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(Circulation. 1995;91:2844-2850.)
© 1995 American Heart Association, Inc.
Articles |
Molecular Bases of the Acute Coronary Syndromes
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Mass.
Correspondence to Peter Libby, MD, Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115.
Key Words: molecular biology • coronary disease
 |
Introduction |
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Top
Introduction
Does the Angiogram Mislead...The acute coronary syndromes, including unstable angina and acute myocardial infarction, currently constitute a major preoccupation of clinical cardiology. This century has witnessed a remarkable evolution in our clinical concepts of these syndromes. Herrick1 described the survival of patients with acute coronary thrombosis early in the century. The introduction of the ECG led to major clinical advances in the definition of acute myocardial infarction during the first half of this century and furnished the basis of modern coronary care.
In the latter half of this century, the advent of coronary arteriography permitted definition in the living patient of coronary stenoses due to atherosclerosis. The introduction of this diagnostic technique allowed the development of rational treatment modalities such as coronary artery bypass surgery and, subsequently, percutaneous transluminal coronary angioplasty. Until recently, it seemed that we had achieved a firm understanding of the pathophysiology of human coronary artery disease and had devised appropriate modes of therapy for its major manifestations. Yet, recent clinical data suggest that we still have much to learn about the pathophysiology of the acute coronary syndromes.
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Does the Angiogram Mislead Us About the Propensity of Plaques to Cause Acute Coronary Syndromes? |
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Bypass surgery and angioplasty aim to restore blood flow to sites beyond hemodynamically significant stenoses in the coronary arteries. These revascularization therapies effectively relieve angina pectoris in many cases (although often not permanently). Quite naturally, the availability of these modalities led the cardiology community to focus on high-grade coronary stenosis, visible by angiography, as the critical issue in coronary heart disease. Much of the basis of contemporary cardiology and cardiac surgery rests on the axiom: the greater the stenosis, the greater the risk of a clinical event such as myocardial infarction or unstable angina pectoris.
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Evolving Concepts of the Pathogenesis of the Acute Coronary Syndromes |
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However, data emerging from clinical and pathological studies over the past decade have occasioned a reassessment of this central dogma of clinical cardiology.2 First, the use of thrombolytic therapy in acute myocardial infarction became widespread in the wake of the GISSI study in 1986.3 Angiographic studies performed after thrombolysis during acute myocardial infarction led to the surprising finding that the atherosclerotic lesions that gave rise to the occlusive thrombus did not cause high-grade stenoses in many cases. Assessment of angiograms obtained before acute myocardial infarctions and those obtained during the infarction corroborated this concept that the lesions most likely to precipitate an infarct-provoking thrombosis often did not appear highly stenotic by angiography.4 5 6 7
Another line of clinical evidence suggested dissociation between the degree of stenosis and coronary events. In the past decade, a number of "regression trials" tested the hypothesis that lipid-lowering regimens would reduce the degree of high-grade coronary stenoses. The angiographic results showed disappointingly minimal effects on established stenotic lesions. Yet, these studies revealed a consistent and resounding decrease in acute clinical coronary events.8 9
Meanwhile, state-of-the-art pathological studies using perfusion fixation of freshly obtained material provided new evidence buttressing the concept that rupture of atherosclerotic plaques precipitates the formation of the occluding thrombus that causes acute myocardial infarction.10 The elegant pathological studies of Davies and colleagues10 11 also sought evidence for plaque disruption in hearts from patients dying of noncardiac causes. They documented evidence for plaque disruption in these patients even without overt symptoms of coronary disease or acute myocardial infarction. These results suggested that not all disruptions of atherosclerotic plaques lead to clinically apparent or symptomatic events. Such subclinical episodes of plaque disruption with local thrombin activation and subsequent healing may indeed represent a major pathway for progression of atherosclerotic lesions.
Taken together, these new results suggest that while angiographically severe coronary artery disease clearly correlates with the propensity to develop or succumb from acute myocardial infarction, the presence of the severe stenoses may merely serve as a marker for the presence of angiographically modest or even inapparent, non–critically stenotic plaques actually more prone to precipitate acute myocardial infarction.
Indeed, pathological studies have shown repeatedly in humans and in experimental animals that over much of its history, growth of an atherosclerotic plaque occurs by outward, abluminal expansion.12 13 14 Hence, most obstructive plaques may pass through a phase that may last many years or even decades of so-called "remodeling" without encroaching on the arterial lumen. Only after the plaque burden approaches half of the luminal area does the plaque usually protrude into the lumen, becoming visible by angiography and capable of impairing flow. It thus appears that high-grade coronary arterial stenoses that can cause angina in the absence of superimposed vasospasm or thrombosis belong to a more advanced or "mature" stage in the life cycle of an atheroma. These recent clinical and pathological studies have focused the attention of those interested in the pathophysiology of the acute coronary syndromes on the plaque itself rather than the lumen as visualized by angiography.
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Characteristics of "Vulnerable Plaque": Primacy of the Integrity of the Atheroma's Fibrous Cap |
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What is it about certain plaques that render them particularly susceptible to disruption and the ensuing acute manifestations such as myocardial infarction or unstable angina? Once again, the pathology of the lesions themselves suggests an answer. Atherosclerotic plaques typically consist of a lipid-rich core in the central portion of the eccentrically thickened intima (Fig 1
). The lipid core
is bounded on its luminal aspect by a fibrous cap, at its edges by the
"shoulder" region, and on its abluminal aspect by the base of the
plaque (area of detail, Fig 1). The central, lipid-rich core of
the
typical lesion contains many lipid-laden macrophage foam cells derived
from blood monocytes. Once resident within the arterial wall, these
cells imbibe lipid, which accounts for their foamy
cytoplasm.15 Such lesional foam cells can produce large
amounts of tissue factor, a powerful procoagulant that potently
stimulates thrombus formation when in contact with
blood.16
|
For this reason, the integrity of the fibrous cap overlying this
lipid-rich core fundamentally determines the stability of an
atherosclerotic plaque. Rupture-prone plaques tend to have thin,
friable fibrous caps.17 18 Plaques not liable to
precipitate acute myocardial events tend to have thicker fibrous caps
that protect the blood compartment in the arterial lumen from
potentially disastrous contact with the underlying thrombogenic lipid
core (Fig 1
).
Biomechanical analyses demonstrate maxima of circumferential stress at sites of plaques prone to rupture.17 19 Thus, mechanical forces concentrate on the fibrous cap, which must resist these high stresses to avoid rupture and the attendant risk of developing an acute coronary event. This stress-laden fibrous cap is all that stands between the blood and the thrombogenic lipid core of the lesion. Recognition of the primacy of the structure of the fibrous cap in determining the clinical activity of a given atherosclerotic lesion led us to study the cellular and molecular bases of the integrity of this critical region of the plaque.
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Vascular Smooth Muscle Cell: Guardian of the Integrity of the Plaque's Fibrous Cap |
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As its name implies, a dense, fibrous extracellular matrix characterizes the plaque's fibrous cap. This extracellular matrix (formerly called connective tissue) contains several well-characterized macromolecules that account for the strength of the fibrous cap. The principal proteinaceous constituents of this extracellular matrix include the interstitial collagens and elastin. Various classes of proteoglycans also contribute to the extracellular matrix of atheroma but presumably contribute less than collagen or elastin to the rupture-resistance of this matrix. Among these macromolecules, collagen occupies an important position because of its abundance in the fibrous cap and its contribution to the structural integrity of this vulnerable "Achilles' heel" region of the plaque.
Collagen comes in many forms. Principally, the interstitial forms of fibrillar collagen concern us in the context of the plaque's fibrous cap. Triple helical coils derived from specific procollagen precursors make up the types I and III collagen found in the fibrils of the plaque. Vascular smooth muscle cells can synthesize and assemble these macromolecules and furnish the bulk of both the collagenous and noncollagenous portions of the extracellular matrix of arteries.
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Evidence for Impaired Collagen Gene Expression at Vulnerable Sites of Human Atheroma |
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For more than a dozen years, our laboratory has studied the role of inflammation in vascular pathobiology. In particular, we have explored the role of cytokines, protein mediators of inflammation and immunity in the pathogenesis of vascular diseases. Data from our laboratory and several others have provided evidence for the presence of various cytokines during different phases of atherogenesis.20 21 22 23 24 25 In view of the importance of the collagenous matrix in determining plaque stability, we set out a number of years ago to investigate whether cytokines or growth factors implicated by us and others in atherosclerosis could regulate the synthesis of the interstitial forms of collagen that govern the integrity of the fibrous cap.
Using standard techniques of biochemistry and molecular biology, we
found that transforming growth factor-ß and platelet-derived growth
factor increased the mRNA and de novo protein synthesis of the
precursors of the interstitial collagens types I and III (Fig
2).26 More notably, we found that a
cytokine known as interferon gamma (IFN-
) markedly decreased the
ability of human smooth muscle cells to express the interstitial
collagen genes both in the basal, unstimulated state and when exposed
to transforming growth factor-ß, the most potent stimulus for
interstitial collagen gene expression known for these cells (Fig
2).
This potent inhibition of interstitial collagen synthesis by human
vascular smooth muscle cells did not result from a nonspecific or toxic
effect of IFN-, since these cells remained viable and this cytokine
selectively increased expression of another specific gene (HLA-DR, see
below).
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How might this observation relate to the human atherosclerotic plaque?
Among the cells found in human atherosclerotic plaques, only T
lymphocytes can elaborate the cytokine IFN-. Work from Hansson's
laboratory some years ago provided evidence for IFN- production by
chronically activated T cells within human atheroma.27
Exciting recent data from van der Wal et al28 in Becker's
laboratory provide further evidence connecting activated T cells and
their products to plaque rupture. These investigators painstakingly
studied the histology of 20 culprit lesions that provoked fatal acute
myocardial infarctions. They found that T cells and macrophages
predominated at sites of plaque disruption (frank rupture or
superficial erosion of the fibrous cap). These workers further noted
that neighboring smooth muscle cells and leukocytes expressed high
levels of a transplantation antigen known as HLA-DR
, a finding they
took to be an indicator of a state of "activation" of the smooth
muscle cells.
How could expression of a transplantation antigen by smooth muscle
cells possibly pertain to stability of atherosclerotic plaques? We
became interested some time ago in the ability of smooth muscle cells
to express transplantation antigens in the context of understanding the
pathophysiology of accelerated coronary atherosclerosis in transplanted
hearts.29 This interest led us to explore the regulation
of expression by smooth muscle cells of these molecules, which are
important in the immune response. Of a wide variety of cytokines
tested, only IFN- could induce the expression HLA-DR in cultures
of human vascular smooth muscle cells.30 Therefore, the
finding of cells bearing this marker of activation indicates the
presence of IFN- at the very sites of fatal plaque disruptions in
humans. Further observations strongly support this concept. Rekhter and
colleagues31 colocalized T lymphocytes with regions of
collagen gene expression within human atherosclerotic lesions. Using
rigorous morphometric analysis of histological sections of the
human atheroma, they found an inverse correlation between the presence
of T lymphocytes and interstitial collagen protein and mRNA.
Taken together, these results concordantly suggest that chronic immune
stimulation within atheroma leads to elaboration of IFN- from T
cells, inhibiting collagen synthesis in vulnerable regions of the
plaque's fibrous cap. This mechanism provides a molecular explanation
for impaired maintenance and repair of the collagenous meshwork in
vulnerable plaques, rendering it weak and prone to rupture in the
critical region of the plaque. Intact ability to synthesize collagen
may sustain the ability of the fibrous cap to resist the concentration
of mechanical forces in stable plaques.
In addition to inhibiting collagen gene expression by human smooth
muscle cells, IFN- can inhibit smooth muscle cell
proliferation.32 33 This cytokine can also contribute
to
activating the program of cell death, or apoptosis, in human vascular
smooth muscle cells (Y-j. Geng and P. Libby, unpublished observations).
These findings may help explain the relative paucity of smooth muscle
cells in vulnerable regions of human atherosclerotic plaques. Moreover,
IFN- can activate macrophage functions related to plaque
vulnerability, including some of those described below. Curiously,
proliferation of smooth muscle cells has dominated our thinking about
the pathogenesis of atherosclerosis for decades. Smooth muscle cell
growth may indeed contribute importantly to earlier phases of lesion
development. Yet the present data, summarized above, suggested that
the aspects of the biology of atheroma that actually lead to acute
clinical manifestations depend on impaired smooth muscle cell growth
and matrix elaboration rather than the contrary. This concept warrants
consideration by those embarking on therapeutic quests seeking
inhibitors of smooth muscle cell proliferation as treatments for
atherosclerosis on the basis of relatively short-term experiments using
simple animal models. Inhibition of smooth muscle cell proliferation in
human patients might produce the undesired effect of destabilizing
vulnerable regions of atherosclerotic plaques by the mechanisms
described above.
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Cells Within Atherosclerotic Plaques Can Inducibly Express Genes Encoding Matrix-Degrading Enzymes |
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In addition to impaired synthesis of collagen, accelerated degradation of collagen and other matrix components could contribute to weakening of the fibrous cap. The macromolecules that form the arterial extracellular matrix generally exhibit considerable metabolic stability. Collagen usually turns over quite slowly in arterial and other tissues. The triple helical structure of fibrillar collagens strongly resists attack by most types of proteolytic enzymes. However, certain enzymes specialize in catabolism of the extracellular matrix. These enzymes doubtless function importantly in normal development, morphogenesis, and wound healing by allowing cells to migrate through the omnipresent extracellular matrix of tissues. They also may contribute to various pathological states such as joint destruction in rheumatoid arthritis or metastasis of malignant cells.
In particular, members of a superfamily of such enzymes known as the matrix metalloproteinases merit consideration in this regard. In contrast to the intracellular proteolytic enzymes found in organelles called lysosomes, the matrix metalloproteinases act extracellularly and at physiological pH. The matrix metalloproteinase superfamily includes interstitial collagenase, an enzyme specialized in the initial cleavage of the usually protease-resistant fibrillar collagens that confer strength upon the fibrous cap of the atheroma. Other matrix metalloproteinase family members (the gelatinases) catalyze further breakdown of collagen fragments. Stromelysins can activate other members of the matrix metalloproteinase family and can degrade a broad spectrum of matrix constituents, including the protein backbones of proteoglycan molecules. Stromelysin and one of the gelatinases (gelatinase B, or 92-kD gelatinase) can also break down elastin, an additional structurally important component of the vascular extracellular matrix.
Two points merit emphasis in consideration of the potential roles of the matrix metalloproteinases in disruption of atherosclerotic plaques. First, these enzymes require activation from proenzyme precursors to attain enzymatic activity. This type of tight control resembles that found in other critical biological regulatory cascades such as blood coagulation, fibrinolysis, and complement. Also, reminiscent of other protease cascades involved in regulation of key biological processes, ubiquitous inhibitors known as tissue inhibitors of metalloproteinases (TIMPs) hold the activity of these enzymes in check under usual circumstances.
In their basal state, human vascular smooth muscle cells express both major isoforms of TIMPs (TIMP 1 and TIMP 2) and one form of gelatinase (gelatinase A, or 72-kD gelatinase).34 Biochemical experiments indicate that this constitutively expressed gelatinase probably exists as a complex with its corresponding inhibitor, TIMP 2, rendering it inactive under normal conditions in vivo. Exposure to inflammatory cytokines such as interleukin-1 or tumor necrosis factor induces smooth muscle cells to express interstitial collagenase, a form of gelatinase not expressed in the basal state (gelatinase B, the form of gelatinase that also exhibits considerable elastolytic activity), and stromelysin.34 Treatment with these cytokines does not alter the expression of TIMPs by these cells. In this manner, cytokines known to localize in atherosclerotic lesions can produce a net increase in the capacity of human smooth muscle cells to degrade constituents of the arterial extracellular matrix.
However, as previously noted, regions of the plaque's fibrous cap
particularly prone to disruption contain relatively few smooth muscle
cells but abundant macrophages and T cells.35 36 For
this
reason, we tested whether macrophage-derived foam cells can
express these matrix-degrading enzymes. Our experimental strategy
involved isolation of lipid-laden macrophages from atherosclerotic
lesions produced experimentally by diet and balloon injury in the
rabbit aorta. Such lesion-derived foam cells expressed stromelysin and
interstitial collagenase both in situ and in vitro. In
contrast, alveolar macrophages from the same animals, exposed to the
same degree of hyperlipidemia, did not display autonomous expression of
these matrix metalloproteinases.37 What activates these
macrophage foam cells to synthesize these matrix-degrading proteinases?
Likely candidates include locally acting cytokines such as IFN-,
tumor necrosis factor, interleukin-1, or macrophage colony–stimulating
factor. Human atherosclerotic plaques can contain each of these
candidate stimuli of matrix metalloproteinase expression by lesional
foam cells.
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Evidence for Increased Degradation of the Extracellular Matrix in Vulnerable Regions of Human Atherosclerotic Plaque |
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To extend our in vitro and animal experiments to the human situation, we studied a number of human atherosclerotic plaques and uninvolved arteries. Just as in the culture dish, smooth muscle cells in the nonatherosclerotic arteries express TIMPs 1 and 2 and gelatinase A (as already noted, probably in an inactive complex with its inhibitor TIMP-2). In human atherosclerotic plaques, however, smooth muscle cells, T cells, and macrophages all expressed interstitial collagenase, gelatinase B, and stromelysin.38 Henney and coworkers39 had previously shown evidence for stromelysin mRNA expression by cells within atheroma as well. Moreover, the endothelial cells overlying atheroma, but not normal vessels, contained interstitial collagenase. In addition, the endothelial cells of the plaque's rich microvasculature expressed this metalloproteinase, which may facilitate new capillary penetration through the dense extracellular matrix of the complicated plaque.
However, the mere presence of immunostainable metalloproteinases does not provide assurance that they exist in an active form. The antibodies available do not distinguish the activated forms of these enzymes from their inactive proenzyme or zymogen forms. Moreover, as already noted, the widely distributed tissue inhibitors of metalloproteinases could neutralize any of these enzymes that might become activated in the plaque and prevent their proteolytic action.
We tested for the presence of a net excess in matrix-degrading activity
by laying frozen sections of human atherosclerotic plaques upon films
of suitable substrates and evaluating lysis of these substrates by
microscopy. This in situ zymographic technique revealed such activity,
particularly in the shoulder region of a series of atherosclerotic
plaques.38 These results actually demonstrated net excess
of matrix-degrading activity in vulnerable regions of human
atherosclerotic plaques, supporting the concept that excessive matrix
degradation may contribute to the lability of atheroma (Fig 3).
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Other Contributors to the Unstable Coronary Syndromes |
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The foregoing discussion has focused on the integrity of the extracellular matrix of the plaque's fibrotic cap as a key to the understanding of the unstable coronary syndromes. Although these mechanisms probably play a prominent role in the pathophysiology of plaque rupture, other factors may contribute to the unstable coronary syndromes as well. Much recent research has established impaired responsiveness to endothelium-dependent vasodilators in diseased portions of human coronary arteries.40 Such findings suggest a propensity to vasospasm that may contribute to impaired flow in these vessels, particularly at sites of underlying stenoses.
Also implicit in the above discussion, the precipitating event in most
cases of acute myocardial infarction involves thrombotic occlusion of
the vessel, usually at sites of plaque disruption. Indeed, thrombus
formation figures prominently in our current concepts of both acute
myocardial infarction and unstable angina. In this regard, the
molecular bases of the acute coronary syndromes involve a critical
intersection of three distinct but interrelated
protease–protease-inhibitor cascades: thrombosis, fibrinolysis, and
the matrix-degrading proteases (Fig 4). By way of
illustration of the interconnections between these cascades, consider
that the fibrinolytic enzyme plasmin can cleave interstitial
collagenase from its latent zymogen to its active form.
Incidentally, this point suggests that administration of plasminogen
activators during acute myocardial infarction might actually promote
destabilization of atheroma by promoting collagen degradation.
|
As noted above, atherosclerotic lesions usually contain abundant plexi of microvessels.41 42 These neovascular channels may themselves be prone to rupture within the plaque, much as the neovessels within the diabetic retina tend to form microaneurysms and hemorrhage. Some episodes of sudden plaque expansion may result from intraplaque hemorrhage due to rupture of the microvessels rather than a disruption of the fibrous cap of the plaque itself.
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Mechanisms of Stabilization of the Atherosclerotic Plaque: A New Therapeutic Target? |
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The above discussion has summarized elements of a new understanding of the pathophysiology of the acute coronary syndromes based on episodes of plaque disruption rather than gradual progression to complete occlusion of fixed coronary stenoses. As noted above, bypass surgery or transluminal angioplasty provide rational and often effective therapies for these fixed, high-grade stenoses. However, these treatments do not address the nonstenotic but vulnerable plaque. It is of interest in this regard that despite the well-accepted benefit of coronary bypass surgery on anginal symptoms, this treatment aimed at severe stenoses does not prevent myocardial infarction.43 To reduce the risk of acute myocardial infarction, one must stabilize lesions to prevent their disruption, particularly the less stenotic plaques.44
How might one achieve such a goal? The results of recent lipid-lowering
trials provide a hint. The reductions in clinical events without
substantial change in the degree of luminal stenosis could reflect a
stabilization of the non–critically stenotic
lesions.8 9
This stabilization might result from reducing the inflammatory stimuli
provided by modified lipoproteins that could contribute to activation
of lesional foam cells and T lymphocytes as described above (Figs
1 and 3). Accumulating physiological evidence in
humans demonstrates that
lipid-lowering and/or antioxidant therapy can improve the vasomotor
response to endothelium-dependent vasodilators such as
acetylcholine.45 46 A reduction in inflammation
induced by
modified lipids might contribute to this salutory effect of
pharmacological lipid lowering.
The recent demonstration that cholesterol lowering with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor decreases cardiac and total mortality under conditions not expected to reduce substantially preexisting high-grade stenoses illustrates the potential of an intervention that could yield plaque stabilization.47 We eagerly await the results of other studies that will include patients with lower cholesterol levels more commonly encountered in our coronary disease populations, and the results of primary prevention studies will also prove quite interesting in this connection.
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Conclusions |
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Atherosclerosis shares many characteristics of a chronic inflammatory process. Many stimuli may incite this ongoing reaction. As alluded to above, many current data suggest that lipoproteins or their derivatives (eg, oxidized lipoproteins) contribute to smoldering inflammation in atherosclerotic plaques.48 Other potential inciting stimuli may include infectious agents and autoantigens such as heat-shock proteins, among other possible activators of T cells.49 The activated T cell secretes IFN-
, which may
impair collagen synthesis. Macrophages and smooth muscle cells
activated by inflammatory mediators such as the cytokines can elaborate
enzymes that weaken the connective tissue framework of the plaque's
fibrous cap. Reduction of inflammation should render atherosclerotic
plaques more stable. The present observations even provide a
potential cellular and molecular mechanism for the marked reduction in
acute coronary events observed with lipid-lowering therapies, as
discussed above. In any case, the foregoing discussion illustrates how new clinical observations have caused us to reevaluate our traditional concepts of the pathogenesis of the acute coronary syndromes. New insight from clinical and pathological studies reviewed above highlighted the importance of probing the biological basis of the unstable plaque to understand the mechanisms that underlie the acute manifestations of atherosclerosis that occupy a large portion of the efforts of modern cardiologists. The results of such clinical investigations inspired basic studies of the cellular and molecular mechanisms of the acute coronary syndromes such as those described here. The new insights from these "bedside to bench" studies should in turn hasten development of strategies aimed at plaque stabilization. The ultimate goal of this basic research is to return from the bench to the bedside with novel therapies and new understanding to help prevent the development of unstable coronary disease in our patients.
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Acknowledgments |
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The studies from our laboratories described in this paper were supported by grants from the National Heart, Lung, and Blood Institute and the American Heart Association. We thank our colleagues E.P. Amento, G.B. Friedman, Z.S. Galis, H. Palmer, G.K. Sukhova, E. Unemori, and S.J.C. Warner, who contributed to the experiments described.
Received February 13, 1995; accepted March 5, 1995.
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References |
|---|
1. Herrick J. Certain clinical features of sudden obstruction of the coronary arteries. Trans Am Assoc Physicians. 1912;27:100-116.
2.
Fuster V, Lewis A. Conner Memorial Lecture.
Mechanisms leading to myocardial infarction: insights from studies of
vascular biology. Circulation. 1994;90:2126-2146. Review.
3. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-402. [Medline] [Order article via Infotrieve]
4.
Hackett D, Davies G, Maseri A. Pre-existing
coronary stenoses in patients with first myocardial infarction are not
necessarily severe. Eur Heart J. 1988;9:1317-1323.
5. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12:56-62. [Abstract]
6. Nobuyoshi M, Tanaka M, Nosaka H, Kimura T, Yokoi H, Hamasaki N, Kim K, Shindo T, Kimura K. Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol. 1991;18:904-910.[Abstract]
7. Giroud D, Li JMM, Urban P, Meier B, Rutishauer W. Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J Cardiol. 1992;69:729-732. See comments. [Medline] [Order article via Infotrieve]
8.
Blankenhorn DH, Hodis HN. Arterial imaging and
atherosclerosis reversal. Arterioscler
Thromb. 1994;14:177-192.
9.
Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid
lowering and plaque regression: new insights into prevention of plaque
disruption and clinical events in coronary disease.
Circulation. 1993;87:1781-1791. Review.
10.
Davies MJ, Thomas AC. Plaque fissuring: the
cause of acute myocardial infarction, sudden ischemic death, and
crescendo angina. Br Heart J. 1985;53:363-373.
11. Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation. 1990;82(suppl II):II-38-II-46.
12.
Clarkson TB, Prichard RW, Morgan TM, Petrick GS, Klein
KP. Remodeling of coronary arteries in human and nonhuman
primates. JAMA. 1994;271:289-294. See comments.
13. Glagov S, Weisenberg E, Zarins C, Stankunavicius R, Kolletis G. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:371-375.
14. Armstrong ML, Megan MB, Heistad DD. Adaptive responses of the artery wall as human atherosclerosis develops. In: Glagov S, Newman WP, Schaffer SA, eds. Pathobiology of the Human Atherosclerotic Plaque. New York, NY: Springer-Verlag; 1989:469-480.
15. Libby P, Clinton SK. The role of macrophages in atherogenesis. Curr Opin Lipidol. 1993;4:355-363.
16.
Wilcox JN, Smith KM, Schwartz SM, Gordon D.
Localization of tissue factor in the normal vessel wall and in
the atherosclerotic plaque. Proc Natl Acad Sci
U S A. 1989;86:2839-2843.
17. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941-944. See comments. [Medline] [Order article via Infotrieve]
18.
Loree HM, Kamm RD, Stringfellow RG, Lee RT.
Effects of fibrous cap thickness on peak circumferential stress
in model atherosclerotic vessels. Circ
Res. 1992;71:850-858.
19.
Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT.
Distribution of circumferential stress in ruptured and stable
atherosclerotic lesions: a structural analysis with histopathologic
correlation. Circulation. 1993;87:1179-1187.
20. Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990;65:297-302. [Medline] [Order article via Infotrieve]
21. Fleet JC, Clinton SK, Salomon RN, Loppnow H, Libby P. Atherogenic diets enhance endotoxin-stimulated interleukin-1 and tumor necrosis factor gene expression in rabbit aortae. J Nutr. 1992;122:294-305.
22. Moyer C, Sajuthi D, Tulli H, Williams K. Synthesis of IL-1 alpha and beta in atherosclerosis. Am J Pathol. 1991;138:951-960. [Abstract]
23. Rosenfeld M, Ylä-Herttuala S, Lipton B, Ord V, Witztum J, Steinberg D. Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans. Am J Pathol. 1992;140:291-300. [Abstract]
24. Clinton S, Underwood R, Sherman M, Kufe D, Libby P. Macrophage-colony stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol. 1992;140:301-316. [Abstract]
25. Nelken N, Coughlin S, Gordon D, Wilcox J. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991;88:1121-1127.
26.
Amento EP, Ehsani N, Palmer H, Libby P.
Cytokines positively and negatively regulate interstitial
collagen gene expression in human vascular smooth muscle cells.
Arterioscler Thromb. 1991;11:1223-1230.
27. Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989;135:169-175. [Abstract]
28.
van der Wal AC, Becker AE, van der Loos CM, Das PK.
Site of intimal rupture or erosion of thrombosed coronary
atherosclerotic plaques is characterized by an inflammatory process
irrespective of the dominant plaque morphology.
Circulation. 1994;89:36-44.
29. Salomon RN, Hughes CCW, Schoen FJ, Payne DD, Pober JS, Libby P. Human coronary transplantation-associated arteriosclerosis: evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol. 1991;138:791-798. [Abstract]
30.
Warner SJC, Friedman GB, Libby P. Regulation of
major histocompatibility gene expression in cultured human vascular
smooth muscle cells. Arteriosclerosis. 1989;9:279-288.
31. Rekhter M, Zhang K, Narayanan A, Phan S, Schork M, Gordon D. Type I collagen gene expression in human atherosclerosis: localization to specific plaque regions. Am J Pathol. 1993;143:1634-1648. [Abstract]
32.
Hansson GK, Jonasson L, Holm J, Clowes MK, Clowes A.
Gamma interferon regulates vascular smooth muscle proliferation
and Ia expression in vivo and in vitro. Circ
Res. 1988;63:712-719.
33. Warner SJC, Friedman GB, Libby P. Immune interferon inhibits proliferation and induces 2'-5'-oligoadenylate synthetase gene expression in human vascular smooth muscle cells. J Clin Invest. 1989;83:1174-1182.
34.
Galis Z, Muszynski M, Sukhova G, Simon-Morrisey E,
Unemori E, Lark M, Amento E, Libby P. Cytokine-stimulated human
vascular smooth muscle cells synthesize a complement of enzymes
required for extracellular matrix digestion.
Circ Res. 1994;75:181-189.
35.
Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J.
Risk of thrombosis in human atherosclerotic plaques: role of
extracellular lipid, macrophage, and smooth muscle cell
content. Br Heart J. 1993;69:377-381.
36.
Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V,
Fallon JT. Macrophage infiltration in acute coronary syndromes:
implications for plaque rupture.
Circulation. 1994;90:775-778.
37.
Galis Z, Sukhova G, Kranzhöfer R, Clark S, Libby
P. Macrophage foam cells from experimental atheroma
constitutively produce matrix-degrading proteinases. Proc
Natl Acad Sci U S A. 1995;92:402-406.
38. Galis Z, Sukhova G, Lark M, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493-2503.
39.
Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R,
Murphy G, Humphries S. Localization of stromelysin gene
expression in atherosclerotic plaques by in situ hybridization.
Proc Natl Acad Sci U S A. 1991;88:8154-8158.
40. Meredith I, Yeung A, Weidinger F, Anderson T, Uehata A, Ryan T, Selwyn A, Ganz P. Role of impaired endothelium-dependent vasodilatation in ischemic manifestations of coronary artery disease. Circulation. 1993;87(suppl V):V-56-V-66.
41. Barger A, Beeuwkes IR, Lainey L, Silverman K. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. N Engl J Med. 1984;310:175-177. [Medline] [Order article via Infotrieve]
42. Brogi E, Winkles J, Underwood R, Clinton S, Alberts G, Libby P. Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and non-atherosclerotic arteries: association of acidic FGF with plaque microvessels and macrophages. J Clin Invest. 1993;92:2408-2418.
43. Hillis L. Coronary artery bypass surgery: risks and benefits and unrealistic expectations. J Invest Med. 1995;43:17-27. [Medline] [Order article via Infotrieve]
44. MacIsaac AI, Thomas JD, Topol EJ. Toward the quiescent coronary plaque. J Am Coll Cardiol. 1993;22:1228-1241. Review. [Abstract]
45.
Anderson T, Meredith I, Yeung A, Frei B, Selwyn A, Ganz
P. The effect of cholesterol lowering and antioxidant therapy on
endothelium-dependent coronary vasomotion.
N Engl J Med. 1995;332:488-493.
46.
Treasure C, Klein J, Weintraub W, Talley J, Stillabower
M, Kosinski A, Zhang J, Bocuzzi S, Cedarholm J, Alexander R.
Beneficial effects of cholesterol-lowering therapy on the
coronary endothelium in patients with coronary artery disease.
N Engl J Med. 1995;332:481-487.
47. Group SSSS. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. [Medline] [Order article via Infotrieve]
48. Berliner J, Navab M, Fogelman A, Frank J, Demer L, Edwards P, Watson A, Lusis A. Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics. Circulation. In press.
49. Libby P. Inflammatory and immune mechanisms in atherogenesis. In: Leaf A, Weber PC, eds. Atherosclerosis Reviews. New York, NY: Raven Press; 1990:79-89.
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|
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|
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|
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|
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|
|
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|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 P. Libby Inflammation and cardiovascular disease mechanisms Am. J. Clinical Nutrition, February 1, 2006; 83(2): 456S - 460S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 B. Barutcuoglu, A. E. Bozdemir, D. Dereli, Z. Parildar, M. I. Mutaf, D. Ozmen, and O. Bayindir Increased Serum Neopterin Levels in Women with Polycystic Ovary Syndrome Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 267 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sdringola, C. Loghin, F. Boccalandro, and K. L. Gould Mechanisms of Progression and Regression of Coronary Artery Disease by PET Related to Treatment Intensity and Clinical Events at Long-Term Follow-up J. Nucl. Med., January 1, 2006; 47(1): 59 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 E. Pearce, D.-A. Tregouet, A. Samnegard, A. R. Morgan, C. Cox, A. Hamsten, P. Eriksson, and S. Ye Haplotype Effect of the Matrix Metalloproteinase-1 Gene on Risk of Myocardial Infarction Circ. Res., November 11, 2005; 97(10): 1070 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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Y. Michowitz, E. Goldstein, A. Roth, A. Afek, A. Abashidze, Y. Ben Gal, G. Keren, and J. George The involvement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in atherosclerosis J. Am. Coll. Cardiol., April 5, 2005; 45(7): 1018 - 1024. [Abstract] [Full Text] [PDF]
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 B. G. Brown and J. Crowley Is There Any Hope for Vitamin E? JAMA, March 16, 2005; 293(11): 1387 - 1390. [Full Text] [PDF]
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R. L. Raffai, S. M. Loeb, and K. H. Weisgraber Apolipoprotein E Promotes the Regression of Atherosclerosis Independently of Lowering Plasma Cholesterol Levels Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 436 - 441. [Abstract] [Full Text] [PDF]
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C. Heeschen, S. Dimmeler, C. W. Hamm, S. Fichtlscherer, M. L. Simoons, A. M. Zeiher, and CAPTURE Study Investigators Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: Comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis J. Am. Coll. Cardiol., January 18, 2005; 45(2): 229 - 237. [Abstract] [Full Text] [PDF]
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J. A Vita Polyphenols and cardiovascular disease: effects on endothelial and platelet function Am. J. Clinical Nutrition, January 1, 2005; 81(1): 292S - 297S. [Abstract] [Full Text] [PDF]
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B Meier Plaque sealing by coronary angioplasty Heart, December 1, 2004; 90(12): 1395 - 1398. [Full Text] [PDF]
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R. Deo, A. Khera, D. K. McGuire, S. A. Murphy, J. de P. Meo Neto, D. A. Morrow, and J. A. de Lemos Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1812 - 1818. [Abstract] [Full Text] [PDF]
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P. L. Weissberg Noninvasive Imaging of Atherosclerosis: The Biology Behind the Pictures J. Nucl. Med., November 1, 2004; 45(11): 1794 - 1795. [Full Text] [PDF]
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J. R. Davies, J. H. Rudd, and P. L. Weissberg Molecular and Metabolic Imaging of Atherosclerosis J. Nucl. Med., November 1, 2004; 45(11): 1898 - 1907. [Abstract] [Full Text] [PDF]
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Y. Fukumoto, J.-o Deguchi, P. Libby, E. Rabkin-Aikawa, Y. Sakata, M. T. Chin, C. C. Hill, P. R. Lawler, N. Varo, F. J. Schoen, et al. Genetically Determined Resistance to Collagenase Action Augments Interstitial Collagen Accumulation in Atherosclerotic Plaques Circulation, October 5, 2004; 110(14): 1953 - 1959. [Abstract] [Full Text] [PDF]
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 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
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T Ishikawa, K Hatakeyama, T Imamura, K Ito, S Hara, H Date, Y Shibata, Y Hikichi, Y Asada, and T Eto Increased adrenomedullin immunoreactivity and mRNA expression in coronary plaques obtained from patients with unstable angina Heart, October 1, 2004; 90(10): 1206 - 1210. [Abstract] [Full Text] [PDF]
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M. L. Rossi, N. Marziliano, P. A. Merlini, E. Bramucci, U. Canosi, G. Belli, D. Z. Parenti, P. M. Mannucci, and D. Ardissino Different Quantitative Apoptotic Traits in Coronary Atherosclerotic Plaques From Patients With Stable Angina Pectoris and Acute Coronary Syndromes Circulation, September 28, 2004; 110(13): 1767 - 1773. [Abstract] [Full Text] [PDF]
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E. Zouridakis, P. Avanzas, R. Arroyo-Espliguero, S. Fredericks, and J. C. Kaski Markers of Inflammation and Rapid Coronary Artery Disease Progression in Patients With Stable Angina Pectoris Circulation, September 28, 2004; 110(13): 1747 - 1753. [Abstract] [Full Text] [PDF]
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K. Edfeldt, A. M Bennet, P. Eriksson, J. Frostegard, B. Wiman, A. Hamsten, G. K Hansson, U. d. Faire, and Z.-q. Yan Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction Eur. Heart J., August 2, 2004; 25(16): 1447 - 1453. [Abstract] [Full Text] [PDF]
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D. J. Schneider, M. Hayes, M. Wadsworth, H. Taatjes, M. Rincon, D. J. Taatjes, and B. E. Sobel Attenuation of Neointimal Vascular Smooth Muscle Cellularity in Atheroma by Plasminogen Activator Inhibitor Type 1 (PAI-1) J. Histochem. Cytochem., August 1, 2004; 52(8): 1091 - 1099. [Abstract] [Full Text] [PDF]
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P Avanzas, R Arroyo-Espliguero, J Cosin-Sales, G Aldama, C Pizzi, J Quiles, and J C Kaski Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes Heart, August 1, 2004; 90(8): 847 - 852. [Abstract] [Full Text] [PDF]
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J. Liu, G. K. Sukhova, J.-S. Sun, W.-H. Xu, P. Libby, and G.-P. Shi Lysosomal Cysteine Proteases in Atherosclerosis Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1359 - 1366. [Abstract] [Full Text] [PDF]
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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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S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, W. J. Sasiela, M. Szarek, P. Ganz, P. Libby, and for the Myocardial Ischemia Reduction with Aggress Effect of Atorvastatin on Risk of Recurrent Cardiovascular Events After an Acute Coronary Syndrome Associated With High Soluble CD40 Ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Circulation, July 27, 2004; 110(4): 386 - 391. [Abstract] [Full Text] [PDF]
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B. Schieffer, C. Bunte, J. Witte, K. Hoeper, R. H. Boger, E. Schwedhelm, and H. Drexler Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease J. Am. Coll. Cardiol., July 21, 2004; 44(2): 362 - 368. [Abstract] [Full Text] [PDF]
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 M. G. Netea, B. J. Kullberg, L. E. H. Jacobs, T. J. G. Verver-Jansen, J. van der Ven-Jongekrijg, J. M. D. Galama, A. F. H. Stalenhoef, C. A. Dinarello, and J. W. M. Van der Meer Chlamydia pneumoniae Stimulates IFN-{gamma} Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release J. Immunol., July 15, 2004; 173(2): 1477 - 1482. [Abstract] [Full Text] [PDF]
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 M. R. Dashwood, R. Anand, A. Loesch, and D. S.R. Souza Hypothesis: A Potential Role for the Vasa Vasorum in the Maintenance of Vein Graft Patency Angiology, July 1, 2004; 55(4): 385 - 395. [Abstract] [PDF]
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M. Ogawa, S. Ishino, T. Mukai, D. Asano, N. Teramoto, H. Watabe, N. Kudomi, M. Shiomi, Y. Magata, H. Iida, et al. 18F-FDG Accumulation in Atherosclerotic Plaques: Immunohistochemical and PET Imaging Study J. Nucl. Med., July 1, 2004; 45(7): 1245 - 1250. [Abstract] [Full Text] [PDF]
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S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]
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J. A. Schaar, E. Regar, F. Mastik, E. P. McFadden, F. Saia, C. Disco, C. L. de Korte, P. J. de Feyter, A. F.W. van der Steen, and P. W. Serruys Incidence of High-Strain Patterns in Human Coronary Arteries: Assessment With Three-Dimensional Intravascular Palpography and Correlation With Clinical Presentation Circulation, June 8, 2004; 109(22): 2716 - 2719. [Abstract] [Full Text] [PDF]
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 A. R. Morgan, K. Rerkasem, P. J. Gallagher, B. Zhang, G. E. Morris, P. C. Calder, R. F. Grimble, P. Eriksson, W. L. McPheat, C. P. Shearman, et al. Differences in Matrix Metalloproteinase-1 and Matrix Metalloproteinase-12 Transcript Levels Among Carotid Atherosclerotic Plaques With Different Histopathological Characteristics Stroke, June 1, 2004; 35(6): 1310 - 1315. [Abstract] [Full Text] [PDF]
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