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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., published version, peerReviewed

Objectives Atherosclerosis (AS) and osteoporosis are common diseases in elderly people and may be metabolically related. The aim of this cross-sectional population-based study was to explore the association between common carotid artery intima-media thickness (cIMT), carotid artery calcification (CAC), and BMD in postmenopausal women. In addition, the association of postmenopausal hormone therapy (HT) and selected diseases with cIMT and carotid calcification was studied. Study design The 290 women (mean age 73.6 years) included in this Bone Brain Atherosclerosis study (OSTPRE-BBA) were randomly selected from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort, Finland. Main outcome measures For this cross-sectional study, cIMT was measured with B-mode ultrasound; femoral neck and total body BMD were measured with dual-energy X-ray absorptiometry. Results There were no statistically significant associations between mean cIMT and femoral neck T-score (p > 0.05). However, an increased maximum cIMT was significantly associated with low femoral neck T-score. In the osteoporotic group (T-score −1, n = 122), it was 1.93 ± 0.64 mm (p = 0.001). The odds of having CAC were approximately four-fold higher in the osteoporotic group compared with the group with a normal femoral neck T-score (odds ratio [OR] = 4.2, p = 0.038). The maximum cIMT was smaller in HT users (1.98 ± 0.56 mm, n = 190) than in non-users (2.16 ± 0.74 mm, n = 156, p = 0.036). Conclusions The results of our population-based study suggest that BMD is related to AS, at least in carotid arteries. They indirectly support the hypothesis of partially shared pathophysiological mechanisms between these two disorders.

Background Previous studies assessing the role of dietary factors in depression have mainly focused on nutrients, while the association between dietary patterns and depression is less studied. Objective The aim was to assess the role of dietary patterns in depression in both cross-sectional and prospective analyses. Design The study population consisted of 1003 Finnish middle-aged or older men from the Kuopio Ischemic Heart Disease Risk Factor Study. Food consumption was assessed by food frequency questionnaire in 1991–1993 and dietary patterns from 25 predefined food groups were extracted by factor analysis. Depressive symptoms were assessed with the self-administered Human Population Laboratory Depression Scale, cut-off point of five or more indicating elevated depressive symptoms. Results Altogether 72 (7.2%) subjects had elevated depressive symptoms. Three dietary patterns were identified: “prudent”, “Western” and “mixed”. In cross-sectional analysis, after adjustments for age, examination year, BMI, smoking, alcohol consumption, education, marital status, leisure-time physical activity , history of mental illness and cardiovascular disease the prudent dietary pattern was associated with a 25% lower prevalence of elevated depressive symptoms (OR: 0.75; 95% CI: 0.57, 0.99; P =0.036), whereas the Western dietary pattern was associated with increased prevalence of elevated depressive symptoms (OR: 1.41; 95% CI: 1.08, 1.84; P =0.011). In the prospective analysis (16.5 follow-up years), the prudent dietary pattern was inversely associated with the risk of getting a hospital discharge diagnosis of depression (HR: 0.66; 95% CI 0.47, 0.93; P =0.018). Conclusions Adherence to healthy dietary pattern is associated with lower risk of getting a hospital discharge diagnosis of depression.

Background Although higher intakes of fruit, berries, and vegetables (FBV) have been associated with reduced risk of type 2 diabetes (T2D) in some observational studies, the evidence is limited and inconclusive. Objective We assessed the relation of FBV intake and T2D incidence in Finnish men. Design We studied 2332 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study who were aged 42-60 y and free of T2D or impaired fasting glucose at baseline in 1984-1989. Food intake was assessed with 4-d food recording. T2D was assessed by using self-administered questionnaires, a fasting blood glucose measurement, a 2-h oral-glucose-tolerance test, and record linkage to a reimbursement register on diabetes medication expenses. In the Cox proportional hazards model, HRs for T2D were computed for the highest compared with lowest quartiles of FBV intake adjusted for age, examination year, body mass index, waist-to-hip ratio, smoking, education, physical activity, family history of diabetes, and energy and alcohol intakes. Results During the mean follow-up time of 19.3 y, 432 new cases of T2D occurred. For the total FBV intake (with the exclusion of potatoes and fruit and berry juices), the extreme-quartile multivariable-adjusted HR for T2D was 0.76 (95% CI: 0.57, 1.02; P-trend = 0.15). In the analysis for FBV components, berries had a corresponding HR of 0.65 (95% CI: 0.49, 0.88; P-trend = 0.003), whereas no significant associations were shown for fruit, fruit and berry juices, and vegetables. Conclusion Fruit and vegetables, particularly berries, may reduce risk of T2D in men.

Data-driven prediction systems used in epidemiological studies are still unsatisfactory from a practical point of view. Different pitfalls should be considered while transferring technologies from research to practice. The proposed k-Nearest Neighbors approach is designed to make disease-related predictions in a more holistic manner: we detect cases of novelty among unobserved subjects to identify situations when model predictions are not reasonably valid. Moreover, it copes with overlapping classes, finds new examples which cannot be labelled with the high confidence and reveals healthy subjects in the training data who might be at risk. Additionally, variable selection is built-in to select relevant predictors. The approach was applied to predict cardiovascular diseases based on the data collected within an ongoing follow-up study undertaken in Eastern Finland. According to the experimental results, our proposal allows increasing the accuracy of predictions made.

Background Zinc is an immunomodulatory trace element suggested to be beneficial in the augmentation of antidepressant therapy. Cross-sectional studies have also suggested an association between low dietary zinc and depression. This study examined the association between dietary zinc intake and depression in a prospective setting in initially depression-free men during a 20-year follow-up. Methods The study formed a part of the population-based Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, and comprised 2317 Finnish men aged 42–61 years. Zinc intake was assessed at baseline by a 4-d food record. Baseline depression severity was recorded with the Human Population Laboratory Depression Scale. In the prospective setting, depression was defined as having received a hospital discharge diagnosis of unipolar depressive disorder. Individuals who at baseline had elevated depressive symptoms were excluded (n=283). Results Altogether, 60 (2.7%) individuals received a hospital discharge diagnosis of depression during the 20-year follow-up. In Cox regression analysis adjusted for age, baseline depression severity, smoking, alcohol use, physical exercise and the use of dietary supplements, belonging to the lowest tertile of energy-adjusted zinc intake was not associated with an increased depression risk (RR 1.06, 95% CI 0.59–1.90). Limitations These observations may not be generalizable to women, or to individuals with a depression level not warranting hospitalization. Conclusions Our findings suggest that a low dietary zinc intake may not longitudinally precede depression in men. Dietary zinc intake may not have relevance for the prevention of depression in middle-aged men with a sufficient dietary zinc intake.

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.

Objective The aim of this study was to investigate associations of serum zinc with incident metabolic syndrome and its components in middle-aged and older Finnish men. Methods An 11-y prospective follow-up study conducted among 683 men from the Kuopio Ischaemic Heart Disease Risk Factor Study who were 42 to 60 y old at baseline in 1984 to 1989. The main outcome was incident metabolic syndrome, defined by the National Cholesterol Education Program (NCEP) criteria. Other outcomes were the individual components of the NCEP metabolic syndrome: Fasting blood glucose, serum triacylglycerols, serum high-density lipoprotein (HDL) cholesterol, hypertension, and waist circumference. Results During the average follow-up of 11 y, 139 men (20.4%) developed metabolic syndrome. Those in the highest tertile of serum zinc had 84% higher risk (95% confidence interval 12 to 201%, P trend across tertiles = 0.015) to develop metabolic syndrome compared with those in the lowest tertile, after adjustment for several potential confounders. The association between serum zinc and incident metabolic syndrome was attenuated by adjustment for waist circumference, serum HDL cholesterol, or hypertension. Serum zinc was also directly associated with higher waist circumference and hypertension and inversely associated with HDL cholesterol at the 11 y examinations. Conclusions We found a direct association between serum zinc and incidence of metabolic syndrome in middle-aged and older eastern Finnish men. Further studies are warranted to explore the mechanisms.

Background Studies of gender difference in type 2 diabetes have been inconclusive. We investigated gender difference in type 2 diabetes and the contribution of body iron, as assessed by serum ferritin to this difference. Methods We performed cross-sectional ( n = 1707) and prospective ( n = 1506) analyses in males and females aged 53–73 years in 1998–2001. Type 2 diabetes diagnosis was determined by questionnaire, blood glucose measurements and record linkage to type 2 diabetes registers. Gender difference in type 2 diabetes and serum ferritin contribution to the difference was examined in multivariable logistic and Cox regression models. Gender difference in fasting plasma glucose and insulin and homeostasis model assessment of insulin resistance was examined in linear regression analysis. Results In the cross-sectional analysis, a total of 201 type 2 diabetes cases were observed (males = 111 [55.2%] vs. female = 90 [44.8%], P = 0.032), and in adjusted models, males had higher odds of type 2 diabetes (OR = 1.61, 95% CI 1.10 to 2.34); higher fasting plasma glucose (β = 0.28, 95% CI 0.15 to 0.41), fasting plasma insulin (β = 0.73, 95% CI 0.26 to 1.19) and homeostasis model assessment of insulin resistance (β = 0.11, 95% CI 0.04 to 0.17). In the prospective analysis, males had increased risk of type 2 diabetes (HR = 1.46, 95% CI 1.03 to 2.07). With serum ferritin introduction (100 µg/L, log-transformed) into the models, the type 2 diabetes prevalence (OR = 1.35, 95% CI 0.91 to 1.99) and incidence (HR = 1.38, 95% CI 0.96 to 1.97) were appreciably attenuated. Conclusions These data suggest a gender difference in type 2 diabetes, with a higher prevalence and increased type 2 diabetes risk in males. Body iron explains about two-fifths and one-fifth of the gender difference in type 2 diabetes prevalence and incidence, respectively.

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

In this paper we compare a number of two-criterion filtering techniques for feature selection in cardiovascular predictive modelling. We design two-objective schemes based on different combinations of four criteria describing the quality of reduced feature sets. To find attribute subsystems meeting the introduced criteria in an optimal way, we suggest applying a cooperative multi-objective genetic algorithm. It includes various search strategies working in a parallel way, which allows additional experiments to be avoided when choosing the most effective heuristic for the problem considered. The performance of filtering techniques was investigated in combination with the SVM model on a population-based epidemiological database called KIHD (Kuopio Ischemic Heart Disease Risk Factor Study). The dataset consists of a large number of variables on various characteristics of the study participants. These baseline measures were collected at the beginning of the study. In addition, all major cardiovascular events that had occurred among the participants over an average of 27 years of follow-up were collected from the national health registries. As a result, we found that the usage of the filtering technique including intra- and inter-class distances led to a significant reduction of the feature set (up to 11 times, from 433 to 38 features) without detriment to the predictive ability of the SVM model. This implies that there is a possibility to cut down on the clinical tests needed to collect the data, which is relevant to the prediction of cardiovascular diseases.

Fish or fish oil consumption has been associated with lower blood pressure. Fish may also contain methylmercury, which has been associated with cardiovascular diseases and higher blood pressure. Our aim was to study the associations of serum long-chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), mainly reflecting fish or fish oil intake, and hair mercury concentration with blood pressure. Data were available for 848 men and 909 women from the Kuopio Ischaemic Heart Disease Risk Factor Study, aged 53-73 years. We excluded participants with ischemic heart disease, stroke, diabetes or hypertension treatment, leaving 396 men and 372 women. Log-transformed values were used to study the associations. The mean serum concentrations were 1.63% (s.d. 0.91) for EPA, 0.77% (s.d. 0.16) for DPA and 2.73% (s.d. 0.90) for DHA of all serum fatty acids. Multivariate-adjusted serum EPA+DPA+DHA was associated with lower systolic blood pressure (β = -4.50, 95% confidence interval (CI) -8.02 - -0.99) and pulse pressure (β = -4.41, 95% CI -6.95 - -1.87), but not with diastolic blood pressure (β = -0.45, 95% CI -2.31-1.52). The associations were similar with EPA, DPA and DHA evaluated individually. The mean hair mercury concentration was 1.42 μg g(-1) (s.d. 1.54). Hair mercury was not associated with blood pressure and it did not modify the association between PUFA and blood pressure. These results suggest that higher serum long-chain n-3 PUFA concentration has a modest inverse association with blood pressure in older men and women.

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

N-3 polyunsaturated fatty acids (PUFAs) have been associated with reduced inflammation. We tested the hypothesis that high serum concentrations of the n-3 PUFAs are associated with lower serum C-reactive protein (CRP) concentrations in healthy middle-aged Finnish men. We also examined whether exposure to mercury, an environmental contaminant in fish, which is also a major source of long-chain n-3 PUFA, was associated with CRP. Data from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study were analyzed cross-sectionally to determine the associations between serum n-3 PUFAs, hair mercury and serum CRP in 1395 healthy men, aged 42–60 years. Linear regression analyses were performed to analyze the associations. In the multivariate models, the mean serum CRP in quartiles of serum total n-3 PUFA concentration was 1.23, 1.27, 1.18 and 1.08 mg/l, P for trend=0.01. Statistically significant inverse associations were also observed with the total serum long-chain n-3 PUFA concentration and with the individual long-chain n-3 PUFAs docosapentaenoic acid and docosahexaenoic acid, but not with eicosapentaenoic acid or with the intermediate-chain n-3 PUFA alpha-linolenic acid. Hair methylmercury content was not associated with serum CRP levels and it did not modify the associations between serum n-3 PUFAs and CRP either. Serum n-3 PUFAs and especially the long-chain n-3 PUFA concentration, a marker of fish or fish oil consumption, were inversely associated with serum CRP in men. Exposure to mercury was not associated with serum CRP.

Our pilot study examined the potential of exhaled breath analysis in studying the metabolic effects of dietary fiber (DF). We hypothesized that a high-fiber diet (HFD) containing whole grain rye changes volatile organic compound (VOC) levels in exhaled breath and that consuming a single meal affects these levels. Seven healthy men followed a week-long low-fiber diet (17 g/d) and HFD (44 g/d) in a randomized crossover design. A test meal containing 50 g of the available carbohydrates from wheat bread was served as breakfast after each week. Alveolar exhaled breath samples were analyzed at fasting state and 30, 60, and 120 minutes after this meal parallel to plasma glucose, insulin, and serum lipids. We used solid-phase microextraction and gas chromatography-mass spectrometry for detecting changes in 15 VOCs. These VOCs were acetone, ethanol, 1-propanol, 2-propanol, 1-butanol, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, 2-methylbutyric acid, hexanoic acid, acetoin, diacetyl, and phenol. Exhaled breath 2-methylbutyric acid in the fasting state and 1-propanol at 120 minutes decreased (P = .091 for both) after an HFD. Ingestion of the test meal increased ethanol, 1-propanol, acetoin, propionic acid, and butyric acid levels while reducing acetone, 1-butanol, diacetyl, and phenol levels. Both DF diet content and having a single meal affected breathVOCs. Exploring exhaled breath further could help to develop tools for monitoring the metabolic effects of DF.

Savonen KP, Kiviniemi V, Laaksonen DE, Lakka TA, Laukkanen JA, Tuomainen T-P, Rauramaa R (Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Kuopio University Hospital, Kuopio; Information Technology Center, University of Eastern Finland, Kuopio Campus, Kuopio; Kuopio University Hospital, Kuopio; Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus; and Lapland Central Hospital, Rovaniemi, Finland). Two-minute heart rate recovery after cycle ergometer exercise and all-cause mortality in middle-aged men. J Intern Med 2011; doi: 10.1111/j.1365-2796.2011.02434.x Background. A slow heart rate recovery (HRR) after an exercise test is associated with an increased risk of all-cause mortality in asymptomatic individuals, but the data regarding additional prognostic information provided by HRR beyond other exercise test variables are inconsistent. We investigated the prognostic significance of HRR for premature death, particularly in relation to other exercise test variables. Methods. The study subjects were a representative population-based sample of 1102 men (42–61 years of age) without cardiovascular disease, cancer or diabetes. HRR was defined as the difference between maximal HR and HR 2 min after a maximal symptom-limited exercise test using a cycle ergometer. The association between HRR and premature mortality was examined with Cox regression models. Results. During an average follow-up of 18 years, 238 deaths occurred. HRR was an independent predictor of death [for a decrease of 12 beats min−1, relative risk (RR) 1.16, 95% CI 1.02–1.33, P = 0.02] after adjustment for age and established risk factors. When added in a Cox model with chronotropic response (decrease of 12 beats min−1, RR 1.09, 95% CI 0.93–1.27, P = 0.26) or cardiorespiratory fitness (decrease of 12 beats min−1, RR 1.12, 95% CI 0.98–1.30, P = 0.08), the association between a slow HRR and an increased risk of death was clearly weaker. Conclusion. A slow 2-min HRR after a cycle ergometer exercise test was an independent predictor of death in healthy middle-aged men after accounting for demographic and clinical characteristics. However, it was no longer predictive after accounting for chronotropic response and exercise capacity.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and is associated with endothelial dysfunction. The aim of the present study was to investigate the relationship between ADMA, indices of arterial stiffness, endothelial function and carotid artery intima-media thickness (IMT) in hypertension patients. Eighty middle-aged (47 ± 10 years) untreated patients with mild to moderate essential hypertension underwent routine physical examination, pulse wave analysis (PWA), measurement of aortic pulse wave velocity (PWV) and IMT. In PWA, administration of salbutamol and nitroglycerine was used to assess endothelium-dependent (EDV) and endothelium-independent vasodilation, respectively. In univariate analysis, ADMA was correlated with EDV (r = -0.26; p = 0.02) and IMT (r = 0.32; p = 0.007). In multiple regression analysis, ADMA was independently associated with the female gender, EDV, IMT and total cholesterol (R(2) = 0.30; p0.001). No correlation was detected between ADMA and augmentation index, central/brachial blood pressure or aortic PWV. In hypertension patients, ADMA is independently correlated with IMT and EDV. Thus, ADMA is a marker of endothelial dysfunction and intima-media thickening in patients with hypertension.

To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] concentration, a marker of vitamin D status, and risk of all-cause and cardiovascular mortality in a general older population with relatively low average serum 25(OH)D concentrations.The study population included 552 men and 584 women aged 53-73 years who were free of CVD and cancer at baseline in 1998-2001 from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Deaths were ascertained by a computer linkage to the national cause of death register. All deaths that occurred from the study entry to December 31, 2008, were included. Cox proportional hazards regression models were used to analyze the association between serum 25(OH)D and risk of death.The mean serum 25(OH)D concentration was 43.7 nmol/L (SD 17.8), with a strong seasonal variation. During the average follow-up of 9.1 years, 87 participants died, 35 from cardiovascular disease (CVD). After multivariable-adjustments, the hazard ratios (HR) for all cause death in the tertiles of serum 25(OH)D were 1, 1.68 (95% CI: 0.92, 3.07) and 2.06 (95% CI: 1.12, 3.80), p for trend = 0.02.Our study supports the accumulating evidence from epidemiological studies that vitamin D deficiency is associated with increased risk of death. Large-scale primary prevention trials with vitamin D supplementation are warranted.

Background— Atrial fibrillation (AF) is a common cardiac arrhythmia. Regular fish consumption has been shown to reduce the risk of AF in some but not all studies. Long-chain n-3 polyunsaturated fatty acids (PUFAs) from fish have been suggested to account for these beneficial effects. We tested this hypothesis by studying the association between the serum long-chain n-3 PUFAs eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid and risk of AF in men. Methods and Results— A total of 2174 men from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor Study, 42 to 60 years old and free of AF at baseline in 1984 to 1989, were studied. During the average follow-up time of 17.7 years, 240 AF events occurred. In the Cox proportional hazards model, the multivariable-adjusted hazard ratio in the highest (>5.33%) versus the lowest (P for trend=0.07). Evaluated individually, only serum docosahexaenoic acid was associated with the risk of AF (hazard ratio in the highest versus the lowest quartile 0.62, 95% confidence interval 0.42 to 0.92, P for trend=0.02). Exclusion of subjects (n=233) with myocardial infarction or congestive heart failure either at baseline or that preceded the AF event during follow-up slightly strengthened the associations. Serum intermediate chain-length n-3 PUFA, α-linolenic acid, or hair methylmercury concentration were not associated with the risk. Conclusions— An increased concentration of long-chain n-3 PUFAs in serum, a marker of fish or fish oil consumption, may protect against AF. Serum docosahexaenoic acid concentration had the greatest impact.

Many measures have been proposed to summarize the prognostic ability of the Cox proportional hazards (CPH) survival model, although none is universally accepted for general use. By contrast, little work has been done to summarize the prognostic ability of the stratified CPH model; such measures would be useful in analyses of individual participant data from multiple studies, data from multi-centre studies, and in single study analysis where stratification is used to avoid making assumptions of proportional hazards. We have chosen three measures developed for the unstratified CPH model (Schemper and Henderson's V , Harrell's C-index and Royston and Sauerbrei's D), adapted them for use with the stratified CPH model and demonstrated how their values can be represented over time. Although each of these measures is promising in principle, we found the measure of explained variation V very difficult to apply when data are combined from several studies with differing durations of participant follow-up. The two other measures considered, D and the C-index, were more applicable under such circumstances. We illustrate the methods using individual participant data from several prospective epidemiological studies of chronic disease outcomes.

Udgivelsesdato: 2009 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.

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.

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.

The authors investigated the shape, sex- and age-dependency, and possible confounding of the association between birth weight and systolic blood pressure (SBP) in 197,954 adults from 20 Nordic cohorts (birth years 1910-1987), one of which included 166,249 Swedish male conscripts. Random-effects meta-regression analyses were performed on estimates obtained from age- and sex-stratified analyses within each of the cohorts. There was an inverse association between birth weight and SBP, irrespective of adjustment for concurrent body mass index. The association was linear for males, but for females with a birth weight greater than 4 kg, SBP increased with birth weight (p < 0.01). The association was stronger in the older age groups (p < 0.05), although this could have been a birth cohort effect. The association was stronger among females than among males (p = 0.005) when birth weight was less than or equal to 4 kg. The estimated effect of birth weight on SBP at age 50 years was -1.52 mmHg/kg (95% confidence interval: -2.27, -0.77) in men and -2.80 mmHg/kg (95% confidence interval: -3.85, -1.76) in women. Exclusion of the Swedish conscripts produced nearly identical results. This meta-analysis supports the evidence of an inverse birth weight-SBP association, regardless of adjustment for concurrent body size. It also reveals important heterogeneity in the shape and strength of the association by sex and age.

Mercury is a heavy metal that exists naturally in the environment. Major sources include the burning of fossil fuels (especially coal) and municipal waste incineration. Mercury can exist in several forms, with the most hazardous being organic methylmercury. In waterways (lakes, rivers, reservoirs, etc.), mercury is converted to methylmercury, which then accumulates in fish, especially in large predatory fish. Fish and fish products are the major--if not the only--source of methylmercury in humans. Mercury has long been recognized as a neurotoxin for humans, but in the last 10 years, its potentially harmful effects on cardiovascular diseases (CVD) have raised a cause for concern, mostly due to the proposed role of mercury in oxidative stress propagation. Some epidemiological studies have indeed found an association between increased levels of mercury in the body and risk of CVD. There are several plausible mechanisms to explain the association; these are discussed in this review. We also review the epidemiological studies that have investigated the association between mercury and CVD.

The transition metal iron is catalytically highly active in vitro, and not surprisingly, body iron has been suggested to promote oxidative stress in vivo. In the current analysis we studied the association of serum ferritin concentration and serum soluble transferrin receptor concentration with daily urinary 8-hydroxydeoxyguanosine excretion, a marker of oxidative stress, in 48 mildly dyslipidemic men in East Finland. In multivariate linear regression analyses allowing for age, smoking, body mass index and physical exercise, serum ferritin concentration predicted the excretion rate at B = 0.17 (95% CI 0.08-0.26, P = 0.001), and serum soluble transferrin receptor to ferritin concentration ratio (TfR/ferritin) predicted the excretion rate at B = - 0.13 (95% CI - 0.21 to - 0.05, P = 0.002). Our data suggest that body iron contributes to excess oxidative stress already at non-iron overload concentrations in these subjects.

Background Depression is a major global public health concern. The aetiology of depression is partly unclear; however, intake of nutrients, such as magnesium, have been suggested to affect depressive symptoms and modify depression risk. Methods This research is a part of the Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, conducted on a sample of 2320 Eastern Finnish men aged 42–61 years old at the baseline. Magnesium intake was assessed by a 4-day food record. Hospital discharge diagnosis of unipolar depressive disorder was used as an outcome variable. Results Participants in the middle tertile of dietary magnesium intake had a statistically significantly decreased risk of getting a hospital discharge diagnosis of depression compared to participants in the lowest tertile of magnesium intake (HR 0.49, CI 0.25–0.95, P =0.035) in the prospective setting after multivariable adjustments. In addition, an inverse association between magnesium intake and the risk of depression was found when the combined middle and highest tertiles of magnesium intake were compared with the lowest tertile (HR 0.53, CI 0.29–0.95, P =0.033). Limitations Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting. Conclusions The results of this study suggest that magnesium intake may have an effect on the risk to develop depression. Further studies are needed to investigate whether sufficient magnesium intake could have implications for prevention or treatment of depression.

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) from fish have been shown to lower blood pressure. However, there is little information about the association with orthostatic hypotension, for which hypertension is a risk factor. We investigated the associations between serum long-chain omega-3 PUFAs and orthostatic hypotension in 1666 middle-aged or older men and women free of cardiovascular disease (CVD), diabetes or hypertension in 1998-2001 in the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) in eastern Finland. We also investigated the associations with mercury exposure, a major source of which is fish, and which has been associated with higher CVD risk in KIHD. Orthostatic hypotension was defined as decrease in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 1 min of standing. Orthostatic hypotension was found in 146 participants (8.8%). The mean serum concentrations were 1.67% (s.d. 0.92) for eicosapentaenoic acid, 0.79% (s.d. 0.16) for docosapentaenoic acid (DPA) and 2.78 (s.d. 0.92) for docosahexaenoic acid of all serum fatty acids. The mean pubic hair mercury concentration was 1.5 μg g(-1) (s.d. 1.6). We did not find statistically significant associations between the serum long-chain omega-3 PUFAs or pubic hair mercury and risk of orthostatic hypotension, except for DPA. Those in the highest vs. the lowest serum DPA tertile had multivariate-adjusted 41% lower odds for orthostatic hypotension (95% confidence interval 7-63%, P-trend=0.02). Serum long-chain omega-3 PUFAs or mercury exposure were not associated with the risk of orthostatic hypotension, except for the inverse association with DPA.

Objectives Zinc may play a role in the development of type 2 diabetes (T2D), because it is involved in antioxidant and anti-inflammatory activities. However, the role of zinc in the etiology of T2D has been poorly investigated. This study was conducted to study the association of serum zinc on T2D risk in middle-aged and older Finnish men. Methods This was a 20-year prospective follow-up study on 2220 Finnish men from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) who were 42 to 60 years old at baseline in 1984–1989. The main outcome was incident T2D. Serum zinc, body mass index (BMI), fasting blood glucose (FBG), serum insulin, C-reactive protein (CRP) and, in a subset of 751 participants, insulin-like growth factor-binding protein-1 (IGFBP-1), were measured. Also, the homeostatic model assessment (HOMA) was used to quantify insulin resistance (HOMA-IR), beta-cell function (HOMA-β) and insulin sensitivity (HOMA-IS). Results At baseline, serum zinc was associated with higher BMI, serum insulin, HOMA-IR, HOMA-β and IGFBP-1 and lower HOMA-IS. During the average follow-up of 19.3 years, 416 men developed T2D. Men in the highest quartile of serum zinc had 60% higher risk (95% CI 20–113%; P-trend

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).

The n-3 and n-6 polyunsaturated fatty acids (PUFAs) have been associated with lower risk of cardiovascular disease (CVD), but little is known about their association with natriuretic peptides (NPs), a marker for CVD risk. The aim of this study was to investigate the association of serum n-3 and n-6 PUFAs with NPs.A cross-sectional analysis of the association between serum n-3 and n-6 PUFAs with plasma N-terminal atrial (NT-proANP) and brain (NT-proBNP) NPs in a population-based sample of 985 men aged 46-65 years from Eastern Finland.After adjustment for age and examination year, only serum n-6 PUFA arachidonic acid (ARA) was inversely associated with NT-proANP (P-trend across quartiles=0.02), but further adjustments for conventional risk factors (body mass index, smoking, alcohol intake, systolic blood pressure, low-density lipoprotein cholesterol and history of CVD) attenuated the association (P-trend=0.10). The associations with the other PUFAs were not statistically significant. Among the PUFAs, only serum n-3 PUFA docosapentaenoic acid (DPA; P-trend=0.03) and ARA (P-trend=0.02) had inverse associations with NT-proBNP after adjustment for age and examination years. The associations were again attenuated after further adjustments but remained statistically significant for DPA (P-trend=0.05). Our results also suggested that the inverse associations may be more evident among those using beta-blockers.Our study suggests little overall impact of serum n-3 or n-6 PUFAs on plasma NPs.

Epidemiological evidence suggests a role for vitamin D in type 2 diabetes prevention. We investigated the effects of vitamin D3supplementation on glucose metabolism and inflammation in subjects with prediabetes. A 5-month randomized, double-blind, placebo-controlled intervention with three arms (placebo, 40 μg/d, or 80 μg/d vitamin D3) was carried out among sixty-eight overweight (BMI 25–35) and aging (≥60 years) subjects from Finland, with serum 25-hydroxyvitamin D3[25(OH)D3] < 75 nmol/L and either impaired fasting glucose or impaired glucose tolerance. Analyses included 66 subjects who completed the trial. Glucose metabolism was evaluated by fasting and 2-hour oral glucose tolerance test-derived indices and glycated hemoglobin. Inflammation was evaluated by high-sensitive C-reactive protein and five cytokines. Although a dose-dependent increase in serum 25(OH)D3over the supplementation period was observed (Ptrend < 0.001), there were no other statistically significant differences in changes in the 13 glucose homeostasis indicators between the study groups other than increase in the 120 min glucose concentration (Ptrend = 0.021) and a decreasing trend both in 30 min plasma insulin (Ptrend = 0.030) and glycated hemoglobin (Ptrend = 0.024) concentrations. A borderline statistically significant decreasing trend in interleukin-1 receptor antagonist concentration was observed (P= 0.070). Vitamin D3supplementation does not improve glucose metabolism in ageing subjects with prediabetes but may have modest anti-inflammatory effects.

To investigate the associations of serum long-chain omega-3 polyunsaturated fatty acids (PUFA) and hair mercury with future blood pressure in an ageing population.Prospective study with baseline measurements in 1998-2001 and follow-up measurements in 2005-2008. The linear relationships (β) of baseline serum fatty acids and hair mercury with future systolic and diastolic blood pressure and pulse pressure were analyzed with multiple linear regression models, using log-transformed values.181 men and 200 women aged 53-73 y from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) population in Eastern Finland, who were free of cardiovascular disease, diabetes or hypertension at baseline.Total serum esterified and nonesterified fatty acids and pubic hair mercury were used as markers for exposure. Anthropometric and other lifestyle and health-related data were collected.The mean serum concentrations were 1.67% (SD 0.92) for eicosapentaenoic acid (EPA), 0.79% (SD 0.16) for docosapentaenoic acid (DPA) and 2.78 (SD 0.92) for docosahexaenoic acid (DHA), of all serum fatty acids. The mean hair mercury concentration was 1.5 µg/g (SD 1.6). We did not find statistically significant associations between the baseline serum long-chain omega-3 PUFA concentrations or hair mercury content and future blood pressure. Hair mercury did not modify the associations with the long-chain omega-3 PUFAs, either.Higher serum long-chain omega-3 PUFA concentration, a biomarker of fish or fish oil consumption, may not have an impact on future blood pressure in an ageing population.

Little is known about the joint impact of C-reactive protein (CRP) and cardiorespiratory fitness (CRF) in lung cancer risk. The aim of this study is to examine the joint impact of CRF and CRP in predicting lung cancer risk.A population-based cohort study of 2276 men with no history of cancer was carried out. Baseline measures of CRP and CRF were divided into median values and categorised. During an average follow-up of 21-years, 73 cases of lung cancer occurred.In a multivariate model, men with the combination of high CRP (50% 1.24 mg/l) and low CRF (maximal oxygen uptake (VO2max)50% 30.08 ml/kg/min) had a fourfold (relative risk (RR) 4.19 95% confidence interval (CI) 1.66-10.57, p0.01) risk of lung cancer as compared to the reference group of low CRP (50% 1.24 mg/l) and high CRF (VO2max50% 30.08 ml/kg/min). Furthermore, men categorised in high CRP and combined with either low/high CRF, had an increased risk for lung cancer as compared to reference group. In further separate independent analysis for CRP and CRF, lung cancer risk was threefold for high CRP (RR 3.22, 95% CI 1.44-7.20, p0.01) and low CRF (RR 3.15, 95% CI 1.27-7.78, p = 0.01) as compared to reference CRP (2.38 mg/l) and CRF (35.15 ml/kg/min).In this study, the joint impact of CRP and CRF is a strong risk marker for lung cancer. Furthermore, men with an increase in CRP were at higher risk for lung cancer than men with low CRP and high CRF may reduce the risk.

Article, Vitamin D3 has transcriptome- and genome-wide effects and activates, via the binding of its metabolite 1α,25-dihydroxyvitamin D3 to the transcription factor vitamin D receptor (VDR), several hundred target genes. Using samples from a 5-month vitamin D3 intervention study (VitDmet), we recently reported that the expression of 12 VDR target genes in peripheral blood mononuclear cells (PBMCs) as well as 12 biochemical and clinical parameters of the study participants are significantly triggered by vitamin D3. In this study, we performed a more focused selection of further 12 VDR target genes and demonstrated that changes of their mRNA expression in PBMCs of VitDmet subjects significantly correlate with alterations of 25-hydroxyvitamin D3 serum levels. Network and self-organizing map analysis of these datasets together with that of the other 24 parameters was followed by relevance calculations and identified changes in parathyroid hormone serum levels and the expression of the newly selected genes STS, BCL6, ITGAM, LRRC25, LPGAT1 and TREM1 as well as of the previously reported genes DUSP10 and CD14 as the most relevant parameters for describing vitamin D responsiveness in vivo. Moreover, parameter relevance ranking allowed the segregation of study subjects into high and low responders. Due to the long intervention period the vitamin D response was not too prominent on the level of transcriptional activation. Therefore, we performed in the separate VitDbol trial a short-term but high dose stimulation with a vitamin D3 bolus. In PBMCs of VitDbol subjects we observed direct transcriptional effects on the selected VDR target genes, such as an up to 2.1-fold increase already one day after supplementation onset. In conclusion, both long-term and short-term vitamin D3 supplementation studies allow monitoring the vitamin D responsiveness of human individuals and represent new types of human in vivo vitamin D3 investigations., publisher version, http://purl.org/eprint/status/PeerReviewed

Breath analysis has been developed for quantification of individual compounds e.g. in disease diagnostics, but new technologies allow also on-line measurement of metabolite profiles. We evaluated the potential of monitoring diet induced changes in metabolism based on breath profiles analyzed by aspiration ion mobility spectrometry (AIMS). Exhaled breath alveolar samples were taken at fasting state after low versus high fibre diets (17 and 44 g/day for one week in randomized order, n=7) and during an aerobic exercise test (30 minutes cycling with cycle ergometer, n=9) and analyzed with ChemPro®100, a hand-held gas detector based on AIMS. Principal component analysis was first carried out as pre-processing and next Hotelling’s T-test and linear discriminate regression models (LDRM) were applied to discriminate the exhaled breath profiles in different metabolic states. The exhaled breath profiles were different between the diets (Hotelling´s test, p= 0.015, LDRM: R2=0.71, sensitivity 0.71, specificity 0.71 and accuracy 0.71) and between the resting and the exercise states (p=0.012, R2= 0.79, sensitivity 1.00, specificity 0.89 and accuracy 0.94).This indicates the potential of utilizing the exhaled breath profiles for detecting dietary changes and monitoring exhaled breath further in studying the mechanisms of dietary effects.

Objective— High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD. Methods and Results— Altogether, 148 members of Finnish low-HDL families and 133 healthy control subjects participated in our study. HDL particle size was significantly smaller in affected family members (HDL ≤10th Finnish age-sex specific percentile) compared with unaffected family members and control subjects (9.1±0.04 nm versus 9.5±0.05 nm, P P 2b particles as well as preβ-HDL concentration were significantly decreased among the affected family members. Mean IMT was significantly higher in the affected family members than in the control subjects (0.85±0.01 mm versus 0.79±0.01 mm; P 2b , systolic blood pressure, and preβ-HDL were significant independent determinants of mean IMT. Conclusions— The decreased levels of HDL 2b and preβ-HDL reflect the potentially efflux-deficient HDL subspecies profile in the affected low-HDL family members. Decreased HDL particle size caused by the decrease of plasma concentration of HDL 2b and decreased preβ-HDL levels correlate with increased IMT.

OBJECTIVE Carotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes. RESEARCH DESIGN AND METHODS In a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33–92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis. RESULTS Average mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12–1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between −0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91–1.08). CONCLUSIONS Despite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.

Aims Cut-offs for C-reactive protein concentrations have been recommended for risk stratification, but little is known about how these cut-offs predict cardiovascular risk in population-based cohorts. We therefore assessed the association of C-reactive protein levels with cardiovascular mortality in a population-based cohort of 2321 middle-aged men stratified by the presence of cardiovascular disease (CVD) at baseline. Methods and results C-reactive protein concentrations were categorized according to current recommendations (1 and 3 mg/L). During the 15 year follow-up, 77 men without CVD and 121 men with CVD at baseline died of CVD. In men without CVD at baseline ( n =1476), age-adjusted cardiovascular mortality was 4.1-fold higher (95% CI 2.1–8.2) for C-reactive protein levels between 3.0 and 9.9 mg/L at baseline than for C-reactive protein levels

In men, hypoandrogenism is associated with features of the metabolic syndrome. It is not known whether men with the metabolic syndrome are at a higher risk of developing hypogonadism. We therefore assessed whether the metabolic syndrome predicts development of hypogonadism 11 yr later in 651 middle-aged Finnish men participating in a population-based cohort study. Men with the metabolic syndrome at baseline as defined by the World Health Organization (n = 114, 20%) had a 2.6-fold increased risk of developing hypogonadism as defined by total testosterone levels less than 11 nmol/liter at the 11-yr follow-up independent of age, smoking, and other potential confounders. Further adjustment for body mass index (OR, 2.0; 95% CI, 1.1-3.8) or baseline total testosterone levels (OR, 1.9; 95% CI, 1.0-3.4) attenuated the association. The association of the metabolic syndrome with hypogonadism as defined by calculated free testosterone levels less than 225 pmol/liter was similar, but weaker. The adjusted decrease in testosterone concentrations during the 11-yr follow-up was also greater in men with than without the metabolic syndrome. Smokers had a nonsignificantly lower risk of developing hypogonadism during follow-up, whereas a decrease in smoking increased the risk of hypogonadism. The metabolic syndrome predisposes to development of hypogonadism in middle-aged men. Prevention of abdominal obesity and the accompanying metabolic syndrome in middle age may decrease the risk of hypogonadism in men, especially in those who quit smoking.

Objective— Mercury has been suggested to have negative effects on cardiovascular health. We investigated the effects of high mercury content in hair on the risk of acute coronary events and cardiovascular and all-cause mortality in men from eastern Finland. Methods and Results— The population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort of 1871 Finnish men aged 42 to 60 years and free of previous coronary heart disease (CHD) or stroke at baseline was used. During an average follow-up time of 13.9 years, 282 acute coronary events and 132 cardiovascular disease (CVD), 91 CHD, and 525 all-cause deaths occurred. Men in the highest third of hair mercury content (>2.03 μg/g) had an adjusted 1.60-fold (95% CI, 1.24 to 2.06) risk of acute coronary event, 1.68-fold (95% CI, 1.15 to 2.44) risk of CVD, 1.56-fold (95% CI, 0.99 to 2.46) risk of CHD, and 1.38-fold (95% CI, 1.15 to 1.66) risk of any death compared with men in the lower two thirds. High mercury content in hair also attenuated the protective effects of high-serum docosahexaenoic acid plus docosapentaenoic acid concentration. Conclusions— High content of mercury in hair may be a risk factor for acute coronary events and CVD, CHD, and all-cause mortality in middle-aged eastern Finnish men. Mercury may also attenuate the protective effects of fish on cardiovascular health.

Association between pre-eclampsia (PEE1) and the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes, which play a role in the regulation of nitric oxide synthesis and release, was studied. In a case –control study design single nucleotide polymorphisms (SNPs) were determined at eight sites in the DDAH1 gene and at one site (Pro231Pro) in the DDAH2 gene from 132 women with pre-eclampsia and 112 healthy controls. Three SNPs in the DDAH1 gene were associated with preeclampsia, showing complete linkage disequilibrium with each other, but none of the associations in the allele or genotype data reached statistical significance in either of the genes after the correction for multiple testing. Haplotype frequencies were estimated using a population based on a maximum likelihood method (EM algorithm). Four common DDAH1 haplotypes were present and a significant association of haplotypes H2 and H3 with pre-eclampsia (P 5 0.03) was found. The risk of pre-eclampsia was greatest in individuals (odds ratio: 3.93; 95% confidence interval: 1.54 –9.99) who had two copies of the high-risk haplotypes (H2 or H3). The observed haplotypic association provides the first evidence of the importance of DDAH1 polymorphisms in pre-eclampsia susceptibility.

Development of hypertension has been linked to chronic low-grade inflammation. However, it is not known whether this connection is mediated by features of the metabolic syndrome or smoking, or their changes, which themselves have been linked to inflammation. We studied the predictive value of highly sensitive C-reactive protein (hs-CRP), smoking, and abdominal obesity to the development of hypertension in an 11-year follow-up of a population-based study cohort comprising 379 middle-aged normotensive men. During the follow-up, 124 men (33%) developed hypertension. Men with hs-CRP ≥3.0 mg/L were 2.8× (95% confidence interval, 1.2 to 6.6) more likely to develop hypertension than with hs-CRP

OBJECTIVE—In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone–binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men. RESEARCH DESIGN AND METHODS—Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome. RESULTS—After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome (odds ratio [OR] 2.3, 95% CI 1.5–3.4; 1.7, 1.2–2.5; and 2.8, 1.9–4.1, respectively) and diabetes (2.3, 1.3–4.1; 1.7, 0.9–3.0; and 4.3, 2.4–7.7, respectively) after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone. CONCLUSIONS—Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.

OBJECTIVE: Mild hypoandrogenism in men is associated with features of the metabolic syndrome, but the association with the metabolic syndrome itself using an accepted definition has not been described. DESIGN: Men with the metabolic syndrome were identified and testosterone and sex hormone-binding globulin (SHBG) levels were determined in a population-based cohort of 1896 non-diabetic middle-aged Finnish men. RESULTS: Calculated free testosterone and SHBG were 11% and 18% lower (P

Cholesterol oxidation products, oxysterols, are thought to play a part in the initiation and development of human atherosclerotic lesions. Excessive body iron has been suggested to promote atherosclerosis and coronary heart disease through its pro-oxidative properties. In the present study, the associations between serum ferritin and plasma oxysterol concentrations were examined in 669 eastern Finnish men. Serum ferritin concentration had statistically significant (p

Background: Human serum paraoxonase eliminates carcinogenic lipid-soluble radicals. Because expression of the main human paraoxonase gene PON1 varies widely in humans, certain PON1 polymorphisms might be associated with increased risks of cancer. We sought new functional mutations in PON1 and determined whether known or new PON1 mutations were associated with the risk for prostate cancer in a prospective, random, population-based sample of Finnish men and in a case–control study. Methods: Serum paraoxonase activity was measured in 835 healthy men in the Kuopio Ischaemic Heart Disease Risk Factor Study. PON1 mutations were identified by hierarchical phenotype-targeted sequencing in DNAs from the 100 men with the lowest paraoxonase activity in this cohort, and 1595 men in the cohort were genotyped for PON1 mutations by restriction fragment length polymorphism. Multivariable analysis was used to investigate the association of known and new PON1 mutations with incident prostate cancer in 1569 cancer-free men in the cohort followed for 9–14 years. In a case–control study of Finnish men, the association of prostate cancer with the PON1 mutation identified in the cohort study was investigated in 69 case patients with familial prostate cancer and 69 unmatched healthy control subjects. Results: We identified a new single-nucleotide PON1 polymorphism associated with decreased serum paraoxonase activity that caused an isoleucine→valine change at codon 102 in exon 4 (I102V). Of the 1569 men cancer-free at baseline, 56 (3.6%) were carriers of the I102V mutation. After adjusting for age and cholesterol-lowering medications, the relative risk for developing prostate cancer during follow-up was 6.3 (95% confidence interval [CI] = 2.1 to 19.2) among 102V allele carriers compared with noncarriers. Other PON1 alleles were not statistically significantly associated with prostate cancer. In the case–control study, patients with familial prostate cancer were more likely to be carriers of the PON1 I102V mutation than control subjects (odds ratio = 4.3, 95% CI = 0.9 to 21.5). Conclusion: The PON1 102V allele appears to be associated with an increased risk for prostate cancer. [J Natl Cancer Inst 2003;95:812–8]