Clinical trials of vitamin E in coronary artery disease: Is it 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.

Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL

“…None of these trials provided evidence that the levels of the specific proinflammatory oxidized phospholipids were decreased by the oral antioxidants tested (71,72). Indeed, these trials did not even show that administration of the antioxidants reduced lipid oxidation in the test subjects (71,72).…”

Systemic Markers of the Redox Balance and Apolipoprotein E Polymorphism in Atherosclerosis: The Relevance for an Integrated Study

“…It is thought to be effective in preventing atherosclerosis (12), because a local or generalized diminution of α-tocopherol concentration caused by dietary or oxidative factors can stimulate cell growth and lead to atherosclerosis progress (48). However, supplements of dietary vitamin E in clinical trials have not prevented consistently cardiac attacks in humans with established coronary heart disease, and vitamin E might become an oxidant agent (2,49,50). Such contradictory results have questioned the role of vitamin E as a protective agent in human atherosclerosis (51).…”

“…Although mortality from coronary heart disease has declined recently, atherosclerosis and related vascular diseases are still the major causes of death in Western countries (1,2), including Portugal. Atherosclerosis is a chronic disease of large and medium-sized arteries, with hardening and loss of elasticity of the arterial walls and narrowing of the arterial lumen (1).…”

Antioxidant Vitamin Supplements and Cardiovascular Disease

“…4 -21 These studies have been the subject of several recent reviews [22][23][24][25][26] and formed the database for the present article. In general, the studies presented in the tables differ with regard to subject populations studied, type and dose of antioxidant/cocktail administered, length of study, and study end points.…”

“…[25][26][27][28]29 This conclusion is consistent with the American College of Cardiology/American Heart Associa- MI indicates myocardial infarction; GISSI, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-prevenzione study; HOPE, Heart Outcomes Protection Evaluation trial; PPP, Primary Prevention Project; MICRO-HOPE, Microalbuminuria Cardiovascular Renal Outcomes-Heart Outcomes Prevention Evaluation trial; ATBC, Alpha-Tocopherol-Beta-Carotene Cancer Prevention study; SCPS, Skin Cancer Prevention Study; PHS, Physicians' Health Study; HPS, Heart Protection Study; and VEAPS, Vitamin E Atherosclerosis Prevention Study. tion 2002 Guideline Update for the management of patients with chronic stable angina, which states that there is no basis for recommending that patients take vitamin C or E supplements or other antioxidants for the express purpose of preventing or treating coronary artery disease (Class III, Level A Evidence).…”