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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 ≥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.

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

Low vitamin D status increases the risk of death. Magnesium plays an essential role in vitamin D metabolism and low magnesium intake may predispose to vitamin D deficiency and potentiate the health problems. We investigated whether magnesium intake modifies the serum 25(OH)D3 concentration and its associations with mortality in middle-aged and older men. We included 1892 men aged 42-60 years without cardiovascular disease or cancer at baseline in 1984-1989 from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Serum 25(OH)D3 was measured with the high-performance liquid chromatography using coulometric electrode array detection. Magnesium intake was assessed with 4-day food recording. Deaths were ascertained by a computer linkage to the national cause of death register. Deaths due accidents and suicides were excluded. Cox proportional hazards regression models were used to analyze the associations. The multivariate-adjusted hazard ratio (HR) for death in the lowest (32.1 nmol/L) versus the highest (49.4 nmol/L) serum 25(OH)D3 tertile was 1.31 (95 % CI 1.07-1.60, Ptrend = 0.01). Stratified by the magnesium intake, the higher risk was observed only in the lower magnesium intake median (414 mg/day); HR = 1.60 (95 % CI 1.19-2.13, Ptrend = 0.002) in the lowest versus the highest 25(OH)D3 tertile, whereas the corresponding HR = 1.07, 95 % CI 0.75-1.36, Ptrend = 0.63) in the higher magnesium intake median, P for interaction = 0.08. In this cohort of middle-aged and older men low serum 25(OH)D3 concentration was associated with increased risk of death mainly in those with lower magnesium intake.

Summary Background Observational studies on the association of chronic hepatitis C with carotid atherosclerosis have yielded varying results. In addition, previous related systematic reviews were limited in synthesis. By more careful selection and further synthesis, we summarize current body of evidence on the relationship between chronic hepatitis C and carotid atherosclerosis. Methods All published observational studies related to the topic identified by systematic searches of PubMed and Scopus were screened based on diagnosis of chronic hepatitis C and diagnosis and estimation of the risk of a carotid atherosclerosis-related outcome. Selected studies were subjected to quality assessment, and eligible studies were used in subsequent narrative and quantitative syntheses. Results The initial search identified 190 unique publications, which were narrowed by preliminary review to 16 potentially relevant original articles. After quality assessment, seven studies were eligible and were used in narrative synthesis. Five studies assessed the risk of increased carotid intimal media thickening using B mode ultrasonography; five studies assessed the risk of carotid plaque formation using B mode ultrasonography. Five of these studies were used in subsequent meta-analysis. The risk of a person with chronic hepatitis C developing carotid intimal media thickening is about 4·03 times the risk of an uninfected person. The risk of a person with chronic hepatitis C developing carotid plaque is about 3·94 times the risk of an uninfected person. Conclusion Current evidence shows that hepatitis C virus (HCV) or factors associated with HCV infection can promote the occurrence and progression of carotid atherosclerosis.

Contains fulltext : 136938.pdf (Publisher’s version ) (Open Access) 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.

Data on the association between body iron and glucose homeostasis by the three glycaemic states are scarce. Thus, we investigated the association between body iron as assessed by a serum ferritin concentration and glucose homeostasis using homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) and beta cell function (HOMA-BcF) in different glycaemic states.A cross-sectional analysis was conducted in 2541 men aged 42-60 years in 1984-1989 in the Kuopio Ischemic Heart Disease Risk Factor Study. Subjects were classified into the three glycaemic states, normoglycaemia, prediabetes and type 2 diabetes (T2D), by fasting plasma glucose measurements and the information collected at study visit. The association between serum ferritin quartiles and HOMA-IR and HOMA-BcF for each glycaemic state was examined by analysis of covariance and linear regression analysis.The mean age and serum ferritin concentrations were 53.1 years (standard deviation = 5.7, range = 42.0-61.3 years) and 166.2 µg/L (standard deviation = 141.7, range = 11-960 µg/L), respectively. After multivariable adjustments, a weak and direct association was observed between serum ferritin quartiles and HOMA-IR in normoglycaemia (P-trend = 0.001) but a direct association in prediabetes (P-trend = 0.007) and in T2D (P-trend = 0.078). In HOMA-BcF, the association was weak and direct in normoglycaemia (P-trend = 0.003), direct in prediabetes (P-trend = 0.005) and inverse in T2D (P-trend = 0.105). Strongest associations were observed in prediabetes (β = 0.25, 95% confidence interval = 0.14-0.36 and P = 0.004 in HOMA-IR; β = 0.23, 95% confidence interval = 0.15-0.31 and P = 0.008 in HOMA-BcF) after a 100-µg/L increase in serum ferritin (log-transformed).These data suggest that both the strength and the direction of the association between body iron stores and glucose homeostasis are dependent on the glycaemic state of the population.

Scope: Vitamin D3, its biologically most active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and the vitamin D receptor (VDR) are important for adipose tissue biology. Methodsandresults: WeextrapolatedgenomicVDRassociationlociinadipocytesfrom55conserved genome-wide VDR-binding sites in nonfat tissues. Taking the genes DUSP10, TRAK1, NRIP1 ,a ndTHBD as examples, we confirmed the predicted VDR binding sites upstream of their transcription start sites and showed rapid mRNA up-regulation of all four genes in SGBS human pre-adipocytes. Using adipose tissue biopsy samples from 47 participants of a 5-month vitamin D3 intervention study, we demonstrated that all four primary VDR target genes can serve as biomarkers for the vitamin D3 responsiveness of human individuals. Changes in DUSP10 gene expression appear to be the most comprehensive marker, while THBD mRNA changes characterized a rather different group of study participants. Conclusion: We present a new approach to predict vitamin D target genes based on conserved genomic VDR-binding sites. Using human adipocytes as examples, we show that such ubiquitous VDR target genes can be used as markers for the individual’s response to a supplementation with vitamin D3.

Aims To investigate the associations of the apolipoprotein E phenotype (apoE) and disturbed glucose metabolism with cognitive function in a random population sample. Methods A cross-sectional study was conducted, in which 528 men aged 54 or 60 years were recruited randomly from a larger population-based sample of 1516 men. A subject was defined as having abnormal glucose tolerance (AGT), if he had a clinical diagnosis of diabetes, with either dietary or oral antidiabetic treatment or showed impaired glucose tolerance in an oral glucose tolerance test. The subjects were divided into three groups according to apolipoprotein E phenotypes: (a) E2/4, E3/4 or E4/4 (apoE E4); (b) E 3/3 (apoE E3); and (c) E2/2 or E2/3 (apoE E2). Memory function was examined using a word-list learning with Buschke’s selective reminding method and test. Executive functions were assessed with the Trail Making Test A and B. Results Those subjects with apoE E2 and abnormal glucose metabolism demonstrated the worst cognitive executive control compared to other groups. Simple cognitive speed did not differ between the groups. Conclusions The exploratory analyses revealed that subjects with apoE E2 allele and AGT had worse glycaemic control and cognitive executive control compared to other groups. Different apolipoprotein phenotypes together with impaired glucose tolerance may have different cumulative adverse effects on age-related cognitive performance. Some subgroups of subjects may be especially vulnerable to cognitive impairment. Diabet. Med. 18, 991‐997 (2001)

A rather common leucine7-to-proline7 (Leu7Pro) polymorphism in the preproneuropeptide Y (prepro-NPY) gene signal peptide may be important in blood pressure regulation, cholesterol metabolism and the pathogenesis of atherosclerosis in humans. We examined the associations of the Leu7Pro polymorphism with carotid atherosclerotic progression, blood pressure and serum lipids in a population-based sample of 966 men aged 42–60 years in Finland. The Pro7 substitution (carrier frequency 12.2%) was associated with accelerated four-year increase in the mean ( P =0.01) and maximal ( P =0.007) common carotid intima-media thickness (IMT) and with slightly increased systolic ( P =0.03) and diastolic ( P =0.02) blood pressures, adjusted for other major risk factors. Men with Pro7 substitution had 30.6% (95% CI 6.9–54.0%) greater increase in the mean IMT and 20.0% (95% CI 5.3–34.4%) greater increase in the maximal IMT than men with Leu7/Leu7 genotype. The Pro7 substitution was also related to increased serum total cholesterol ( P =0.01) and LDL cholesterol ( P =0.02) in obese (body mass index (BMI)>30 kg/m 2 ) men. This study provides important evidence suggesting that the Pro7 substitution in the prepro-NPY is an important risk factor for accelerated atherosclerotic progression, increased blood pressure and increased serum cholesterol in humans.

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

Vitamin D(3) belongs to the few nutritional compounds that has, via the binding of its metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. The relation of thousands of genomic VDR-binding sites to a few hundred primary 1,25(OH)(2)D(3) target genes is still largely unresolved. We studied chromatin domains containing genes for the adhesion molecules CD97 and LRRC8A, the glucose transporter SLC37A2 and the coactivator NRIP1. These domains vary significantly in size (7.3 to 956 kb) but contain each one major VDR-binding site. In monocytic cells these four sites are associated with open chromatin and occupied by VDR, while in macrophage-like cells only the sites of LRRC8A, SLC37A2 and NRIP1 are accessible and receptor bound. The VDR site of CD97 does, in contrast to the three other loci, not carry any DR3-type binding sequence. CD97, LRRC8A, SLC37A2 and NRIP1 are early responding 1,25(OH)(2)D(3) target genes in monocytic cells, while in macrophage-like cells they respond less and, in part, delayed. In primary human peripheral blood mononuclear cells from 71 prediabetic subjects of a vitamin D(3) intervention study (VitDmet) CD97, LRRC8A, SLC37A2 and NRIP1 can be used as transcriptomic biomarkers for classifying human individuals for their possible benefit from vitamin D(3) supplementation. In particular, NRIP1 exceeds the potential of the previously identified marker CD14 by more than 40% and seems to be a well-suited molecular marker for the vitamin D(3) status in the hematopoietic system.

Neuropeptide Y (NPY) plays an important role in the hypothalamic regulation of food intake and energy balance. According to recent findings in animals, NPY also seems to be a potent regulator of alcohol consumption. We used the recently identified Leu(7) to Pro(7) polymorphism in the signal peptide part of NPY to investigate whether the NPY system is associated with alcohol consumption in humans. The subjects (N = 889) were an ethnically homogeneous, nonselected population sample of middle-aged men from Eastern Finland. The gene variant producing Pro(7) substitution was associated with a 34% higher average alcohol consumption, even after adjustment for a number of covariates (P = 0.03). The proportion of heavy drinkers (over 230 g of ethanol/week) was also somewhat higher in this group (13.1% vs. 8.2%, P = 0.10). Our study provides the first evidence that alcohol preference in humans is likely to be regulated by the NPY system.

Background A common functional genetic polymorphism in the catechol-0-methyltransferase (COMT) gene (Val158 Met) results in 3- to 4-fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes. Methods: We studied alcohol consumption and the COMT genotype in middle-aged Finnish men (n = 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes. Results: Men with LL genotype (30% of all subjects) reported 27% higher weekly alcohol consumption compared with the two other genotype groups (p < 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p = 0.031). Conclusions: The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population.

Background —Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated ( HFE ) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results —Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1.1 to 4.8; P =0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions —Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.

Iron deficiency anemia is customarily treated by iron supplementation. However, iron can act as a catalyst of lipid peroxidation in vitro, and high intake of heme iron has been associated with an increased risk of myocardial infarction in some, but not in all epidemiologic studies. We carried out a 6-month trial of the effects of supplementation of men (n=48) with low iron stores with ferrous sulfate (180 mg of iron per day), iron polymaltose complex (200 mg of iron per day) or placebo. The in vitro susceptibility of very low and low density lipoproteins to oxidation increased in the ferrous sulfate group by 8.8% (P

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

OBJECTIVE The relationship between fish or omega-3 polyunsaturated fatty acids (PUFAs) and type 2 diabetes is inconclusive. Even contaminants in fish, such as mercury, may modify the effects. We investigated the associations between serum omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA), hair mercury, and risk of incident type 2 diabetes in middle-aged and older Finnish men. RESEARCH DESIGN AND METHODS A total of 2,212 men from the prospective, population-based Kuopio Ischemic Heart Disease Risk Factor study, aged 42–60 years and free of type 2 diabetes at baseline in 1984–1989, were investigated. Serum PUFA and hair mercury were used as biomarkers for exposure. Dietary intakes were assessed with 4-day food recording. Type 2 diabetes was assessed by self-administered questionnaires and fasting and 2-h oral glucose tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 years after the baseline and by record linkage to hospital discharge registry and reimbursement register on diabetes medication expenses. Cox proportional hazards models were used to analyze associations. RESULTS During the average follow-up of 19.3 years, 422 men developed type 2 diabetes. Men in the highest versus the lowest serum EPA + DPA + DHA quartile had 33% lower multivariate-adjusted risk for type 2 diabetes (95% CI 13–49; P trend 0.01). No statistically significant associations were observed with serum or dietary ALA, dietary fish or EPA + DHA, or hair mercury. CONCLUSIONS Serum long-chain omega-3 PUFA concentration, an objective biomarker for fish intake, was associated with long-term lower risk of type 2 diabetes.

Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants. The genes CD14 and thrombomodulin (THBD) are up-regulated primary vitamin D targets and showed to be suitable gene expression markers for vitamin D signaling in both primary tissues. However, in a ranking of the samples concerning their expected response to vitamin D only the top half showed a positive correlation between the changes of CD14 or THBD mRNA and serum 25(OH)D3 concentrations. Interestingly, this categorization allows unmasking a negative correlation between changes in serum concentrations of 25(OH)D3 and the inflammation marker interleukin 6. We propose the genes CD14 and THBD as transcriptomic biomarkers, from which the effects of a vitamin D3 supplementation can be evaluated. These biomarkers allow the classification of subjects into those, who might benefit from a vitamin D3 supplementation, and others who do not.

ObjectiveWe investigated the risk of type 2 diabetes mellitus (T2DM) over a wide range of body iron stores.MethodsProspective cohort of 1613 men in the Kuopio Ischemic Heart Disease Risk Factor study, aged 42–60 years, free of T2DM and hereditary hemochromatosis at baseline in 1984–1989. Baseline serum ferritin (sF) and serum-soluble transferrin receptor (sTfR) concentrations were used to predict incident T2DM. T2DM was assessed by questionnaires, blood glucose measurements, and medication reimbursement register.ResultsThere were 331 cases of incident T2DM during the mean follow-up of 16.8 years (27 098 person-years). At baseline, subjects who later developed T2DM had average sF concentrations of 191 μg/l (s.d.155) vs 151 μg/l (s.d.119) among those who remained healthy,PP=0.009) risk of developing T2DM. In a Cox regression, a markedly increased risk of developing T2DM was observed from the fourth sF quintile (185 μg/l, the median) upward (hazard ratio (HR) first vs fifth quintile=1.5, 95% CI 1.0–2.2,P-trend=0.05). In a corresponding Cox model in sTfR, the subjects in the third quintile (1840 μg/l, the median) had the least risk (HR=0.63, 95% CI 0.42–0.97,P=0.04).ConclusionsBody iron within the sF reference range is not an important determinant of T2DM risk, whereas high normal and above is associated with markedly increased risk. Iron depletion toward iron deficiency as assessed by sTfR is not protective against T2DM. A rule of thumb safe range could be 30–200 μg/l of sF.

Background Vitamin D has been suggested to have a role in infection defence and on the immune system. We therefore investigated the effect of serum 25-hydroxyvitamin D 3 (25(OH)D 3 ) on the risk of incident hospitalised pneumonia in an ageing general population in eastern Finland. Methods The study population included 723 men and 698 women aged 53–73 years from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor study who were free of pneumonia, other pulmonary diseases and cancer at baseline in 1998–2001. Incident pneumonia episodes leading to hospitalisation were collected by record linkage to the hospital discharge register. The serum vitamin D status was assayed as 25(OH)D 3 concentration. Cox proportional hazards regression models were used to analyse the effect of serum 25(OH)D 3 on the risk of incident pneumonia. Results The mean (SD) serum 25(OH)D 3 concentration of the study population was 43.5 (17.8) nmol/l. 73 subjects had at least one hospitalisation episode due to pneumonia during an average follow-up of 9.8 years. After multivariable adjustments, the subjects in the lowest serum 25(OH)D 3 tertile had a 2.6-fold (95% CI 1.4 to 5.0, p trend across tertiles=0.005) higher risk of developing pneumonia compared with the subjects in the highest tertile. This significant result remained even after adjustment for the determinants of serum 25-hydroxyvitamin D 3 . Conclusions These data suggest an inverse effect of serum 25(OH)D 3 concentration on the risk of incident pneumonia in the general ageing population.

Objective: To investigate whether low vitamin E status is a risk factor for incident non-insulin dependent diabetes mellitus. Design: Population based follow up study with diabetes assessed at baseline and at four years. Setting: Eastern Finland. Subjects: Random sample of 944 men aged 42-60 who had no diabetes at the baseline examination. Intervention: Oral glucose tolerance test at four year follow up. Main outcome measures: A man was defined diabetic if he had either (a) a fasting blood glucose concentration >/=6.7 mmol/l, or (b) a blood glucose concentration >/=10.0 mmol/l two hours after a glucose load, or (c) a clinical diagnosis of diabetes with either dietary, oral, or insulin treatment. Results: 45 men developed diabetes during the follow up period. In a multivariate logistic regression model including the strongest predictors of diabetes, a low lipid standardised plasma vitamin E (below median) concentration was associated with a 3.9-fold (95% confidence interval 1.8-fold to 8.6-fold) risk of incident diabetes. A decrement of 1 µmol/l of uncategorised unstandardised vitamin E concentration was associated with an increment of 22% in the risk of diabetes when allowing for the strongest other risk factors as well as serum low density lipoprotein cholesterol and triglyceride concentrations. Conclusions: There was a strong independent association between low vitamin E status before follow up and an excess risk of diabetes at four years. This supports the theory that free radical stress has a role in the causation of non-insulin dependent diabetes mellitus.

Objectives. The purpose of this study was to test the hypothesis that the reduction of body iron stores by venesection (blood letting) would reduce the susceptibility to oxidation of atherogenic serum lipoproteins. Design. This is a randomized, controlled cross-over trial in 14 regularly smoking men with elevated serum ferritin concentration. The study design comprised two 14-week study periods, with a 14-week wash-out period in between, with either blood donations or control. Setting. The study site was the Research Institute of Public Health, University of Kuopio. Investigators from the Division of Epidemiology, University of Minnesota, Minneapolis, participated in the planning of the study. Subjects. Fourteen volunteers who were heavy smokers and had previous experience in blood letting were recruited for the study. Interventions. During the intervention periods, the subjects donated 450 mg (500 mL) of blood three times in 14 weeks. Main outcome measurements. Oxidation resistance of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) was measured after inducing oxidation with haemin and H2O2. Results. Serum ferritin concentration was reduced by 44% [95% confidence interval (CI) 8–82%, P = 0.021] during the venesection periods, the maximal oxidation velocity was decreased by 20% (95% CI 3–30%, P = 0.032), and the lag time to start of oxidation was lengthened (oxidation resistance increased) by 33% (95% CI 1–64%, P = 0.036). Conclusions. These observations indicate that the reduction of body iron stores by venesection can increase the oxidation resistance of serum VLDL/LDL in regularly smoking men.

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.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.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.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.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 diode array detector in our high-performance liquid chromatography (HPLC) method for 25-hydroxyvitamin D(3) (25OHD(3)) and 25-hydroxyvitamin D(2) (25OHD(2)) did not perform satisfactorily for measuring human serum concentrations below 30nM. Because of a need for a reliable self-managed method in ongoing and starting vitamin D studies of the laboratory, we decided to develop a chromatographic method applying coulometric electrode array detector (CEAD) and evaluate reliability of the method by participating in the Vitamin D External Quality Assessment Scheme (DEQAS). The limit of quantification for 25OHD(3) and 25OHD(2) of the new method was 0.36pmol on column (3.6nM), and linearity ranged from 5 to 2400nM. Accuracy of the method was 90% for 25OHD(3) and 69% for 25OHD(2). The HPLC-CEAD results from five DEQAS rounds were in line with those of the other participating laboratories using HPLC methods. The HPLC-CEAD results for 25OHD(3) also corresponded to the results obtained with the Chromsystems HPLC method in a certified laboratory. The long-term coefficients of variation for 25OHD(3) were 6.2%, 7.8%, 5.2%, 6.7%, and 7.3% in concentrations of 27.5, 38.7, 48.4, 78.4, and 88.0nM, respectively. The developed HPLC-CEAD method was shown to be applicable for determining 25OHD(3) and 25OHD(2) in human serum samples.

BACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association. METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis. FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02). INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. FUNDING: Deutsche Forschungsgemeinschaft., Deutsche Forschungsgemeinschaft.

Background: Fish consumption has been associated with reduced risk of sudden cardiac death. It has been suggested that the long-chain omega-3 fatty acids from fish are responsible for the beneficial effects of fish consumption. The QT interval on the ECG measures the duration of ventricular repolarization, and a long QT interval is one of the major risk factors for sudden cardiac death. Our goal was to study the association between the serum long-chain omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) and QT interval duration in middle aged men. As fish is also the major source of methylmercury, an environmental contaminant proposed to have adverse cardiovascular effects, we also evaluated the impact of methylmercury exposure on the QT duration. Methods: A total of 1411 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 years and free of cardiovascular disease, were included. A standardized resting 12-lead ECG was used for recording. Men with QRS ≥120 ms were excluded. The heart rate-corrected QT interval (QTc) was calculated using the Bazett’s formula. Prolonged QTc was defined as QTc >440 ms. Quartiles of the percentage of EPA, DPA and DHA of all serum fatty acids were used as the exposure. Hair mercury in quartiles was used as a marker for methylmercury exposure. Results: The mean±SD concentrations were 4.70±1.61% for EPA+DPA+DHA, 1.69±0.92% for EPA, 0.55±0.10% for DPA and 2.46±0.74% for DHA, of all serum fatty acids. The mean QTc interval in the quartiles of serum EPA+DPA+DHA was 417, 417, 415 and 414 ms (P for trend 0.02), after adjustment for age, examination year, smoking, alcohol intake, physical activity, body mass index, education, income, diabetes, treated hypertension and arrhythmia medication. Prolonged QTc was found in 169 of the 1411 men (12%). The multivariate-adjusted odds ratio (OR) for prolonged QTc in the quartiles of EPA+DPA+DHA was 1, 0.90, 0.83 and 0.63 [95% confidence interval (CI) 0.39–1.02, P for trend 0.05]. The OR in the highest vs. the lowest quartile was 0.58 (95% CI 0.36–0.93, P for trend 0.03) for EPA, 0.68 (95% CI 0.43–1.09, P for trend 0.06) for DPA and 0.59 (95% CI 0.35–0.98, P for trend 0.04) for DHA. The mean±SD hair mercury concentration was 1.9±2.0 μg/g. Hair mercury was not associated with QTc, unadjusted or adjusted. The multivariate-adjusted OR for prolonged QTc in the quartiles of hair mercury was 1, 0.97, 0.99 and 1.04 (95% CI 0.64–1.69), P for trend 0.80. Conclusions: Increased concentration of long-chain omega-3 fatty acids in serum, a marker of fish or fish oil consumption, appears to protect against prolonged QTc in eastern Finnish middle-aged men. Methylmercury exposure is not associated with QTc in this study population.

Vitamin D insufficiency and type 2 diabetes are both common in Finland, and low vitamin D status has been suggested as a risk factor for type 2 diabetes. Our aim was to study the associations between serum 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D status, and glucose homeostasis and type 2 diabetes in a general population sample in Eastern Finland.Cross-sectional analysis in the Kuopio Ischaemic Heart Disease Risk Factor Study. A total of 850 men and 906 women, aged 53-73 years, were analysed. Relative risk (RR) of prevalent diabetes was estimated as odds ratios by logistic regression. Associations between serum 25(OH)D and markers of impaired glucose metabolism in tertiles of serum 25(OH)D concentration were assessed by linear regression.The mean serum 25(OH)D concentration was 43.4 nmol/L (SD 17.6, range 8.5-122.8 nmol/L) in the study population. Serum 25(OH)D concentration50 nmol/L were observed in 65.5% of the participants. Serum 25(OH)D was inversely associated with fasting serum insulin, fasting blood glucose and oral glucose tolerance test (OGTT) 2-h glucose levels after adjustment for age, gender and examination year. Association with the OGTT 2-h glucose remained statistically significant after multivariate adjustments. The RR (95% confidence interval) for type 2 diabetes in tertiles of serum 25(OH)D were 1, 1.26 (0.86, 1.85) and 1.44 (0.96, 2.15) after multivariate adjustments (p for trend = 0.08).Our results suggest that low serum 25(OH)D is associated with impaired glucose and insulin metabolism.

Background— Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results— To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT mean , IMT max , and IMT mean-max ), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1 ) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P =6.75×10 −7 for IMT max ; replication P =7.24×10 −6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort ( P =0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P =6.53×10 −6 , n=13 591; and 0.95 [0.92–0.98], P =1.83×10 −4 , n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions— This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

ObjectivesFish consumption has been associated with reduced risk of cardiovascular diseases (CVD), especially sudden cardiac death (SCD). Fish is the major source of long-chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid and docosahexaenoic acid. It is also a major source of methylmercury, which was associated with increased risk of CVD in this study population. Impact of interaction between long-chain n-3 PUFA and methylmercury on the SCD risk is unknown.MethodsA total of 1857 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor study, aged 42-60 years and free of CVD at baseline in 1984-1989, were studied. Serum long-chain n-3 PUFA was used as the marker for long-chain n-3 PUFA intake and hair mercury as the marker for mercury exposure.ResultsDuring the mean follow-up of 20.1 years, 91 SCD events occurred. In the multivariate Cox proportional hazards regression models, serum long-chain n-3 PUFA concentration was not associated with the risk of SCD until hair mercury was accounted for; then the hazard ratio (HR) in the highest vs. lowest tertile was 0.54 [95% confidence interval (CI) 0.32 to 0.91, p for trend = 0.046]. When the analyses were stratified by hair mercury content, among those with lower hair mercury, each 0.5 percentage unit increase in the serum long-chain n-3 PUFA was associated with HR of 0.77 (95% CI 0.64 to 0.93), whereas no association was seen among those with higher hair mercury (p for interaction = 0.01). Among the individual long-chain n-3 PUFA, docosahexaenoic acid was most strongly associated with the risk.ConclusionHigh exposure to mercury may reduce the benefits of long-chain n-3 PUFA on SCD.

Background: Studies on the association between alcohol consumption and myocardial infarction (MI) have typically used baseline data on alcohol consumption and potential confounders. This study aimed at investigating the association between alcohol consumption and MI considering time-varying alcohol consumption and time-varying confounders. Methods: Data were available for 1030 males participating in the Kuopio Ischaemic Heart Disease Risk Factor Study (Finland). Baseline data for the present study were collected in 1991–93. MIs were ascertained from national registries until December 2005. Alcohol consumption was categorized into four groups. Data were analysed using conventional discrete-time hazard and marginal structural models (MSMs). Time-invariant covariates were age, working status, diabetes and cigarette-years. Time-varying covariates in the MSM were prior alcohol consumption, smoking, history of cardiovascular diseases, body mass index, high-density lipoprotein cholesterol, systolic blood pressure, insulin and fibrinogen. Results: An insignificant increase of MI risk among the heaviest alcohol consumers (168 g week1) compared with the reference group (12–83 g week1) was observed when using a conventional model including baseline alcohol consumption and confounders measured prior to baseline [relative risk (RR) = 1.20, 95%confidence interval (95% CI) = 0.68–2.12]. When using a conventional model with time-varying alcohol consumption and adjusting for prior confounders, an increased risk of MI among the heaviest alcohol consumers was revealed (RR = 1.71, 95%CI = 1.03–2.85). There was also a trend towards increased risk among the heaviest consumers using the MSM (RR = 1.59, 95%CI = 0.93–2.72). Conclusion: Our findings suggest that standard methods using only baseline data on alcohol consumption and confounders may lead to biased estimates on the association between alcohol consumption and MI. Refereed/Peer-reviewed

Background: Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide production and is associated with endothelial dysfunction. Elevated plasma levels of ADMA have been demonstrated in patients with hypertension. The aim of the present study was to investigate the relationship between ADMA and the structural and functional indices of arteries in patients with hypertension. Methods and results: Eighty middle-aged (47±1.0 years, 41 male and 39 female) untreated mild to moderate essential hypertension patients underwent routine medical examination, pulse wave analysis (PWA) with salbutamol and nitroglycerin test, carotid-femoral pulse wave velocity (PWV) and duplex ultrasound measurements of the carotid artery intima media thickness (IMT). PWA with the administration of salbutamol and nitroglycerin was used to assess endothelium dependent (EDV) and independent vasodilation. In patients with hypertension ADMA was significantly associated with EDV (r=-0.26; p=0.02) and IMT (r=0.32; p=0.007). In multiple regression analysis ADMA was significantly independently correlated with peripheral diastolic blood pressure, EDV and IMT (R2=0.28; p

The role of dietary glycemic index (GI) and glycemic load (GL) in coronary heart disease (CHD) is unclear. Our aim was to study the association between the dietary GI and GL and the risk of acute myocardial infarction (AMI).The study population consisted of 1981 Finnish men from the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study, aged 42-60 years and free of CHD at baseline. During an average follow-up time of 16.1 years, 376 new AMI events occurred. In multivariable-adjusted Cox proportional hazards models, the relative risk (RR) for AMI in the highest quartile of GI was 1.25 (95% CI: 0.92-1.69; P for trend=0.08) and for GL 1.11 (95% CI: 0.79-1.57; P for trend=0.21) when compared with the lowest quartile. For overweight (BMI ≥ 27.5 kg/m²) men, the multivariable-adjusted RR for AMI in the highest compared to the lowest tertile of GI and GL were 1.58 (95% CI: 1.03-2.43; P for trend=0.04, P for interaction=0.01) and 2.05 (95% CI: 1.30-3.23; P for trend=0.002, P for interaction=0.002), respectively. For physically less active men; energy expenditure for leisure-time physical activity50 kcal/d, the RR for AMI was 1.72 (95% CI: 1.07-2.76; P for trend=0.04, P for interaction 0.80) with higher GL.Our results suggest that both high dietary GI and GL are associated with increased risk of AMI among overweight and GL possibly among less physically active men.

ObjectivesThe 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.BackgroundSome 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.MethodsA 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.ResultsIMT 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.ConclusionsFenofibrate 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)

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.

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.

Ageing, plasma circulating C-reactive protein (CRP), oxidized low-density lipoprotein (OxLDL) and homocysteine (Hcy) are associated with atherosclerosis. The aim of this study was to evaluate the relationship between age, inflammatory and oxidative stress-related markers with functional and structural changes of the arteries in asymptomatic persons.CRP, OxLDL and Hcy were measured in 175 clinically healthy subjects, aged 40-70 years. Ultrasonography and pulse wave analysis were used to measure carotid intima-media thickness (IMT) and augmentation index (AIx).OxLDL was correlated with IMT (r = 0.24, P = 0.003), whereas CRP was correlated with AIx (r = 0.21, P = 0.005). No correlation was detected between Hcy and AIx or age-adjusted IMT. There was a significant association between AIx and ageor=50 years (r = 0.33; P = 0.001) and between IMT and age50 years (r = 0.40; P = 0.001). In stepwise regression analysis age, weight, white blood cell count, OxLDL, heart rate and timing of the reflected waveform adjusted for height were significantly and independently associated with IMT (R = 0.41; P0.001). At the same time, AIx as the dependent variable correlated positively with age, gender, CRP and mean arterial pressure, and negatively with heart rate, weight and height, in stepwise regression analysis (R = 0.63; P0.001).The results of the present study showed that CRP, OxLDL, Hcy and age are not similarly related to AIx and IMT in asymptomatic persons. The results suggest that CRP and younger age are related to arterial stiffness, whereas OxLDL and older age become more important determinants of structural changes of the arteries in asymptomatic persons.

Hepcidin is a peptide hormone with both paracrine and endocrine functions that help in maintaining body iron stores. Type 2 diabetes (T2D) is one of the sequelae of excess body iron stores; thus, iron regulatory hormone hepcidin may have a direct or at least an indirect role in the aetiopathogenesis of T2D. Both human and animal studies at molecular and genetic levels have attempted to establish a role for hepcidin in the development of T2D, and a few epidemiologic studies have also showed a link between hepcidin and T2D at population level, but the findings are still inconclusive. Recent data have suggested different pathways in which hepcidin could be associated with T2D with much emphasis on its primary or secondary role in insulin resistance. Some of the suggested pathways are via transcription modulator of hepcidin (STAT3); ferroportin 1 expression on the cells involved in iron transport; transmembrane protease 6 enzyme; and pro-inflammatory cytokines, interleukin (IL)-1, IL-6, tumor necrosis factor-α and IL-10. This review briefly reports the existing evidence on the possible links between hepcidin and T2D and concludes that more data are needed to confirm or refute hepcidin's role in the development of T2D. Examining this role could provide a further evidence base for iron in the aetiopathogenesis of T2D.

Background The role of circulating levels of total homocysteine tHcy in the development of coronary heart disease (CHD) is still under debate. One reason for conflicting results between previous studies on homocysteine and heart diseases could be consequence of different interactions between homocysteine and genes in different study populations. Many genetic factors play a role in folate-homocysteine metabolism, like functional polymorphism (Val108Met) in the Catechol-O-methyltransferase (COMT) gene. Methodology and Findings Our aim was to examine the role of COMT Val158Met polymorphism and interaction of this polymorphism with serum tHcy and folate concentration on the risk of acute coronary and events in middle-aged men from eastern Finland. A population-based prospective cohort of 792 men aged 46–64 years was examined as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up of 9.3 years, there were 69 acute coronary events in men with no previous history of CHD. When comparing the COMT low activity genotype with the others, we found an age and examination year adjusted hazard rate ratio (HRR) of 1.73 (95% confidence interval (CI), 1.07–2.79), and an age, examination year, serum LDL and HDL cholesterol, and triglyceride concentration, systolic blood pressure and smoking adjusted HRR of 1.77 (95% CI, 1.05–2.77). Although serum tHcy concentration was not statistically significantly associated with acute coronary events (HRR for the highest third versus others 1.52, 95% CI, 0.93–2.49), subjects with both high serum tHcy and the COMT low activity genotype had an additionally increased adjusted risk of HRR 2.94 (95% CI 1.50–5.76) as compared with other men. Conclusions This prospective cohort study suggests that the functional COMT Val158Met polymorphism is associated with increased risk of acute coronary events and it may interact with high serum tHcy levels.

The crucial role of nitric oxide (NO) for normal endothelial function is well known. In many conditions associated with increased risk of cardiovascular diseases such as hypercholesterolemia, hypertension, abdominal obesity, diabetes and smok ing, NO biosynthesis is dysregulated, leading to endothelial dysfunction. The grow ing evidence from animal and human studies indicates that endogenous inhibitors of endothelial NO synthase such as asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (L-NMMA) are associated with the endothelial dysfunc tion and potentially regulate NO synthase. The major route of elimination of ADMA is metabolism by the enzymes dimethylarginine dimethylaminohydrolase-1 and -2 (DDAH). In our recent study 16 men with either low or high plasma ADMA concen trations were screened to identify DDAH polymorphisms that could potentially be associated with increased susceptibility to cardiovascular diseases. In that study a novel functional mutation of DDAH-1 was identified; the mutation carriers had a significantly elevated risk for cardiovascular disease and a tendency to develop hypertension. These results confirmed the clinical role of DDAH enzymes in ADMA metabolism. Furthermore, it is possible that more common variants of DDAH genes contribute more widely to increased cardiovascular risk.

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.

Human biomonitoring of the lipid peroxidation DNA modification 1,N6-ethenodeoxyadenosine (epsilondA) excreted into urine is thought to be a potential marker for oxidative stress-related DNA damage and human cancer. We have tested this hypothesis in a prospective, nested case-control study. During the years 1984-1989, 24-h urines were collected from 1956 men in the Kuopio Ischaemic Heart Disease (KIHD) Risk Factor Study. epsilondA concentrations were measured by LC-MS/MS in 24-h urine samples from 47 men with cancer diagnosed at follow up until 2001 and from 31 cancer free smoking-matched control subjects. Odds ratio for having higher than control median epsilon dA excretion rate and cancer, estimated by binary logistic regression, was 0.73 (95% CI 0.29-1.80, p = 0.49). In this study, the urinary excretion of epsilondA provides no additional prediction of cancer development in males after controlling for smoking.

Background and Purpose— Low maximal oxygen uptake (VO 2max ) has been shown to predict the risk of stroke. However, VO 2max does not take into account the differences in cardiac afterload between subjects. The aim of this study was to examine the relationship of exercise cardiac power (ECP), defined as a ratio of VO 2max with peak systolic blood pressure (SBP) during exercise, with the risk for stroke. Methods— Population-based cohort study with an average follow-up of 12 years from eastern Finland. A total of 1761 men with no history of stroke or coronary heart disease at baseline participated. Among these men, 91 strokes occurred, of which 69 were attributable to ischemic causes. Results— The relative risk of any stroke in men with low ECP (P =0.01; P =0.02 for the trend across the quartiles), and the relative risk for ischemic stroke was 2.7 (95% CI, 1.1 to 7.0; P =0.03; P =0.04 for trend across the quartiles) compared with men having high ECP (>14.3 mL/mm Hg) during exercise after adjusting for age, examination year, cigarette smoking, alcohol consumption, body mass index, diabetes, serum total cholesterol level, energy expenditure of physical activity, exercise-induced myocardial ischemia, and the use of antihypertensive medication. After further adjustment for resting SBP, results were statistically nonsignificant. Conclusions— Low ECP provides noninvasive and easily available measure for stroke risk. One of the most potential explanations for the association between ECP and the increased risk of stroke is an elevated afterload and peripheral resistance indicated by elevated SBP.

Background: Several, but not all, prospective studies have shown that low folate intakes, low circulating folate concentrations, or high plasma total homocysteine (tHcy) concentrations are associated with an increased risk of coronary artery disease (CAD). Objective: We examined the relations of both serum folate and serum tHcy concentrations with acute coronary events in middle-aged men from eastern Finland who had no CAD at baseline. Design: In a population-based prospective cohort study, 1027 men aged 46-64 y were examined in 1991-1993 as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up of 7.7 y (7900 person-years of follow-up), 114 acute coronary events were observed in 61 men who had no previous history of CAD (n = 810). Results: In a Cox model, compared with men whose serum folate concentrations were in the lowest tertile, those whose concentrations were in the highest tertile had a risk factor-adjusted relative risk of acute coronary events of 0.35 (95% CI: 0.17, 0.73; P = 0.005). Serum tHcy concentrations were not significantly associated with the risk of acute coronary events (for the highest tertile compared with the lowest, adjusted relative risk = 1.03; 95% CI: 0.57, 1.87; P = 0.932). Conclusions: The results of this prospective cohort study do not support the hypothesis that a high circulating tHcy concentration is a risk factor for acute coronary events in a male population free of prior heart disease. However, they do suggest that moderate-to-high serum folate concentrations are associated with a greatly reduced incidence of acute coronary events.

Different C18 monohydroxy fatty acids (OHFAs) were evaluated for their usefulness as markers of plasma lipid peroxidation (unsaturated fatty acid oxidation) ex vivo and in vivo. First, plasma samples (n = 5) were exposed for 3 h to different radical fluxes ex vivo. The formation of OHFAs was assessed by using varying concentrations of Cu2+ ions and AAPH (2,2'-azobis(2-amidinopropane) hydrochloride) as radical flux initiators. Secondly, a cross-sectional study was carried out in 47 middle-aged men. In this study, plasma concentrations of different in vivo OHFAs were compared with other indices of lipid peroxidation. Under mild oxidation conditions (heparin plasma containing 4.2 or 8.3 mM AAPH), concentrations of all the measured OHFAs (8, 9, 10, 11, 12, 13, 15 and 16-OH acids) increased in an identical manner, but under highly oxidative conditions (heparin plasma containing 83 mM AAPH or 4.2 to 8.3 mM CuSO4) mainly 9 and 13-OHFAs were formed. In the cross-sectional study, plasma 11 and 13-OHFA levels were associated statistically significantly with plasma free F2alpha-isoprostanes, recognized index of in vivo lipid peroxidation (r = 0.305, p = 0.037 and r = 0.308, p = 0.035, respectively). In addition, 16-OHFA levels correlated with the ratio of electronegatively charged LDL to total LDL (r = 0.335, p = 0.021). With respect to the other OHFAs, 15-OHFA had no correlation with either other OHFAs or the reference substances used. In addition, occasionally there were contamination problems in the assessment of 12-OHFA. It is concluded that all of the measured C18 OHFAs can be used as indicators of plasma lipid peroxidation under mild oxidation conditions, though the 12 and 15-OHFAs may need to be used with some caution. Under high oxidation conditions, 9-and 13-OHFAs seem to be the most useful indices because of their high formation capacity.

Low-grade inflammation has been implicated in the development of Type 2 diabetes and cardiovascular disease, but its role in the pathogenesis of the metabolic syndrome is unclear. We investigated the association between C-reactive protein (CRP) levels and the development of the metabolic syndrome and diabetes in men.Serum CRP concentrations and factors related to insulin resistance were determined in middle-aged Finnish men who participated in a population-based cohort study and were free of diabetes at baseline.At the 11-year follow-up, 143 of 680 men had developed the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) and 103 of 598 men had developed the metabolic syndrome as defined by the World Health Organization (WHO). Our analyses excluded men with the metabolic syndrome by the respective definition at baseline. In all, 78 of 762 men developed diabetes over the same period. Men with CRP concentrationsor =3 mg/l had a several-fold higher age-adjusted risk of developing the metabolic syndrome (NCEP definition: odds ratio [OR]=3.2, 95% CI 1.9-5.5; WHO definition: OR=3.4, 95% CI 2.0-6.1) or diabetes (OR=4.1, 95% CI 2.1-8.0) than men whose CRP levels were1.0 mg/l. Even after further adjustment for potentially confounding lifestyle factors and factors related to insulin resistance, the risk of diabetes (OR=2.3, 95% CI 1.0-5.1) was still increased in men with CRP concentrationsor =3 mg/l, but the association with the metabolic syndrome was no longer significant.Low-grade inflammation may increase the risk of the metabolic syndrome and diabetes in middle-aged men, but some of the risk is mediated through obesity and factors related to insulin resistance.