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Mechanisms of plaque vulnerability and rupture

^* 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

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.

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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