Treatment of Atherosclerosis in the New Millennium: Is There a Role for Vitamin E?

Abstract

Oxidative stress appears to be of fundamental relevance to diseases as diverse as atherosclerosis, cancer, and Alzheimer's disease. Observational data in humans have suggested that antioxidant vitamin intake is associated with reduced cardiovascular disease. Animal studies are largely consistent with the concept that dietary supplementation with antioxidant vitamins reduces the progression of atherosclerosis. However, recent prospective, controlled clinical trials of vitamin E, including the Cardiovascular Disease, Hypertension and Hyperlipidemia, Adult-Onset Diabetes, Obesity, and Stroke (CHAOS) study, the Heart Outcomes Prevention Evaluation (HOPE) trial, Gruppo Italiano per lo Studio della Sopravvivvenza nell'Infarto Miocardico (GISSI)-Prevenzione trial, the Secondary Prevention with Antioxidants of Cardiovascular Disease in End Stage Renal Disease (SPACE) trial, and the Heart Protection Study (HPS) present a confused picture. The various possibilities that have been advanced to explain this discrepancy are discussed in this review. A striking feature of these and other trials of antioxidants is the absence of a biochemical basis for patient inclusion or, indeed, dose selection. Patients with high levels of oxidant stress or depletion of natural antioxidant defense systems may be the most likely to benefit from antioxidant therapy. If this is the case, then reliable, quantitative indices of in vivo oxidant stress such as urinary isoprostane levels should be considered as an inclusion criterion for patient selection. Future trials of antioxidant therapy in cardiovascular disease should then be targeted toward such patients with high levels of oxidant stress or patients with depletion of natural antioxidant defense systems. Furthermore, the dose of antioxidant should be chosen based on a surrogate readout that is a reliable, reproducible, and easily obtainable in vivo measure of oxidant stress. In the interim, although the safety of vitamin E up to doses of 800 IU/day has been determined, the conflicting nature of the results published to date encourages us to avoid making premature recommendations with respect to vitamin E supplementation in the prevention and treatment of cardiovascular disease.

Antioxidant vitamins induce angiogenesis in the normal pig kidney

“…The dependence of the effects of antioxidant vitamins on preexisting redox status (43) suggests that their beneficial effect can be achieved mainly in conditions characterized by high basal oxidative stress but can be otherwise neutral or even detrimental in unselected subjects. Indeed, this dual effect could partially account for the controversial results of recent clinical trials on cardiovascular outcomes after chronic administration of vitamins in different populations (26).…”

Mitochondrially Targeted Antioxidants for the Treatment of Cardiovascular Diseases

“…Population, retrospective and prospective observational studies seem to suggest that antioxidants have beneficial effects in coronary artery disease [12]. However, in welldesigned placebo-controlled randomized trials that were adequately powered to detect clinical events (ATBC, CARET, Physician's Health, HOPE, GISSI, PPP, HPS and HATS trials) there was lack of efficacy for vitamin E orcarotene [12,13]. These conflicting data on the clinical utility of antioxidant supplements may be due to several factors including absence of biochemical basis for patient inclusion and dose selection and lack of reliable quantitative indices of in vivo oxidant stress that might identify subjects who would benefit [12,13].…”

“…Antioxidant therapy therefore, has great potential for attenuating or reversing oxidative stress leading to atherosclerotic diseases. Despite success in animal models of disease, clinical trials of antioxidant therapy in humans have had mixed results [12,13].…”

Biological Functions and Metabolic Fate of Vitamin E Revisited

“…Although the scientific rationale, epidemiological data, and retrospective studies largely support the assumption that an increased intake of vitamin E is associated with a reduced risk of degenerative diseases, prospective, randomized, placebo-controlled trials have failed to verify a consistent benefit [21,43,47,48,64,74]. Based on the totality of available scientific evidence, the US Food and Drug Administration did not approve the health claims associated with vitamin E intake and risk of cancer or cardiovascular disease.…”