Does 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor Therapy Exert a Direct Anti-Ischemic Effect?
To the Editor:
The most important finding of the study is that in selected patients with documented coronary artery disease associated with myocardial ischemia on ambulatory ECG monitoring, dietary treatment and lovastatin therapy induced, after 4 to 6 months, a significant reduction of ischemic events compared with the control group (dietary treatment). Andrews et al1 concluded that the importance of their study is the evidence that cholesterol lowering is related to clinical manifestations of coronary artery disease and reduces cardiac events in the medium term.
Two points we would consider in the discussion of these results:
(2) Clinical and experimental data5 6 suggest that hypercholesterolemia affects endothelial function (abnormal constriction provoked by acetylcholine, reduction of endothelial nitric oxide production), but the time course of these alterations is still unknown.
In our opinion, the positive effects of statin therapy on myocardial ischemia may also be related to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition rather than only to the total and LDL cholesterol reduction. This hypothesis, at least in part, is supported by the evidence of best result, regarding mortality and ischemic events, obtained by statin therapy with respect to dietary treatment or therapy with fibrates.
We think that an important role in myocardial ischemia reduction and long-term prognosis improvement during HMG-CoA reductase inhibitor therapy may be due to a direct anti-ischemic effect of statin therapy, which potentially also provides a benefit during acute ischemia. In isolated working hearts of normolipidemic rats subjected to 15 minutes of global ischemia, our preliminary data suggest that short-term administration of simvastatin (50 μM) induces a significant reduction in ischemia-reperfusion damage and coronary endothelium dysfunction (endothelial permeability). At this time, we have no definitive data regarding the mechanism of this acute protective effect (reduction of postischemic coronary permeability changes via nitric oxide production or local modulation of coronary arterial tone?), but our observation, if not definitive evidence of a direct anti-ischemic effect of statins, suggests that further investigation is needed and may contribute to providing an explanation of the positive effects of statin therapy in short-term follow-up, which positive effect paradoxically also occurs in ischemic patients with normal total and LDL cholesterol.
- Copyright © 1998 by American Heart Association
Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, Selwyn AP. Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease. Circulation. 1997;95:324–328.
Frye RL. Clinical reality of lowering total and LDL cholesterol. Circulation. 1997;95:306–307.
Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm C, Alendander RW. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481–487.
van Boven AJ, Jukema W, Zwinderman AH, Crijns HJ, Lie KI, Bruschke AVG. Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris. Circulation. 1996;94:1503–1505.