EPIDEMIOLOGICAL STUDIES LINKING ANTIOXIDANTS AND LDL OXIDATION
Vitamin E
Two large longitudinal studies in the United States examined the association between "tamin E intake and risk of CHD. In a group of 39, 910 male health professionals, those who took vitamin E supplements in doses of at least lOOIU per day for over 2 yr had a 37% lower ::elative risk of CHD compared to men who did not take vitamin E supplements, after TIijustment for age, coronary risk factors, and intake of vitamin C and B-carotene. In the -,urses' Health Study of 87,245 female nurses, women who took vitamin E supplements for more than 2 yr had a 41 % lower relative risk of major coronary disease. This effect persisted after adjustment for age, smoking, obesity, exercise, blood pressure, plasma cholesterol, and e of postmenopausal estrogen replacement, aspirin, vitamin C, and p-carotene.
It must be noted that this effect was limited to vitamin E supplement use.
High vitamin E intakes from dietary sources were not associated with a significant decrease in risk, although even the highest dietary vitamin E intakes were far lower than intakes among supplement users. Support from case-control studies based on biological samples is sparse, although Gey and coworkers found that plasma levels of vitamin E in men aged 40 49 yr correlated strongly and inversely with the age-specific mortality from CHD in 16 European regions. A population case-control study also evaluated the relation between undiagnosed angina pectoris and plasma antioxidant levels in men aged 35 - 54 yr. Plasma levels of vitamin C, vitamin E, and carotene manifested a significant inverse correlation with undiagnosed angina.
The inverse association between vitamin E levels and angina remained signifi-cant after adjustment for smoking habits, age, blood pressure, relative weight, and blood lipid levels. However, these results have been offset by several negative studies. There was no association between plasma vitamin E and prevalence of CHD in a cross-sectional survey of 1132 Finnish men. Similarly, most nested case-control studies found no relationship between plasma vitamin E levels and subsequent coronary mortality or risk of MI. The reason for these disparate results is unknown, but may include changes in diet following disease diagnosis, poor classification of controls, and lack of variation in plasma levels within populations not using supplements.
Vitamin C
The evidence linking the water-soluble vitamin C with cardiovascular disease is less strong than that for vitamin E. In the Physicians' Follow-Up Study, a high intake of vitamin C was not associated with a lower risk of CHD in men, whereas in women from the Nurses Health Survey, an initial effect was attenuated after adjustment for multivitamin use. Only one prospective study, which involved 11,348 adults, demonstrated all inverse relationship between vitamin C intake and cardiovascular mortality. This effect was due largely to the use of vitamin C in supplements and may have been a reflection of other antioxidant vitamins in multivitamin preparations. A link between intake and carotid artery wall thickness has also been suggested.
Plasma levels were not correlated with coronary mortality rates among four European populations or with prevalent coronary disease in Finland. In the Basle Prospective Study, low levels of vitamin C alone did not increase the risk of CHD, although the risk of disease at low levels of both vitamin C and B-carotene was greater than that for B-carotene alone. However, a prospective population study of 1605 healthy men aged 42 - 60 in Finland has recently shown that men who had vitamin C deficiency had a relative risk of MI of 2.5 after adjusting for the main risk factors for MI.
B-Carotene
There is some indication that increased dietary intake of B-carotene is associated with reduced risk of CHD although again the evidence is less convincing than that for vitamin E. In the prospective Nurses Health Survey, consumption of vitamin A and B-carotene in food and supplements weakly predicted the incidence of CHD; Gaziano and Hennekens reported a 22% risk reduction for women in the highest quintile of B-carotene compared with those in the lowest. No adjustment was made for the potentially confounding effect of other antioxidant vitamins in multivitamin preparations. However, a small prospective study on 1271 elderly people also demonstrated an inverse relationship between B-carotene intake in fruit, and vegetables and subsequent cardiovascular death. Similar findings have been shown for serum carotenoid level and CHD risk, and carotenoid intake and carotid artery plaque thickness.
Several studies indicate that dietary and circulating levels of B-carotene affect smokers more than nonsmokers. In the Health Professionals Follow-Up Study, high B-carotene intake was associated with reduced CHD risk in current smokers and exsmokers (70% risk reduction' but not never-smokers, after adjustment for cardiovascular risk factors and vitamin C and E intake. It was suggested that a high dietary intake of ~-carotene is especially important in smokers who have both an increased demand for antioxidants (to combat smoking-induced free radicals) and a correspondingly lower circulating level for a given dietary intake. However, (B-carotene supplements in smokers may have harmful effects as discussed in the next section.
