Exhaustive exercise increases plasma/serum total oxidation resistance in moderately trained men and women, whereas their VLDL + LDL lipoprotein fraction is more susceptible to oxidation.

The purpose of this study was to evaluate the effects of exhaustive exercise (marathon run) on different lipid peroxidation measurements, including copper-induced serum lipids and VLDL + LDL oxidation susceptibility, and on plasma total antioxidative capacity (TRAP), muscular damage and plasma antioxidants in healthy moderately trained male (n = 21) and female (n = 25) volunteers. Blood samples were taken before and just after the 42-km run. In women, baseline levels of several antioxidative compounds (serum albumin and uric acid, plasma free thiols and blood glutathione) were lower, resulting in 21.5% lower plasma total antioxidative capacity and 70.3% higher serum oxidation susceptibility, compared to men. To compare effects in men and women, the exercise-induced variable changes were adjusted for their baseline levels. After this adjustment, there were no statistically significant differences between the genders in the extent of muscular damage (serum creatine kinase, (CK)), or in the change in serum lipids or VLDL + LDL oxidation susceptibility, or that of plasma antioxidative capacity. A possible beneficial effect of exercise was that serum HDL cholesterol levels increased significantly in both genders, but especially in women. In the group of pooled genders (n=46), the increases in serum CK and in plasma lactate were 190% (95% CI, 133% to 246%) and 109% (95% CI, 65% to 175%), respectively. On the basis of our lipid peroxidation and TRAP measurements, uric acid was observed to be the most important plasma antioxidant. The effect of exercise was to decrease the oxidation susceptibility of serum lipids by 24.8% (95% CI 13.4% to 36.2%) and to elevate plasma TRAP by 14.6% (95% CI, 11.4% to 17.7%). Nonetheless, the oxidation susceptibility of the VLDL + LDL fraction increased by 11.0% (95% CI, 1.9% to 20.2%). Our results suggest that there are no gender-based differences in exhaustive exercise-induced lipid peroxidation or muscular damage. Secondly, even though exhaustive exercise can increase plasma/serum total resistance towards oxidation, the oxidation resistance of the atherogenic lipoprotein fraction might be diminished. On the basis of these results, several in vitro measurements of lipid peroxidation assessing both water and lipid soluble plasma fractions are needed if a true perspective of the plasma redox status is to be obtained.

Gene transfer of extracellular superoxide dismutase to atherosclerotic mice.

Clinical and epidemiological studies have provided circumstantial evidence that oxidized low-density lipoprotein (LDL) and antioxidants are involved in the pathogenesis of atherosclerosis. Superoxide dismutases (SODs) have been shown in vitro to protect LDL from deleterious effects of superoxide anions. In the present study, we have used adenoviral gene transfer to determine effect of extracellular SOD (EC-SOD) on atherogenesis in LDL receptor -/- mice. Intravenous administration of EC-SOD adenovirus (2 x 10(9) plaque forming units) into tail vein targeted transgene mainly to liver and induced a 3.5- to sevenfold increase in plasma total SOD activity. EC-SOD was secreted into circulation for 2-3 weeks mostly in a truncated B-form, suggesting that endogenous proteolytic mechanisms control the level and distribution of the enzyme. Therapeutic potential was determined by measuring plasma resistance against copper oxidation and analyzing atherosclerotic lesion areas in aortas of LDL receptor -/- mice. Mice were kept on a cholesterol diet for 10 weeks before gene transfer and 3 or 6 weeks after the gene transfer. Results showed a tendency for a reduction in the overall lesion area after EC-SOD gene transfer as compared with LacZ transduced control mice, but the difference did not reach statistical significance. It is concluded that short-term overexpression of EC-SOD in vivo does not affect atherogenesis in LDL receptor -/- mice.

Supplementation with vitamin E but not with vitamin C lowers lipid peroxidation in vivo in mildly hypercholesterolemic men.

Although the use of vitamin E supplements has been associated with a reduction in coronary events, assumed to be due to lowered lipid peroxidation, there are no previous long-term clinical trials into the effects of vitamin C or E supplementation on lipid peroxidation in vivo. Here, we have studied the long-term effects of vitamins C and E on plasma F2-isoprostanes, a widely used marker of lipid peroxidation in vivo. As a study cohort, a subset of the "Antioxidant Supplementation in Atherosclerosis Prevention" (ASAP) study was used. ASAP is a double-masked placebo-controlled randomized clinical trial to study the long-term effect of vitamin C (500 mg of slow release ascorbate daily), vitamin E (200 mg of D-alpha-tocopheryl acetate daily), both vitamins (CellaVie), or placebo on lipid peroxidation, atherosclerotic progression, blood pressure and myocardial infarction (n = 520 at baseline). Lipid peroxidation measurements were carried out in 100 consecutive men at entry and repeated at 12 months. The plasma F2-isoprostane concentration was lowered by 17.3% (95% CI 3.9-30.8%) in the vitamin E group (p = 0.006 for the change, as compared with the placebo group). On the contrary, vitamin C had no significant effect on plasma F2-isoprostanes as compared with the placebo group. There was also no interaction in the effect between these vitamins. In conclusion, long-term oral supplementation of clinically healthy, but hypercholesterolemic men, who have normal vitamin C and E levels with a reasonable dose of vitamin E lowers lipid peroxidation in vivo, but a relatively high dose of vitamin C does not. This observation may provide a mechanism for the observed ability of vitamin E supplements to prevent atherosclerosis.

Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis.

OBJECTIVES: To study the efficacy of vitamin E and C supplementation on the progression of carotid atherosclerosis, hypothesizing an enhanced preventive effect in men and in smokers and synergism between vitamins. DESIGN AND SUBJECTS: Double-masked two-by-two factorial trial, randomization in four strata (by gender and smoking status) to receive twice daily either 91 mg (136 IU) of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these or placebo for three years. A randomized sample of 520 smoking and nonsmoking men and postmenopausal women aged 45-69 years with serum cholesterol >/= 5.0 mmol L-1 were studied. SETTING: The population of the city of Kuopio in Eastern Finland. INTERVENTION: Twice daily either a special formulation of 91 mg of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these (CellaVie(R)) or placebo for three years. MEASUREMENTS: Atherosclerotic progression, defined as the linear regression slope of ultrasonographically assessed common carotid artery mean intima-media thickness (IMT), was calculated over semi-annual assessments. RESULTS: The average increase of the mean IMT was 0.020 mm year-1 amongst men randomized to placebo and 0.018 mm year-1 in vitamin E, 0.017 mm year-1 in vitamin C and 0.011 mm year-1 in the vitamin combination group (P = 0.008 for E + C vs. placebo). The respective means in women were 0.016, 0.015, 0.017 and 0.016 mm year-1. The proportion of men with progression was reduced by 74% (95% CI 36-89%, P = 0.003) by supplementation with the formulation containing both vitamins, as compared with placebo. CONCLUSIONS: Our study shows that a combined supplementation with reasonable doses of both vitamin E and slow-release vitamin C can retard the progression of common carotid atherosclerosis in men. This may imply benefits with regard to other atherosclerosis-based events.

Antioxidative efficacy of parallel and combined supplementation with coenzyme Q10 and d-alpha-tocopherol in mildly hypercholesterolemic subjects: a randomized placebo-controlled clinical study.

It has been claimed that coenzyme Q10 (Q10) would be an effective plasma antioxidant since it can regenerate plasma vitamin E. To test separate effects and interaction between Q10 and vitamin E in the change of plasma concentrations and in the antioxidative efficiency, we carried out a double-masked, double-blind clinical trial in 40 subjects with mild hypercholesterolemia undergoing statin treatment. Subjects were randomly allocated to parallel groups to receive either Q10 (200 mg daily), d-alpha-tocopherol (700 mg daily), both antioxidants or placebo for 3 months. In addition we investigated the pharmacokinetics of Q10 in a separate one-week substudy. In the group that received both antioxidants, the increase in plasma Q10 concentration was attenuated. Only vitamin E supplementation increased significantly the oxidation resistance of isolated LDL. Simultaneous Q10 supplementation did not increase this antioxidative effect of vitamin E. Q10 supplementation increased and vitamin E decreased significantly the proportion of ubiquinol of total Q10, an indication of plasma redox status in vivo. The supplementations used did not affect the redox status of plasma ascorbic acid. In conclusion, only vitamin E has antioxidative efficiency at high radical flux ex vivo. Attenuation of the proportion of plasma ubiquinol of total Q10 in the vitamin E group may represent in vivo evidence of the Q10-based regeneration of the tocopheryl radicals. In addition, Q10 might attenuate plasma lipid peroxidation in vivo, since there was an increased proportion of plasma ubiquinol of total Q10.

Long-term effects of vitamin E, vitamin C, and combined supplementation on urinary 7-hydro-8-oxo-2'-deoxyguanosine, serum cholesterol oxidation products, and oxidation resistance of lipids in nondepleted men.

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-alpha-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 alpha-tocopherol during the first 12 months by 68.2% and 65.2% (P:<0. 001 for both), respectively, and reduced serum 7beta-hydroxycholesterol by 50.4% (P:=0.013) and 44.0% (P:=0.041), respectively. The net change of lipid standardized alpha-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% (P:=0.043) in 12 months and by 91.1% (P:=0. 001) in 36 months. Neither vitamin E, vitamin C, nor the combination influenced the urinary excretion rate of 7-hydro-8-oxo-2'-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.

Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.

OBJECTIVE: To test the hypothesis that low serum folate concentrations are associated with an increased risk of acute coronary events in men free of prior coronary heart disease. SETTING: Research Institute of Public Health, University of Kuopio, Kuopio, Finland. DESIGN: Prospective study in a cohort of 734 men aged 46-64 y examined in 1991-1993 as part of the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) and followed for 5 y and 3 months. INTERVENTION: Acute coronary events during the follow-up period were obtained by national hospital discharge registry. Baseline serum folate concentrations were measured by radioimmunoassay. RESULTS: During the follow-up, six (2.5%) men with higher serum folate concentrations (highest third>11.3 nmol/1) and 28 (5.7%) men with lower serum folate (two lowest thirds) developed an acute coronary event (P=0.008). In a Cox model adjusting for age, examination years, and plasma lycopene concentration, in men with higher serum folate concentrations the relative risk for an acute coronary event was 0.31 (95% CI 0.11-0.90, P=0.031) when compared with men with lower serum folates. CONCLUSION: This prospective cohort study in middle-aged men from eastern Finland indicates that moderate-to-high levels of serum folate are associated with a greatly reduced incidence of acute coronary events.

A randomized, single-blind, placebo-controlled trial of the effects of 200 mg alpha-tocopherol on the oxidation resistance of atherogenic lipoproteins.

Supplementation with high doses of alpha-tocopherol has increased the oxidation resistance of LDL in many clinical trials. There have been only a few placebo-controlled trials in healthy persons of alpha-tocopherol doses usually contained in dietary supplements. We carried out a single-blind, placebo-controlled, randomized trial to examine the effect of 200 mg RRR-alpha-tocopheryl acetate/d on the oxidation resistance of atherogenic lipoproteins (VLDL+LDL including intermediate-density lipoproteins) in 40 smoking men. VLDL+LDL oxidation resistance was assessed as conjugated dienes after copper induction and hemin degradation after hydrogen peroxide induction. Also, the LDL total peroxyl-radical trapping antioxidant parameter (LDL TRAP) and plasma malondialdehyde were measured at baseline and after 2 mo of supplementation. Plasma RRR-alpha-tocopherol concentrations were measured at 2-h intervals for 12 h at baseline and after 2 mo of supplementation. Compared with placebo, 200-mg RRR-alpha-tocopheryl acetate supplementation elevated plasma and VLDL+LDL alpha-tocopherol concentrations, LDL TRAP, and oxidation resistance of VLDL+LDL. Plasma alpha-tocopherol increased by 88% (P < 0.0001), VLDL+LDL alpha-tocopherol increased by 90% (P < 0.0001), and LDL TRAP by 58% (P < 0.0001). The time to the start of oxidation (lag time) was prolonged by 34% when assessed with a copper-induced method and by 109% when assessed with a hemin + hydrogen peroxide-induced method; the time to maximal oxidation was prolonged by 21% (copper-induced method) in the vitamin E-supplemented group. Changes in plasma alpha-tocopherol, lipid-standardized alpha-tocopherol, and VLDL+LDL alpha-tocopherol correlated significantly with changes in LDL TRAP, lag time, and time to maximal oxidation. Differences in changes between groups in the area under the curve for plasma alpha-tocopherol were significant (P < 0.009). Our results suggest that 200 mg oral RRR-alpha-tocopheryl acetate/d had a clear effect on the in vitro oxidation of VLDL+LDL in smoking men.

Effect of combined coenzyme Q10 and d-alpha-tocopheryl acetate supplementation on exercise-induced lipid peroxidation and muscular damage: a placebo-controlled double-blind study in marathon runners.

To test the effects of combined coenzyme Q10 (Q10) and d-alpha-tocopheryl acetate supplementation on exercise-induced oxidative stress and muscular damage we conducted a double-blind study in 37 moderately trained male marathon runners. These were randomly allocated to receive either an antioxidant cocktail: 90 mg of Q10 and 13.5 mg of d-alpha-tocopheryl acetate daily (18 men) or placebo (19 men) for three weeks before a marathon (42km) run. Just before the run, plasma Q10 was 282% (p < 0.0001) and plasma vitamin E 16% (p < 0.007) higher in the supplemented group, than in the placebo group. Also the proportion of plasma ubiquinol of total Q10, an indication of plasma redox status in vivo, was significantly higher in the supplemented group. Furthermore, the susceptibility of the VLDL + LDL fraction, to copper-induced oxidation, was significantly reduced in the supplemented group, compared to the placebo group. The exercise increased lipid peroxidation significantly in both study groups, as assessed by the elevated proportion LDL of LDL and the increased susceptibility of lipoproteins to copper induced oxidation. However, the supplementation had no effect on lipid peroxidation or on the muscular damage (increase in serum creatine kinase activity or in plasma lactate levels) induced by exhaustive exercise. Plasma ascorbate, Q10, whole blood glutathione and serum uric acid concentrations increased during the exercise, elevating significantly the TRAP value of plasma by 10.3% and the proportion of plasma ubiquinol of total Q10 by 4.9%. These results suggest that even though exercise increases plasma lipid peroxidation, it also elevates the antioxidative capacity of plasma, as assessed by the increased plasma TRAP and the proportion of Q10H2 of total Q10. However, prior supplementation with small doses of Q10 and d-alpha-tocopheryl acetate neither attenuates the oxidation of lipoproteins nor muscular damage induced by exhaustive exercise such as encountered in a marathon run.

Ascorbate and urate are the strongest determinants of plasma antioxidative capacity and serum lipid resistance to oxidation in Finnish men.

Copper-induced plasma lipoprotein oxidation resistance has usually been determined in separated low density lipoprotein (LDL) fractions, that do not contain water-soluble antioxidants present in blood plasma. The aim of this study was to find the main determinants of the measurements of copper-induced lipid oxidation resistance (lag time) in whole serum and plasma total peroxyl radical trapping capacity (TRAP) in a population sample of smoking (n = 25) or non-smoking (n = 26) middle aged men at high risk of cardiovascular diseases. Smokers had significantly lower plasma ascorbic acid values, but only slightly lower alpha-tocopherol, beta-carotene and serum urate values than non-smokers. Plasma ascorbic acid concentration explained 23.5% of the lag time variation (standardized regression coefficient beta = 0.48; P = 0.004) in smokers and 5.6% in non-smokers. Serum urate concentration was the strongest determinant of lag time in non-smokers (beta = 0.64, P < 0.001). In addition, serum albumin, lipid standardized alpha-tocopherol and serum high density lipoprotein (HDL) cholesterol entered the multivariate regression mode for lag time. For plasma TRAP, only urate and ascorbic acid entered the multivariate regression model. Lag times in serum and in isolated very low density lipoprotein (VLDL) and LDL fraction did not correlate, but the maximal rate of these reactions correlated significantly. These results confirm that lipid peroxidation resistance in serum or plasma are associated with ascorbic acid, urate, alpha-tocopherol, albumin and HDL concentrations. The measurement of lipid oxidation resistance in whole serum might be more physiological than in isolated lipoprotein fraction, as the effects of water-soluble antioxidants are not artificially removed.

Effect of supplementation of smoking men with plain or slow release ascorbic acid on lipoprotein oxidation.

OBJECTIVE: To study the effects of two month ascorbic acid supplementation on in vitro lipoprotein oxidation resistance and on in vivo lipid peroxidation, and to compare the absorption of two ascorbic acid preparations. DESIGN: Randomized, single blinded and placebo-controlled clinical trial. SETTING: Men, aged 36-65 y, smoking 11-40 cigarettes daily. SUBJECTS: Sixty-two subjects were recruited by newspaper advertisements and randomized. Fifty-nine subjects completed the study. INTERVENTION: Subjects were randomized into three groups to receive 250 mg BID of plain or slow release ascorbic acid tablets or placebo daily for two months. In the pharmacokinetic part of the study, the absorption of the ascorbic acid preparations was followed for 12 h. MAIN OUTCOME MEASURES: Plasma malondialdehyde (MDA) concentration and the oxidation resistance of VLDL + LDL. For the pharmacokinetic study, the area under the plasma concentration curve (AUC) of ascorbic acid. RESULTS: Plasma reduced ascorbic acid increased by 32% in the plain ascorbate group and by 54% in the slow release group during a two month supplementation. Plasma MDA increased in the plain ascorbic acid group compared with placebo group (P < 0.05), but there were no significant differences in the changes in lipoprotein oxidation reactions induced by copper or by hemin and H2O2. Plasma reduced and total ascorbic acid AUC values were significantly higher in both plain and slow release ascorbate groups compared with placebo group. CONCLUSIONS: Oral supplementation of 500 mg of ascorbic acid daily for two months alone without any other antioxidant does not appear to have protective effect on either in vitro lipoprotein oxidation resistance or in vivo lipid peroxidation in smoking men, but might even promote the formation of MDA.

Lipoprotein oxidation and progression of carotid atherosclerosis.

BACKGROUND: Epidemiological studies and animal experiments have provided evidence supporting the role of lipid peroxidation in atherogenesis and cardiovascular diseases. Direct evidence linking lipid oxidation to atherosclerotic progression in humans, however, has been lacking. We investigated the association of lipid oxidation products with the progression of early carotid atherosclerosis in hypercholesterolemic men from eastern Finland. METHODS AND RESULTS: Twenty subjects with a fast progression and 20 with no progression of carotid atherosclerosis in 3 years were selected from > 400 participants in the Kuopio Atherosclerosis Prevention Study. Progression of carotid atherosclerosis was assessed by high-resolution B-mode ultrasonography. Serum 7 beta-hydroxycholesterol, a major oxidation product of cholesterol in membranes and lipoproteins, and seven other cholesterol oxidation products were measured by isotope dilution-mass spectrometry, lipid hydroperoxides in LDL fluorometrically as thiobarbituric acid-reactive substances (TBARS) and oxidation susceptibility of LDL and VLDL kinetically. High concentrations of serum 7 beta-hydroxycholesterol (beta = 47, P = .0005), cigarette smoking (beta = .35, P = .0167), and LDL TBARS (beta = .23, P = .0862) and an increased oxidation susceptibility of VLDL + LDL (beta = .22 P = .1114) were the strongest predictors of a 3-year increase in carotid wall thickness of more than 30 variables tested in step-up least-squares regression models. A 10-variable model explained 60% of the atherosclerotic progression. In a multivariate logistic model, the risk of experiencing a fast progression increased by 80% (P = .013) per unit (microgram/L) of 7 beta-hydroxycholesterol. CONCLUSIONS: The findings of this study provide further evidence to support an association between lipid oxidation and atherogenesis in humans.

Effect of oral coenzyme Q10 supplementation on the oxidation resistance of human VLDL+LDL fraction: absorption and antioxidative properties of oil and granule-based preparations.

Coenzyme Q10 (Q10) is supposed to be an important endogenous lipid-soluble antioxidant. We studied 60 healthy 46 +/- 7 (mean +/- SD)-year-old smoking men. They were randomized into three groups to receive oil-based or granular Q10 (90 mg/d) or placebo for 2 months. Oil-based capsule elevated Q10 in plasma by 178% and in VLDL+LDL fraction by 160%. The granular preparation increased Q10 in plasma by 168% and in VLDL+LDL by 127%. However, the 2-month Q10 supplementation did not increase the oxidation resistance of VLDL+LDL fraction, as assessed by copper induced VLDL+LDL oxidation, haemin+H(2)O(2)-induced VLDL+LDL oxidation, total antioxidative capacity of LDL, and plasma malondialdehyde measurements. The first and the last dose was used to carry out a 12 h pharmacokinetic study (five subjects per group), which indicated that only a small part of supplemented Q10 was absorbed to the circulation in 12 h and that the absorption varied extensively between subjects. Our results suggest that at least among smoking men, 90 mg of orally supplemented Q10 daily does not increase the oxidation resistance of VLDL+LDL. Bioavailability of both the granular and the oil-based Q10 preparation was similar during the long-term supplementation, but one dose of 30 mg had only a marginal effect on the plasma levels of Q10.

Increased oxidation resistance of atherogenic plasma lipoproteins at high vitamin E levels in non-vitamin E supplemented men.

The oxidative modification of human low density lipoprotein (LDL) has been widely investigated. However, there are no data concerning the oxidation susceptibility of combined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein fraction, although all of them are atherogenic and contain antioxidants such as alpha-tocopherol. We investigated the oxidation susceptibility and oxidation resistance of VLDL + LDL (including IDL) fraction by induction with CuCl2 and its relation to plasma alpha-tocopherol concentration and lipid standardised alpha-tocopherol concentration in 406 non-vitamin E-supplemented men from eastern Finland. Even thought we did not give oral vitamin E or any other antioxidant supplementation to our study participants, we observed a significant, consistent relationship between measurements of oxidation resistance and plasma content of vitamin E. In the multivariate regression model, a high plasma content of vitamin E or lipid standardised vitamin E concentration were the most important determinants of lag time to maximal oxidation rate (standardised regression coefficient = 0.244, P < 0.0001 for vitamin E and 0.211, P < 0.0001 for lipid standardised vitamin E). After statistical adjustment for age, use of cigarettes, hypolipidemic medication (yes vs. no), month of the measurements, plasma concentrations of total ascorbic acid (ascorbic acid + dehydroascorbic acid), beta-carotene and phospholipids, serum concentrations of LDL cholesterol and triglycerides and dietary intake of linoleic acid, the lag time to maximal oxidation rate was 10% (95% C.I. 6.0-13.5%) longer in men in the highest fifth than in the lowest fifth of plasma vitamin E content (P < 0.0001 for trend). When the fifths of lipid standardised vitamin E were compared, the lag time to maximal oxidation rate was 6% (95% C.I. 1.8-10.1%) longer in men in the highest than in the lowest fifth (P < 0.0001 for trend). Our data suggest that alpha-tocopherol is an important antioxidant preventing the in vitro oxidation of VLDL + LDL fraction even in non-supplemented subjects.

Linoleic acid intake and susceptibility of very-low-density and low density lipoproteins to oxidation in men.

Lipoprotein peroxidation is thought to play an important role in atherogenesis. In the Kuopio Atherosclerosis Prevention Study (KAPS) the intake of fat and fatty acids, the oxidation susceptibility of the plasma very-low-density + low-density lipoprotein (VLDL+LDL) fraction (by induction with copper or hemin and hydrogen peroxide), and concentrations of plasma antioxidants, serum lipids, and lipoproteins were measured in 393 men. In the multivariate-regression model dietary linoleic acid was the most important determinant of the maximal oxidation velocity for the hemin assay (standardized regression coefficient = 0.294, P<0.0001). In the copper assay the association of dietary linoleic acid and maximal oxidation velocity was second in order of strength (standardized regression coefficient = 0.324, P< 0.0001). We conclude that high linoleic acid intake is associated with increased oxidation susceptibility of atherogenic lipoproteins in men.

The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression.

The Kuopio Atherosclerosis Prevention Study is the first population-based, double-blind trial in the primary prevention of carotid and femoral atherosclerosis. A total of 447 subjects with serum low density lipoprotein (LDL) cholesterol levels > or = 155 mg/dl (> or = 4.0 mmol/liter) and total cholesterol levels < 290 mg/dl (< 7.5 mmol/liter) were randomly assigned to receive either pravastatin 40 mg/day or placebo for 3 years. Atherosclerotic progression in 424 men was assessed with B-mode ultrasonography. Pravastatin reduced the rate of progression by 45% (95% confidence interval [CI]: 16-69%, p = 0.005) in carotid arteries and by 66% (95% CI: 30-90%, p = 0.002) in the common carotid arteries. The treatment effect in the carotid arteries was greater in subjects with thick arterial walls at baseline, in smokers, and in subjects with low plasma alpha-tocopherol. Subjects who received pravastatin had a higher antioxidative capacity of LDL, a longer oxidation lag of very low density lipoprotein (VLDL) plus LDL, and a reduced oxidation rate of VLDL plus LDL in vitro. These data establish the antiatherogenic effect of lowering LDL cholesterol levels by pravastatin therapy in hypercholesterolemic men in a primary prevention setting and suggest that part of the antiatherogenic effect of pravastatin may be due to an improvement in the resistance of atherogenic lipoproteins to oxidation.