of agents, such as aminophenylmercuric acetate, trypsin,
plasmin, or SDS.31 In vivo, the mechanism of activation is
less clear but may involve plasmin,32 urokinase-type
plasminogen activator, membrane-type MMPs, or
even autoactivation. Even after MMPs are activated, they may be
inhibited. This third level of MMP regulation involves a family of
specific endogenous inhibitors called tissue
inhibitors of metalloproteinases (TIMPs).27 33
TIMPs have an amino-terminal domain that binds to available MMP active
sites on a 1:1 stoichiometric basis, thereby inhibiting these
enzymes.
The expression of MMPs increases in the human atheroma. Henney et al34 found evidence for increased stromelysin-1 expression in the human atheroma by in situ hybridization and increased protein expression of MMP-3 (stromelysin-1), MMP-1 (interstitial collagenase) and gelatinases were identified by immunohistochemistry in human lesions. Nikkari et al35 found intense MMP-1 expression at the borders of lipid cores as well as subsets of smooth muscle cells and endothelial cells of human carotid atherosclerotic lesions.
Brown et al36 found increased levels of MMP-9 in human coronary atherectomy specimens. However, increased gene expression or the presence of immunoreactive enzymes does not necessarily indicate excess matrix degradation, because to acquire activity, these enzymes must undergo a conformational change (usually by cleavage) and even when activated, endogenous TIMPs can inhibit the MMPs. By the technique of in situ zymography we have demonstrated that excess matrix-degrading activity is indeed present in the human atheroma, particularly in the shoulder region of the atheroma, where mechanical stresses are highest.37 We also studied the localization of MMP-1 by systematically comparing the distribution of stress in human coronary lesions with the expression of MMP-1. We found that expression of MMP-1 increased severalfold in regions of increased mechanical stress.38 Because this region is where pathologists have frequently noted plaque rupture to occur, it is attractive to speculate that the combination of excess matrix degradation and excess mechanical stress at these locations leads to failure of the fibrous cap.
Which cells secrete MMPs at these high-stress locations, and what
stimulates them to turn on the matrix degradation system? Turning to
cell culture experiments helps to define factors that may regulate MMP
expression by cell type, such as the macrophage and the
vascular smooth muscle cell. Vascular smooth muscle cells in culture
constitutively express MMP-2, a gelatinase that degrades nonfibrillar
collagen and participates in cellular migration.39 40
However, this MMP-2 appears to be in its inactive precursor form and
bound to its selective inhibitor TIMP-2. Resting vascular
smooth muscle cells in vitro express little MMP-1, an enzyme required
to cleave fibrillar collagens I and III, or MMP-3, a metalloproteinase
that may activate MMP-1 and also degrade vascular
proteoglycans. However, in the presence of cytokines such as
tumor necrosis factor-
(TNF-) or interleukin (IL)-1ß,
smooth muscle cells markedly increase synthesis of MMP-1 and MMP-3. One
potential sequence of events is that infiltrating macrophages
secrete cytokines that stimulate smooth muscle cells to produce
MMPs. In support of this potential mechanism, we have found that
coculture of human monocytes with vascular smooth muscle cells provokes
a dramatic induction of MMP-1 and MMP-3.41 The source of
these MMPs is the vascular smooth muscle cell, and this induction can
be abolished by inhibiting IL-1ß.
However, the human monocyte/macrophage can also be an abundant source of MMPs.42 The differentiated macrophage of the atheroma differs in important ways from the circulating monocyte. The macrophage accumulates lipid through several surface molecules that bind modified lipoproteins and may also be differentiated by locally secreted factors, including macrophage colony stimulating factor and monocyte chemotactic protein-1, which are found at increased levels in the atheroma. Galis et al43 studied macrophage foam cells from arterial lesions in cholesterol-fed rabbits and compared them with macrophages isolated by bronchoalveolar lavage. Alveolar macrophages harvested from hypercholesterolemic rabbits did not express MMP-1 MMP-3, but could produce these enzymes when exposed to phorbol esters. In contrast, foam cells from the atheromatous aortas of these animals expressed these MMPs without additional stimulation. This suggests that the environment of the atheroma provides sufficient signals to promote MMP synthesis by macrophages. Lendon et al15 found that the mechanical strength of human aortic plaques was reduced when macrophage density was increased, and Shah et al44 have demonstrated that macrophages in culture may promote collagen breakdown of human fibrous caps. Because macrophage infiltration of the fibrous cap is a ubiquitous finding in unstable lesions,45 46 these studies provide a direct link between the macrophage and fibrous cap weakening, even in the absence of smooth muscle cell–derived MMPs.
The Necrotic Lipid Core
The typical unstable atheroma has a substantial volume
of necrotic, lipid-laden debris beneath the fibrous cap. This
relatively avascular and hypocellular pool contains
cholesterol monohydrate, cholesterol esters,
and phospholipids. The lipid core is several orders of magnitude softer
than the typical fibrous cap,47 with a semifluid
consistency at body temperature. This mechanical property
is likely to be a critical factor in determining plaque stability; the
softer the lipid core, the more stress the overlying fibrous cap must
bear. One potentially important effect of
cholesterol-lowering therapy might be to change the
proportions of the constituents of the lipid core. Early in
experimental cholesterol-lowering studies, the proportion
of cholesterol esters decreased owing to hydrolysis,
leading to an increase in the proportion of insoluble
cholesterol monohydrate. The net effect is a stiffening of
the lipid core region; in vitro experiments suggest that the lipid core
may become as much as fivefold stiffer during regression of the
atheroma.47 If such changes occur in humans,
decreased stress in the fibrous cap and improved lesion stability
should result.
In addition to prominently contributing to the biomechanical instability of the atheroma, the lipid core is a source of prothrombotic material. Fernandez-Ortiz et al48 reported that compared with matrix derived from foam cell–rich lesions, sclerotic plaques, or fibrolipid plaques, the atheromatous core was markedly more thrombogenic in vitro. Tissue factor (TF; thromboplastin) binds the serine protease coagulation factor VIIa, leading to activation of factors IX and X.49 TF protein and mRNA colocalize with foam cells in human atheromatous plaques, and TF can be found in both the necrotic core and cellular areas of the plaque. Interestingly, TF expression is diminished in restenotic lesions (which rarely cause acute thrombosis) but is associated with plaque thrombus in human atherectomy specimens.50 Thus, when the fibrous cap fractures, contact of the blood with the lipid core may initiate thrombosis.
Cellular Death
A fascinating pathological observation is that fibrous caps that
have ruptured have not only twice as many macrophages as
unruptured fibrous caps but also half as many smooth muscle
cells.10 Therefore, at the same time that inflammation and
matrix degradation decrease plaque strength, inadequate numbers of
smooth muscle cells may be present to repair the degradation. The
relative decrease in smooth muscle cell number in these regions might
result from growth inhibition due to the lymphokine interferon-,
which is secreted by T cells that localize in this very
region.51 In addition, smooth muscle cells may die in this
zone of the plaque. Cellular death in the vasculature may sometimes
result from lytic injury and necrosis, but recent findings suggest that
smooth muscle cells of the atheroma undergo programmed cell
death, or apoptosis.51 52 The apoptotic
pathway of cell death requires de novo gene induction and protein
synthesis. A mammalian cysteine protease, IL-1ß–converting enzyme,
catalyzes the cleavage of the precursor of IL-1ß to its active form.
This enzyme and/or other closely related proteinases participate in the
induction of apoptosis. In human atheromas, regions
of cells with DNA damage characteristic of apoptosis, as
disclosed by labeling with the TUNEL technique (terminal
deoxynucleotidyl transferase–mediated dUTP
nick-end labeling), colocalize with IL-1ß–converting
enzyme.53
The precise signals that regulate apoptosis in the
atheroma are unknown, as multiple stimuli can provoke this
process. Some proteins, including IL-1ß–converting enzyme, TNF-,
interferon-, or the tumor suppressor p53 sometimes function as
"apoptosis on" signals, while genes such as
bcl-2 can function as "apoptosis off"
genes.54 Bennett et al54 found that stable
expression of bcl-2 can protect vascular smooth muscle cells
from apoptosis and that specific cytokines and growth
factors, such as insulin-like growth factor-1 and platelet-derived
growth factor, are potent survival factors. It is possible that
withdrawal of these factors "steers" smooth muscle cells in the
atheroma toward apoptosis. Lack of sufficient
smooth muscle cells to secrete and organize the matrix in response to
mechanical stress could render the fibrous cap even more vulnerable to
weakening by extracellular matrix degradation.
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Clinical Correlations With the Biology of the Unstable Lesion |
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Our knowledge of the importance of plaque rupture has primarily grown from careful pathological studies, since we do not have routine tools for diagnosing and treating unstable lesions prior to a vascular catastrophe. It is therefore not surprising that our proven clinical successes have largely focused on decreasing the impact of plaques that have already ruptured, such as thrombolytic therapy, angiotensin-converting enzyme therapy, and aspirin. However, a number of clinical studies provide perspectives on the potential impact of a therapy that could prevent plaque rupture.
Lessons From Angiography
Although considered almost heretical only a decade ago, it is now
widely accepted that stenosis severity assessed by
coronary angiography poorly predicts the propensity of that
lesion to rupture. Ambrose et al55 showed that the average
degree of stenosis of lesions that progressed to acute
myocardial infarction was only 48% and that fewer than half of
myocardial infarctions are caused by the most severe coronary
stenosis. Clinical-angiographic studies of this relation have
been consistent.56 With our current understanding
of plaque rupture, it is not surprising that angiography cannot
reliably predict lesion stability, particularly since the calculated
mechanical stress in the lesion actually decreases in more severe
stenoses.13
Angiography can sometimes detect the irregular or ulcerated lesions of ruptured plaques, particularly after thrombolytic therapy, but cannot determine the intimal structure or biological features characteristic of the unstable lesion. Intravascular ultrasound and angioscopy57 58 59 have promise for visualizing some of these features, but systematic prospective evaluation of these techniques for predicting subsequent plaque rupture has not been performed.
Lessons From Cholesterol Lowering
The marked clinical success of cholesterol-lowering
therapy has reinforced the inadequacy of coronary arteriography
in assessing lesion vulnerability and has raised new questions
regarding the mechanism of this success.60 These studies
have constantly shown a pattern of a decrease in acute
cardiovascular events in the absence of impressive
changes in coronary artery stenosis severity by
angiography. The answer to this apparent paradox seems to lie on the
surface or beneath the lumen that is visualized by angiography. The two
dominant hypotheses for the benefit of
cholesterol-reduction therapy are plaque stabilization and
improved endothelial function.61
Restoration of endothelial vasodilator properties could
surely benefit "demand"-induced ischemia. The recovery of
endothelial dysfunction and improved vasomotor function
following lipid-lowering therapy could also limit vasospasm that
accompanies plaque rupture, decrease recruitment of inflammatory cells,
and promote fibrinolysis. The improvement in
endothelium-dependent vasomotor function occurs rapidly
after lipid lowering, in only a matter of weeks following effective
pharmacotherapy.62
The second hypothesis is that lipid lowering alters intimal plaque stability in an endothelium-independent manner. Not only do lipids in the atheroma create mechanical instability but also biologically active lipids participate in promoting the oxidative stress and inflammatory responses such as monocyte migration. Lipid lowering may therefore influence the matrix degradation cascade that appears most active in macrophage-rich areas of the atheroma. These nonendothelial mechanisms of event reduction probably require many months or even years. It is important to consider that the hypotheses of endothelial recovery and plaque stabilization are not mutually exclusive explanations for the benefits of lipid lowering. In fact, the dramatic benefits (such as the 34% reduction in coronary deaths in the 4S Study4 ) may be the synergistic result of improved endothelial function at the blood-atheroma interface and improved stability of the extracellular matrix in the fibrous cap.
Complex Aortic Lesions and Stroke
Strong evidence has emerged that complex
atheromatous lesions of the aortic arch are a cause of
stroke, particularly among patients without severe carotid artery
stenoses. This association first emerged from pathological
observations63 but has been confirmed repeatedly through
new methods of imaging the thoracic aorta, particularly with
transesophageal
echocardiography.64 65 Aortic lesions
frequently develop inflammation and surface fractures, and
macrophage infiltration of these aortic lesions decreases their
strength. Although a prospective study demonstrating that unruptured
aortic atheromas evolve into complex lesions that cause
stroke has not been performed, current data suggest that strategies to
decrease plaque rupture would also affect this mechanism of stroke.
Systemic Inflammation in Acute Coronary Syndromes: Cause
or Consequence?
Up to this point we have focused attention on the characteristics
that make an individual lesion unstable. The foci of inflammation and
matrix degradation that weaken the fibrous cap are so small that
systemic signs of inflammation might not be expected. However,
acute-phase reactants are increased in unstable coronary
syndromes, even without myocardial infarction. Berk et
al66 reported increases in C-reactive protein in patients
with unstable angina, and Liuzzo et al67 found that
elevations in C-reactive protein and serum amyloid A protein in
patients with unstable angina predicted poor clinical outcomes. Jude et
al68 reported that the circulating peripheral
monocytes in patients with unstable angina expressed higher levels of
TF than those in patients with acute myocardial infarction or stable
angina. TF expression suggests activation of monocytes and could
promote coagulation. These studies raise the intriguing possibility
that a systemic state of inflammation promotes the plaque rupture
process. However, it is also possible that C-reactive protein increases
in response to a lesion that has ruptured or to many lesions in the
arterial system that may have become inflamed. Thus, it is
unclear whether acute-phase reactants are risk factors that will
predict future unstable coronary lesions, are markers of
generally inflamed lesions in the arterial system, or are
markers of a single, highly active lesion that may become
symptomatic. Prospective clinical studies that follow
C-reactive protein or other markers of inflammation in
asymptomatic patients would provide insight into this
distinction. At this point, the relationship of such systemic markers
of inflammation to the individual unstable coronary lesion
remains undefined.
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Major Gaps in Our Understanding of Plaque Rupture |
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Time: A Critical Dimension of Plaque Rupture
As much as pathological studies have revealed the mechanisms of plaque rupture, these studies represent "snapshots" in the life of the atheroma. We do not know the time course of inflammation in the fibrous cap or of changes in the lipid pool, two key determinants of plaque stability. Is it possible that inhibition of matrix degradation or inflammatory infiltration could be limited to specific time periods, or would such therapy be required long-term? Insight into the time dimension of plaque instability could be provided by high-resolution imaging techniques that define intimal structure, such as optical coherence tomography or magnetic resonance imaging. In addition, a truly representative animal model would also allow us to serially examine the sequence of events that lead to plaque rupture.
Plaque Rupture and Asymptomatic Lesion Growth
Davies and colleagues14 have reported that
plaque ruptures can be found in 9% of subjects who died of noncardiac
causes and in as many as 22% of patients with diabetes or
hypertension. Fractured fibrous caps with intense inflammation are also
a common finding in the abdominal aorta at necropsy, and
asymptomatic carotid plaque rupture may be found in almost
one fifth of elderly persons at autopsy.69 Thus, not all
plaque ruptures cause catastrophic arterial occlusion, and
in fact, most plaque ruptures are probably asymptomatic.
Lack of symptoms may result from limited, nonocclusive mural or
intramural thrombus or from maintained perfusion by collateral vessels.
Angiographic studies have suggested that progression of the
atheroma may occur in a stepwise fashion. Chester et
al70 reported that angiographically complex lesions in
patients awaiting balloon angioplasty were more likely to progress in
severity, even in the absence of acute coronary
ischemic symptoms. Thus, it is likely that many lesions grow
through plaque rupture, asymptomatic healing of the mural
thrombus, and wound repair of the breached fibrous cap. Prevention of
rupture of nonobstructive plaques could therefore be an important
strategy for limiting their evolution to more stenotic lesions
that might provoke chronic ischemia as well as acute
ischemic syndromes.
Sudden Death
While the evidence that plaque rupture causes most acute
myocardial infarctions is overwhelming, the role of plaque rupture in
sudden death is less clear. Sudden death is usually precipitated by
ventricular arrhythmia in the setting of extensive
coronary disease. Friedman et al71 found 19
ruptured plaques with thrombi in 37 patients (51%). Farb et
al72 studied 50 consecutive cases of sudden cardiac death
and found that typical plaque rupture with fibrous cap tearing was
present in 28 of 50 cases (65%). However, the remaining 22 cases
had thrombi without rupture, and the thrombi were associated with
superficial erosions of a proteoglycan-rich plaque. Erosions were less
often associated with calcification and infiltration by
macrophages and T cells and more often associated with clusters
of smooth muscle cells adjacent to the thrombi. Thus, it appears that
acute plaque rupture plays a role in at least half of the cases of
sudden death but that the pathophysiological
sequence that leads to thrombosis in the remaining cases may be
different from fibrous cap fracture.
Lack of a Representative Animal Model
While numerous models of intimal thickening,
restenosis, and intravascular thrombosis have contributed to
vascular biology, an animal model of plaque rupture remains elusive.
Abela et al73 reported characterization of a rabbit model
of intra-aortic thrombosis that was initially developed by
Constantinides and Chakravarti in 1961. In this model,
cholesterol-fed rabbits undergo balloon injury and are
later injected with Russell's viper venom (which contains potent
procoagulant and endothelial toxin activity) and
histamine. These animals frequently develop acute thrombi of the aorta,
but the thrombi appear to be associated with
endothelial toxicity rather than the more typical
collagenous, fibrous cap fracture found in human lesions. In this
regard, this model may be more representative of the
inflammatory erosions that accompany sudden death.
Mouse models of atherosclerosis develop aortic lesions with many features of those in humans, including foam cells and collagenous fibrous caps. Spontaneous plaque rupture has not been a feature of the apoE- or LDL receptor–deficient mouse, however. One potential explanation is simply that the mouse aorta has a diameter on the order of a millimeter. Since circumferential stress, the mechanical component most associated with plaque rupture, is directly proportional to the radius of the artery, it follows that the tensile forces on the mouse atheroma are much smaller than those in the human fibrous cap.
Skinner et al75 reported a study of a double balloon injury–hypercholesterolemic rabbit model in which they found one rabbit aortic thrombus 14 months after beginning the protocol. This thrombus developed over a lesion very similar to the typical fibrous cap fracture of human myocardial infarction. An exciting component of this report was the use of magnetic resonance imaging with a phased-array receiving coil, which allowed the investigators to visualize the features of plaque rupture while the animal was still alive. This study demonstrated not only the potential of noninvasive imaging for revealing the natural history of the atheroma, but also the likely necessity of long observation periods to develop spontaneous plaque rupture in animal models.
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Steps to Prevent Plaque Rupture |
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The current information available on the mechanism of plaque rupture suggests that several potential therapeutic options could provide additional clinical benefit beyond our current therapies. First, we could identify unstable lesions with improved imaging modalities and intervene on the lesion before it ruptures. Second, we could modulate the strength of the extracellular matrix of the fibrous cap by directly delivering growth factors, drugs, or genes that can regulate extracellular matrix, steps that are analogous to the intense efforts to improve dermal wound healing. Third, we can attempt to inhibit a step in the inflammation sequence between monocyte recruitment, migration, differentiation, and secretion of cytokines and proteases. Fourth, we can directly inhibit matrix degradation and weakening in the extracellular space. MMP inhibition is attractive for this purpose because the enzymes are extracellular and orally active inhibitors are already in clinical trials for noncardiovascular indications. MMP inhibition could have the added benefit of inhibiting smooth muscle cell migration into the intima. However, not all of the matrix-degrading enzymes in the plaque are MMPs, and the contribution of these non-MMPs to plaque destabilization requires consideration as well. Currently, we can only speculate about the potential risks and benefits of these strategies.
While coronary death rates have fallen in the United States, our appreciation of the broad implications of the unstable atheroma have just as dramatically increased. Attacking this problem could benefit the prevention not only of acute myocardial infarction but also acute peripheral vascular ischemia, stroke, and even the general progression of atherosclerosis. However, the pursuit of plaque rupture as a primary end point in clinical trials using any of the above strategies will likely require convincing vascular biology evidence that a particular strategy holds promise.
Establishing a robust, representative animal model of plaque rupture is imperative. Anecdotal evidence indicates that this is possible, and the cardiovascular community should recognize that establishing this model will require more patience and perseverance than animal models of intimal thickening or restenosis have required. In addition, we need improved imaging modalities, both for studying animal models and for following individual human atherosclerotic lesions, preferably noninvasively. The combination of a suitable animal model and imaging would likely turn the snapshots of postmortem examination of plaque rupture into a moving picture of vascular biology that should improve our understanding of when and how to intervene to prevent plaque rupture.
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Acknowledgments |
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This study was supported in part by a Grant-in-Aid from the American Heart Association and grants from the National Heart, Lung, and Blood Institute (HL-47840, HL-48743, HL-54759).
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Footnotes |
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Arterioscler Thromb Vasc Biol. 1997;17:1859-1867.
Received May 13, 1997; accepted July 27, 1997.
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References |
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TopIntroductionThe Unstable Lesion and...Clinical Correlations With the...Major Gaps in Our...Steps to Prevent Plaque...References |
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K. A. Lindstedt, M. J. Leskinen, and P. T. Kovanen Proteolysis of the Pericellular Matrix: A Novel Element Determining Cell Survival and Death in the Pathogenesis of Plaque Erosion and Rupture Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1350 - 1358. [Abstract] [Full Text] [PDF]
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G. G. Neri Serneri, M. Boddi, P. A. Modesti, M. Coppo, I. Cecioni, T. Toscano, M. L. Papa, M. Bandinelli, G. F. Lisi, and M. Chiavarelli Cardiac Angiotensin II Participates in Coronary Microvessel Inflammation of Unstable Angina and Strengthens the Immunomediated Component Circ. Res., June 25, 2004; 94(12): 1630 - 1637. [Abstract] [Full Text] [PDF]
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J. Herrmann, A. Ciechanover, L. O Lerman, and A. Lerman The ubiquitin-proteasome system in cardiovascular diseases--a hypothesis extended Cardiovasc Res, January 1, 2004; 61(1): 11 - 21. [Abstract] [Full Text] [PDF]
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R. Wolk, P. Berger, R. J. Lennon, E. S. Brilakis, and V. K. Somers Body Mass Index: A Risk Factor for Unstable Angina and Myocardial Infarction in Patients With Angiographically Confirmed Coronary Artery Disease Circulation, November 4, 2003; 108(18): 2206 - 2211. [Abstract] [Full Text] [PDF]
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T. Suzuki, K. Fukuo, T. Suhara, O. Yasuda, N. Sato, Y. Takemura, M. Tsubakimoto, and T. Ogihara Eicosapentaenoic Acid Protects Endothelial Cells Against Anoikis Through Restoration of cFLIP Hypertension, September 1, 2003; 42(3): 342 - 348. [Abstract] [Full Text] [PDF]
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R. Elhage, J. Jawien, M. Rudling, H.-G. Ljunggren, K. Takeda, S. Akira, F. Bayard, and G. K Hansson Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice Cardiovasc Res, July 1, 2003; 59(1): 234 - 240. [Abstract] [Full Text] [PDF]
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W. Jin, G.-S. Sun, D. Marchadier, E. Octtaviani, J. M. Glick, and D. J. Rader Endothelial Cells Secrete Triglyceride Lipase and Phospholipase Activities in Response to Cytokines as a Result of Endothelial Lipase Circ. Res., April 4, 2003; 92(6): 644 - 650. [Abstract] [Full Text] [PDF]
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P. M. Kris-Etherton, W. S. Harris, L. J. Appel, and for the Nutrition Committee Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): e20 - 30. [Full Text] [PDF]
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M. J. Leskinen, K. A. Lindstedt, Y. Wang, and P. T. Kovanen Mast Cell Chymase Induces Smooth Muscle Cell Apoptosis by a Mechanism Involving Fibronectin Degradation and Disruption of Focal Adhesions Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 238 - 243. [Abstract] [Full Text] [PDF]
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P. M. Kris-Etherton, W. S. Harris, L. J. Appel, and for the Nutrition Committee Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease Circulation, November 19, 2002; 106(21): 2747 - 2757. [Full Text] [PDF]
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K. Nishi, H. Itabe, M. Uno, K. T. Kitazato, H. Horiguchi, K. Shinno, and S. Nagahiro Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1649 - 1654. [Abstract] [Full Text] [PDF]
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H. Yabushita, B. E. Bouma, S. L. Houser, H. T. Aretz, I.-K. Jang, K. H. Schlendorf, C. R. Kauffman, M. Shishkov, D.-H. Kang, E. F. Halpern, et al. Characterization of Human Atherosclerosis by Optical Coherence Tomography Circulation, September 24, 2002; 106(13): 1640 - 1645. [Abstract] [Full Text] [PDF]
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T. C. Major, L. Liang, X. Lu, W. Rosebury, and T. M.A. Bocan Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1200 - 1207. [Abstract] [Full Text] [PDF]
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M. R. Cusack, M. S. Marber, P. D. Lambiase, C. A. Bucknall, and S. R. Redwood Systemic inflammation in unstable angina is the result of myocardial necrosis J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1917 - 1923. [Abstract] [Full Text] [PDF]
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J. L. Mehta and D. Li Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1429 - 1435. [Abstract] [Full Text] [PDF]
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L. Vincent, C. Soria, F. Mirshahi, P. Opolon, Z. Mishal, J.-P. Vannier, J. Soria, and L. Hong Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 623 - 629. [Abstract] [Full Text] [PDF]
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M. D. Rekhter How to evaluate plaque vulnerability in animal models of atherosclerosis? Cardiovasc Res, April 1, 2002; 54(1): 36 - 41. [Abstract] [Full Text] [PDF]
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C.L. de Korte, S.G. Carlier, F. Mastik, M.M. Doyley, A.F.W. van der Steen, P.W. Serruys, and N. Bom Morphological and mechanical information of coronary arteries obtained with intravascular elastography. Feasibility study in vivo Eur. Heart J., March 1, 2002; 23(5): 405 - 413. [Abstract] [Full Text] [PDF]
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I.-K. Jang, B. E. Bouma, D.-H. Kang, S.-J. Park, S.-W. Park, K.-B. Seung, K.-B. Choi, M. Shishkov, K. Schlendorf, E. Pomerantsev, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound J. Am. Coll. Cardiol., February 20, 2002; 39(4): 604 - 609. [Abstract] [Full Text] [PDF]
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T. W.G. Carrell, K. G. Burnand, G. M.A. Wells, J. M. Clements, and A. Smith Stromelysin-1 (Matrix Metalloproteinase-3) and Tissue Inhibitor of Metalloproteinase-3 Are Overexpressed in the Wall of Abdominal Aortic Aneurysms Circulation, January 29, 2002; 105(4): 477 - 482. [Abstract] [Full Text] [PDF]
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P. N. Seshiah, D. J. Kereiakes, S. S. Vasudevan, N. Lopes, B. Y. Su, N. A. Flavahan, and P. J. Goldschmidt-Clermont Activated Monocytes Induce Smooth Muscle Cell Death: Role of Macrophage Colony-Stimulating Factor and Cell Contact Circulation, January 15, 2002; 105(2): 174 - 180. [Abstract] [Full Text] [PDF]
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P. Fernandez, P. Marco, F. Marin, V. Roldan, and F. Sogorb The role of tissue plasminogen activator on the progression of the coronary disease Eur. Heart J., January 1, 2002; 23(1): 88 - 88. [Full Text] [PDF]
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M. S. Elkind, J. Cheng, B. Boden-Albala, T. Rundek, J. Thomas, H. Chen, L. E. Rabbani, R. L. Sacco, and A. G. Thrift Tumor Necrosis Factor Receptor Levels Are Associated With Carotid Atherosclerosis * Editorial Comment Stroke, January 1, 2002; 33(1): 31 - 38. [Abstract] [Full Text] [PDF]
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Z. Mallat, A. Corbaz, A. Scoazec, S. Besnard, G. Leseche, Y. Chvatchko, and A. Tedgui Expression of Interleukin-18 in Human Atherosclerotic Plaques and Relation to Plaque Instability Circulation, October 2, 2001; 104(14): 1598 - 1603. [Abstract] [Full Text] [PDF]
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M Emdin, C Passino, C Michelassi, F Titta, A L'abbate, L Donato, A Pompella, and A Paolicchi Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction Eur. Heart J., October 1, 2001; 22(19): 1802 - 1807. [Abstract] [PDF]
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Z. Mallat, A. Corbaz, A. Scoazec, P. Graber, S. Alouani, B. Esposito, Y. Humbert, Y. Chvatchko, and A. Tedgui Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Atherosclerotic Lesion Development and Stability Circ. Res., September 28, 2001; 89 (7): e41 - e45. [Abstract] [Full Text] [PDF]
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M. T. Johnstone, R. M. Botnar, A. S. Perez, R. Stewart, W. C. Quist, J. A. Hamilton, and W. J. Manning In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in a Rabbit Model Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1556 - 1560. [Abstract] [Full Text] [PDF]
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H. Sakamoto, M. Aikawa, C. C. Hill, D. Weiss, W. R. Taylor, P. Libby, and R. T. Lee Biomechanical Strain Induces Class A Scavenger Receptor Expression in Human Monocyte/Macrophages and THP-1 Cells : A Potential Mechanism of Increased Atherosclerosis in Hypertension Circulation, July 3, 2001; 104(1): 109 - 114. [Abstract] [Full Text] [PDF]
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M. Takano, K. Mizuno, K. Okamatsu, S. Yokoyama, T. Ohba, and S. Sakai Mechanical and structural characteristics of vulnerable plaques: analysis by coronary angioscopy and intravascular ultrasound J. Am. Coll. Cardiol., July 1, 2001; 38(1): 99 - 104. [Abstract] [Full Text] [PDF]
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V. K BHATIA and D. O HASKARD Markers of inflammation in unstable angina Heart, June 1, 2001; 85(6): 603 - 604. [Full Text]
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M. Leskinen, Y. Wang, D. Leszczynski, K. A. Lindstedt, and P. T. Kovanen Mast Cell Chymase Induces Apoptosis of Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 516 - 522. [Abstract] [Full Text] [PDF]
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S. Sugiyama, Y. Okada, G. K. Sukhova, R. Virmani, J. W. Heinecke, and P. Libby Macrophage Myeloperoxidase Regulation by Granulocyte Macrophage Colony-Stimulating Factor in Human Atherosclerosis and Implications in Acute Coronary Syndromes Am. J. Pathol., March 1, 2001; 158(3): 879 - 891. [Abstract] [Full Text] [PDF]
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S. Peng, W. Guo, J. D. Morrisett, M. T. Johnstone, and J. A. Hamilton Quantification of Cholesteryl Esters in Human and Rabbit Atherosclerotic Plaques by Magic-Angle Spinning 13C-NMR Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2682 - 2688. [Abstract] [Full Text] [PDF]
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Rainer de Martin, M. Hoeth, R. Hofer-Warbinek, and J. A. Schmid The Transcription Factor NF-{kappa}B and the Regulation of Vascular Cell Function Arterioscler Thromb Vasc Biol, November 1, 2000; 20 (11): e83 - e88. [Abstract] [Full Text] [PDF]
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C von Birgelen, W Klinkhart, G S Mintz, H Wieneke, D Baumgart, M Haude, T Bartel, S Sack, J Ge, and R Erbel Size of emptied plaque cavity following spontaneous rupture is related to coronary dimensions, not to the degree of lumen narrowing. A study with intravascular ultrasound in vivo Heart, November 1, 2000; 84(5): 483 - 488. [Abstract] [Full Text]
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K. J. Haley, C. M. Lilly, J.-H. Yang, Y. Feng, S. P. Kennedy, T. G. Turi, J. F. Thompson, G. H. Sukhova, P. Libby, and R. T. Lee Overexpression of Eotaxin and the CCR3 Receptor in Human Atherosclerosis : Using Genomic Technology to Identify a Potential Novel Pathway of Vascular Inflammation Circulation, October 31, 2000; 102(18): 2185 - 2189. [Abstract] [Full Text] [PDF]
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H. Obara, A. Takayanagi, J. Hirahashi, K. Tanaka, G. Wakabayashi, K. Matsumoto, M. Shimazu, N. Shimizu, and M. Kitajima Overexpression of Truncated I{kappa}B{alpha} Induces TNF-{alpha}-Dependent Apoptosis in Human Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, October 1, 2000; 20(10): 2198 - 2204. [Abstract] [Full Text] [PDF]
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F. D. Kolodgie, J. Narula, A. P. Burke, N. Haider, A. Farb, Y. Hui-Liang, J. Smialek, and R. Virmani Localization of Apoptotic Macrophages at the Site of Plaque Rupture in Sudden Coronary Death Am. J. Pathol., October 1, 2000; 157(4): 1259 - 1268. [Abstract] [Full Text] [PDF]
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C. L. de Korte, G. Pasterkamp, A. F. W. van der Steen, H. A. Woutman, and N. Bom Characterization of Plaque Components With Intravascular Ultrasound Elastography in Human Femoral and Coronary Arteries In Vitro Circulation, August 8, 2000; 102(6): 617 - 623. [Abstract] [Full Text] [PDF]
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H. C. McGill Jr, C. A. McMahan, A. W. Zieske, R. E. Tracy, G. T. Malcom, E. E. Herderick, and J. P. Strong Association of Coronary Heart Disease Risk Factors With Microscopic Qualities of Coronary Atherosclerosis in Youth Circulation, July 25, 2000; 102(4): 374 - 379. [Abstract] [Full Text] [PDF]
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U. J. F. Tietge, C. Maugeais, W. Cain, D. Grass, J. M. Glick, F. C. de Beer, and D. J. Rader Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I J. Biol. Chem., March 31, 2000; 275(14): 10077 - 10084. [Abstract] [Full Text] [PDF]
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Z. Mallat, H. Benamer, B. Hugel, J. Benessiano, P. G. Steg, J.-M. Freyssinet, and A. Tedgui Elevated Levels of Shed Membrane Microparticles With Procoagulant Potential in the Peripheral Circulating Blood of Patients With Acute Coronary Syndromes Circulation, February 29, 2000; 101(8): 841 - 843. [Abstract] [Full Text] [PDF]
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M. D. Rekhter, G. W. Hicks, D. W. Brammer, H. Hallak, E. Kindt, J. Chen, W. S. Rosebury, M. K. Anderson, P. J. Kuipers, and M. J. Ryan Hypercholesterolemia Causes Mechanical Weakening of Rabbit Atheroma : Local Collagen Loss as a Prerequisite of Plaque Rupture Circ. Res., January 7, 2000; 86(1): 101 - 108. [Abstract] [Full Text] [PDF]
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Y. Feng, J.-H. Yang, H. Huang, S. P. Kennedy, T. G. Turi, J. F. Thompson, P. Libby, and R. T. Lee Transcriptional Profile of Mechanically Induced Genes in Human Vascular Smooth Muscle Cells Circ. Res., December 3, 1999; 85(12): 1118 - 1123. [Abstract] [Full Text] [PDF]
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Z. Mallat, S. Besnard, M. Duriez, V. Deleuze, F. Emmanuel, M. F. Bureau, F. Soubrier, B. Esposito, H. Duez, C. Fievet, et al. Protective Role of Interleukin-10 in Atherosclerosis Circ. Res., October 15, 1999; 85 (8): e17 - e24. [Abstract] [Full Text] [PDF]
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C. A. Gunnett, D. J. Berg, F. M. Faraci, and G. Feuerstein Vascular Effects of Lipopolysaccharide Are Enhanced in Interleukin-10-Deficient Mice • Editorial Comment Stroke, October 1, 1999; 30(10): 2191 - 2196. [Abstract] [Full Text] [PDF]
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A. B. Zaltsman, S. J. George, and A. C. Newby Increased Secretion of Tissue Inhibitors of Metalloproteinases 1 and 2 From the Aortas of Cholesterol Fed Rabbits Partially Counterbalances Increased Metalloproteinase Activity Arterioscler Thromb Vasc Biol, July 1, 1999; 19(7): 1700 - 1707. [Abstract] [Full Text] [PDF]
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K. R. Coleman, G. A. Braden, M. C. Willingham, and D. C. Sane Vitaxin, a Humanized Monoclonal Antibody to the Vitronectin Receptor ({alpha}vß3), Reduces Neointimal Hyperplasia and Total Vessel Area After Balloon Injury in Hypercholesterolemic Rabbits Circ. Res., June 11, 1999; 84(11): 1268 - 1276. [Abstract] [Full Text] [PDF]
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W. Y. Craig, M. W. Rawstron, C. A. Rundell, E. Robinson, S. E. Poulin, L. M. Neveux, P. M. Nishina, and L. M. Keilson Relationship Between Lipoprotein- and Oxidation-Related Variables and Atheroma Lipid Composition in Subjects Undergoing Coronary Artery Bypass Graft Surgery Arterioscler Thromb Vasc Biol, June 1, 1999; 19(6): 1512 - 1517. [Abstract] [Full Text] [PDF]
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A. J. Moss, R. E. Goldstein, V. J. Marder, C. E. Sparks, D. Oakes, H. Greenberg, H. J. Weiss, W. Zareba, M. W. Brown, C.-S. Liang, et al. Thrombogenic Factors and Recurrent Coronary Events Circulation, May 18, 1999; 99(19): 2517 - 2522. [Abstract] [Full Text] [PDF]
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Z. Mallat, C. Heymes, J. Ohan, E. Faggin, G. Leseche, and A. Tedgui Expression of Interleukin-10 in Advanced Human Atherosclerotic Plaques : Relation to Inducible Nitric Oxide Synthase Expression and Cell Death Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 611 - 616. [Abstract] [Full Text] [PDF]
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A. C Newby and A. B Zaltsman Fibrous cap formation or destruction -- the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation Cardiovasc Res, February 1, 1999; 41(2): 345 - 360. [Abstract] [Full Text] [PDF]
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M. D. Rekhter Collagen synthesis in atherosclerosis: too much and not enough Cardiovasc Res, February 1, 1999; 41(2): 376 - 384. [Abstract] [Full Text] [PDF]
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M. Braun, P. Pietsch, K. Schror, G. Baumann, and S. B. Felix Cellular adhesion molecules on vascular smooth muscle cells Cardiovasc Res, February 1, 1999; 41(2): 395 - 401. [Abstract] [Full Text] [PDF]
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R. Rabbani and E. J. Topol Strategies to achieve coronary arterial plaque stabilization Cardiovasc Res, February 1, 1999; 41(2): 402 - 417. [Abstract] [Full Text] [PDF]
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E. Lutgens, E. D. de Muinck, P. J.E.H.M. Kitslaar, J. H.M. Tordoir, H. J.J. Wellens, and M. J.A.P. Daemen Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques Cardiovasc Res, February 1, 1999; 41(2): 473 - 479. [Abstract] [Full Text] [PDF]
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G. Pasterkamp, A. H. Schoneveld, A. C. van der Wal, D.-J. Hijnen, W. J. A. van Wolveren, S. Plomp, H. L. J. M. Teepen, and C. Borst Inflammation of the Atherosclerotic Cap and Shoulder of the Plaque Is a Common and Locally Observed Feature in Unruptured Plaques of Femoral and Coronary Arteries Arterioscler Thromb Vasc Biol, January 1, 1999; 19(1): 54 - 58. [Abstract] [Full Text] [PDF]
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M. D. Rekhter, G. W. Hicks, D. W. Brammer, C. W. Work, J.-S. Kim, D. Gordon, J. A. Keiser, and M. J. Ryan Animal Model That Mimics Atherosclerotic Plaque Rupture Circ. Res., October 5, 1998; 83(7): 705 - 713. [Abstract] [Full Text] [PDF]
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N. Kume, T. Murase, H. Moriwaki, T. Aoyama, T. Sawamura, T. Masaki, and T. Kita Inducible Expression of Lectin-like Oxidized LDL Receptor-1 in Vascular Endothelial Cells Circ. Res., August 10, 1998; 83(3): 322 - 327. [Abstract] [Full Text] [PDF]
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