T his review will reconsider the current paradigm for understanding the critical, final steps in the progression of atherosclerotic lesions. That scheme, largely an outgrowth of observations of autopsy tissues by Davies and colleagues, 1,2 asserts that the cause of death in atherosclerotic coronary artery disease is rupture of an advanced atherosclerotic lesion. Although this assumption may be partially true, recent autopsy studies suggest that it is incomplete. See p 1177To reconsider this paradigm, we reexamined the morphological classification scheme for lesions proposed by the American Heart Association (AHA). 3,4 This scheme is difficult to use for 2 reasons. First, it uses a very long list of roman numerals modified by letter codes that are difficult to remember. Second, it implies an orderly, linear pattern of lesion progression. This tends to be ambiguous, because it is not clear whether there is a single sequence of events during the progression of all lesions. We have therefore tried to devise a simpler classification scheme that is consistent with the AHA categories but is easier to use, able to deal with a wide array of morphological variations, and not overly burdened by mechanistic implications. The Current ParadigmThe current paradigm is based on the belief that type IV lesions, or "atheromas," described by the AHA are stable because the fatty, necrotic core is contained by a smooth muscle cell-rich fibrous cap. Virchow's analysis 5 in 1858 pointed out that historically, the term "atheroma" refers to a dermal cyst ("Grützbalg"), a fatty mass encapsulated within a cap. Extending Virchow's argument, the fibrous cap over the lipid mass of an atherosclerotic plaque is analogous to the capsule containing an abscess, and like an abscess, the plaque can be ruptured. Rupture of the fibrous cap exposes thrombogenic material, initiating platelet aggregation and coagulation in the infiltrating and overlying blood. These thrombotic changes result from activation of the clotting cascade by tissue factor, and further propagation of the thrombosis results from the interaction of platelets with the active thrombogenic matrix. 6 Platelet activation and thrombin formation combined with the evulsion of thrombogenic plaque contents into the lumen then result in sudden occlusion. 7 This widely held concept of atherosclerotic death is based on morphological data from autopsies as well as clinical angiographic studies, in which the presence of surface irregularities has been interpreted as plaque rupture. 8 -10 Previous pathological studies of sudden coronary death have demonstrated evidence of plaque rupture associated with thrombosis in 73% of cases. 2 Of the remaining cases, 8% consist of plaque fissure with intraplaque fibrin deposition and hemorrhage, while 19% show no evidence of thrombi. 2 Consequently, recent reviews of atherosclerosis have uniformly accepted plaque rupture as the critical event leading to coronary artery death. 6

The majority of patients with acute coronary syndromes (ACS) present with unstable angina, acute myocardial infarction, and sudden coronary death. The most common cause of coronary thrombosis is plaque rupture followed by plaque erosion, whereas calcified nodule is infrequent. If advances in coronary disease are to occur, it is important to recognize the precursor lesion of ACS. Of the three types of coronary thrombosis, a precursor lesion for acute rupture has been postulated. The non-thrombosed lesion that most resembles the acute plaque rupture is the thin cap fibroatheroma (TCFA), which is characterized by a necrotic core with an overlying fibrous cap measuring<65 microm, containing rare smooth muscle cells but numerous macrophages. Thin cap fibroatheromas are most frequently observed in patients dying with acute myocardial infarction and least common in plaque erosion. They are most frequently observed in proximal coronary arteries, followed by mid and distal major coronary arteries. Vessels demonstrating TCFA do not usually show severe narrowing but show positive remodeling. In TCFAs the necrotic core length is approximately 2 to 17 mm (mean 8 mm) and the underlying cross-sectional area narrowing in over 75% of cases is <75% (diameter stenosis <50%). The area of the necrotic core in at least 75% of cases is < or =3 mm2. These lesions have lesser degree of calcification than plaque ruptures. Thin cap fibroatheromas are common in patients with high total cholesterol (TC) and high TC/high-density lipoprotein cholesterol ratio, in women >50 years, and in those patients with elevated high levels of high sensitivity C-reactive protein. It has only recently been recognized that their identification in living patients might help reduce the incidence of sudden coronary death.

Among men with coronary disease who die suddenly, abnormal serum cholesterol concentrations - particularly elevated ratios of total cholesterol to HDL cholesterol - predispose patients to rupture of vulnerable plaques, whereas cigarette smoking predisposes patients to acute thrombosis.

Background-The US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensitivity reactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined.