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 (1–5).
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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 (6–17).
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 (9,13,14,18–20). 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 (1,15,16,21–27). 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 (30–32). 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 (1,3,30,34–43) (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;336:1276–82.
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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 (33,35,44–46) (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 (48–52).
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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;336:1276–82.
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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 (37,53–57). 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 (43,58–63). 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 components—specifically, fibrillar collagens—from 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 (64–73). 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 (65,74–76). 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 (56,70,71,77–83). 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 cell–derived 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 (86–97). Other stimuli that may induce SMC death in atherosclerosis include oxidized lipids and the epidermal growth factor–like 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 Russel’s 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 (106–114).
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 factor–laden 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 basis—though uncommon—for 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" (4,123–128). 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 (129–136). 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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Abstract
Plaque rupture: the basis...