Tocopherols and Cardiovascular Disease Epidemiological Evidence

The effects of dietary vitamin E have been examined in several studies, many of which have reported a clear association between the reduction in the relative risk of CVD and high intake or supplement of vitamin E, although some have shown no such association. The Vitamin Substudy of the WHO/MONICA Project showed that in European populations whose classical risk factors for CVD were very similar, the 7-fold differences in CVD mortality could be explained at least to approximately 60% by differences in the plasma levels of vitamin E and up to 90% by the combination of vitamins E, A, and C. The Edinburgh Case Control Study and Basel Prospective Study consistently revealed an increased risk of ischemic heart disease and stroke for low plasma levels of vitamin E. However, other European population studies have not found an association between blood levels of vitamin E and end points of CVD. In the EURA-MIC study, the adipose levels of vitamin E did not correlate with the relative risk of myocardial infarction.

A number of prospective studies have examined the association between vitamin E intake and risk of CHD. The Nurses' Health Study, conducted on

87245 women, showed a 34% reduction in CHD in women who had consumed vitamin E supplements containing more than 67 mg a-TE daily for more than 2 years. However, there was no significant effect of vitamin E obtained from food sources. The Established Populations for Epidemiolodic Studies of the Elderly (EPESE) trials showed that the use of vitamin E supplements significantly decreased risks for all-cause-mortality and mortality from heart disease. Another prospective study, performed in Canada, reported a consistent inverse association between CVD and vitamin E supplement usage. The Health Professionals Study, conducted on 39 910 men aged 40-75 years, also showed that dietary intakes of vitamin E were not significantly correlated with reduced risk of CHD or death. A protective effect was seen in those who took 67-160 mg supplemental a-TE daily for more than 2 years. In contrast, the Iowa Women's Health Study reported that dietary vitamin E (mainly 7-tocopherol) was inversely associated with the risk of death from CVD. This association was particularly striking in the subgroup of women who did not consume vitamin supplements. There was little evidence that the intake of vitamin E from supplements (mainly a-tocopherol) was associated with a decreased risk of death from CVD. The reasons for the differences between dietary and supplemental vitamin E are not clear. However, some epidemiological studies point to the potential importance of 7-tocopherol in preventing heart disease. High dietary intake of nuts, an excellent source of 7-tocopherol, lowered serum cholesterol, improved plasma lipid profiles, and was inversely associated with the risk of death from heart disease.

The ability of a-tocopherol supplementation to prevent cardiovascular events in different populations was tested in four larger prospective clinical trials: The a-Tocopherol, ^-Carotene Cancer Prevention (ATBC) study, the Cambridge Heart Anti-oxidant Study (CHAOS), the Gruppo Italiano per lo studio della Sopravvivenza nell'Infarto Miocar-dito (GISSI) trial, and the Heart Outcome Prevention Evaluation (HOPE) study. In addition, at least two smaller prospective clinical trials have been completed: the Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) study and the Antioxidant Supplementation in Atherosclerosis Prevention Study (ASAP).

In the ATBC study, the subjects who were supplemented with 50 mg all rac-a-tocopheryl acetate day-1 for 5-8 years had only a moderately lower incidence (4%) of angina pectoris than did the control subjects, and among male smokers, cardiovascular mortality did not differ significantly between those who received supplementation and those who did not. However, subjects who received supplementation had a significantly higher incidence of haemorrhagic stroke than did the control subjects. Note that the ATBC study was not designed to investigate cardiovascular disease development. The results of the CHAOS trial, the first prospective trial with cardiovascular disease as an end point, were encouraging. The risks of nonfatal myocardial infarction declined 77% and total (fatal plus nonfatal) myocardial infarction declined 47% when patients with established coronary artery disease were treated with 268 or 536 mg a-TE daily for approximately 500 days. The GISSI study showed that feeding 211 mg a-TE day-1 for 3.5 years did not significantly reduce the rate of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. However, in a later four-way reanalysis in which each individual variable was considered as an end point, there were significantly fewer (20%) cardiovascular deaths in the a-tocopherol group than in the control group. The HOPE study reported that vitamin E (400IU (268 mg) day-1 RRR-a-tocopherol) treatment of CVD patients had no effect on reducing the primary end points, which included nonfatal myocardial infarction, stroke, and cardiovascular death. In the SPACE trial, haemodialysis patients with preexisting cardiovascular disease received 536 mg (RRR)-a-tocopherol or placebo day-1. Patients who received vitamin E had a striking 54% reduction in cardiac events compared with control subjects.

In the ASAP study, men and women (all subjects had hypercholesterolemia at entry) were given vitamin E (91 mg twice daily), slow-release vitamin C (250 mg twice daily), a combination of both, or placebo for 3 years. The progression of atherosclerosis (the mean intima-media thickness of the common carotid artery measured) was significantly retarded only in the men who smoked and took both vitamins. It is important to note that, in general, women develop fewer cardiovascular events than do men. Thus, women may profit less from vitamin E treatment than men. In studies in which many women are enrolled, the low incidence of CVD may weaken the statistical power of the overall trial.

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