Mechanisms of plaque vulnerability and rupture
Prediman K. Shah, MD, FACC*,*
* Division of Cardiology and Atherosclerosis Research Center, Burns and Allen Research Institute and Department of Medicine, Cedars Sinai Medical Center and UCLA School of Medicine, Los Angeles, California, USA
Manuscript received May 7, 2002;
revised manuscript received October 17, 2002,
accepted October 31, 2002.
*
Reprint requests and correspondence: Dr. Prediman K. Shah, Director, Division of Cardiology and Atherosclerosis Research Center, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Room 5347, Los Angeles, California 90048, USA.
shahp{at}cshs.org
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Abstract
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Rupture of atherosclerotic plaque has been identified as the proximate event in the majority of cases of acute ischemic syndromes. Plaque rupture exposes thrombogenic components of the plaque, activating the clotting cascade and promoting thrombus formation. Future culprit lesions are difficult to identify, however, and angiographic assessment of stenosis severity is prone to underestimation. Compared with plaques that cause severe luminal stenosis, vulnerable plaques may cause relatively minor stenosis, although they account for more cases of rupture and thrombosis. Such unstable, vulnerable plaques may be associated with outward remodeling of the vessel. Because severely stenotic plaques are more likely to stimulate collateral circulation to the post-stenotic segment, plaque rupture and thrombosis at such sites may be clinically silent. Characteristic histomorphologic features of vulnerable plaques include a high lipid content, increased numbers of inflammatory cells, and extensive adventitial and intimal neovascularity. The fibrous cap of an atherosclerotic plaque may become thin and rupture as a result of the depletion of matrix components through the activation of enzymes, such as matrix-degrading proteinases and cystcine and aspartate proteases, and through the reduction in the number of smooth muscle cells. Activated T cells may also inhibit matrix synthesis through the production of interferon-gamma. A number of triggers of plaque rupture have been identified. Also, some thrombi may occur without rupture of the fibrous cap. Reducing the lipid component and inflammation in atherosclerotic plaques may help reduce the risk of plaque rupture. This may account for the clinical benefit of risk-factor reduction gained from changes in lifestyle and from drug therapy.
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Abbreviations and Acronyms
| | HDL | = high-density lipoprotein | | MI | = myocardial infarction | | MMP | = matrix-degrading metalloproteinase | | PA | = plasminogen activator | | SMC | = smooth muscle cell | | TIMP | = tissue inhibitor of metalloproteinase |
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Atherosclerotic cardiovascular disease is the leading cause of death for both men and women in the U.S. and much of the western world. Atherosclerosis is responsible for coronary heart disease, the majority of strokes, and limb ischemia. Although luminal narrowing by an atherosclerotic plaque and exaggerated or anomalous vasoconstriction contribute to some of the clinical manifestations of atherosclerotic arterial disease, it is the superimposition of an arterial thrombus over an underlying disrupted plaque that causes the most acute and serious clinical manifestations of this disease. Coronary thrombosis, therefore, is responsible for the vast majority of acute ischemic syndromes: unstable angina, acute myocardial infarction (MI), and sudden death (15).
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Plaque rupture: the basis for coronary thrombosis in acute ischemia
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A causal role for coronary thrombosis superimposed on an atherosclerotic plaque in acute MI was first suggested around the early 1900s. A substantial body of data derived from angiography, surgical exploration, angioscopy, biochemical markers, and autopsy studies in the late 1970s and early 1980s provided compelling evidence to support the concept that coronary thrombosis was the proximate cause for abrupt coronary occlusion leading to acute MI, unstable angina, and many cases of sudden cardiac death (617).
Several autopsy studies have demonstrated that 70% to 80% of coronary thrombi occur at sites where the fibrous cap of an atherosclerotic plaque has ruptured, with extension of the thrombus into the plaque as well as into the lumen, and with propagation of the thrombus upstream from the site of cap rupture (9,13,14,1820). Coronary stenoses that contain plaques with a ruptured fibrous cap and superimposed thrombosis often produce a distinctive pattern on contrast angiography characterized as a "complex lesion." These lesions have eccentric stenoses bearing irregular or overhanging margins and lucencies or filling defects (9,21). Thus, according to current pathophysiologic concepts, rupture of the fibrous cap leads to the exposure of the thrombogenic parts of the atherosclerotic plaque, with subsequent activation of the clotting cascade and platelet adhesion, activation, and aggregation. This leads to thrombosis with an abrupt luminal compromise.
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Plaque size, stenosis severity, plaque composition, and vulnerability
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Retrospective analysis of serial angiograms, as well as prospective serial angiographic observations, have suggested that in nearly two-thirds of all patients presenting with acute ischemic syndromes, a coronary angiogram performed weeks or months before the acute event had shown the culprit lesion site to have <70% (often <50%) diameter narrowing (1,15,16,2127). Thus, plaques producing non-flow-limiting stenoses account for more cases of plaque rupture and thrombosis than plaques producing a more severe stenosis. Similarly, stress testing in stable coronary disease patients has demonstrated that the site of ischemia on stress myocardial perfusion scintigraphy does not accurately predict the future site of acute MI (28). This seeming paradox may be attributed to the factors itemized in the following text (29).
Vulnerable plaques may produce less luminal stenosis.
Recent studies have shown that in addition to plaque size, positive remodeling versus negative remodeling can play an important role in determining the net effect on lumen size. In other words, greater outward remodeling of unstable or vulnerable plaques may minimize luminal encroachment despite large plaque size. Human studies using intravascular ultrasound have, in fact, shown that outward arterial expansion caused by positive remodeling is more common at culprit lesion sites in unstable angina, whereas inward or negative remodeling is more common in stable angina (3032). Similarly, computer models using the Laplace Law show that larger lumens create greater circumferential stress on the fibrous caps, thereby increasing their likelihood of rupture (33).
Angiographic assessment of stenosis severity is prone to underestimation.
This may occur because the proximal reference segment used for stenosis severity measurement, though presumed to be normal, may in fact be atherosclerotic with luminal narrowing.
Less-stenotic plaques outnumber the more severely stenotic plaques.
In any given coronary disease patient, less severely stenotic plaques are 5 to 10 times more common than severely stenotic plaques. Thus, more plaque ruptures and thrombi may evolve from less-stenotic plaques in part because of their larger number.
Severely stenotic plaques are more likely to stimulate collateral circulation to the post-stenotic segment.
Subsequent plaque rupture and thrombosis at such sites may therefore be clinically silent because of the protective effect of collateral recruitment.
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Histomorphologic features of vulnerable plaques
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Ruptured plaques have been shown to have several histomorphologic features that are different from intact plaques (Table 1). When these features are present in plaques before rupture, they are thought to indicate vulnerability to plaque rupture. This hypothesis is the basis for the concept of "plaque vulnerability." Plaques that rupture tend to be large, to demonstrate outward or positive remodeling, have a large lipid core often occupying
40% plaque volume, show inflammatory cell infiltration of the fibrous cap and adventitia, possess a thin cap depleted of smooth muscle cells (SMCs), and have increased neovascularity (1,3,30,3443) (Fig. 1).

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Figure 1 Panel A shows a cross-section of the epicardial coronary artery, demonstrating a thin fibrous cap (arrowheads) overlying a crescentic, lipid-rich core (x30). Panel B, with a higher magnification of the margin of the cap, demonstrates dense infiltration by foamy macrophages (x300) (Hematoxylin and eosin). Copyright 2002, Massachusetts Medical Society. All rights reserved. N Engl J Med 1997;336:127682.
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The extracellular lipid core is composed of free cholesterol, cholesterol crystals, and cholesterol esters derived from lipids that have infiltrated the arterial wall and also lipids derived from the death of foam cells. A large, eccentric lipid core may confer a mechanical disadvantage to the plaque by redistributing circumferential stress to the shoulder regions of the plaque. In nearly 60% of cases, this is the area at which fibrous caps tend to rupture (33,35,4446) (Fig. 2). Recent observation of selective expression of perilipin in ruptured human plaques is of considerable interest in this regard because perilipin inhibits lipid hydrolysis and could contribute to an accumulation of lipids in the core, thereby contributing to plaque vulnerability (47). In addition, the lipid core contains prothrombotic, oxidized lipids and is impregnated with tissue factor derived from macrophages. These make the lipid core materials highly thrombogenic when exposed to circulating blood (4852).

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Figure 2 Panel A shows a cross-section of the epicardial coronary artery, demonstrating a rupture of the shoulder region of the plaque with a luminal thrombus (x30). Panel B, at a higher magnification than Panel A, shows a ruptured thin cap densely infiltrated by macrophages and an adjacent fibrin-platelet thrombus (black reflects the post-mortem injection of contrast material) (x120). In Panel C, showing an eroded plaque, a subocclusive luminal thrombus is visible in cross-section of the epicardial coronary artery (x20). Panel D, at a higher magnification, demonstrated a luminal thrombus (left) overlying SMC fibrin-rich plaque (x100). (Movat pentachrome) Copyright 2002, Massachusetts Medical Society. All rights reserved. N Engl J Med 1997;336:127682.
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A number of histopathologic observations have shown that ruptured plaques contain more inflammatory cells than intact plaques. These cells are mostly monocyte-macrophages, but they can be activated T cells and mast cells and are found adjacent to the sites of cap rupture as well as in the adventitia around areas of neovascularization (37,5357). Inflammatory cells are probably recruited into the atherosclerotic plaques by adhesion molecules, such as vascular cell adhesion molecule-1, and chemokines, such as monocyte chemoattractant protein-1. They are then activated in the vessel wall. Another potential avenue for the entry and recruitment of inflammatory cells inside the atherosclerotic lesion may be through the adventitial neovasculature, which is enhanced in atherosclerosis. Factors that may contribute to recruitment of inflammatory cells and their activation in atherosclerosis include oxidized lipids, cytokines such as macrophage colony-stimulating factor, increased angiotensin II activity, elevated arterial pressure, diabetes, chronic infections remote from the arterial wall, possible infectious organisms in the vessel wall (e.g., Chlamydia pneumoniae, cytomegalovirus, and the like), and activation of the immune system (4) (Table 2).
The structural components of the fibrous cap include matrix molecules such as collagen, elastin, and proteoglycans, derived from SMCs. The cap protects the deeper components of the plaque from contact with circulating blood, but it thins out in the vicinity of a rupture. Thinning of the fibrous cap is generally considered to be a prelude to rupture and is a sign of vulnerability. Fibrous caps from ruptured plaques contain less extracellular matrix (collagen and proteoglycans) and fewer SMCs than caps from intact plaques (38).
Atherosclerotic plaques often show increased adventitial and intimal neovascularity, particularly those constituting acute culprit lesions of unstable angina (43,5863). Increased vascularity may provide a source for recruitment of inflammatory cells into the plaque. Rupture of the thin-walled vasa in the plaque intima may lead to hemorrhage, with secondary plaque rupture.
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The matrix dysregulation hypothesis of plaque rupture
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Recently, researchers have hypothesized that depletion of matrix componentsspecifically, fibrillar collagensfrom the fibrous cap, caused by an imbalance between synthesis and breakdown, leads to cap thinning. This predisposes the fibrous cap to rupture, either spontaneously or in response to hemodynamic or other triggers (Fig. 3) (1,35). Enhanced matrix breakdown has been attributed primarily to a family of matrix-degrading metalloproteinases (MMPs) that are expressed in atherosclerotic plaques by inflammatory cells (macrophages, foam cells) and, to a lesser extent, by SMCs and endothelial cells (6473). This family of enzymes can degrade all components of the extracellular matrix and have been shown to be catalytically active both in vitro as well as in vivo (65,7476). The activity of MMPs is tightly regulated at the level of gene transcription and is also regulated by their secretion in an inactive zymogen form that requires extracellular activation and co-secretion of the tissue inhibitors of metalloproteinases (TIMPs) (75). Thus, increased gene transcription, enhanced activation, and reduced activity of TIMPs can individually or together create a milieu for increased matrix proteolysis.

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Figure 3 Conceptual model depicting the potential pathophysiologic mechanisms of plaque vulnerability, rupture, and thrombosis. Ox-LDL = oxidized low-density lipoprotein; MMP = matrix degrading metalloproteinases; SMC = smooth muscle cells; TF = tissue factor.
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Latent MMPs can be activated by plasmin (produced by the plasminogen activator [uPA] from plasminogen by macrophages), trypsin, and chymase (derived from degranulating mast cells). Increased MMP production can be induced by oxidized lipids, reactive oxygen species, chlamydial heat shock protein, CD-40 ligation, inflammatory cytokines, tenascin-C derived from macrophages, and hemodynamic stress (56,70,71,7783). All the components necessary for the activation of the MMP pathway, therefore, exist in atherosclerotic plaques. Furthermore, increased expression of cysteine and aspartate proteases of the cathepsin family, as well as reduced expression of their inhibitor, cystatin-c, in human atherosclerotic lesions, may also contribute to matrix breakdown in plaques (84,85).
Matrix depletion may also result from reduced synthesis owing to a decrease in the number of SMCs or a reduction in their synthetic function (37,38). The activated T cellderived cytokine, interferon gamma, inhibits collagen gene expression in SMCs in vitro. This suggests that activated T cells in the plaque may inhibit matrix synthesis by producing interferon-gamma. Several investigators have demonstrated increased SMC death by apoptosis in human plaques, and several key players of the death-signaling pathway have been identified in atherosclerotic lesions (8697). Other stimuli that may induce SMC death in atherosclerosis include oxidized lipids and the epidermal growth factorlike domain of macrophage-derived tenascin-C (normally cryptic, but exposed when MMPs cleave the intact tenascin-C molecule) (Sharifi B, personal communication).
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Experimental models of plaque rupture
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Despite numerous attempts, no convincing animal model of spontaneous atherosclerotic plaque rupture and thrombosis was available until very recently. In the past, investigators have injected catecholamines, lipopolysaccharide, and Russels viper venom to trigger thrombosis in rabbits with atherosclerosis, but such models bear little resemblance to human plaque rupture or thrombosis (98). In another rabbit model, Rekhter et al. (99) used a balloon incorporated in the arterial wall to study the role of lipid accumulation and macrophage infiltration in bringing about vulnerability to rupture. However, this model also bears little resemblance to human disease. Similarly, endothelin injections in apo E null mice have been shown to trigger acute myocardial necrosis, but coronary plaque rupture and thrombosis were not the underlying mechanism (100). Recent research with apo E null mice revealed that there were frequent atherosclerotic lesions resembling vulnerable plaques in the innominate artery. Although intraplaque hemorrhage was observed, frank rupture and thrombosis were not demonstrated (101). Other investigators have described findings suggestive of plaque rupture and thrombosis in the innominate artery of apo E null mice that were fed a lard-based high-fat diet (102). Rekhter reported evidence of plaque rupture in the aortic plaques of apo E null mice after corticotropin-releasing factor was injected intracranially to simulate a stress response (presented at the annual Vascular Biology meeting in Geneva 2000).
Over-expression of MMP-1 has failed to produce plaque rupture in mice; paradoxical reduction in atherosclerosis was actually observed with MMP-1 over-expression, raising some questions about the role of MMPs as the critical mediator of plaque rupture (103). Recently, Calara et al. (104) reported findings suggestive of plaque rupture and thrombosis in apo E and low-density-lipoprotein receptor null mice, but the overall frequency was quite low. von der Thüsen et al. (105) reported evidence of plaque rupture in murine models of atherosclerosis with over-expression of the pro-apoptotic gene p53.
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Potential triggers for plaque rupture
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Sudden rupture of a vulnerable plaque may occur spontaneously without obvious triggers. By contrast, it may follow a particular event, such as extreme physical activity (especially in someone unaccustomed to regular exercise), severe emotional trauma, sexual activity, exposure to illicit drugs (cocaine, marijuana, amphetamines), exposure to cold, or acute infection (106114).
While plaque rupture often leads to thrombosis with the clinical manifestations of an acute coronary syndrome, it may also occur without clinical consequences (silent plaque rupture). In approximately 40% of cases of acute coronary syndrome, multiple plaque ruptures have been demonstrated in arteries remote from the acute culprit site (115). The thrombotic response to a plaque rupture is probably regulated by the thrombogenicity of the exposed plaque constituents, the local hemorheology (determined by the severity of underlying stenosis), shear-induced platelet activation, and also by systemic thrombogenicity and fibrinolytic activity (1). Lipid-rich plaques may be more thrombogenic than fibrous plaques, probably because of the high content of tissue factor in the lipid core (52). The major source of tissue factor appears to be the macrophage. Apoptosis of macrophages may impregnate the lipid core with tissue factorladen microparticles, making the lipid-core highly thrombogenic (50). Inflammatory cells, therefore, may be a key factor in influencing plaque thrombogenicity.
Recent studies in our laboratory have shown that plaques of smokers contain more tissue factor and inflammatory cells (macrophages) than plaques of non-smokers, perhaps contributing to the high thrombotic risk in smokers (116). Furthermore, coronary collaterals may also influence the clinical consequences of acute coronary occlusion. Several investigators have suggested that organization and healing at the site of plaque rupture and thrombosis may eventually lead to rapid progression of plaque and worsening of stenosis, thereby providing a mechanism for the progression of atherosclerosis (117).
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Erosion of plaque and calcified nodules as a basis for thrombosis
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Coronary thrombi have been observed overlying atherosclerotic plaques in 20% to 40% of cases, without rupture of the fibrous cap (2,13,118,119). Such thrombi occur over plaques with superficial endothelial erosion. These erosions are particularly common in young victims of sudden death, in smokers, and in women. Plaques under such thrombi have a proteoglycan-rich matrix rather than a large lipid core, and the prevalence of inflammation is also lower than that found in plaque rupture. The precise mechanisms of thrombosis in this scenario are unknown. It is conceivable that thrombosis in such cases is triggered by an enhanced systemic thrombogenic state (enhanced platelet aggregability, increased circulating tissue factor levels, depressed fibrinolytic state) (4). Activated circulating leukocytes may transfer active tissue factor by shedding microparticles and transferring them onto adherent platelets (120,121). It is possible that these circulating sources of tissue factor (rather than plaque-derived tissue factor) contribute to thrombosis at sites of superficial endothelial denudation such as those found in plaque erosion. Furthermore, severe deficiencies of antithrombotic molecules, thrombomodulin, and protein-c receptor in advanced atherosclerotic lesions may also contribute to thrombosis (122). Erosion of a calcified nodule within an atherosclerotic plaque has also been reported as a basisthough uncommonfor thrombosis.
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Plaque stabilization
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Several angiographic studies have shown that risk-factor modification leads to reduced new lesion formation, less lesion progression, and in some cases, actual regression. However, these studies have also shown that the magnitude of clinical-event reduction is far greater than that accounted for by the relatively small changes in stenosis severity. This apparent discrepancy has led to the following hypotheses: 1) risk-factor modification may induce plaque regression and reverse remodeling, with little net change in stenosis severity; or 2) risk-factor modification may not change plaque mass or stenosis severity but might reduce the propensity for plaque rupture and thrombosis by changing the composition of the plaque. The latter possibility is referred to as "plaque stabilization" (4,123128). Studies in animals have in fact shown that lowering lipids through diet, statin therapy, or direct administration of apo A-1 and high-density lipoprotein (HDL)-like particles, can deplete lipids, reduce inflammation, sometimes reduce MMP and tissue factor levels, and increase the collagen content of atherosclerotic lesions (129136). Thus, change in plaque composition can be achieved in animal models.
We have recently demonstrated that three months of therapy with pravastatin also favorably modifies human carotid plaque composition to a more stable phenotype, providing the first human data paralleling the results from animal models (137). It can be postulated, therefore, that reducing lipids and inflammation in atherosclerotic plaques may help lower the risk of plaque rupture and subsequent thrombosis. Also, such a plaque-stabilizing effect may account for the clinical benefits of risk-factor modification gained through changes in lifestyle and by drug therapy (lipid-modifying drugs, angiotensin converting enzyme, angiotensin-II receptor blockers) (4). Future additional approaches may include direct administration of HDL and its apolipoproteins, and novel HDL-boosting compounds such as the rexinoids (138,139).
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Acknowledgments
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The generous support of the Milken Foundation, the Eisner Foundation and the Entertainment Industry Foundation is acknowledged.
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Footnotes
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Please refer to the Trial Appendix at the back of this supplement for the complete list of clinical trials.
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References
|
|---|
- Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657671
- Virmani R, Burke AP, Farb A. Plaque rupture and plaque erosion. Thromb Haemost. 1999;82(Suppl 1):13
- Davies MJ. The pathophysiology of acute coronary syndromes. Heart. 2000;83:361366
- Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev. 2000;8:3139
- Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365372
- DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897902
- DeWood MA, Spores J, Hensley GR, et al. Coronary arteriographic findings in acute transmural myocardial infarction. Circulation. 1983;68:139149
- DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after nonQ-wave myocardial infarction. N Engl J Med. 1986;315:417423
- Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation. 1982;66:316320
- Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986;315:913919
- Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med. 1987;317:13611365
- Folts JD. Platelet aggregation in stenosed coronary or cerebral arteries: a mechanism for sudden death? Wis Med J. 1980;79:2426
- Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310:11371140
- Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J. 1983;50:127134
- Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol. 1985;5:609616
- Ambrose A, Winters SL, Arora RR, et al. Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction. J Am Coll Cardiol. 1985;6:12331238
- Gorlin R, Fuster V, Ambrose JA. Anatomic-physiologic links between acute coronary syndromes. Circulation. 1986;74:69
- Friedman M. Pathogenesis of coronary thrombosis, intramural and intraluminal hemorrhage. Adv Cardiol. 1970;4:2046
- Friedman M. The pathogenesis of coronary plaques, thromboses, and hemorrhages: an evaluative review. Circulation. 1975;52(Suppl 6):III3440
- Constantinides P. Atherosclerosisa general survey and synthesis. Surv Synth Pathol Res. 1984;3:477498
- Ambrose JAk, Hjemdahl-Monsen C, Borrico S, et al. Quantitative and qualitative effects of intracoronary streptokinase in unstable angina and nonQ-wave infarction. J Am Coll Cardiol. 1987;9:11561165
- Ambrose JA, Winters SL, Arora RR, et al. Angiograhic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol. 1986;7:472478
- Ambrose JA, Monsen C. Significance of intraluminal filling defects in unstable angina. Am J Cardiol. 1986;57:10031004
- Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:11571166
- Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J. 1988;9:13171323
- Giroud D, Li JM, 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;69:729732
- Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:12891298
- Naqvi TZ, Hachamovitch R, Berman D, Buchbinder N, Kiat H, Shah PK. Does the presence and site of myocardial ischemia on perfusion scintigraphy predict the occurrence and site of future myocardial infarction in patients with stable coronary artery disease? Am J Cardiol. 1997;79:15211524
- Shah PK. Plaque size, vessel size and plaque vulnerability: bigger may not be better. J Am Coll Cardiol. 1998;32:663664
- Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation. 2000;101:598603
- von Birgelen C, Klinkhart W, Mintz GS, et al. Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol. 2001;37:18641870
- Takano M, Mizuno K, Okamatsu K, Yokoyama S, Ohba T, Sakai S. Mechanical and structural characteristics of vulnerable plaques: analysis by coronary angioscopy and intravascular ultrasound. J Am Coll Cardiol. 2001;38:99104
- Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res. 1992;71:850858
- Guyton JR, Klemp KF. Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol. 1996;16:411
- Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941944
- 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;69:377381
- Felton CV, Crook D, Davies MJ, Oliver MF. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterioscler Thromb Vasc Biol. 1997;17:13371345
- Burleigh MC, Briggs AD, Lendon CL, Davies MJ, Born GV, Richardson PD. Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span- wise variations. Atherosclerosis. 1992;96:7181
- Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation. 1994;90:775778
- Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:30903097
- Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis. 1991;87:8790
- Depre C, Havaux X, Wijns W. Neovascularization in human coronary atherosclerotic lesions. Cathet Cardiovasc Diagn. 1996;39:215220
- Tenaglia AN, Peters KG, Sketch MH Jr, Annex BH. Neovascularization atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J. 1998;135:1014
- Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation. 1993;87:11791187
- Loree HM, Tobias BJ, Gibson LJ, Kamm RD, Small DM, Lee RT. Mechanical properties of model atherosclerotic lesion lipid pools. Arterioscler Thromb. 1994;14:230234
- Huang H, Virmani R, Younis H, Burke AP, Kamm RD, Lee RT. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation. 2001;103:10511056
- Faber BC, Cleutjens KB, Niessen RL, et al. Identification of genes potentially involved in rupture of human atherosclerotic plaques. Circ Res. 2001;89:547554
- Essler M, Retzer M, Bauer M, Zangl KJ, Tigyi G, Siess W. Stimulation of platelets and endothelial cells by mildly oxidized LDL proceeds through activation of lysophosphatidic acid receptors and the Rho/Rho-kinase pathway. Inhibition by lovastatin. Ann NY Acad Sci. 2000;905:282286
- Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594599
- Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999;99:348353
- Badimon JJ, Lettino M, Toschi V, et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation. 1999;99:17801787
- Fernandez-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol. 1994;23:15621569
- 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;89:3644
- Kovanen PT. The mast cella potential link between inflammation and cellular cholesterol deposition in atherogenesis. Eur Heart J. 1993;14(Suppl K):105117
- Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation. 1995;92:10841088
- Kaartinen M, van der Wal AC, van der Loos CM, et al. Mast cell infiltration in acute coronary syndromes: implications for plaque rupture. J Am Coll Cardiol. 1998;32:606612
- Laine P, Kaartinen M, Penttila A, Panula P, Paavonen T, Kovanen PT. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation. 1999;99:361369
- Barger AC, Beeuwkes R 3rd, Lainey LL, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med. 1984;310:175177
- Kamat BR, Galli SJ, Barger AC, Lainey LL, Silverman KJ. Neovascularization and coronary atherosclerotic plaque: cinematographic localization and quantitative histologic analysis. Hum Pathol. 1987;18:10361042
- Barger AC, Beeuwkes R 3rd. Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction. Am J Cardiol. 1990;66:41G43G
- Heistad DD, Armstrong ML. Blood flow through vasa vasorum of coronary arteries in atherosclerotic monkeys. Arteriosclerosis. 1986;6:326331
- Williams JK, Heistad DD. The vasa vasorum of the arteries. J Mal Vasc. 1996;21:266269
- Kwon HM, Sangiorgi G, Ritman EL, et al. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest. 1998;101:15511556
- Henney AM, Wakeley PR, Davies MJ, et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci USA. 1991;88:81548158
- Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:24932503
- Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation. 1995;91:21252131
- Nikkari ST, OBrien KD, Ferguson M, et al. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995;92:13931398
- Li Z, Li L, Zielke HR, et al. Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am J Pathol. 1996;148:121128
- Galis ZS, Sukhova GK, Libby P. Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue. FASEB J. 1995;9:974980
- Xu XP, Meisel SR, Ong JM, et al. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation. 1999;99:993998
- Rajavashisth TB, Xu XP, Jovinge S, et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation. 1999;99:31033109
- Rajavashisth TB, Liao JK, Galis ZS, et al. Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase. J Biol Chem. 1999;274:1192411929
- Herman MP, Sukhova GK, Libby P, et al. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation. 2001;104:18991904
- Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:15651569
- Shah PK. Role of inflammation and metalloproteinases in plaque disruption and thrombosis. Vasc Med. 1998;3:199206
- Sukhova GK, Schonbeck U, Rabkin E, et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation. 1999;99:25032509
- Lee RT, Schoen FJ, Loree HM, Lark MW, Libby P. Circumferential stress and matrix metalloproteinase 1 in human coronary atherosclerosis. Implications for plaque rupture. Arterioscler Thromb Vasc Biol. 1996;16:10701073
- Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Libby P. Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann NY Acad Sci. 1995;748:501507
- Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci USA. 1995;92:402406
- Kol A, Sukhova GK, Lichtman AH, Libby P. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation. 1998;98:300307
- Mach F, Schonbeck U, Fabunmi RP, et al. T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism: implications for tubule formation. Am J Pathol. 1999;154:229238
- Schonbeck U, Mach F, Sukhova GK, et al. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res. 1997;81:448454
- Wallner K, Li C, Shah PK, et al. Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque. Circulation. 1999;99:12841289
- Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998;102:576583
- Shi GP, Sukhova GK, Grubb A, et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest. 1999;104:11911197
- Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest. 1995;95:22662274
- Bjorkerud S, Bjorkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol. 1996;149:367380
- Kockx MM, Knaapen MW. The role of apoptosis in vascular disease. J Pathol. 2000;190:267280
- Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. J Pathol. 1998;185:303312
- Crisby M, Kallin B, Thyberg J, et al. Cell death in human atherosclerotic plaques involves both oncosis and apoptosis. Atherosclerosis. 1997;130:1727
- Bennett MR. Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc Res. 1999;41:361368
- Galle J, Heermeier K, Wanner C. Atherogenic lipoproteins, oxidative stress, and cell death. Kidney Int. 1999;71(Suppl):S6265
- Vieira O, Escargueil-Blanc I, Jurgens G, et al. Oxidized LDLs alter the activity of the ubiquitin-proteasome pathway: potential role in oxidized LDL-induced apoptosis. FASEB J. 2000;14:532542
- Rossig L, Dimmeler S, Zeiher AM. Apoptosis in the vascular wall and atherosclerosis. Basic Res Cardiol. 2001;96:1122
- Geng YJ, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. Arterioscler Thromb Vasc Biol. 1996;16:1927
- Geng YJ, Henderson LE, Levesque EB, Muszynski M, Libby P. Fas is expressed in human atherosclerotic intima and promotes apoptosis of cytokine-primed human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997;17:22002208
- Mallat Z, Tedgui A. Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol. 2000;130:947962
- Abela GS, Picon PD, Friedl SE, et al. Triggering of plaque disruption and arterial thrombosis in an atherosclerotic rabbit model. Circulation. 1995;91:776784
- Rekhter MD, Hicks GW, Brammer DW, et al. Animal model that mimics atherosclerotic plaque rupture. Circ Res. 1998;83:705713
- Caligiuri G, Levy B, Pernow J, Thoren P, Hansson GK. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Natl Acad Sci USA. 1999;96:69206924
- Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000;20:25872592
- Johnson JL, Jackson CL. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis. 2001;154:399406
- Lemaitre V, OByrne TK, Borczuk AC, Okada Y, Tall AR, DArmiento J. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest. 2001;107:12271234
- Calara F, Silvestre M, Casanada F, Yuan N, Napoli C, Palinski W. Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol. 2001;195:257263
- von der Thüsen JH, van Vlijmen BJ, Hoeben RC, Kockx MM, Van Berkel TJ. Induction of atherosclerotic plaque rupture in apolipoprotein E/ mice after adenovirus-mediated transfer of p53. Circulation 2002;105:206470
- Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733743
- Muller JE. Morning increase of onset of myocardial infarction. Implications concerning triggering events. Cardiology. 1989;76:96104
- Muller JE, Tofler GH. Triggering and hourly variation of onset of arterial thrombosis. Ann Epidemiol. 1992;2:393405
- Willich SN, Jimenez AH, Tofler GH, DeSilva RA, Muller JE. Pathophysiology and triggers of acute myocardial infarction: clinical implications. Clin Invest. 1992;70(Suppl 1):S7378
- Willich SN, Maclure M, Mittleman M, Arntz HR, Muller JE. Sudden cardiac death. Support for a role of triggering in causation. Circulation. 1993;87:14421450
- Peters A, Dockery DW, Muller JE, Mittleman MA. Increased particulate air pollution and the triggering of myocardial infarction. Circulation. 2001;103:28102815
- Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001;103:28052809
- Muller JE. Circadian variation and triggering of acute coronary events. Am Heart J. 1999;137:S18
- Muller JE. Triggering of cardiac events by sexual activity: findings from a case-crossover analysis. Am J Cardiol. 2000;86:14F18F
- Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, ONeill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343:915922
- Matetzky S, Tani S, Kangavari S, et al. Smoking increases tissue factor expression in atherosclerotic plaques: implications for plaque thrombogenicity. Circulation. 2000;102:602604
- Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103:934940
- Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:12761282
- Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996;93:13541363
- Rauch U, Bonderman D, Bohrmann B, et al. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood. 2000;96:170175
- Mallat Z, Benamer H, Hugel B, et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation. 2000;101:841843
- Laszik ZG, Zhou XJ, Ferrell GL, Silva FG, Esmon CT. Down-regulation of endothelial expression of endothelial cell protein C receptor and thrombomodulin in coronary atherosclerosis. Am J Pathol. 2001;159:797802
- Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Cayatte AJ, Mowery J. Atherosclerosis. Potential targets for stabilization and regression. Circulation. 1992;86(Suppl 6):III117123
- Waters D. Plaque stabilization: a mechanism for the beneficial effect of lipid-lowering therapies in angiography studies. Prog Cardiovasc Dis. 1994;37:107120
- Shah PK. Pathophysiology of plaque rupture and the concept of plaque stabilization. Cardiol Clin. 1996;14:1729
- Shah PK. Plaque disruption and coronary thrombosis: new insight into pathogenesis and prevention. Clin Cardiol. 1997;20(Suppl 2):II3844
- Kullo IJ, Edwards WD, Schwartz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med. 1998;129:10501060
- Lee RT. Plaque stabilization: the role of lipid lowering. Int J Cardiol. 2000;74(Suppl 1):S1115
- Aikawa M, Rabkin E, Okada Y, et al. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation. 1998;97:24332444
- Aikawa M, Libby P. Lipid lowering reduces proteolytic and prothrombotic potential in rabbit atheroma. Ann NY Acad Sci. 2000;902:140152
- Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001;103:276283
- Fukumoto Y, Libby P, Rabkin E, et al. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits. Circulation. 2001;103:993999
- Ameli S, Hultgardh-Nilsson A, Cercek B, et al. Recombinant apolipoprotein A-1 Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. Circulation. 1994;90:19351941
- Shah PK, Nilsson J, Kaul S, et al. Effects of recombinant apolipoprotein A-I (Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 1998;97:780785
- Shah PK, Yano J, Reyes O, et al. High-dose recombinant apolipoprotein A-I (Milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein c- deficient mice: potential implications for acute plaque stabilization. Circulation. 2001;103:30473050
- Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103:926933
- Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part I. Circulation. 2001;104:23762383
- Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part II. Circulation. 2001;104:24982502
- Claudel T, Leibowitz MD, Fievet C, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc Natl Acad Sci USA. 2001;98:26102615
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