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n -6 PUFA, especially linoleic acid (LA) but also arachidonic acid (AA), have been inversely associated with CHD. However, mechanisms underlying these associations are not fully known. We investigated the associations of the serum concentrations of total n -6 PUFA, LA, AA, γ -linolenic acid (GLA) and dihomo- γ -linolenic acid (DGLA), with the odds of myocardial ischaemia during exercise, a predictor of future cardiac events. A total of 1871 men without a history of CHD from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) aged 42-60 years were included. All participants performed a maximal symptom-limited exercise stress test, using an electrically braked bicycle ergometer. Multivariable-adjusted logistic regression was used to assess the OR for exercise-induced myocardial ischaemia in quartiles of the serum n -6 PUFA concentrations. After multivariable adjustment, men in the highest v . the lowest serum AA concentration had 50 % lower odds for exercise-induced myocardial ischaemia (OR 0·50, 95 % CI 0·34, 0·76; P -trend across quartiles < 0·001). For the other PUFA, the OR (95 % CI) were 1·00 (0·69, 1·46; P -trend = 0·89) for LA, 1·07 (0·75, 1·53; P -trend = 0·40) for GLA and 0·74 (0·51, 1·07; P -trend = 0·16) for DGLA. Among the n -6 PUFA, higher serum concentration of AA was associated with lower odds for myocardial ischaemia during an exercise test in middle-aged and older men. This may provide one mechanism for the previously observed possible cardioprotective properties of AA. Our findings also suggest that n -6 PUFA should not be considered as one homogenous group.

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., (© 2023. The Author(s).)

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., Competing Interests: Disclosures Dr Murphy reports having worked as a consultant for Pharmavite (until 2021). The remaining authors have reported no relationships relevant to the contents of this article. Dr Psaty serves on the steering committee of the Yale Open Data Access Project, funded by Johnson and Johnson.

Low intake or tissue concentrations of the n -6 PUFA, especially to the major n -6 PUFA linoleic acid (LA), and low exercise cardiac power (ECP) are both associated with CVD risk. However, associations of the n -6 PUFA with ECP are unknown. The aim of the present study was to explore cross-sectional associations of the serum total n -6 PUFA, LA, arachidonic acid (AA), γ -linolenic acid (GLA) and dihomo- γ -linolenic acid (DGLA) concentrations with ECP and its components. In total, 1685 men aged 42-60 years from the Kuopio Ischaemic Heart Disease Risk Factor Study and free of CVD were included. ANCOVA was used to examine the mean values of ECP (maximal oxygen uptake (VO 2max )/maximal systolic blood pressure (SBP)) and its components in quartiles of the serum total and individual n -6 PUFA concentrations. After multivariable adjustments, higher serum total n -6 PUFA concentration was associated with higher ECP and VO 2max (for ECP, the extreme-quartile difference was 0·77 ml/mmHg (95 % CI 0·38, 1·16, P for trend across quartiles < 0·001) and for VO 2max 157 ml/min (95 % CI 85, 230, P for trend < 0·001), but not with maximal SBP. Similar associations were observed with serum LA concentration. Higher serum AA concentration was associated with higher ECP but not with VO 2max or maximal SBP. The minor serum n -6 PUFA GLA and DGLA were associated with higher maximal SBP during exercise test and DGLA also with higher VO 2max but neither with ECP. In conclusion, especially LA concentration was associated with higher ECP. This may provide one mechanism for the cardioprotective properties of, especially, LA.

Background The major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid-intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations. Methods and Results Cross-sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B-mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 2-stage individual participant data meta-analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09-0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01-0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06-0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High-density lipoprotein-cholesterol had significant protective effects in African American (beta coefficient, -0.31; 95% CI, -0.42 to -0.21) and African (beta coefficient, -0.26; 95% CI, -0.31 to -0.19) populations only. Conclusions The strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race- ethnicity-specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

Purpose: To investigate if dairy, meat, and fish intakes associate with dementia and cognitive performance., Methods: We included 2497 dementia-free men from Eastern Finland, aged 42-60 years in 1984-1989 at the baseline examinations. Data on cognitive tests [Mini Mental State Exam (MMSE), trail making test (TMT), verbal fluency test (VFL), selective reminding test (SRT), and Russell's adaptation of the visual reproduction test (VRT)] at the 4-year re-examinations were available for 482 men and on the ApoE phenotype for 1259 men. Data on dementia events were obtained by linkage to national health registers. Diet was assessed with baseline 4-day food records. Cox regression and analysis of covariance were used for analyses., Results: During a mean 22-year follow-up, 337 men had a dementia diagnosis. Among the foods, only cheese intake associated with dementia risk (hazard ratio in the highest vs. the lowest quartile = 0.72, 95% confidence interval = 0.52-0.99, P-trend = 0.05). In the cognitive tests, higher non-fermented dairy and milk intakes associated with worse verbal fluency (VFT). Higher processed red meat intake associated with worse verbal (SRT) and visual memory (VRT), whereas higher unprocessed red meat intake associated with better general cognitive functioning (MMSE) and processing speed and executive functioning (TMT). Higher fish intake associated with better verbal memory (SRT). Among APOE-ε4 carriers, especially non-fermented dairy intake associated with higher risk of dementia outcomes, and higher fish intake indicated better cognitive performance., Conclusion: Although higher intake of some food groups associated with cognitive performance, we found little evidence for associations with dementia risk., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10-9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results., (© The Author(s) 2021. Published by Oxford University Press.)

Healthy Nordic diet has been beneficially associated with CHD risk factors, but few studies have investigated risk of developing CHD. We investigated the associations of healthy Nordic diet with major CHD risk factors, carotid atherosclerosis and incident CHD in middle-aged and older men from eastern Finland. A total of 1981 men aged 42-60 years and free of CHD at baseline in 1984-1989 were investigated. Diet was assessed with 4-d food recording and the healthy Nordic diet score was calculated based on the Baltic Sea Diet Score. Carotid atherosclerosis was assessed by ultrasonography of the common carotid artery intima-media thickness in 1053 men. ANCOVA and Cox proportional hazards regression analyses were used for analyses. Healthy Nordic diet score was associated with lower serum C-reactive protein (CRP) concentrations (multivariable-adjusted extreme-quartile difference 0·66 mg/l, 95 % CI 0·11, 1·21 mg/l) but not with serum lipid concentrations, blood pressure or carotid atherosclerosis. During the average follow-up of 21·6 years (sd 8·3 years), 407 men had a CHD event, of which 277 were fatal. The multivariable-adjusted hazard ratios in the lowest v. the highest quartile of the healthy Nordic diet score were 1·15 (95 % CI 0·87, 1·51) for any CHD event (Ptrend 0·361) and 1·44 (95 % CI 0·99, 2·08) (Ptrend 0·087) for fatal CHD event. We did not find evidence that adherence to a healthy Nordic diet would be associated with a lower risk of CHD or with carotid atherosclerosis or major CHD risk factors, except for an inverse association with serum CRP concentrations.

High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

Infections are one of the main causes of mortality in elderly due to the decrease of immune response, for which copper (Cu) and zinc (Zn) are claimed to be crucial. High serum copper-to-zinc-ratio (Cu/Zn-ratio) has been reported with infections, but little is known whether it could also predict the incidence of infections. The study cohort consisted of 1975 men aged 42-60 years and free of severe infectious disease at baseline in 1984-1989 from the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. The main outcome was an incident infection leading to hospitalization. Cox proportional hazards regression models were used for statistical analysis. During the average follow-up of 19.2 years, 636 incident first cases of infections were diagnosed. The hazard ratio (HR) of developing an incident infectious disease in the highest compared to the lowest Cu/Zn-ratio quartile after adjustment for age and baseline examination year was 1.35 [95% confidence interval (CI) = 1.07-1.69, P-trend across quartiles = 0.005]. The association was slightly attenuated after additional adjustment for potential confounders (HR = 1.21, 95% CI = 0.96-1.53, P-trend = 0.054). Furthermore, higher serum Cu concentration was associated with higher risk of an incident infection. The multivariable-adjusted HR was 1.39 (95% CI = 1.10-1.75, P-trend = 0.005) in the highest versus the lowest serum Cu quartile. Serum Zn concentration was not associated with the risk (multivariable-adjusted extreme-quartile HR = 0.83, 95% CI = 0.67-1.04, P-trend = 0.218). In conclusion, our data suggest that an increased Cu/Zn-ratio and especially serum Cu concentration are associated with increased risk of incident infections in middle-aged and older men in Eastern Finland.

Background: Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline., Objectives: We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study., Methods: A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-ε4 compared with other phenotypes). These data were available for 1259 men., Results: The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations., Conclusion: Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127., (Copyright © American Society for Nutrition 2019.)

Background: Epidemiologic studies suggest inverse associations between consumption of egg, a major source of dietary cholesterol, and stroke. However, the evidence of the relation remains limited, especially among carriers of apolipoprotein E4 (apoE4), which influences cholesterol metabolism., Objective: The aim of this study was to investigate associations of egg and cholesterol intakes with risk of stroke and with the major stroke risk factor, blood pressure, in middle-aged and older men from eastern Finland and whether apoE phenotype could modify these associations., Methods: A total of 1950 men aged 42-60 y in 1984-1989 were included at the baseline examinations of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on apoE phenotype were available for 1015 men. Dietary intakes were assessed with 4-d food records at baseline and incident stroke events were assessed by record linkage to hospital discharge registries. Cox proportional hazards regression analyses were used to estimate associations with stroke risk. Associations with baseline blood pressure were evaluated with ANCOVA., Results: During the mean ± SD follow-up of 21.2 ± 7.2 y, there were 217 incidences of any stroke: 166 of ischemic stroke and 55 of hemorrhagic stroke. Comparing the highest egg intake quartile with the lowest, the multivariable-adjusted HRs were 0.81 for total stroke (95% CI: 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI: 0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective HRs for the highest cholesterol intake quartile compared with the lowest were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75). Diastolic blood pressure was 1.6 mm Hg (P-trend = 0.04) lower in the highest egg intake quartile compared with the lowest, but there were no associations with systolic blood pressure or with cholesterol intake. ApoE phenotype (32% had apoE4 phenotype) did not modify the associations., Conclusion: Neither egg nor cholesterol intakes were associated with stroke risk in this cohort, regardless of apoE phenotype.This trial was registered at www.clinicaltrials.gov as NCT03221127., (Copyright © American Society for Nutrition 2019.)

Background: Previous studies investigating protein intake in relation to mortality have provided conflicting results., Objective: We investigated the associations of dietary protein and protein sources with risk of disease death in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study., Methods: The study population consisted of 2641 Finnish men, aged 42-60 y at baseline in 1984-1989. We estimated protein intakes with 4-d dietary records at baseline and collected data on disease deaths from the national Causes of Death Register. Cox proportional hazards regression models were used to estimate HRs and 95% CIs., Results: During the average follow-up of 22.3 y, we observed 1225 deaths due to disease. Higher intakes of total protein and animal protein had borderline statistically significant associations with increased mortality risk: multivariable-adjusted HR (95% CI) in the highest compared with the lowest quartile for total protein intake = 1.17 (0.99, 1.39; P-trend across quartiles = 0.07) and for animal protein intake = 1.13 (0.95, 1.35; P-trend = 0.04). Higher animal-to-plant protein ratio (extreme-quartile HR = 1.23; 95% CI: 1.02, 1.49; P-trend = 0.01) and higher meat intake (extreme-quartile HR = 1.23; 95% CI: 1.04, 1.47; P-trend = 0.01) were associated with increased mortality. When evaluated based on disease history at baseline, the association of total protein with mortality appeared more evident among those with a history of type 2 diabetes, cardiovascular disease, or cancer (n = 1094) compared with those without disease history (n = 1547) (P-interaction = 0.05 or 0.07, depending on the model). Intakes of fish, eggs, dairy, or plant protein sources were not associated with mortality., Conclusions: Higher ratio of animal to plant protein in diet and higher meat intake were associated with increased mortality risk. Higher total protein intake appeared to be associated with mortality mainly among those with a predisposing disease. This trial was registered at clinicaltrials.gov as NCT03221127., (Copyright © American Society for Nutrition 2019.)

The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Aims: Epidemiological evidence indicates a protective effect of light to moderate alcohol consumption compared to non-drinking and heavy drinking. Although several mechanisms have been suggested, the effect of alcohol on atherosclerotic changes in vessel walls is unclear. Therefore, we explored the relationship between alcohol consumption and common carotid intima media thickness, a marker of early atherosclerosis in the general population., Methods: Individual participant data from eight cohorts, involving 37,494 individuals from the USE-IMT collaboration were used. Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) with alcohol consumption., Results: The mean age was 57.9 years (SD 8.6) and the mean CIMT was 0.75 mm (SD 0.177). About, 40.5% reported no alcohol consumed, and among those who drank, mean consumption was 13.3 g per day (SD 16.4). Those consuming no alcohol or a very small amount (<5 g per day) had significantly lower common CIMT values than those consuming >10 g per day, after adjusting for a range of confounding factors., Conclusion: In this large CIMT consortium, we did not find evidence to support a protective effect of alcohol on CIMT., (© The Author 2017. Medical Council on Alcohol and Oxford University Press.)

Background: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation., Methods: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group., Results: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women., Conclusion: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

Background: There is little information about the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with the risk of cognitive decline in general populations or in carriers of apolipoprotein E ɛ4 (APO-E4), a major risk factor for dementia., Objective: We investigated the associations of cholesterol and egg intakes with incident dementia, Alzheimer disease (AD), and cognitive performance in middle-aged and older men from Eastern Finland., Design: A total of 2497 dementia-free men, aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, were included in the study. Information on the apolipoprotein E (Apo-E) phenotype was available for 1259 men. Data on cognitive performance tests at the 4-y re-examinations were available for 480 men. Dietary intakes were assessed with the use of 4-d food records at baseline. Dementia and AD diagnoses were based on Finnish health registers. Cox regression and ANCOVA were used for the analyses., Results: During the 21.9-y follow-up, 337 men were diagnosed with dementia, and 266 men were diagnosed with AD. Neither cholesterol nor egg intake was associated with a higher risk of incident dementia or AD. For example, when evaluated continuously, each intake of 100 mg cholesterol/d was associated with a multivariable-adjusted HR of 0.90 (95% CI: 0.79, 1.02) for incident dementia, and each additional 0.5 egg (27 g)/d was associated with an HR of 0.89 (95% CI: 0.78, 1.01). However, egg intake was associated with better performance on neuropsychological tests of the frontal lobe and executive functioning, the Trail Making Test, and the Verbal Fluency Test. The Apo-E4 phenotype did not modify the associations of cholesterol or egg intake (P-interactions > 0.11)., Conclusions: Neither cholesterol nor egg intake is associated with an increased risk of incident dementia or AD in Eastern Finnish men. Instead, moderate egg intake may have a beneficial association with certain areas of cognitive performance., (© 2017 American Society for Nutrition.)

Previous cross-sectional studies examining whether John Henryism (JH), or high-effort coping with socioeconomic adversity, potentiates the inverse association between socioeconomic position (SEP) and cardiovascular health have focused mainly on hypertension in African Americans. We conducted the first longitudinal test of this hypothesis on incident acute myocardial infarction (AMI) using data from the Kuopio Ischemic Heart Disease Risk Factor Study in Finland (N = 1405 men, 42-60 years). We hypothesized that the expected inverse gradient between SEP and AMI risk would be stronger for men scoring high on JH than for those scoring low. John Henryism was measured by a Finnish version of the JH Scale for Active Coping. Four different measures of SEP were used: childhood SEP, education, income, and occupation. AMI hazard ratios (HR) by SEP and JH were estimated using COX proportional hazard models, before and after adjustment for study covariates. 205 cases of AMI occurred over a median of 14.9 years. Men employed in lower rank (farmer, blue-collar) occupations who scored high on JH had significantly higher age-adjusted risks of AMI than men in higher rank (white-collar) occupations (HR = 3.14, 95% CI: 1.65-5.98 for blue collar; HR = 2.33, 95% CI: 1.04-5.22 for farmers) who also scored high on JH. No socioeconomic differences in AMI were observed for men who scored low on JH (HR = 1.36, 95% CI: 0.74-2.47 for blue collar; HR = 0.93, 95% CI: 0.59-1.48 for farmers; p = 0.002 for the SEP × JH interaction). These findings persisted after adjustment for sociodemographic, behavioral, and biological factors. Results for other SEP measures were in the same direction, but did not reach statistical significance. Repetitive high-effort coping with adversity (John Henryism) was independently associated with increased risk for AMI in Finnish men, underscoring the potential relevance of the John Henryism hypothesis to CVD outcomes other than hypertension and to populations other than African Americans., (Copyright © 2016. Published by Elsevier Ltd.)

Background: In general populations, the effects of dietary cholesterol on blood cholesterol concentrations are modest. However, the relation is stronger in those with an ɛ4 allele in the apolipoprotein E gene (APOE). There is little information on the association between cholesterol intake and the risk of coronary artery disease (CAD) among those with the ApoE4 phenotype., Objective: We investigated the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with carotid intima-media thickness and the risk of incident CAD in middle-aged and older men from eastern Finland., Design: The study included 1032 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on common carotid artery intima-media thickness (CCA-IMT) were available for 846 men. Dietary intakes were assessed with 4-d food records. Associations with incident CAD and baseline CCA-IMT were analyzed by using Cox regression and ANCOVA, respectively., Results: The ApoE4 phenotype was found in 32.5% of the men. During the average follow-up of 20.8 y, 230 CAD events occurred. Egg or cholesterol intakes were not associated with the risk of CAD. Each 1 additional egg (55 g)/d was associated with a multivariable-adjusted HR of 1.17 (95% CI: 0.85, 1.61) in the ApoE4 noncarriers and an HR of 0.93 (95% CI: 0.50, 1.72) in the ApoE4 carriers (P-interaction = 0.34). Each 100-mg/d higher cholesterol intake was associated with an HR of 1.04 (95% CI: 0.89, 1.22) in the ApoE4 noncarriers and an HR of 0.95 (95% CI: 0.73, 1.25) in the ApoE4 carriers (P-interaction = 0.81). Egg or cholesterol intakes were also not associated with increased CCA-IMT., Conclusion: Egg or cholesterol intakes were not associated with increased CAD risk, even in ApoE4 carriers (i.e., in highly susceptible individuals)., (© 2016 American Society for Nutrition.)

Importance: The prevalence of cardiometabolic multimorbidity is increasing., Objective: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity., Design, Setting, and Participants: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates., Exposures: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI)., Main Outcomes and Measures: All-cause mortality and estimated reductions in life expectancy., Results: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy., Conclusions and Relevance: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Background: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events., Methods: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity., Results: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites., Conclusion: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.

Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavorable risk factor burden., (© 2015 American Heart Association, Inc.)

Background: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably., Objectives: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components., Data Sources: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE., Study Eligibility Criteria: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men., Methods: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied., Results: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension., Conclusions: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

Importance: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain., Objective: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk., Design, Setting, and Participants: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment., Main Outcomes and Measures: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk., Results: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels., Conclusions and Relevance: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

It has been suggested that low density lipoprotein-containing circulating immune complexes (LDL-CIC) play a role in atherogenesis and are involved in the formation of early atherosclerotic lesion. These complexes, as well as anti-LDL autoantibodies, have been found in the blood and in the atherosclerotic lesions of patients with different cardiovascular diseases, as well as in the blood of animals with experimental atherosclerosis. It can be suggested that the presence of anti-LDL antibodies in the blood is a result of immune response induced by lipoprotein modification. LDL-CIC differs from native LDL in many aspects. It has much lower sialic acid content, smaller diameter, and higher density and is more electronegative than native LDL. Fraction of LDL-CICs is fundamental to the serum atherogenicity manifested at the cellular level. LDL-CIC, unlike native LDL, is able to induce intracellular accumulation of neutral lipids, especially esterified cholesterol, in cells cultured from uninvolved human aortic intima and in macrophage cultures. After removal of LDL-CIC, the CHD patient's sera lose their atherogenic properties. Titer of LDL-CIC in blood serum significantly correlates with progression of atherosclerosis in human in vivo and has the highest diagnostic value among other measured serum lipid parameters. Elevated CIC-cholesterol might well be a possible risk factor of coronary atherosclerosis.

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 β-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.

In human pathology, several diseases are associated with somatic mutations in the mitochondrial genome (mtDNA). Even though mitochondrial dysfunction leads to increased oxidative stress, the role of mitochondrial mutations in atherosclerosis has not received much attention so far. In this study we analyzed the association of mitochondrial genetic variation with the severity of carotid atherosclerosis, as assessed by carotid intima-media thickness (cIMT) and the presence of coronary heart disease (CHD) in 190 subjects from Moscow, Russia, a population with high CHD occurrence. cIMT was measured by high-resolution B-mode ultrasonography and mtDNA heteroplasmies by a pyrosequencing-based method. We found that heteroplasmies for several mutations in the mtDNA in leukocytes, including C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A mutations, were significantly (p<0.001) associated with both the severity of carotid atherosclerosis and the presence of CHD. These findings indicate that somatic mitochondrial mutations have a role in the development of atherosclerosis.

Background: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events., Methods: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen., Results: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years., Conclusions: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).

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.

Context: The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent., Objective: To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score., Data Sources: Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion., Study Selection: Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke., Data Extraction: Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease., Results: We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women., Conclusion: The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Context: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated., Objective: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction., Design, Setting, and Participants: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years)., Main Outcome Measures: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk., Results: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines., Conclusion: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling., Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6., Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes., Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease., Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Methylmercury (MeHg), a worldwide contaminant found in fish and seafood, has been linked to an increased risk of cardiovascular mortality., Objective: We examined 42 Faroese whaling men (30-70 years of age) to assess possible adverse effects within a wide range of MeHg exposures from consumption of pilot whale meat., Methods: We assessed exposure levels from mercury analysis of toenails and whole blood (obtained at the time of clinical examination), and a hair sample collected 7 years previously. Outcome measures included heart rate variability (HRV), blood pressure (BP), common carotid intima-media thickness (IMT), and brainstem auditory evoked potentials (BAEP). We carried out multiple regression and structural equation model (SEM) analyses to determine the confounder-adjusted effect of mercury exposure. Taking into account correlations among related measures, we categorized exposure and outcomes in groups to derive latent exposure and response variables in SEMs. We used multiple regression analysis to compare the predictive validity of individual exposure biomarkers and the latent exposure variable on individual and latent outcomes., Results: The toenail mercury concentrations varied widely and had a geometric mean of 2.0 microg/g; hair concentrations averaged about 3-fold higher. Mercury exposure was significantly associated with increased BP and IMT. This effect was reflected by SEMs, but mercury in toenails tended to be the best effect predictor., Conclusions: The results support the notion that increased MeHg exposure promotes the development of cardiovascular disease.

Introduction: Studies of the relationship between work time and health have been inconclusive. Consequently, we sought to examine the effect of work time on progression of atherosclerosis., Methods: This prospective study of 621 middle-aged Finnish men evaluated effects of baseline and repeat measures of work time on 11-year progression of ultrasonographically assessed carotid intima-media thickness (IMT) and interactions with cardiovascular disease. Multiple linear regression models adjusted for 21 biological, behavioral, and psychosocial risk factors, Results: Working 3 (minimum), 5 (medium), or 7 (maximum) days per week at baseline was associated with 23%, 31%, and 40% 11-year increases in IMT, respectively. The relative change ratio (RCR) at maximum vs minimum was 1.14 for baseline days worked per week and 1.10 for hours worked per year of follow-up. Significant interactions existed between cardiovascular disease and work time. Men with ischemic heart disease (IHD) who worked the maximum of 14.5 hours per day experienced a 69% increase in IMT compared with a 29% increase in men without IHD. The RCR ratio for IHD (RCRIHD/RCRno IHD) was 1.44 for hours per day. Similarly, the RCR ratio for baseline carotid artery stenosis was 1.29 for hours per day and 1.22 for hours per year., Conclusion: Increases in work time are positively associated with progression of carotid atherosclerosis in middle-aged men, especially in those with preexisting cardiovascular disease. Our findings are consistent with the hemodynamic theory of atherosclerosis.

Objectives: The aim of this substudy was to ascertain whether long-term treatment with fenofibrate reduces surrogate measures of atherosclerosis, biomarkers of inflammation, and endothelial activation in patients with type 2 diabetes., Background: Some fibrates may decrease cardiovascular events, improve endothelial function, and reduce levels of acute-phase proteins. In the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study, fenofibrate failed to decrease the primary end point of coronary events in patients with type 2 diabetes., Methods: A total of 170 patients with type 2 diabetes of the FIELD Helsinki cohort were randomly assigned to micronized fenofibrate 200 mg/day or placebo in a double-blind design. Carotid intima-media thickness (IMT) and the augmentation index (a measure of large artery stiffness) were measured at baseline and at second- and fifth-year visits. Plasma levels of interleukin (IL)-6, C-reactive protein (CRP), serum amyloid A (SAA), secretory phospholipase A2 IIA (SPLA2), E-selectin, vascular cellular adhesion molecule (VCAM)-1, and intercellular adhesion molecule (CAM)-1 were determined by commercial enzyme-linked immunosorbent assay kits at the same visits., Results: IMT and the augmentation index increased similarly in both treatment groups during the study. Plasma levels of CRP, IL-6, SPLA2, SAA, VCAM-1, ICAM-1, and E-selectin remained unchanged in both groups., Conclusions: Fenofibrate treatment was not associated with beneficial changes in IMT, augmentation index, or biomarkers of inflammation and endothelial function. (Fenofibrate Intervention and Event Lowering in Diabetes; NCT00132886).

Aims: Dyslipidaemia and hypertension are features of the metabolic syndrome, but the role of dyslipidaemia in the development of hypertension is less clear. We assessed the association of dyslipidaemia with incident hypertension during a 7-year follow-up in a population-based cohort of middle-aged men without hypertension at baseline., Methods and Results: In all, 88 of 311 men developed hypertension during the follow-up. A 1-SD increment in triglyceride concentrations was associated with a 1.6-fold [95% CI(confidence interval) 1.2-2.3] increased risk of developing hypertension, independently of features related to the metabolic syndrome. In separate multivariable models, the triglyceride content of high-density lipoprotein (HDL) cholesterol and apolipoprotein B concentrations were also associated with new-onset hypertension. In a stepwise backwards logistic regression model, concentrations of low-density lipoprotein (LDL) cholesterol [odds ratio (OR) 1.3, 95% CI 1.0-1.7 for a 1-SD change] and triglyceride content of HDL cholesterol (OR) 1.5, 95% CI 1.1-1.9) were positively associated with incident hypertension, whereas HDL concentrations (OR 0.7, 95% CI 0.5-0.9) seemed protective. In factor analyses, elevated triglyceride levels and related disturbances in lipid and cholesterol metabolism were associated with new-onset hypertension., Conclusion: Dyslipidaemia characteristic of the metabolic syndrome predicts the development of hypertension during a 7-year follow-up of eastern Finnish men, independently of features related to insulin resistance. The recognition of dyslipidaemia and initiation of lifestyle treatment even in the absence of hypertension is likely to reduce the long-term burden of cardiovascular disease.

The role of flavonoids in CVD, especially in strokes, is unclear. Our aim was to study the role of flavonoids in CVD. We studied the association between the intakes of five subclasses (flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins), a total of twenty-six flavonoids, on the risk of ischaemic stroke and CVD mortality. The study population consisted of 1950 eastern Finnish men aged 42-60 years free of prior CHD or stroke as part of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up time of 15.2 years, 102 ischaemic strokes and 153 CVD deaths occurred. In the Cox proportional hazards model adjusted for age and examination years, BMI,systolic blood pressure, hypertension medication, serum HDL- and LDL-cholesterol, serum TAG, maximal oxygen uptake, smoking, family history of CVD, diabetes, alcohol intake, energy-adjusted intake of folate, vitamin E, total fat and saturated fat intake (percentage of energy), men in the highest quartile of flavonol and flavan-3-ol intakes had a relative risk of 0.55 (95% CI 0.31, 0.99) and 0.59 (95% CI 0.30, 1.14) for ischaemic stroke, respectively, as compared with the lowest quartile. After multivariate adjustment, the relative risk for CVD death in the highest quartile of flavanone and flavone intakes were 0.54 (95% CI 0.32, 0.92) and 0.65 (95% CI 0.40, 1.05), respectively. The present results suggest that high intakes of flavonoids may be associated with decreased risk of ischaemic stroke and possibly with reduced CVD mortality.

Limited amount of evidence suggests that high intake of flavonoids could be associated with decreased risk of lung and colorectal cancer, but more studies are needed. In this prospective cohort study, we assessed the relation between the intakes of 26 flavonoids from 5 subclasses; flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins, and the risk of lung, prostate and colorectal cancer. The study population consisted of 2,590 middle-aged eastern Finnish men of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. The mean intake of flavonoids was 131.0 +/- 214.7 mg/day. During the mean follow-up time of 16.2 years, 62 lung, 138 prostate, and 55 colorectal cancers occurred. All lung cancer cases occurred among either current smokers (n = 50) or previous smokers (n = 12). After adjustment for age, examination years, body mass index, smoking status, pack-years of smoking, physical activity and intakes of alcohol, total fat, saturated fat, fiber, vitamin C and E, relative risk (RR) for lung cancer was 0.27 (95% CI: 0.11-0.66) for the highest quarter of total flavonoid intake as compared with the lowest quarter. Out of 5 flavonoid subclasses, flavonols and flavan-3-ols were associated with lung cancer, for the highest quarter of intake the RR were 0.29 (95% CI: 0.11-0.78) and 0.24 (95% CI: 0.09-0.64), respectively. No association between flavonoid intake and risk of prostate or colorectal cancer were found. We conclude that high intake of flavonoids is associated with decreased risk of lung cancer in middle-aged Finnish smoking men.

Aims: The objective is to study whether a heart rate (HR) increase from 40 to 100% of maximal work capacity in the exercise test (HR40-100) independently predicts mortality in men with known or suspected coronary heart disease (CHD)., Methods and Results: The subjects were 294 men, 42-61 years of age, from eastern Finland with known or suspected CHD but without use of HR-lowering medication at baseline. HR was measured at rest and during a maximal, symptom-limited exercise test. During an average follow-up of 11.0 years, there were 61 all-cause deaths. In Cox-multivariable model, mortality increased by 41% (95% confidence interval, 12-79%) with a 1-SD (15 b.p.m.) decrement in HR40-100. HR increase from rest to 40% of maximal work capacity was not associated with an increased risk of death. Synergism was observed between HR40-100 and workload achieved at HR of 100 b.p.m. so that men having low values for both these HR variables had a particularly adverse prognosis compared with men with high values for these variables., Conclusion: An attenuated HR increase particularly during the latter half of a maximal exercise test is an independent predictor of death in men with known or suspected CHD.

An attenuated heart rate (HR) response to exercise, or chronotropic incompetence, has been shown to predict adverse cardiac events in subjects without known cardiovascular disease (CVD). The aim of the present study was to investigate whether chronotropic incompetence independently predicts acute myocardial infarction (AMI) in middle-aged men. In addition to previously established chronotropic incompetence variables, we focused on a new chronotropic incompetence variable, the HR increase from 40% to 100% of maximal work capacity (HR40-100), as a predictor of AMI. The subjects were a representative sample of 1,176 middle-aged men who did not have CVD and did not use HR-lowering medication at baseline. The association of chronotropic incompetence variables with the risk of AMI was examined by Cox regression models including numerous known risk factors for AMI. During an average follow-up of 11.0 years, there were 106 AMIs (9.0%). In Cox multivariable model, the risk of AMI increased by 33% for each SD decrement of 13 beats/min in HR40-100 (95% confidence interval [CI] 9 to 64). When considered concurrently, HR40-100 was the only chronotropic incompetence variable that improved the predictive value of the model containing other risk factors for AMI. Men with a low HR40-100 (<46 beats/min) and a heightened increase in systolic blood pressure (SBP) (>67 mm Hg) were at particularly high risk, with a 3.1-times higher incidence of AMI than those with a normal HR40-100 and SBP increase (95% CI 1.7 to 5.7). In conclusion, a low HR40-100 predicted AMI in men without previous CVD independent of other exercise test or clinical variables.

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.

Objectives: This study prospectively assessed the effects of occupational physical activity on atherosclerosis progression., Methods: This population-based prospective study of ultrasonographically assessed carotid intima media thickness (IMT) used repeated measures of occupational physical activity during baseline, 4-year, and 11-year examinations of 612 Finnish men 42-60 years of age at baseline. The association between five measures of energy expenditure and the 11-year change in maximum IMT was evaluated in regression models adjusting for 21 potential confounders, including biological factors, leisure-time physical activity, smoking, socioeconomic status, psychosocial job factors, and baseline health status., Results: At baseline, 31% of all the men and 51% of those with ischemic heart disease (IHD) exceeded the recommended maximum levels of relative aerobic strain. All five measures of energy expenditure were significantly associated with adjusted 11-year IMT change. Significant interactions were found between IHD and several measures of energy expenditure. Maximum relative aerobic strain resulted in a 90% increase in IMT among the men with IHD compared with a 46% increase among those without IHD. The men with preexisting carotid stenosis also had higher rates of IMT progression than the men without this condition., Conclusions: This study shows that high energy expenditures at work are associated with an accelerated progression of atherosclerosis even after control for virtually all known cardiovascular risk factors, especially among older workers and workers with preexisting IHD or carotid artery stenosis. The findings support the hemodynamic theory of atherosclerosis and have important implications for workplace surveillance and disease prevention.

Objective: In culture studies matrix metalloproteinase (MMP)-8 thins the protecting fibrous cap of the atherosclerotic plaque thereby increasing its vulnerability. Results on the association of serum MMP-8 concentrations and cardiovascular diseases (CVD) are, however, scarce and contradictory., Methods and Results: We analyzed the association between CVD or subclinical atherosclerosis and serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations of 1018 men with the follow-up time of 10 years. MMP-8 concentrations or MMP-8/TIMP-1 ratios were higher in men with prevalent CVD or subclinical atherosclerosis at baseline than those without. In men free of CVD at baseline, MMP-8 concentrations associated with acute myocardial infarction, death from coronary heart disease (CHD), CVD, or from any cause with relative risks (RR) (95% CI) of 1.138 (1.009 to 1.284), 1.188 (1.034 to 1.365), 1.171 (1.026 to 1.338), and 1.136 (1.018 to 1.269), respectively, and MMP-8/TIMP-1 ratio with CHD death with an RR of 1.206 (1.028 to 1.414) per standard deviation (SD) increase. In men with no prevalent CVD but with subclinical atherosclerosis at baseline, elevated serum MMP-8 concentration predicted CVD death with an RR of 3.03 (1.09 to 8.44). TIMP-1 concentrations alone had no predictive value., Conclusions: The results indicate that serum MMP-8 concentrations are elevated in prevalent or subclinical atherosclerosis and associate with the worst cardiovascular outcome.

The role of flavonoids in CVD is still unclear. In this cross-sectional study we assessed the relation between the intakes of twenty-six flavonoids from five subclasses: flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins, and the mean common carotid artery intima-media thickness (CCA-IMT). The study population consisted of 1380 middle-aged eastern Finnish men for whom the mean CCA-IMT examinations were carried out as a part of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD). The mean intake of flavonoids was 128.5 (sd 206.7) mg/d and the mean CCA-IMT was 0.78 (sd 0.17) mm. In the lowest quartile of total flavonoid intake the non-adjusted mean CCA-IMT was 0.79 (sd 0.19) mm, while the mean CCA-IMT was 0.76 (sd 0.15) in the highest quartile (P < 0.001). After adjustment for age, variables related to CCA-IMT measurement, history of atherosclerosis, smoking, BMI, diabetes, systolic blood pressure, serum HDL- and LDL-cholesterol, VO2 max, and intakes of alcohol, SFA, folate, vitamins C and E, the total flavonoid intake was inversely associated with the mean CCA-IMT (P = 0.018). Out of different flavonoid subclasses, flavan-3-ols were inversely associated with CCA-IMT (P = 0.025) after statistical adjustment. There was a trend for an inverse association between intake of flavonols and mean CCA-IMT (P = 0.055). We conclude that high intake of flavonoids is associated with decreased carotid atherosclerosis in middle-aged Finnish men.