Dietary antioxidants and the prevention of CHD: epidemiological evidence

A large number of epidemiological studies have evaluated potential relationships between dietary intake of antioxidants and coronary heart disease (CHD). Among these, the Nurses’ Health study, included over 87 000 female nurses 34 to 59 years of age, who completed dietary questionnaires that assessed their consumption of a wide range of nutrients, including vitamin E. During follow-up of up to 8 years 552 cases of major coronary disease were documented. As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66 after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients, including other antioxidants, had little effect on the results. Similarly, the Health Professionals’ Follow-up study, among almost 40 000 males of 40±75 years, followed up for four years, showed a lower risk of coronary disease among men with higher intakes of vitamin E.

Kushi et al. studied over 34 000 postmenopausal women with no cardio­vascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E and C from food sources and supplements. After 7 years of follow-up, results suggested that in post­menopausal women the intake of vitamin E from food was inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21 809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42 and 0.42; P for trend = 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32 and 0.38; P for trend = 0.004). By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease.

On the other hand, a negative result came from the Rotterdam Study in which 4802 participants aged 55±95 years, who were free of myocardial infarction (MI) at baseline and for whom dietary data assessed by a semiquantitative food frequency questionnaire were available, were followed up for 4 years: an association between vitamin C or vitamin E and MI was not observed.

Other studies have evaluated plasma levels of different antioxidants, such as vitamins E, C and ,3-carotene in populations affected or not by CHD. The WHO/ Monica project has been one of the largest studies that have analysed the intake of these vitamins in populations with different incidence of CHD mortality. In populations with similar values of serum cholesterol and blood pressure, an inverse correlation between CHD mortality and vitamin E plasma levels was observed; conversely, no relation existed between CHD mortality, and other vitamins. In areas with low and medium coronary mortality, plasma levels of vitamin E were 26±28 pM, while at sites with most frequent CHD mortality plasma levels were 20±21.5 µM.

 

The authors also estimated that the threshold risk for cardiovascular disease would be <25 µM, which, in this particular population, corresponds to < 4.3 µmol vitamin E/mmol cholesterol. This finding is consistent with other studies showing an inverse correlation between vitamin E plasma levels and cardiovascular mortality. It was noticed, in particular, that in persons with high risk for cardiovascular mortality the vitamin E/cholesterol ratio was 3.5, while in persons with low risk the ratio was almost 5. The inverse correlation between vitamin E levels and CHD was also noted in another observational study in which 110 people with angina were compared with 394 controls. The study demonstrated that patients with a history of angina had a lower vitamin E/cholesterol ratio than controls (3.66 vs. 3.86 µmol/mol, P < 0.01) with a significant adjusted odds ratio for angina between patients in the lowest and highest quartile.

In a cross-sectional survey within a random sample of a single urban setting in India, the relation between risk of cardiovascular disease (CVD) and plasma levels of vitamin E was examined in 595 elderly subjects. Plasma levels of vitamin E appeared significantly inversely related to CVD. The adjusted odds ratios for CVD between the lowest and the highest quintiles of vitamin E levels were 2.53, after adjustment for confounding variables.

Another study, designed to assess the degree of association between vitamin E and CHD in a sample of the Tunisian population, included 62 angio­graphically confirmed coronary atherosclerotic patients and 65 age- and sex-matched controls. A trend toward a meaningful decrease of plasma tocopherol was observed in affected patients compared with controls (P = 0.06). Vitamin E concentrations standardised for cholesterol and lipid concentrations were significantly lower (P < 0.02) in coronary patients than in controls (4.35 Ô 1.03 vs. 4.82 Ô 1.23 mmol/mol) for cholesterol-adjusted vitamin E. This association between vitamin E and CHD remained unchanged independent of age, sex, smoking habit, hypertension and diabetes.

These findings have been further corroborated by another study in which 102 apparently healthy subjects were followed up for 47.4 months. A higher risk of cardiovascular events in subjects in the lowest quartile of vitamin E plasma levels compared with those in the highest was found.

In a recent study the association between preclinical carotid atherosclerosis and both the intake and plasma concentrations of antioxidant vitamins was evaluated. Among 5062 participants in Progetto Atena, a population-based study on the aetiology of cardiovascular disease and cancer in women, 310 women were examined by B-mode ultrasound to detect early signs of carotid atherosclerosis. The participants answered a food-frequency questionnaire, and their plasma concentrations of vitamin E, vitamin A and carotenoids were measured. The occurrence of atherosclerotic plaques at the carotid bifurcation was inversely associated with tertiles of vitamin E intake. Similarly, the ratio of plasma vitamin E to plasma cholesterol was inversely related to the presence of plaques at the carotid bifurcation. No association was found between the intake of other antioxidant vitamins (vitamins A and C and carotenoids) or their plasma concentrations and the presence of carotid plaques. The results of a few similar previous studies were instead unclear.

Taken together, these data suggest that vitamin E is an important predictor of CHD and may represent an independent risk factor for atherosclerosis and its complication. Owing to the lack of standardization and a somewhat large dispersion of vitamin E/cholesterol ratio values, accurate analysis of vitamin E levels in patients and healthy subjects is crucial in developing clinical practice and interventional trials. Very recently, for instance, healthy subjects were shown to have values of vitamin E of 3.6 µmol/mmol cholesterol, which is much less than that reported in control population. This finding also raises serious concerns on the methodology used for measuring vitamin and strongly suggests the need for standardization of the assay.