Evolution and stabilization of vulnerable atherosclerotic plaques.

Abstract

mammals, have resident smooth muscle cells in the tunica intima underneath the endothelial monolayer, even before atherosclerotic changes begin.1,2 The thickness of the intimal layer increases progressively as humans age from fetus to child to young adult, and its complex structure probably favors the formation of atheroma. When atherogenesis begins, the artery wall becomes host to inflammatory cells, including macrophages and T lymphocytes,3 and an excess of risk factors accelerates the pathological changes in the artery. Presently, the most understood risk factor is low-density lipoprotein (LDL). Epidemiological and clinical studies suggest that elevated levels of plasma cholesterol, especially LDL particles, increase the risk of acute coronary events.4,5 Beginning with Anitschkow and Chalatow’s description in 1913 of a diet rich in cholesterol that induced atherosclerosis in rabbits, 6 a number of animal studies have linked hypercholesterolemia to atherosclerosis. 7–9 In vitro studies, however, suggested that native LDL itself does not induce vascular cell activation and foam cell formation, the features that are related to atherosclerosis. In the late 1980s, the ‘oxidized LDL’ hypothesis postulated the missing link between hypercholesterolemia and atherosclerosis;10 that is, excess LDL in the artery wall can be modified, which instigates an inflammatory response on the endothelial surface of the artery.11 Endothelial activation, in turn, causes an infiltration of macrophages, one of the hallmarks of the atherosclerotic lesion. 12–15 Macrophage-rich atheroma, which are prone to rupture and thrombus formation, result in the onset of acute coronary syndromes such as unstable angina and myocardial infarction.16–19 Recent clinical and preclinical studies have repeatedly suggested that lipid lowering can stabilize these vulnerable plaques and improve clinical outcomes.20 This review will discuss the current understanding of the biology of vascular inflammation, the pathophysiolgy of acute thrombotic complications, and the likely mechanisms responsible for the effects of lipid-lowering therapy.