Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Dietary fat quality and serum androgen concentrations in middle-aged men.

BACKGROUND/OBJECTIVES: Average testosterone concentrations in men have declined over the last few decades. The reasons for this are not fully known, but changes in dietary fat quality have been suggested to have a role. This study aimed to investigate the associations of different dietary fatty acids with serum androgen concentrations. SUBJECTS/METHODS: A total of 2546 men with a mean age of 53 from the Kuopio Ischaemic Heart Disease Risk Factor Study were included in this cross-sectional study. Associations between dietary saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA) and trans (TFA) fatty acids and concentrations of serum total and free testosterone and steroid hormone binding globulin (SHBG) were analyzed with analysis of covariance and linear regression analysis. Associations of isocaloric replacement of nutrients and androgen concentrations were analyzed with multivariate nutrient-density models. RESULTS: After adjustment for age, examination year and energy intake, higher SFA intake was associated with higher serum total and free testosterone and SHBG concentrations, and higher PUFA intake with lower concentrations. However, the associations were attenuated and not statistically significant after further adjustments for potential confounders. MUFA and TFA intakes were not associated with androgen concentrations. In isocaloric substitution models, replacing dietary protein with SFA was associated with higher serum total testosterone and SHBG concentrations. After excluding men with history of CVD or diabetes (n = 1021), no statistically significant associations were found. CONCLUSIONS: Dietary fat quality was not independently associated with serum androgen concentrations in middle-aged men. However, replacing protein with SFA may be associated with higher serum androgen concentrations.

Serum n-6 polyunsaturated fatty acids and risk of atrial fibrillation: the Kuopio Ischaemic Heart Disease Risk Factor Study.

PURPOSE: N-6 polyunsaturated fatty acids (PUFA), particularly linoleic acid (LA), have been associated with lower risk of coronary heart disease (CHD), but little is known about their antiarrhythmic properties. We investigated the association of the serum n-6 PUFAs with the risk of atrial fibrillation (AF), the most common type of cardiac arrhythmia. METHODS: The study included 2450 men from the Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 years at baseline. The total n-6 PUFA includes linoleic acid (LA), arachidonic acid (AA), γ-linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA). Cox proportional hazards regression was used to estimate hazard ratio (HR) of incident events. RESULTS: During the mean follow-up of 22.4 years, 486 AF cases occurred. The multivariable-adjusted HR in the highest versus the lowest quartile of total serum n-6 PUFA concentration was 0.79 (95% CI 0.58-1.08, P trend = 0.04). When evaluated individually, only serum LA concentration was inversely associated with AF risk (multivariable-adjusted extreme-quartile HR 0.69, 95% CI 0.51-0.94, P trend = 0.02). These associations were stronger among the men without history of CHD or congestive heart failure at baseline, compared to men with such disease history (P for interaction = 0.05 for total n-6 PUFA and LA). Similar associations were observed with dietary LA and AA intakes. No significant associations were observed with serum AA, GLA or DGLA concentrations. CONCLUSIONS: Higher circulating concentration and dietary intake of n-6 PUFA, mainly LA, are associated with lower risk of AF, especially among men without history of CHD or congestive heart failure.

Fatty acids as determinants of in-vivo lipid peroxidation: the EFFGE study in Eastern Finnish hypertensive and non-hypertensive subjects.

BACKGROUND: The degree of fatty acid (FA) unsaturation as a determinant of lipid peroxidation has been inadequately studied. METHODS: We examined associations of plasma free F2α-isoprostanes (F2-IsoPs), an indicator of in-vivo lipid peroxidation, with the levels/intake of FAs, adjusted for the risk factors of cardiovascular disease (CVD) in 1211 Finnish men and women, of whom 50% were hypertensive, aged 59.3 ± 8.3 years, mean ± SD. RESULTS: Elevated age- and sex-adjusted plasma free levels of omega-6 and omega-3 polyunsaturated Fas (PUFAs), saturated FAs (SFAs), and the PUFA/SFA and the omega-6/omega-3 PUFA ratios were all associated with decreased F2-IsoPs. High dietary SFA intake was associated with elevated F2-IsoP concentrations. In a multivariable regression (with clinical, nutritional, and behavioral CVD risk factors), female gender, body mass index (BMI), serum apolipoprotein A1, and NT-proBNP (natriuretic peptide) were positively associated with the F2-IsoPs, whereas the dietary PUFA/SFA ratio, plasma ß-carotene, the omega-6/omega-3 PUFA ratio, and protein intake showed inverse associations. CONCLUSIONS: We propose that elevated lipid peroxidation is associated with several risk factors of CVD, such as a low PUFA/SFA ratio, whereas the FA precursors of lipid peroxidation, i.e. omega-3 and omega-6 PUFAs are associated with attenuated F2-IsoP levels. These findings provide mechanistic support for earlier observations linking PUFA to improved cardiovascular health.

Myocardial infarction in relation to mercury and fatty acids from fish: a risk-benefit analysis based on pooled Finnish and Swedish data in men.

BACKGROUND: Exposure to methylmercury from fish has been associated with increased risk of myocardial infarction (MI) in some studies. At the same time, marine n-3 (omega-3) PUFAs are an inherent constituent of fish and are regarded as beneficial. To our knowledge, no risk-benefit model on the basis of data on methylmercury, PUFA, and MI risk has yet been presented. OBJECTIVE: The objective of this study was to describe how exposure to both marine n-3 PUFAs and methylmercury relates to MI risk by using data from Finland and Sweden. DESIGN: We used matched case-control sets from Sweden and Finland that were nested in population-based, prospective cohort studies. We included 361 men with MI from Sweden and 211 men with MI from Finland. MI risk was estimated in a logistic regression model with the amount of mercury in hair (hair-Hg) and concentrations of n-3 PUFAs (EPA and DHA) in serum (S-PUFA) as independent variables. RESULTS: The median hair-Hg was 0.57 µg/g in Swedish and 1.32 µg/g in Finnish control subjects, whereas the percentage of S-PUFA was 4.21% and 3.83%, respectively. In combined analysis, hair-Hg was associated with higher (P = 0.005) and S-PUFA with lower (P = 0.011) MI risk. Our model indicated that even a small change in fish consumption (ie, by increasing S-PUFA by 1%) would prevent 7% of MIs, despite a small increase in mercury exposure. However, at a high hair-Hg, the modeled beneficial effect of PUFA on MI risk was counteracted by methylmercury. CONCLUSIONS: Exposure to methylmercury was associated with increased risk of MI, and higher S-PUFA concentrations were associated with decreased risk of MI. Thus, MI risk may be reduced by the consumption of fish high in PUFAs and low in methylmercury.

The effect of olive oil polyphenols on antibodies against oxidized LDL. A randomized clinical trial.

BACKGROUND & AIM: Oxidized LDL (oxLDL) is a highly immunogenic particle that plays a key role in the development of atherosclerosis. Some data suggest a protective role of OxLDL autoantibodies (OLAB) in atherosclerosis. Our aim was to assess the effect of olive oil polyphenols on the immunogenicity of oxLDL to autoantibody generation. METHODS: In a crossover, controlled trial, 200 healthy men were randomly assigned to 3-week sequences of 25 mL/day of 3 olive oils with high (366 mg/kg), medium (164 mg/kg), and low (2.7 mg/kg) phenolic content. RESULTS: Plasma OLAB concentration was inversely associated with oxLDL (p < 0.001). Olive oil phenolic content increased OLAB generation, with the effect being stronger at higher concentrations of oxLDL (p = 0.020 for interaction). A direct relationship was observed between OLAB and the total olive oil phenol content in LDL (r = 0.209; p = 0.014). OLAB concentrations, adjusted for oxLDL, increased directly in a dose-dependent manner with the polyphenol content of the olive oil administered (p = 0.023). CONCLUSION: Olive oil polyphenols promote OLAB generation. This effect is stronger at higher concentrations of lipid oxidative damage.

Changes in LDL fatty acid composition as a response to olive oil treatment are inversely related to lipid oxidative damage: The EUROLIVE study.

OBJECTIVE: The aim of our study was to assess the changes in the fatty acid composition of low density lipoproteins (LDL) after sustained consumption of olive oil at real-life doses (25 mL/day) and their relationship with lipid oxidative damage. METHODS: A multi-center randomized, cross-over, clinical trial with 3 similar types of olive oils, but with differences in the phenolic content, was conducted on 200 healthy European subjects. Intervention periods were of 3 weeks separated by 2-week washout periods. The LDL fatty acid content was measured in samples drawn at baseline and after the last intervention period. RESULTS: After olive oil ingestion oleic acid concentration in LDL increased (1.9%; p < 0.001) and those of linoleic (1.1%; p < 0.002) and arachidonic acid (0.5%; p < 0.001) decreased. Monounsaturated/polyunsaturated fatty acid and oleic/linoleic acid ratios in LDL increased after olive oil consumption. An inverse relationship between the oleic/linoleic acid ratio and biomarkers of oxidative stress was observed. One unit increase in the oleic/linoleic acid ratio was associated with a decrease of 4.2 microg/L in plasma isoprostanes. CONCLUSION: Consumption of olive oil at real-life doses improved the fatty acid profile in LDL, the changes being associated with a reduction of the oxidative damage to lipids.

Effects of astaxanthin supplementation on lipid peroxidation.

Astaxanthin, the main carotenoid pigment in aquatic animals, has greater antioxidant activity in vitro (protecting against lipid peroxidation) and a more polar configuration than other carotenoids. We investigated the effect of three-month astaxanthin supplementation on lipid peroxidation in healthy non-smoking Finnish men, aged 19-33 years by using a randomized double-blind study design. Also absorption of astaxanthin from capsules into bloodstream and its safety were evaluated. The intervention group received two 4-mg astaxanthin (Astaxin) capsules daily, and the control group two identical-looking placebo capsules. Astaxanthin supplementation elevated plasma astaxanthin levels to 0.032 pmol/L (p < 0.001 for the change compared with the placebo group). We observed that levels of plasma 12- and 15-hydroxy fatty acids were reduced statistically significantly in the astaxanthin group (p = 0.048 and p = 0.047 respectively) during supplementation, but not in the placebo group and the change of 15-hydroxy fatty acid was almost significantly greater (p = 0.056) in the astaxanthin group, as compared with the placebo group. The present study suggests that intestinal absorption of astaxanthin delivered as capsules is adequate, and well tolerated. Supplementation with astaxanthin may decrease in vivo oxidation of fatty acids in healthy men.

Effect of olive oils on biomarkers of oxidative DNA stress in Northern and Southern Europeans.

High consumption of olive oil in the Mediterranean diet has been suggested to protect DNA against oxidative damage and to reduce cancer incidence. We investigated the impact of the phenolic compounds in olive oil, and the oil proper, on DNA and RNA oxidation in North, Central, and South European populations. In a multicenter, double-blind, randomized, controlled crossover intervention trial, the effect of olive oil phenolic content on urinary oxidation products of guanine (8-oxo-guanine, 8-oxo-guanosine and 8-oxo-deoxyguanosine) was investigated. Twenty-five milliliters of three olive oils with low, medium, and high phenolic content were administered to healthy males (n=182) daily for 3 wk. At study baseline the urinary excretion of 8-oxo-guanosine (RNA oxidation) and 8-oxo-deoxyguanosine (DNA oxidation) was higher in the Northern regions of Europe compared with Central and Southern European regions (P=0.035). Urinary excretion of the 8 hydroxylated forms of guanine, guanosine, deoxyguanosine and their nonoxidized forms were not different when comparing olive oils with low, medium, and high phenolic content given for 2 wk. Testing the effect of oil from urinary 8-oxo-deoxyguanosine changes from baseline to post-treatment showed a reduction of DNA oxidation by 13% (P=0.008). These findings support the idea that ingestion of olive oil is beneficial and can reduce the rate of oxidation of DNA. This effect is not due to the phenolic content in the olive oil. The higher DNA and RNA oxidation in Northern European regions compared with that in Central and Southern regions supports the contention that olive oil consumption may explain some of the North-South differences in cancer incidences in Europe.

The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial.

BACKGROUND: Virgin olive oils are richer in phenolic content than refined olive oil. Small, randomized, crossover, controlled trials on the antioxidant effect of phenolic compounds from real-life daily doses of olive oil in humans have yielded conflicting results. Little information is available on the effect of the phenolic compounds of olive oil on plasma lipid levels. No international study with a large sample size has been done. OBJECTIVE: To evaluate whether the phenolic content of olive oil further benefits plasma lipid levels and lipid oxidative damage compared with monounsaturated acid content. DESIGN: Randomized, crossover, controlled trial. SETTING: 6 research centers from 5 European countries. PARTICIPANTS: 200 healthy male volunteers. MEASUREMENTS: Glucose levels, plasma lipid levels, oxidative damage to lipid levels, and endogenous and exogenous antioxidants at baseline and before and after each intervention. INTERVENTION: In a crossover study, participants were randomly assigned to 3 sequences of daily administration of 25 mL of 3 olive oils. Olive oils had low (2.7 mg/kg of olive oil), medium (164 mg/kg), or high (366 mg/kg) phenolic content but were otherwise similar. Intervention periods were 3 weeks preceded by 2-week washout periods. RESULTS: A linear increase in high-density lipoprotein (HDL) cholesterol levels was observed for low-, medium-, and high-polyphenol olive oil: mean change, 0.025 mmol/L (95% CI, 0.003 to 0.05 mmol/L), 0.032 mmol/L (CI, 0.005 to 0.05 mmol/L), and 0.045 mmol/L (CI, 0.02 to 0.06 mmol/L), respectively. Total cholesterol-HDL cholesterol ratio decreased linearly with the phenolic content of the olive oil. Triglyceride levels decreased by an average of 0.05 mmol/L for all olive oils. Oxidative stress markers decreased linearly with increasing phenolic content. Mean changes for oxidized low-density lipoprotein levels were 1.21 U/L (CI, -0.8 to 3.6 U/L), -1.48 U/L (-3.6 to 0.6 U/L), and -3.21 U/L (-5.1 to -0.8 U/L) for the low-, medium-, and high-polyphenol olive oil, respectively. LIMITATIONS: The olive oil may have interacted with other dietary components, participants' dietary intake was self-reported, and the intervention periods were short. CONCLUSIONS: Olive oil is more than a monounsaturated fat. Its phenolic content can also provide benefits for plasma lipid levels and oxidative damage. International Standard Randomised Controlled Trial number: ISRCTN09220811.

Consumption of juice fortified with oregano extract markedly increases excretion of phenolic acids but lacks short- and long-term effects on lipid peroxidation in healthy nonsmoking men.

Oregano has been shown to possess antioxidant capacity in various in vitro models and has thus been suggested to be potentially beneficial to human health, but studies in humans are lacking. The aim of this study was to investigate the bioavailability and the effects of Origanum vulgare extract supplementation on serum lipids and lipid peroxidation in healthy nonsmoking men. A four-week double-blinded supplementation trial was concluded in which volunteers (n = 45) were randomized to consume daily mango-orange juice (placebo), mango-orange juice enriched with 300 mg/d total phenolic compounds from oregano extract, or mango-orange juice enriched with 600 mg/d total phenolic compounds from oregano extract. The excretion of phenolic compounds was markedly increased in the higher phenolic group as compared to the placebo group, but no significant changes were observed in the safety parameters, serum lipids, or biomarkers of lipid peroxidation.

Catechol-o-methyltransferase gene polymorphism modifies the effect of coffee intake on incidence of acute coronary events.

BACKGROUND: The role of coffee intake as a risk factor for coronary heart disease (CHD) has been debated for decades. We examined whether the relationship between coffee intake and incidence of CHD events is dependent on the metabolism of circulating catecholamines, as determined by functional polymorphism of the catechol-O-methyltransferase (COMT) gene. METHODOLOGY/PRINCIPAL FINDINGS: In a cohort of 773 men who were 42 to 60 years old and free of symptomatic CHD at baseline in 1984-89, 78 participants experienced an acute coronary event during an average follow-up of 13 years. In logistic regression adjusting for age, smoking, family history of CHD, vitamin C deficiency, blood pressure, plasma cholesterol concentration, and diabetes, the odds ratio (90% confidence interval) comparing heavy coffee drinkers with the low activity COMT genotype with those with the high activity or heterozygotic genotypes was 3.2 (1.2-8.4). Urinary adrenaline excretion increased with increasing coffee intake, being over two-fold in heavy drinkers compared with nondrinkers (p = 0.008 for trend). CONCLUSIONS/SIGNIFICANCE: Heavy coffee consumption increases the incidence of acute coronary events in men with low but not high COMT activity. Further studies are required to determine to which extent circulating catecholamines mediate the relationship between coffee intake and CHD.

Polyphenol-rich phloem enhances the resistance of total serum lipids to oxidation in men.

In humans, polyphenol supplementation studies have resulted in inconsistent findings in lipid peroxidation. Our aim was to investigate the effects of a 4-week consumption of polyphenol-rich phloem on serum lipids and lipid peroxidation in the hydrophilic fraction of serum and on isolated lipoproteins. We conducted a randomized double-blind supplementation study consisting of 75 nonsmoking hypercholesterolemic men. Participants consumed 70 g daily of either rye bread (placebo) or phloem-fortified rye bread containing 31 mg (low polyphenol, LP) or 62 mg (high polyphenol, HP) of catechins. The ex vivo susceptibility of total serum lipids and VLDL and LDL to oxidation after copper induction was measured as a lag time to the maximal oxidation rate at the baseline and after the supplementation. In the HP group, an increase in the oxidation resistance of total serum lipids was observed (11.4%), while no effect was seen in the LP group (-0.8%) or in the placebo group (-1.0%) (p = 0.007). No differences were observed in the oxidation resistance of VLDL and LDL between the study groups. The phloem also increased in vitro oxidation resistance of serum lipids and radical scavenging activity (DPPH.) in a dose-dependent manner. Our results suggest that polyphenols may inhibit lipid peroxidation in the hydrophilic fraction of serum.

Prediction of cardiovascular mortality in middle-aged men by dietary and serum linoleic and polyunsaturated fatty acids.

BACKGROUND: Substitution of dietary polyunsaturated for saturated fat has long been recommended for the primary prevention of cardiovascular disease (CVD), but only a few prospective cohort studies have provided support for this advice. METHODS: We assessed the association of dietary linoleic and total polyunsaturated fatty acid (PUFA) intake with cardiovascular and overall mortality in a population-based cohort of 1551 middle-aged men. Dietary fat composition was estimated with a 4-day food record and serum fatty acid composition. RESULTS: During the 15-year follow-up, 78 men died of CVD and 225 of any cause. Total fat intake was not related to CVD or overall mortality. Men with an energy-adjusted dietary intake of linoleic acid (relative risk [RR] 0.39; 95% confidence interval [CI], 0.21-0.71) and PUFA (RR, 0.38; 95% CI, 0.20-0.70) in the upper third were less likely to die of CVD than men with intake in the lower third after adjustment for age. Multivariate adjustment weakened the association somewhat. Mortality from CVD was also lower for men with proportions of serum esterified linoleic acid (RR, 0.42; 95% CI, 0.21-0.80) and PUFA (RR, 0.25; 95% CI, 0.12-0.50) in the upper vs lower third, with some attenuation in multivariate analyses. Serum and to a lesser extent dietary linoleic acid and PUFA were also inversely associated with overall mortality. CONCLUSIONS: Dietary polyunsaturated and more specifically linoleic fatty acid intake may have a substantial cardioprotective benefit that is also reflected in overall mortality. Dietary fat quality seems more important than fat quantity in the reduction of cardiovascular mortality in men.

The effects of coffee consumption on lipid peroxidation and plasma total homocysteine concentrations: a clinical trial.

Despite extensive research, the cardiovascular effects of coffee consumption in humans remain controversial. Our aim was to investigate the excretion of coffee phenols and the effects of filtered coffee consumption on oxidative stress and plasma homocysteine (tHcy) concentration in humans. The study consisted of a multiple-dose clinical supplementation trial and a single-dose study. In the long-term trial, 43 healthy nonsmoking men optionally consumed daily either no coffee, 3 cups (450 mL), or 6 cups (900 mL) of filtered coffee for 3 weeks, while in the short-term study 35 subjects consumed a single dose of 0, 1 (150 mL), or 2 cups (300 mL) of coffee. Long-term consumption of coffee increased the urinary excretion of caffeic and ferulic acid. The change in the total excretion of phenolic acids in 3 and 6 cups groups represented 3.8 and 2.5% of the amount ingested daily. Plasma tHcy concentrations increased nonsignificantly, but the consumption of coffee had neither short-nor long-term effects on lipid peroxidation or the activity of measured antioxidant enzymes. In conclusion, the consumption of filtered coffee does not have any detectable effects on lipid peroxidation in healthy nonsmoking men. The effect of coffee consumption on tHcy concentrations needs further investigation.

Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans.

Cocoa powder is rich in polyphenols and, thus, may contribute to the reduction of lipid peroxidation. Our aim was to study the effects of long-term ingestion of chocolate, with differing amounts of polyphenols, on serum lipids and lipid peroxidation ex vivo and in vivo. We conducted a 3 week clinical supplementation trial of 45 nonsmoking, healthy volunteers. Participants consumed 75 g daily of either white chocolate (white chocolate, WC group), dark chocolate (dark chocolate, DC group), or dark chocolate enriched with cocoa polyphenols (high-polyphenol chocolate, HPC group). In the DC and HPC groups, an increase in serum HDL cholesterol was observed (11.4% and 13.7%, respectively), whereas in the WC group there was a small decrease (-2.9%, p < 0.001). The concentration of serum LDL diene conjugates, a marker of lipid peroxidation in vivo, decreased 11.9% in all three study groups. No changes were seen in the total antioxidant capacity of plasma, in the oxidation susceptibility of serum lipids or VLDL + LDL, or in the concentration of plasma F2-isoprostanes or hydroxy fatty acids. Cocoa polyphenols may increase the concentration of HDL cholesterol, whereas chocolate fatty acids may modify the fatty acid composition of LDL and make it more resistant to oxidative damage.

Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.

Heavy coffee consumption has been associated with increased coronary heart disease (CHD) risk although many studies have not observed any relation. We studied the effect of coffee consumption, assessed with a 4-d food record, on the incidence of nonfatal acute myocardial infarction or coronary death in a cohort of 1971 men who were 42 to 60 y old and free of symptomatic CHD at baseline in 1984-1989. During a mean follow-up of 14 y, 269 participants experienced an acute coronary event. After adjustment for age, smoking, exercise ischemia, diabetes, income, and serum insulin concentration, the rate ratios (95% CIs) in daily nondrinkers and light (375 mL or less), moderate (reference level), and heavy (814 mL or more) drinkers were 0.84 (0.41-1.72), 1.22 (0.90-1.64), 1.00, and 1.43 (1.06-1.94). To address time dependence of the effect, the analysis was repeated for 75 CHD events that occurred during the first 5 y; the respective rate ratios were 0.42 (0.06-3.10), 2.00 (1.16-3.44), 1.00, and 2.07 (1.17-3.65). Further adjustment for serum HDL and LDL cholesterol concentration, diastolic blood pressure, maximal oxygen uptake, and waist-hip ratio slightly increased the rate ratio for heavy coffee intake. Neither the brewing method (boiling vs. filtering) nor the serum LDL cholesterol concentration had any impact on the risk estimates for coffee intake. In conclusion, heavy coffee consumption increases the short-term risk of acute myocardial infarction or coronary death, independent of the brewing method or currently recognized risk factors for CHD.

Long-term combined supplementations with alpha-tocopherol and vitamin C have no detectable anti-inflammatory effects in healthy men.

Inflammatory and oxidative stresses play a pivotal role in atherogenesis. Vitamin E and vitamin C are the two most important dietary antioxidants; moreover, vitamin E has anti-inflammatory effects. Combined supplementations with vitamin E and vitamin C twice daily for 3 y reduced lipid peroxidation and retarded the progression of common carotid atherosclerosis in healthy men in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. To further elucidate the underlying mechanisms that retarded the progression of atherosclerosis in the ASAP study, we investigated the effect of a combined intake of vitamin E and vitamin C on inflammatory markers in vivo. Circulating levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and C reactive protein (CRP) were measured in 45- to 69-y-old men from the ASAP study with cholesterol >5.0 mmol/L before and after treatment with either placebo (n = 52) or a combined supplementation with 91 mg (136 IU) alpha-tocopherol and 250 mg of slow-release vitamin C twice a day (n = 55) for 3 y. Antioxidant treatment for 36 mo had no effect on circulating levels of TNF-alpha, IL-6 or CRP. In conclusion, long-term combined supplementations with alpha-tocopherol and vitamin C in reasonable doses have no detectable systemic anti-inflammatory effects in a healthy population of men with slight hypercholesterolemia and no overt signs of inflammation.

Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study.

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 > or =5.0 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, P=0.014), in men by 33% (95% CI, 4 to 62, P=0.024) 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, P=0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P=0.028). 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.