Abstract. Salonen JT, Nyysso Ènen K, Salonen R, Lakka H-M, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Lakka TA, Rissanen T, Leskinen L, tuomainen T-P, Valkonen V-P, Ristonmaa

Background-Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). Methods and Results-The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol Ն5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, Pϭ0.014), in men by 33% (95% CI, 4 to 62, Pϭ0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, Pϭ0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, Pϭ0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. Conclusions-These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.

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In the present study, we assessed the strongest determinants of plasma coenzyme Q IH (Q IH ) in 518 men and women (aged 45^70 years) with a stepwise multivariate regression model. Male gender (P 6 0.001), serum cholesterol (P 6 0.001), serum Q Q-glutamyltransferase (P 6 0.001), serum triglycerides (P 6 0.001), age (P = 0.017) and 4-day alcohol consumption (P = 0.03) were the most important factors which were directly associated with plasma Q IH . The intensity of conditioning exercise (P = 0.03) and use of statins (P 6 0.05) showed an inverse association with plasma Q IH . None of the assessed nutrients increased plasma Q IH levels significantly. Our results suggest that many confounding factors, in addition to serum cholesterol and triglycerides, should be taken into account when the role of plasma Q IH is examined in epidemiological research.z 1999 Federation of European Biochemical Societies.

Abstract-We studied the long-term effects of vitamins E and C and their combination on lipid peroxidation in vivo and in vitro. The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) trial is a double-masked placebo-controlled randomized clinical trial to study the effects of vitamin C (500 mg of slow release ascorbate per day), vitamin E (182 mg of RRR-␣-tocopherol acetate per day), and the combination of both antioxidants. Lipid peroxidation measurements were carried out for 48 male participants at entry and at 12 and 36 months. Compared with placebo, vitamin E and the vitamin combination increased plasma lipid-standardized ␣-tocopherol during the first 12 months by 68.2% and 65.2% (PϽ0.001 for both), respectively, and reduced serum 7␤-hydroxycholesterol by 50.4% (Pϭ0.013) and 44.0% (Pϭ0.041), respectively. The net change of lipid standardized ␣-tocopherol was 63.8% after 36 months of vitamin E supplementation and 43.3% for the combination. Vitamin C supplementation elevated plasma total ascorbate level by 30.1% (Pϭ0.043) in 12 months and by 91.1% (Pϭ0.001) in 36 months.Neither vitamin E, vitamin C, nor the combination influenced the urinary excretion rate of 7-hydro-8-oxo-2Ј-deoxyguanosine or the antioxidative capacity of plasma. Vitamin E and the combination of vitamins E and C enhanced the oxidation resistance of isolated lipoproteins and total serum lipids. Our data indicate that long-term supplementation of nondepleted men with a reasonable dose of vitamin E alone or in combination with slow release vitamin C reduces lipid peroxidation in vitro and in vivo, whereas a relatively high dose of vitamin C alone does not. Key Words: antioxidants Ⅲ lipid peroxidation Ⅲ oxidation resistance Ⅲ 7-hydro-8-oxo-2Ј-deoxyguanosine Ⅲ oxysterols V itamins E 1-4 and C 5,6 are widely regarded as important dietary antioxidants. However, this concept is based on in vitro studies and on supplementation trials in which only measurements of lipid peroxidation ex vivo have been performed. 3 The evidence of the lipid peroxidation-inhibiting effects of vitamins E and C in vitro is plentiful. [1][2][3][4][5][6][7] In addition, oral vitamin E supplementation has consistently increased the oxidation resistance of isolated lipoproteins in vitro. 8 -13 Vitamin C has had been shown to have a similar effect in a few 14 -16 but not in all 17 studies. Vitamin C can also act as a pro-oxidant in certain conditions. 17,18 In theory, vitamin E could function as a mediator of lipid peroxidation if sufficient coantioxidants are not present. 19,20 However, this theory has not been tested in oral supplementation studies with in vivo measurements. There are no previous long-term placebocontrolled oral supplementation trials concerning the effects of these vitamins on lipid peroxidation in nonsmoking clinically healthy subjects.The assessment of oxidative stress and lipid peroxidation in vivo in humans is problematic. 7-Hydro-8-oxo-2Ј-deoxyguanosine (8-oxodG), a repair product of oxidative damage to DNA, has been used as an indicator...