Transformation From Stable To Vulnerable Atherosclerotic Plaque

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There is considerable heterogeneity in the structure of atherosclerotic plaques, and numerous investigations have attempted to identify special features of plaques that are involved in acute ischemic syndromes (5-12). It has been observed in patients experiencing acute myocardial infarction, who have coincidentally undergone coronary arteriography at some point prior to the acute event, that the site of coronary occlusion is often not the site of the most stenotic lesion in the coronary tree (15,16). It is now recognized that acute ischemic syndromes are often precipitated at atherosclerotic sites that are only minimally obstructive, suggesting that features other than plaque bulk contribute to the risk of a given plaque acting as the site of an acute coronary occlusion (15,16). Detailed anatomic studies of plaque structure at the site of rupture and thrombosis in patients who have died from acute myocardial infarction have identified a variety of morphologic features that are more likely to be found in these plaques compared to plaques at other, presumably more stable, sites (5-12). These features include a relatively large physically soft lipid pool and a fibrous cap overlying the plaque, which is relatively thin (5-12). There is evidence that plaques with a thinner cap and larger underlying lipid pool may be more susceptible to physical forces that cause the cap to fissure, usually at the edge of the plaque, thus setting in motion the thrombogenic cascade leading to an occlusive clot (5-12). The fibrous cap, separating the thrombogenic core material from the blood, is figuratively the "no-man's land" between stable and unstable coronary artery disease. It appears to be a site of intense biologic activity and is a dynamic structure (11,12).

Two important findings in the caps of vulnerable plaques are a reduced smooth muscle cell content and increased numbers of inflammatory cells, such as activated macrophages,

Fig. 1. Substrate, triggering events, and the physiologic processes linking the two. Atherosclerotic plaques with varying structural, cellular, and biochemical characteristics form the substrate for acute coronary events. The plaque is in contact with circulating cellular elements, coagulation proteins, and vasoactive substances produced locally in the endothelium and circulating systemically. The plaque also is acted upon by physical forces related to systemic hemodynamics and coronary blood flow. Triggering events exert their effects by modifying local physiologic processes to promote plaque disruption and intracoronary thrombosis.

Fig. 1. Substrate, triggering events, and the physiologic processes linking the two. Atherosclerotic plaques with varying structural, cellular, and biochemical characteristics form the substrate for acute coronary events. The plaque is in contact with circulating cellular elements, coagulation proteins, and vasoactive substances produced locally in the endothelium and circulating systemically. The plaque also is acted upon by physical forces related to systemic hemodynamics and coronary blood flow. Triggering events exert their effects by modifying local physiologic processes to promote plaque disruption and intracoronary thrombosis.

T cells, and mast cells. Smooth muscle cells produce collagen and other proteins, which thicken and strengthen the cap. The inflammatory cells produce a variety of substances which inhibit collagen formation or degrade that which exists. Substances produced by inflammatory cells can also induce smooth muscle cell apoptosis (programmed cell death). These changes in the composition of the cap reduce its strength, favoring rupture or erosion. Recent studies in patients have shown that higher serum levels of systemic markers of inflammation predict a higher risk of acute coronary disease (17-19). The specific mechanisms by which these proinflammatory modulators become augmented in the vessel wall are as yet unknown. The possibility that infectious agents, either within the vascular wall or at remote sites, might constitute this link is under investigation, but conclusions are still controversial (20,21).

The susceptability of an individual to plaque disruption and resulting coronary disease events may also depend on the presence of specific inherited polymorphisms of genes controlling proteins involved in the development of atherosclerotic plaque and in thrombosis. For example, in a prospective study of3052 men in the Northwick Park Heart Study, initially free of coronary heart disease, cigarette smokers who were carriers of the E4 allele of apolipoprotein E had a significantly increased risk (2.79-fold, 95% confidence interval 1.59-4.91) of myocardial infarction or coronary artery surgery, with no increased risk imparted by this allele in exsmokers (22). In another study of444 patients with angio-graphically severe severe coronary disease, those with certain alleles of the Factor VII gene were significantly less likely to have experienced a myocardial infarction (23).

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