ANTIOXIDANTS AND PREVENTION OF EARLY ATHEROSCLEROSIS

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BACKGROUND. There is evidence from epidemiologic studies, and one unpublished trial, that greater intake of antioxidant vitamins (AV) is associated with reduced risk of CHD and stroke. Findings from an animal model indicate that increased intake of AV prevents progression of aortic fatty streaks induced by an atherogenic diet but not advanced injury- induced lesions. These observations suggest the hypothesis that increased AV intake may prevent further progression of early atherosclerosis, possible via reduced susceptibility of LDL to oxidative modification and consequent cytotoxic, chemotactic, chemostatic and unregulated uptake effects. A new automated method for determining intima-media thickness (IMT) of the common carotid artery (CCA) makes it feasible to test the primary prevention impact of AV on early atherosclerosis. Results of two trials at our institute demonstrate the LDL lowering effects on CCA IMT can be detected rapidly (within 12 to 24 months) in small samples (less than 30 per group) with automated IMT. Retardation of IMT progression was achieved in both studies without significant changes in average vessel diameter -- suggesting effects on early lesions. Furthermore, a Finish study found an inverse association between 12 month change in plasma alpha-tocopherol levels and change in carotid IMT. These findings imply that if there is an effect of alpha-tocopherol supplement on early atherosclerosis then it may be detectible with automated IMT in a small study within 12 to 24 months. HYPOTHESIS. Epidemiologic studies indicate cardiac protection after two years of vitamin E supplementation. It is thus hypothesized that, relative to placebo, vitamin E supplements (800 USP units/day) can retard the progression rate of CCA IMT over a period of 24 months. The hypothesis will be tested among African Americans since, relative to whites, cardiovascular mortality is sharply elevated in blacks under age 65, and they have been found to have increased CCA IMT in cross-sectional surveys. FEASIBILITY. The feasibility of the study stems from [1] recent development of an automated ultrasound IMT measure that reduces reproducibility error and required sample size; [2] portability and low- cost of the ultrasound system so that imaging can be conducted in a mobile van; [3] safety of both vitamin E supplementation at 573 mg/day and ultrasound exposure; [4] availability of subjects from a demonstrably cooperative community/school district that is participating in ongoing studies; and [15] increased compliance relative to longer term studies among persons at risk for cardiac events. DESIGN. Volunteering female and male African Americans aged 35-59 will be screened for carotid IMT at a school or at home (Screen 1). After 12 months, those subjects above the age and sex adjusted 66th percentile at Screen I will be rescreened (Screen II); those showing the greatest progression will be invited to participate in a run-in. Those subjects found to be cooperative and compliant (by plasma alpha-tocopherol level) will be randomized to vitamin E (573 mg/day) and placebo conditions. CCA IMT will be observed at 12 and 24 months follow ups. The primary outcome will be 24 month rate of change in average CCA IMT.