Antioxidant vitamin supplements and cardiovascular disease.

The American Heart Association (AHA) has had a longstanding commitment to provide information about the role of nutrition in cardiovascular disease (CVD) risk reduction. Many activities have been and are currently directed toward this objective, including issuing AHA Dietary Guidelines periodically (most recently in 20001) and Science Advisories and Statements on an ongoing basis to review emerging nutrition-related issues. The objective of the AHA Dietary Guidelines is to promote healthful dietary patterns. A consistent focus since the inception of the AHA Dietary Guidelines has been to reduce saturated fat (and trans fat) and cholesterol intake, as well as to increase dietary fiber consumption. Collectively, all the AHA Dietary Guidelines have supported a dietary pattern that promotes the consumption of diets rich in fruits, vegetables, whole grains, low-fat or nonfat dairy products, fish, legumes, poultry, and lean meats. This dietary pattern has a low energy density to promote weight control and a high nutrient density to meet all nutrient needs. As reviewed in the first AHA Science Advisory2 on antioxidant vitamins, epidemiological and population studies reported that some micronutrients may beneficially affect CVD risk (ie, antioxidant vitamins such as vitamin E, vitamin C, and -carotene). Recent epidemiological evidence3 is consistent with the earlier epidemiological and population studies (reviewed in the first Science Advisory).2 These findings have been supported by in vitro studies that have established a role of oxidative processes in the development of the atherosclerotic plaque. Underlying the atherosclerotic process are proatherogenic and prothrombotic oxidative events in the artery wall that may be inhibited by antioxidants. The 1999 AHA Science Advisory2 recommended that the general population consume a balanced diet with emphasis on antioxidant-rich fruits, vegetables, and whole grains, advice that was consistent with the AHA Dietary Guidelines at the time. In the absence of data from randomized, controlled clinical trials, no recommendations were made with regard to the use of antioxidant supplements. In the past 5 years, a number of controlled clinical studies have reported the effects of antioxidant vitamin and mineral supplements on CVD risk (see Tables 1 through 3).4–21 These studies have been the subject of several recent reviews22–26 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. Overall, the studies have been conducted on post–myocardial infarction subjects or subjects at high risk for CVD, although some studied healthy subjects. In addition to dosage differences in vitamin E studies, some trials used the synthetic form, whereas others used the natural form of the vitamin. With regard to the other antioxidants, different doses were administered (eg, for -carotene and vitamin C). The antioxidant cocktail formulations used also varied. Moreover, subjects were followed up for at least 1 year and for as long as 12 years. In addition, a meta-analysis of 15 studies (7 studies of vitamin E, 50 to 800 IU; 8 studies of -carotene, 15 to 50 mg) with 1000 or more subjects per trial has been conducted to ascertain the effects of antioxidant vitamins on cardiovascular morbidity and mortality.27 Collectively, for the most part, clinical trials have failed to demonstrate a beneficial effect of antioxidant supplements on CVD morbidity and mortality. With regard to the meta-analysis, the lack of efficacy was demonstrated consistently for different doses of various antioxidants in diverse population groups. Although the preponderance of clinical trial evidence has not shown beneficial effects of antioxidant supplements, evidence from some smaller studies documents a benefit of -tocopherol (Cambridge Heart AntiOxidant Study,13 Secondary Prevention with Antioxidants of Cardiovascular disease in End-stage renal disease study),15 -tocopherol and slow-release vitamin C (Antioxidant Supplementation in Atherosclerosis Prevention study),16 and vitamin C plus vitamin E (Intravascular Ultrasonography Study)17 on cardio-