Plaque stabilization: the role of lipid lowering

The unstable atheroma characteristically has a thin, eccentric fibrous cap and a large necrotic core of lipid and cellular debris. This plaque configuration is particularly unstable because large mechanical stresses develop in the thinnest portions of the fibrosis cap over the lipid pool. Numerous recent observations tell us that critical biological factors other than lesion morphology also contribute to the ultimate fracture of the fibrous cap. Matrix-degrading enzymes, particularly members of the metalloproteinase family, are overexpressed in atherosclerotic tissue. The regions with the greatest amounts of these enzymes are the critical high stress regions, which are usually also infiltrated with inflammatory cells. At the cellular level a number of factors regulate expression of these enzymes by vascular smooth muscle cells. These factors include mechanical stimuli and cytokines known to be overexpressed in atheroma by both smooth muscle cells and macrophages. Low density lipoprotein cholesterol in the lesion plays a significant role in most or all of these processes, and our current understanding of the unstable atheroma is consistent with the dramatic clinical successes of lipid-lowering therapy.