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Previous cross-cultural comparisons of the mortality from ischemic heart disease in European communities with associated plasma levels of essential antioxidants have revealed strong inverse correlations for vitamin E and relatively weak correlations for other antioxidants. Similarly, in a case-control study in Edinburgh low plasma levels of vitamin E were significantly associated with an increased risk of previously undiagnosed angina pectoris whereas low levels of other essential antioxidants lacked statistical significance. The current Basel Prospective Study is particularly well suited to elucidate the impact of antioxidants other than vitamin E. In this population (which was recently evaluated regarding cancer mortality) the plasma levels of vitamins E and A are exceptionally high and above the presumed threshold level of risk for ischemic heart disease. The present 12-year follow-up of cardiovascular mortality in this study reveals a significantly increased relative risk of ischemic heart disease and stroke at initially low plasma levels of carotene (< 0.23 µmol/l) and/or vitamin C (< 22.7 µmol/l), independently of vitamin E and of the classical cardiovascular risk factors. Low levels of both carotene and vitamin C increase the risk further, in the case of stroke even with significance for overmultiplicative interaction. In conclusion, in cardiovascular disease independent inverse correlations may exist for every major essential antioxidant although the latter can also interact synergistically. Therefore future intervention trials of antioxidants in the prevention of ischemic heart disease should primarily test the simultaneous optimization of the status of all principal essential antioxidants.

Plasma antioxidant vitamins A, C, and E and carotene were measured in a group of 2,974 men participating in the third examination of the prospective Basel Study in 1971-1973. In 1985, the vital status and mortality of all participants were assessed. A total of 204 men had died from cancer, including 68 with bronchus cancer and 37 with gastrointestinal cancer (20 with stomach cancer and 17 with large bowel cancer excluding cancer of the rectum). Overall mortality from cancer was associated with low mean plasma levels of carotene adjusted for cholesterol (p less than 0.01) and of vitamin C (p less than 0.01). Bronchus and stomach cancers were associated with a low mean plasma carotene level (p less than 0.01). Subjects with subsequent stomach cancer also had lower mean vitamin C and lipid-adjusted vitamin A levels than did survivors (p less than 0.05). After calculation of the relative risk using the Cox model with exclusion of mortality during the first 2 years of follow-up, low plasma carotene (below quartile 1) was associated with a significantly increased risk for bronchus cancer (relative risk (RR) = 1.8, p less than 0.05), low plasma levels of carotene and vitamin A with all cancers (RR = 2.47, p less than 0.01), and low plasma retinol in older subjects (greater than age 60 years) with lung cancer (RR = 2.17, p less than 0.05). Low levels of vitamin C increased the risk of stomach cancer (RR = 2.38) and gastrointestinal cancer (RR = 2.46) in older subjects, but only significantly with the inclusion of the first 2 years. The authors conclude that low plasma levels of antioxidant vitamins are associated with an increased risk of subsequent cancer mortality. This effect was stronger in men above age 60 years at blood sampling, and the effect seems to be site-specific.