Clinical trials of vitamin E in coronary artery disease: is it time to reconsider the low-density lipoprotein oxidation hypothesis?

A wide range of structurally unrelated antioxidants inhibit atherosclerosis in animal models of hypercholesterolemia, implicating oxidation of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, most prospective, randomized trials of one proposed antioxidant, vitamin E, have failed to demonstrate any reduction in cardiovascular events in humans with established coronary artery disease. Recent clinical studies suggest that vitamin E is also ineffectual in the primary prevention of atherosclerosis. These observations have led many to question the relevance of LDL oxidation to the pathogenesis of human cardiovascular disease. However, vitamin E's ineffectiveness in clinical trials might result from its failure to act as a physiologically relevant antioxidant. Indeed, vitamin E does not consistently inhibit atherosclerosis in hypercholesterolemic animals, and there is remarkably little evidence that clinically relevant doses of vitamin E result in inhibition of lipid peroxidation in vivo. Collectively, these observations indicate that there is little rationale for using vitamin E to prevent coronary artery disease in humans. They also strongly suggest that it will be critically important to establish that compounds with antioxidant activity in vitro actually prevent oxidative reactions in vivo before embarking on any new clinical trials.