Cardiovascular Benefit of Cholesterol-Lowering Therapy

ipid-lowering therapy with HMG-CoA reductase in- hibitors (statins) has been shown in large clinical trials to reduce cardiovascular morbidity and mortality in otherwise healthy hypercholesterolemic subjects and in pa- tients with coronary artery disease. The magnitude of risk reduction is greatest in individuals with the highest pretreat- ment cholesterol levels, although those with mild elevation in LDL cholesterol may also benefit from statin therapy. Be- cause angiographic trials with lipid-lowering therapy have shown little reduction in atherosclerotic plaque size, alternate mechanisms of therapeutic benefit to the arterial wall have been proposed, the most testable of which is improvement in endothelial vasodilator function. See p 846 Endothelial Vasodilator Function Testing, Myocardial Ischemia, and Cardiovascular Risk The endothelium maintains a nonthrombogenic surface for blood flow, prevents platelet and leukocyte adhesion to the vessel surface, modulates cellular composition of the arterial wall, and promotes dilator tone of arteries and veins, homeo- static properties regulated in part by the local synthesis of nitric oxide. Several groups have shown that endothelial release of nitric oxide is reduced or absent in patients with atherosclerosis, as well as in patients with risk factors for atherosclerosis, including hypercholesterolemia. Thus, ace- tylcholine, the agonist used in Furchgott and Zawadzki's experiments that showed release of relaxant factor from the endothelium,1 commonly constricts coronary arteries of pa- tients with atherosclerosis at doses that dilate arteries of patients whose coronary angiograms appear normal, espe- cially if they are free of risk factors for atherosclerosis. 2,3 Consistent with the notion that an important mechanism of cardiovascular risk reduction with statin therapy is improve- ment in nitric oxide-regulated endothelial function, several groups have shown that statin therapy reduces the constrictor effect of acetylcholine on coronary arteries of patients with