Atherosclerotic plaque rupture: emerging insights and opportunities

Abstract

Reduction in acute coronary events requires interventions that affect the mechanisms leading to formation of atherosclerotic lesions, as well as the molecular events that precipitate acute myocardial infarction. Data from clinical trials indicate that it is the vulnerability of atherosclerotic plaque to rupture, rather than the degree of atherosclerosis, that is the primary determinant of thrombosis-mediated acute coronary events. The characteristics of a plaque that is vulnerable to rupture include a thin fibrous cap separating the circulation from procoagulants in the plaque’s lipid core; increased numbers of inflammatory cells (e.g., macrophages and T cells); and a relative paucity of vascular smooth muscle cells (VSMC). Plaque stability reflects various dynamic factors: interaction of inflammatory cells, VSMC production of the extracellular matrix that is the bulwark of the fibrous cap, inhibition of this process by certain cytokines, and increased degradation of the matrix by matrix metalloproteinases. There is growing interest in the concept that intervention in the inflammatory processes of atherogenesis might reduce lesion formation and/or progression. There has also been substantial progress in understanding the transcriptional regulation of proteins that are critically involved in atherogenesis. Recently, peroxisomal proliferator–activated receptors (PPARs) have been identified as a potential link between insulin resistance and atherosclerosis. This concept is supported by the discovery through drug screening of thiazolidinediones (troglitazone, rosiglitazone), compounds that are not only ligands for PPARγ, a nuclear receptor involved in adipogenesis, but also are antidiabetic agents.