Oral α-tocopherol supplementation inhibits lipid oxidation in established human atherosclerotic lesions

Background : Much experimental evidence suggests that lipid oxidation is important in atherogenesis and in epidemiological studies dietary antioxidants appear protective against cardiovascular events. However, most large clinical trials failed to demonstrate benefit of oral antioxidant vitamin supplementation in high-risk subjects. This paradox questions whether ingestion of antioxidant vitamins significantly affects lipid oxidation within established atherosclerotic lesions. Methods and results : This placebo-controlled, double blind study of 104 carotid endarterectomy patients determined the effects of short-term alpha-tocopherol supplementation (500 IU/day) on lipid oxidation in plasma and advanced atherosclerotic lesions. In the 53 patients who received alpha-tocopherol there was a significant increase in plasma alpha-tocopherol concentrations (from 32.66+/-13.11 at baseline to 38.31+/-13.87 (mean+/-SD) mumol/l, p <0.01), a 40% increase (compared with placebo patients) in circulating LDL-associated alpha-tocopherol ( p <0.0001), and their LDL was less susceptible to ex vivo oxidation than that of the placebo group (lag phase 115.3+/-28.2 and 104.4+/-15.7 min respectively, p <0.02). Although the mean cholesterol-standardised alpha-tocopherol concentration within lesions did not increase, alpha-tocopherol concentrations in lesions correlated significantly with those in plasma, suggesting that plasma alpha-tocopherol levels can influence lesion levels. There was a significant inverse correlation in lesions between cholesterol-standardised levels of alpha-tocopherol and 7beta-hydroxycholesterol, a free radical oxidation product of cholesterol. Conclusions : These results suggest that within plasma and lesions alpha-tocopherol can act as an antioxidant. They may also explain why studies using <500 IU alpha-tocopherol/day failed to demonstrate benefit of antioxidant therapy. Better understanding of the pharmacodynamics of oral antioxidants is required to guide future clinical trials.