[The promise of statins].Ital Heart J Suppl. 2001 Mar; 2(3):224-9.IH
Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are a class of drugs with a potent lipid-lowering effect that have been shown to reduce LDL cholesterol by 35-45% at therapeutic doses. Recent trials have demonstrated that in subjects with coronary artery disease, an aggressive treatment with high doses of statins, which lowers LDL cholesterol below 100 mg/dl, can obtain better results in terms of reduction of cardiovascular events, compared to the currently used dosage of statins. The pharmacologic effect of statins is far beyond the mere reduction of LDL cholesterol, in that it has been demonstrated that they are able to inhibit the proliferation of smooth muscle cells and macrophages, to restore the endothelial activity, and to inhibit the inflammatory response of macrophages. These effects have been called "pleiotropic effects" of statins. These metabolic activities of statins play an important role in contrasting the inflammatory elements of the atherosclerotic plaque. The atherosclerotic plaque is formed by a lipid core and a fibrous cap. Smooth muscle cells, macrophages and T lymphocytes are present in the plaque, particularly in the fibrous cap. In stable plaques, smooth muscle cells produce extracellular matrix, i.e. collagen and elastin, which strengthens the fibrous cap. In the presence of inflammatory stimuli, primarily oxidized LDL, T lymphocytes activate macrophage and smooth muscle cells to secrete cytokines and proteolytic enzymes, the collagenolytic metalloproteases, that can weaken the extracellular matrix and rupture the fibrous cap. A local thrombotic mechanism starts in the ruptured plaque, promoted by the tissue factor released by macrophages in the lipid core of the plaque, which can propagate to the coronary lumen with total occlusion. Statins have been demonstrated to contrast the inflammatory activity of macrophages and smooth muscle cells, inducing smooth muscle cells to secrete extracellular matrix which strengthens the fibrous cap and prevents rupture. At present, the primary target of statins is LDL cholesterol reduction, but with additional effects on the inflammatory cell of the plaque with a reduction in macrophages and secretion of collagenolytic metalloproteases and reinforcing the fibrous skeleton of the plaque by increasing the content of interstitial collagen.