Mechanisms modifying atherosclerotic disease — from lipids to vascular biology

Abstract

Recent clinical trials of three statins, pravastain, simvastatin and lovastatin, have demonstrated a major reduction in acute coronary events typically precipitated by plaque rupture. However, angiographic studies with several statins have shown that they do not appear to greatly affect the size of pre-existing plaques. These findings strongly suggest that the demonstrated protective effect of these statins is mediated through changes in plaque composition rather than size, highlighting the greater importance of composition than size in determining clinical outcome. Atherosclerotic plaques are composed of a thrombogenic lipid-rich core protected by a fibrous cap comprising smooth muscle cells (SMCs) and inflammatory cells, predominantly macrophages. SMCs are the only cell type in the atherosclerotic plaque capable of synthesizing a strong fibrous cap. Their survival is therefore crucial to plaque stability. In contrast, inflammatory cells such as macrophages increase the risk of plaque rupture by a number of mechanisms. Thus, in atherosclerosis, there is a balance between the influence of inflammatory cells tending towards plaque instability and the reparative influence of SMCs tending to plaque stability. The implication of the successful outcome studies is that the statins tested may beneficially influence this balance either by decreasing inflammation or promoting repair or both. However, because statins do not have a uniform effect on all the biological processes contributing to plaque rupture and subsequent thrombosis, the potential benefit from treating with a statin cannot necessarily be presumed or predicted from its lipid lowering potency alone. Therefore prescription of statins to prevent cardiovascular events should be based on the evidence of outcome trials.