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

Abstract:

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.

In contrast to other lipid-soluble antioxidants, vitamin E at doses that fail to lower cholesterol levels has not consistently inhibited atherosclerosis in hypercholesterolemic
animals. It is important to note that LDL isolated from the animals was protected from oxidation ex vivo, implying that vitamin E was incorporated effectively into the lipoprotein. A key issue raised by these studies is whether vitamin E is able to inhibit LDL oxidation in the artery wall. Two recent studies provided convincing evidence that very high levels of dietary vitamin E (0.2% of the diet; approximately 8 IU/d per mouse and approximately 10,000 IU/d per human) inhibit atherosclerosis in mice deficient in apolipoprotein E. Importantly, the intervention also lowered tissue levels of isoprostanes , which are sensitive and specific markers of lipid peroxidation . These observations emphasize the importance of documenting that a proposed antioxidant intervention actually inhibits oxidative reactions in vivo. Studies of mice with genetically engineered vitamin E deficiency also suggest that vitamin E has little impact on atherosclerosis. In animals with targeted disruption of the α-tocopherol transport protein, plasma vitamin E levels were less than 10% of those in wild-type mice. Despite the marked decline in plasma levels of vitamin E, the genetically altered animals exhibited only 30% more atherosclerosis and a moderate twofold increase in tissue levels of F2-isoprostanes, markers of lipid oxidation. Collectively, these observations suggest that vitamin E is not a potent inhibitor of atherogenesis in animal models of atherosclerosis. They also raise major questions regarding the ability of vitamin E at clinically relevant levels of dietary supplementation to inhibit lipid peroxidation and LDL oxidation in the artery wall.