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We examined the longitudinal associations of fat mass, lean mass, and blood pressure (BP) from childhood through young adulthood with changes in carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT). We included 3863 participants from the Avon Longitudinal Study of Parents and Children birth cohort. Fat mass and lean mass, measured by dual-energy X-ray absorptiometry, and BP were measured at ages 9, 17 and 24 years and classified into low, moderate, and high tertiles. cfPWV and cIMT were measured at 17 and 24 years of age. Associations were examined via linear mixed effect models and adjusted for cardiometabolic and lifestyle factors. Among 1720 [44.5%] male and 2143 [55.5%] female participants, cumulative high exposures to lean mass (effect estimate 0.006 m/s [95% CI 0.001 to 0.010; p = 0.022]), systolic BP (0.013 m/s [0.009 to 0.017; p p p p = 0.001]), and systolic BP (0.010 mm; [0.006 to 0.014; p

Background: We investigated the temporal causal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) progression with the risk of dysglycemia, insulin resistance, and dyslipidemia. Methods: We included 3862, 17.7-year-old, participants from the Avon Longitudinal Study of Parents and Children, followed up for 7 years. cfPWV, cIMT, and fasting plasma samples were repeatedly measured. We computed homeostatic model assessment (HOMA) of insulin resistance and percent pancreatic beta-cell function. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models. Results: A higher cfPWV at 17.7 years was associated with higher insulin at age 24.5 years (odds ratio, 1.25 [CI, 1.08–1.44]; P =0.003), which slightly attenuated after covariates adjustment. Higher cIMT at 17.7 years was associated with lower insulin (odds ratio, 0.06 [0.01–0.95]; P =0.046) at 24.5 years, after covariate adjustments. In mixed-effect models, the 7-year progression in cfPWV (predictor) was directly associated with the increase in triglyceride (outcome). cIMT progression was associated with the 7-year increase in LDL (low-density lipoprotein), triglyceride, and glucose. In cross-lagged models, higher cfPWV at 17.7 years was associated with higher insulin ( β =0.06, SE, 0.12, P =0.014), HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years. However, insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 17.7 years were not associated with cfPWV at 24.5 years. Higher cIMT at 17.7 years was associated with reduced insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years, but not vice versa. Higher glucose at 17.7 years was associated with higher cfPWV and cIMT at 24.5 years only. Conclusions: Arterial stiffness in adolescence may be a causal risk factor for hyperinsulinemia and insulin resistance in young adulthood.

Supplemental digital content is available in the text., Purpose This study aimed to determine whether estimated cardiorespiratory fitness (CRF), fat mass (FM), lean mass (LM), and adiponectin bidirectionally associate with arterial function and structure and if CRF mediates the relationship between cardiometabolic health and arterial outcomes in 9- to 11-yr-old children drawn from the Avon Longitudinal Study of Parents and Children birth cohort, United Kingdom. Methods Brachial artery flow-mediated dilation (FMD), distensibility coefficient (DC), and carotid–radial pulse wave velocity (PWV) were measured by ultrasonography; CRF was measured during the submaximal ergometer test; total FM, trunk FM, and LM were measured by dual-energy x-ray absorptiometry; plasma adiponectin was measured by enzyme assay; and cardiometabolic health was computed based on the International Diabetes Federation criteria for diagnosing metabolic syndrome. We tested bidirectionality by including CRF, FM, LM, and adiponectin as exposures and FMD, DC, and PWV as outcomes, alternatively. Results Among 5566 participants (2816 (51%) girls; median age, 9.75 yr), CRF per body mass0.21 was directly related to DC (β (95% confidence interval) = 0.004 (

Purpose To investigate the association between healthy Nordic diet and risk of type 2 diabetes (T2D) in middle-aged and older men from eastern Finland. Methods A total of 2332 men aged 42–60 years and free of T2D at baseline in 1984–1989 were included. Diet was assessed with 4-day food records at baseline and the healthy Nordic diet score was calculated based on a modified Baltic Sea Diet Score. T2D diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Cox proportional hazards regression and analysis of covariance were used for analyses. Results During the mean follow-up of 19.3 years, 432 men (18.5%) were diagnosed with T2D. The multivariable-adjusted hazard ratio for T2D in the lowest vs. the highest quartile of the healthy Nordic diet score was 1.35 (95% CI 1.03–1.76) (P trend across quartiles 0.028). Lower adherence to healthy Nordic diet was also associated with higher plasma glucose and insulin concentrations. Conclusions In this prospective population-based cohort study among middle-aged and older men from eastern Finland, lower adherence to healthy Nordic diet was associated with higher risk of T2D and higher plasma glucose and serum insulin concentrations.

Purpose Atherosclerosis (AS) and osteoporosis (OP) are common causes of morbidity and mortality in postmenopausal women and are connected via an unknown mechanistic link. Metabolite profiling of blood samples may allow the identification of new biomarkers and pathways for this enigmatic association. Patients and methods We studied the difference in 148 metabolite levels from serum samples in postmenopausal women with AS and OP compared with those in healthy participants in this cross-sectional study. Quantitative AS was assessed by carotid artery intima-media thickness (cIMT) and carotid artery calcifications (CACs) by ultrasound, as well as OP by femoral neck (FN) bone mineral density (BMD) and 148 metabolic measures with high-throughput proton (1H) nuclear magnetic resonance (NMR) in serum samples from 280 postmenopausal (PM) women. Subjects were a randomly selected subsample from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The final study population included the following groups: OP with CAC (n=16, group I), non-OP with no CAC (n=59, group II), high cIMT tertile with OP (n=11, group III) and low cIMT tertile without OP (n=48, group IV). Results There were differences in several metabolite levels between groups I and II. The acetate level was lower in group I compared to that in group II (group I mean ± SD: 0.033 ± 0.0070; group II: 0.041 ± 0.014, CI95%: 0.018‒0.15, p=0.014). The result was similar with diacylglycerol (p=0.002), leucine (p=0.031), valine (p=0.022) and several very low-density lipoprotein (VLDL) metabolite levels, which were lower in group I compared to those in group II. However, no associations were found in adjusted analyses with total body (TB) fat mass (FM), age and statin use (p>0.05). Conclusion Our novel study found differences in the metabolite profiling of altered amino acid and lipoprotein metabolism in participants with OP and AS compared with those in healthy women. The causative mechanisms remain unknown and further studies are needed.

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

Purpose To investigate associations of total dietary choline intake and its major dietary form, phosphatidylcholine, with type 2 diabetes risk. Methods We included 2332 men aged 42–60 years at baseline in 1984–1989 from the Kuopio Ischaemic Heart Disease Risk Factor Study in eastern Finland. Dietary intakes were assessed with 4-d food recording at baseline. Type 2 diabetes diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Multivariable-adjusted Cox proportional hazards regression models were used for statistical analysis. Results During the mean 19.3-year follow-up, 432 men had type 2 diabetes diagnosis. After multivariable adjustments, those in the highest vs. lowest choline intake quartile had 25% (95% CI 2–43%) lower relative risk (P trend across quartiles = 0.02) and those in the highest vs. lowest phosphatidylcholine quartile had 41% (95% CI 22–55%) lower relative risk (P trend Conclusions Higher choline intake, especially phosphatidylcholine, was associated with lower type 2 diabetes risk among men.

Purpose To investigate the association between healthy Nordic diet and risk of disease death in middle-aged and older men from eastern Finland. Methods A total of 1547 men aged 42–60 years and free of cardiovascular disease (CVD), cancer and type 2 diabetes at baseline in 1984–1989 were included. Diet was assessed with 4-day food records at baseline and the healthy Nordic diet score was calculated based on the Baltic Sea Diet Score. The incidence of death was assessed by a computer linkage to the national cause of death register. Cox proportional hazards regression analyses were used to estimate the associations between the healthy Nordic diet score and mortality. Results During the mean follow-up of 23.6 years (SD 7.0), 576 men died due to disease: 250 due to CVD, 194 due to cancer and 132 due to other diseases. The multivariable-adjusted hazard ratios (95% confidence interval) in the lowest vs. the highest quartile of the healthy Nordic diet score were 1.27 (1.01–1.59) for any disease death (P-trend across quartiles P-trend = 0.049) for CVD death, 1.26 (0.84–1.89, P-trend = 0.316) for cancer death and 1.04 (0.65–1.68, P-trend = 0.563) for other disease deaths. Conclusions In this prospective population-based cohort study among middle-aged and older men, low adherence to a healthy Nordic diet was associated with a higher risk of any disease death, possibly largely attributable to higher CVD mortality.

Atherosclerosis - the pathophysiological mechanism shared by most cardiovascular diseases - can be directly or indirectly assessed by a variety of clinical tests including measurement of carotid intima-media thickness, carotid plaque, ankle-brachial index, pulse wave velocity, and coronary artery calcium. the Prospective Studies of Atherosclerosis (Proof-ATHERO) consortium (https://clinicalepi.i-med.ac.at/research/proof-athero/) collates de-identified individual-participant data of studies with information on atherosclerosis measures, risk factors for cardiovascular disease, and incidence of cardiovascular diseases. It currently comprises 74 studies that involve 106,846 participants from 25 countries and over 40 cities. in summary, 21 studies recruited participants from the general population (n = 67,784), 16 from high-risk populations (n = 22,677), and 37 as part of clinical trials (n = 16,385). Baseline years of contributing studies range from April 1980 to July 2014; the latest follow-up was until June 2019. Mean age at baseline was 59 years (standard deviation: 10) and 50% were female. Over a total of 830,619 person-years of follow-up, 17,270 incident cardiovascular events (including coronary heart disease and stroke) and 13,270 deaths were recorded, corresponding to cumulative incidences of 2.1% and 1.6% per annum, respectively. the consortium is coordinated by the Clinical Epidemiology Team at the Medical University of Innsbruck, Austria. Contributing studies undergo a detailed data cleaning and harmonisation procedure before being incorporated in the Proof-ATHERO central database. Statistical analyses are being conducted according to pre-defined analysis plans and use established methods for individual-participant data meta-analysis. Capitalising on its large sample size, the multi-institutional collaborative Proof-ATHERO consortium aims to better characterise, understand, and predict the development of atherosclerosis and its clinical consequences. (c) 2020 S. Karger AG, Basel, Austrian Science Fund (FWF)Austrian Science Fund (FWF) [P 32488]; Dr.-Johannes-and-Hertha-Tuba Foundation, This work was funded by the Austrian Science Fund (FWF) (P 32488) and the Dr.-Johannes-and-Hertha-Tuba Foundation. Funders of individual studies contributing to the present analysis arelisted onthe Proof-ATHERO webpage(https://clinicalepi.i-med.ac.at/research/proof-athero/studies/).

Background Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline. Objectives We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Methods A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-e4 compared with other phenotypes). These data were available for 1259 men. Results The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations. Conclusion Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127.

Supplemental Digital Content is available in the text., We examined the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) with the risk of overweight/obesity and elevated blood pressure (BP)/hypertension. We studied 3862 adolescents aged 17.7 years from the Avon Longitudinal Study of Parents and Children, followed-up for 7 years. cfPWV and cIMT were measured by ultrasound. Total and trunk fat mass and lean mass were assessed by dual-energy X-ray absorptiometry. Body mass index and BP were measured. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models, with covariate adjustments. Among 1719 male and 2143 female participants, higher cfPWV at 17.7 years was associated with the risk of elevated systolic BP/hypertension (odds ratio, 1.20 [1.02–1.41]; P=0.026), elevated diastolic BP/hypertension (1.77 [1.32–2.38]; P

Background The American Heart Association's scientific statement on the importance of arterial stiffness recommended that future studies investigate whether increasing arterial stiffness with advancing age results from the age-associated increase in systolic blood pressure (BP). The statement also recommended investigating the natural history of arterial stiffness and BP vis-à-vis the rate at which arterial stiffness and BP increase with age. These questions remain largely unanswered in a population sample of apparently healthy adolescence and young adults. Purpose To investigate whether carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, during adolescence predicts increased systolic and diastolic blood pressure in young adulthood. Methods We studied 3862 British (56% females) participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, Bristol, UK. cfPWV was measured by Vicorder device ultrasound scan, total fat mass and lean mass were measured by dual-energy Xray absorptiometry, and systolic and diastolic BP by Omron BP/pulse monitor. We conducted multivariable linear regression analyses and adjusted for baseline covariates such as age, sex, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, high sensitivity C-reactive protein, fasting blood glucose, fasting insulin concentration, heart rate, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, total fat mass, lean mass and systolic or diastolic BP depending on the outcome. All variables were measured both at age 17.7 and 24.5 years. Results Participants mean (SD) age in years at different time points were [17.72 (0.33) and 24.54 (0.73)]. Over a 7-year follow-up period, cfPWV was directly and independently associated with systolic BP [β = 10.762 (CI: 3.107 to 18.417); p=0.006] and diastolic BP [19.535 (12.879 to 26.191); p Conclusion Our findings showed that increasing arterial stiffness independently predicts higher systolic and diastolic BP with advancing age. Besides, a 0.1 m/s increase in arterial stiffness at age 17.7 years may result in a 1 mmHg increase in systolic BP and a 2 mmHg increase in diastolic BP seven years later. Therefore, public health effort should be targeted at preventing or reducing arterial stiffness during adolescence in order to decrease the risk of elevated BP in later life. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Jenny and Antti Wihuri Foundation and the Finnish Cultural Foundation

Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. While the two conditions are established as separate predictors of CV outcomes, FLD and hypertension are interrelated in multiple ways. A biological interaction in respect to CV disease outcomes could exist between FLD and hypertension. In this study, we investigated the joint effect and interaction of FLD and hypertension regarding CV mortality using an interaction framework. Using a population-based cohort, we followed 1,569 middle-aged non-diabetic Finnish men for 34 years. We computed the fatty liver index and considered values ≥60 as indicative of FLD. We defined hypertension as either i) self-reported hypertension and a confirmed use of antihypertension medication, or ii) a mean systolic ≥160 or diastolic ≥105 blood pressure on baseline examination. The choice of the blood pressure measurement threshold to define hypertension was based on a sensitivity analysis. With adjustment for age, body mass index, smoking, and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Among the men, 372 had FLD and 342 had hypertension. FLD and hypertension coexisted in 134 men. FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-cardiovascular mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction [RERI], -0.97; 95% confidence interval [CI], -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.50). The interaction was also found on a multiplicative scale. We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. Our findings were robust to different definitions of hypertension but were more relevant at high blood pressure thresholds. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men and call for further research on the topic.

Background A temporal association where better arterial function and structure predicts adiponectin level and skeletal muscle mass during childhood remains uninvestigated. Methods We studied 5566 children and adolescents (51% girls) aged 9-11 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, Bristol, UK. Brachial artery endothelial function was determined using flow-mediated dilation (FMD), expressed as the percentage change in diameter from baseline after reactive hyperemia; arterial elasticity as distensibility coefficient (DC) expressed in mean percentage change in cross-sectional area relative to blood pressure (BP); and arterial stiffness by carotid to radial pulse wave velocity (crPWV). Skeletal muscle mass and total fat mass were assessed by dual-energy Xray absorptiometry. We conducted multivariable linear regressions with Sidak correction and adjusted for age, sex, total fat mass, cardiorespiratory fitness, pubertal status, brachial artery diameter, systolic BP, low-density lipoprotein cholesterol, mother’s social-economic class, and time (years) between the measurement of predictors and outcomes. Results FMD (β [95% CI]) = (0.027 [0.007 to 0.047]; P = 0.009) and DC (0.229 [0.088 to 0.369]; P = 0.001) were directly associated with skeletal muscle mass. FMD had a borderline inverse association with adiponectin (-0.004 [-0.008 to Conclusions Better endothelial function and arterial elasticity were associated with higher skeletal muscle mass while arterial stiffness was unrelated to adiponectin and lean mass. Key message Healthy arterial function and structure may enhance muscle growth in children.

Background and objectives Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. The two conditions are related in multiple ways. This work aimed to study the joint effect and interaction of FLD and hypertension in respect to overall and CV mortality. Methods The population-based cohort, Kuopio Ischaemic Disease Risk Factor Study, followed 1569 middle-aged non-diabetic Finnish men for 34 years. Considering adjustment for age, body mass index, smoking and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Results FLD and hypertension coexisted in 8.54% of the men (n = 134). FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-CV mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction (RERI), -0.97; 95% confidence interval (CI), -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.5). The interaction was also found on a multiplicative scale. Conclusions We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men.

Background While the impact of low glomerular filtration rate (eGFR) on various outcomes has been extensively studied, the other adverse occurrence, renal hyperfiltration (RHF), remains understudied, poorly defined, and, therefore, its impact on mortality unestablished. Methods Using a population-based subcohort from the Kuopio Ischaemic Disease Risk Factor Study restricted to non-diabetic Finnish men aged 54 or 55 years, we followed up n = 1179 study participants for up to 35 years. We evaluated the hazard of all-cause mortality associated to RHF at different cutoff points defining eGFR. Based on models’ accuracy we suggested an optimal eGFR cutoff point for the definition of RHF. We divided the RHF category to three subgroups and evaluated them in terms of baseline characteristics and mortality hazard. Results The eGFR value of 97 mL/min/1.73 m2 corresponded to the models with the highest accuracy. Overall RHF associated with an increased risk of mortality (hazard ratio [HR] 1.42; 95% confidence interval [CI] 1.21 to 1.67). Moderate RHF associated with a decreased HR of mortality when compared to mild (0.64; 95% CI 0.46 to 0.9) or to extreme RHF (0.61; 95% CI 0.43 to 0.85), suggesting a rather U-shaped relationship between RHF’s eGFR values and mortality hazard. Conclusion The burden of increased eGFR within what is still considered normal eGFR category was highly underestimated. RHF’s eGFR values had a U-shaped association with the risk of overall mortality. A more uniform consensual definition of RHF is needed, as higher to normal eGFR values that are not without consequences.

Background We carried out this study to demonstrate the effects of outcome sensitivity, participant exclusions, and covariate manipulations on results of the epidemiological analysis of coronary heart disease (CHD) and its behaviour-related risk factors. Material and methods Our study population consisted of 1592 54-year-old men, who participated in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. We used the Cox proportional-hazards model to predict the hazard of CHD and applied different sets of outcomes concerning outcome sensitivity and data preprocessing procedures regarding participant exclusions and covariate manipulations. Results The mean follow-up time was 23 years, and 730 men received the CHD diagnosis. Cox regressions based on data with no participant exclusions most often discovered statistically significant associations. Loose inclusion criteria for study participants with any CVD during the follow-up and strict exclusion criteria for participants with no CVD were best in discovering the associations between risk factors and CHD. Outcome sensitivity affected the associations, whereas the covariate type, continuous or categorical, did not. Conclusions This study suggests that excluding study participants who are not disease-free at baseline is probably unnecessary for epidemiological analyses. Epidemiological research reports should present results based on no data exclusions together with results based on reasoned exclusions.

Introduction: Evidence on the associations of fat mass and lean mass with changes in carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT), markers of pre-clinical atherosclerosis, from adolescence through young adulthood is lacking. Previous studies have reported strong associations of body mass index (BMI), a measure of adiposity, with these markers. However, it is unclear if increased BMI in relation to these markers represents a pathological process or physiological adaptation. A knowledge gap also exists on the independent associations of blood pressure (BP) measured from childhood through young adulthood with changes in cfPWV and cIMT between ages 17 and 24.5 years. Hypothesis: We assessed the hypothesis whether lean mass and systolic BP, independent of fat mass, cardiometabolic and lifestyle factors, measured at age 9, 17, and 24.5 years drive a 7-year change in cfPWV and cIMT. Methods: We studied 3863 British children from the Avon Longitudinal Study of Parents and Children's birth cohort (56% females). fat mass and lean mass were measured by dual-energy Xray absorptiometry, systolic and diastolic BP by Omron BP/pulse monitor, cfPWV by Vicorder device, and cIMT by CardioHealth ultrasound scan. All exposures were categorized in tertiles of low, normal, and high, with the low category as the reference group. We conducted linear mixed effect model analyses and adjusted for age, sex, low-density lipoprotein, C-reactive protein, fasting blood glucose, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, time in years between measure at 9 and 24.5 years, and systolic BP, fat mass, and/or lean mass depending on the predictor. Results: Participants mean (SD) age in years at different time points were [9.83 (0.30); 17.72 (0.33); 24.54 (0.73)]. Over a 15-year follow-up period, persistent exposure to high lean mass effect estimate =0.006 (CI 0.001 - 0.010, p=0.022), high systolic BP 0.013 (0.009 - 0.017, p Conclusion: For the first time, we showed in a healthy cohort that persistent exposure to higher lean mass and BP from childhood independently drives arterial wall adaptation in early adulthood. These arterial changes are likely normal responses to growth and maturation rather than subclinical signs of arterial diseases. Thus, cumulative exposure to high BMI in relation to higher cfPWV and cIMT may not indicate a deleterious effect of adiposity.

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

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

ObjectiveLong-chain omega-3 polyunsaturated fatty acids (PUFA) from fish have been inversely associated with coronary heart disease (CHD) risk. Fish may also contain methylmercury, which has been associated with higher CHD risk and may diminish the cardioprotective effect of long-chain omega-3 PUFA. We investigated the associations of serum long-chain omega-3 PUFA and hair mercury with the odds for myocardial ischaemia during exercise.MethodsA total of 2199 men from the Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 years were studied in 1984–89. Of the 2199 men, 342 had history of CHD. The men performed a maximal symptom-limited exercise stress test using an electrically braked bicycle ergometer. ORs for exercise-induced myocardial ischaemia were estimated with logistic regression.ResultsIn the multivariable analysis, those in the highest versus lowest serum long-chain omega-3 PUFA quartile had 33% lower odds of myocardial ischaemia (OR 0.67, 95% CI 0.51 to 0.87, p-trend=0.006). The association was stronger among those with CHD history (OR 0.10, 95% CI 0.03 to 0.39, p-trend ConclusionHigher circulating concentrations of the long-chain omega-3 PUFAs, a marker for fish consumption, were associated with lower occurrence of exercise-induced myocardial ischaemia, but only among men with CHD history. Hair mercury concentration was directly associated with the occurrence of exercise-induced myocardial ischaemia in the entire study population.

In the vitamin D intervention study VitDbol (NCT02063334) blood samples were drawn directly before an oral bolus (2000 μg vitamin D3) and 24 h later. The focus of phase II of VitDbol was the transcriptome-wide analysis of the effects of vitamin D gene expression in human peripheral blood mononuclear cells (PBMCs). All five participants responded in an individual fashion to the bolus by increases in serum levels of the vitamin D metabolites 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). RNA sequencing identified 15.040 commonly expressed genes in PBMCs, 702 (4,7%) of which were significantly (p

In vitro cell culture studies showed that the hormonal form of vitamin D3, 1α,25-dihydroxyvitamin D3, significantly (p

The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction 0.13).Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.

Vitamin D3 has via its metabolites 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) direct effects on the transcriptome and the epigenome of most human cells. In the VitDbol study we exposed 35 healthy young adults to an oral vitamin D3 dose (2000μg) or placebo and took blood samples directly before the supplementation as well as at days 1, 2 and 30. Within 24h the vitamin D3 intake raised the average serum levels of both 25(OH)D3 and 1,25(OH)2D3 by approximately 20%. However, we observed large inter-individual differences in these serum levels, reflected by the average ratios between 25(OH)D3 and 1,25(OH)2D3 concentrations ranging from 277 to 1365. Interestingly, average serum parathyroid hormone (PTH) levels increased at day 1 by some 10% but then decreased within the following four weeks to levels 5% below baseline. In peripheral blood mononuclear cells (PBMCs) that were isolated at the same time points we determined vitamin D-modulated chromatin accessibility by FAIRE-qPCR at selected genomic loci. This method is well suited to evaluate both short-term and long-term in vivo effects of vitamin D on the epigenome of human subjects. The differential vitamin D responsiveness of the VitDbol study participants was determined via individual changes in their PTH levels or chromatin accessibility in relation to alterations in 25(OH)D3 concentrations. This led to the segregation of the subjects into 14 high, 11 mid and 10 low responders. In summary, the vitamin D responsiveness classification provides additional information compared to a vitamin D status assessment based on single 25(OH)D3 serum measurements. The study was registered at Clinicaltrials.gov (NCT02063334).

Background Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation. Methods A 20-year prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) follow-up study was conducted from 1984 to 1989 with 2179 middle-aged and older Finnish men (42–60 years old at baseline). The baseline concentrations of serum fatty acids, including DGLA, were determined. A hospital discharge diagnosis of depression was used as the main outcome and obtained from linkage to National Hospital Discharge Register. Serum C-reactive protein (CRP) levels were measured to assess inflammation. Results An inverse association between serum DGLA concentration and incidence of depression was found after adjustment for several potential confounders (Hazard ratio HR 0.53, CI 0.36–0.79, P=0.002). The association between DGLA and depression was not dependent on inflammation (P-interaction=0.618). 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 Higher serum DGLA concentrations may predict lower risk of develop depression in elderly men. Further studies are warranted to address potential mechanisms as mechanism behind this association remains unclear., final draft, peerReviewed

Stroke is a leading cause of morbidity and mortality. The role of PUFA in reducing the risk of stroke is uncertain. The concentrations of PUFA in the human body are determined both by dietary intake and by activities of desaturase enzymes. Desaturase enzymes have been associated with chronic diseases, but little is known about their association with stroke risk. We investigated the associations of Δ-6-desaturase (D6D) and Δ-5-desaturase (D5D) activities with stroke risk factors and risk of stroke among 1842 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. ANCOVA and Cox regression models were used for the analyses. Whole serum desaturase activities were estimated as product:precursor ratios – γ-linolenic acid:linoleic acid for D6D and arachidonic acid:dihomo-γ-linolenic acid for D5D. Higher D6D activity was associated with higher systolic and diastolic blood pressure, BMI, serum insulin and TAG concentrations and worse homoeostatic model assessment (HOMA) indices. In contrast, higher D5D activity was associated with lower systolic and diastolic blood pressure, BMI, serum insulin, LDL-cholesterol, TAG and C-reactive protein concentrations, higher HDL-cholesterol concentration, and better HOMA indices. During the mean follow-up of 21·2 years, 202 stroke cases occurred. Neither D6D activity (multivariable-adjusted extreme-quartile hazard ratios (HR) 1·18; 95 % CI 0·80, 1·74) nor D5D activity (HR 1·06; 95 % CI 0·70, 1·60) were associated with stroke risk. In conclusion, higher D5D activity was favourably associated and higher D6D activity unfavourably associated with several stroke risk factors, but not with the risk of incident stroke.

ObjectiveFatty liver disease (FLD) has been associated with extrahepatic morbidity outcomes. However, reports on the association of FLD, assessed using fatty liver index (FLI), with mortality outcomes have been inconsistent. Our objective was to examine the effect of metabolic factors (blood pressure, insulin, fasting glucose, lipoproteins) on the associations of FLI with mortality outcomes among middle-aged men.Study designProspective cohort study.MethodsOur subjects were 1893 men at baseline from 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort. Multivariable Cox regression models were used to analyse the association of baseline FLI, with the HRs for all-cause, disease, cardiovascular, non-cardiovascular and cancer mortality outcomes.ResultsThe mean FLI in the FLI categories were 16.2 in the low and reference category (FLIConclusionHigh FLI (FLD) is associated with increased risks of mortality outcomes. The FLI-CVD mortality association can be largely explained by metabolic factors. Persons with FLD should be monitored for metabolic deterioration and extrahepatic morbidity to improve their prognoses.

AimsAveraged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.Methods and resultsAn individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration ( n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.ConclusionAveraged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

Postmenopause is associated with elevated levels of follicle stimulating hormone (FSH) compared to premenopause. There is evidence to suggest that high levels of FSH may influence lipid levels; however, the association between FSH and lipid levels in postmenopausal women has been largely unexplored. OBJECTIVE: The purpose of this study was to evaluate the relation between FSH and lipid levels in postmenopausal women from the Kuopio Ischaemic Heart Disease Risk Factor Study. METHODS: Postmenopausal women (n=588) aged 53–73 and not using hormone therapy were included. The relation between FSH and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) was evaluated using linear regression, adjusting for estradiol, body mass, smoking and other hormonal and lifestyle factors. The relation between FSH, dyslipidemia and abnormal lipid levels were also evaluated. RESULTS: FSH was positively and linearly associated with TC (p=0.001) and LDL-C (p=0.01) in all participants, with stronger relations seen in younger compared to older postmenopausal women. FSH was less strongly associated with HDL-C and TG. FSH was not associated with dyslipidemia; however, higher FSH was associated with increased risk of high TC (p=0.02) and high LDL-C (p=0.03). CONCLUSIONS: These data suggest that higher FSH in postmenopausal women is related to higher levels of both TC and LDL-C.

Purpose: To estimate the maximum mass-specific oxygen uptake (VO2max) from the ratio of the heart rate at maximal exercise (HRmax) to heart rate at rest (HRrest) in middle-aged men. VO2max is an essential measure of cardiorespiratory fitness, but it is difficult to utilize in clinical practice. The proportionality factor HRmax to HRrest is known to approximate 15 in young welltrained adults. Presumably, the same value is inaccurate for middle-aged men. Materials and Methods: Six-hundred thirty-four men belonging to the Kuopio Ischaemic Heart Disease Risk Factor Study. Their mean age, body mass index (BMI), the daily total physical activity (TPA), VO2max, HRmax, and HRrest were: 49.4±6.4 years, 26.3±3.2 kg/m2, 48.5±10.1 metabolic equivalent hours per day, 33.7±7.6 mL/min/kg, 170.1±15.4 beats/min, and 63.3±10.8 beats/min. They included never-smokers 38%, former smokers 29%, and current smokers 33%. Results: The proportionality factor HRmax to HRrest in around 50-year-old men approximated 12. One year in age, one step change in BMI (normal weight, overweight, obese), smoking status (never, former, current), and TPA (moderately active, active, highly active) reduced the proportionality factor by 0.1, 0.6, 0.4, and 0.1, respectively. The proportionality factor in obese or current smoking middle-aged men was one point lower compared to normal weight or never-smoking peers. This corresponds to approximately 10 years in chronological age. Conclusions: In around 50-year-old men with no cardiovascular diseases, bronchial asthma, or cancer, the HRmax to HRrest ratio should be multiplied by approximately 12 to estimate VO2max. BMI and smoking status can be considered in calculations to improve accuracy.

Background Observational studies on the association of chronic hepatitis C with coronary atherosclerosis have shown varying results and previous related reviews have been inconclusive. By careful outcome classification and further data syntheses, we aimed to clarify current evidence on the association between hepatitis C infection and coronary atherosclerosis. Methods Through systematic searches of PubMed and Scopus, related published observational studies were identified. These were narrowed by review of abstract, full review and quality assessment to yield eligible studies. These were used in qualitative and quantitative syntheses. Results The initial search identified 274 unique publications, which were narrowed to 15 by means of preliminary reviews, and narrowed further to 10 by quality assessment. The endpoints assessed varied, representing different attributes of the disease. The 10 studies were used in the subsequent meta-analyses. The risk of a person with chronic hepatitis C developing coronary atherosclerosis is about triple the risk in uninfected persons (OR = 3.06, 95% CI = 1.99–4.72). Coronary atherosclerosis in persons with chronic hepatitis C is also more severe. The pooled risk of coronary atherosclerosis-related events in persons with chronic hepatitis C was null (OR = 1.10 95% CI = 0.80–1.52). Conclusion The current evidence indicates that hepatitis C virus or factors associated with HCV infection are apparently associated with increased risk of occurrence of coronary atherosclerosis and probably, increased severity of coronary atherosclerosis. Evidence of association with coronary atherosclerosis-related events is yet indeterminate.

Purpose Long-chain omega-3 polyunsaturated fatty acids (PUFA) from fish have been associated with risk of cardiovascular diseases (CVD), especially sudden cardiac death (SCD). Mercury exposure, mainly due fish consumption, has been associated with higher risk. However, the impact of PUFAs or mercury on the ventricular cardiac arrhythmias, which often precede SCD, is not completely known. We investigated the associations of the serum long-chain omega-3 PUFAs and hair mercury with ventricular repolarization, measured by heart rate-corrected QT and JT intervals (QTc and JTc, respectively). Methods A total of 1411 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 years and free of CVD in 1984–1989, were studied. Results Serum long-chain omega-3 PUFA concentrations were inversely associated with QTc and JTc (multivariate-adjusted P trend across quartiles = 0.02 and 0.002, respectively) and, during the mean 22.9-year follow-up, with lower SCD risk. However, further adjustments for QTc, JTc or hair mercury did not attenuate the associations with SCD. Hair mercury was not associated with QTc, JTc or SCD risk, but it slightly attenuated the associations of the serum long-chain omega-3 PUFA with QTc and JTc. Conclusions Higher serum long-chain omega-3 PUFA concentrations, mainly a marker for fish consumption, were inversely associated with QTc and JTc in middle-aged and older men from Eastern Finland, but QTc or JTc did not attenuate the inverse associations of the long-chain omega-3 PUFA with SCD risk. This suggests that prevention of prolonged ventricular repolarization may not explain the inverse association of the long-chain omega-3 PUFA with SCD risk., final draft, peerReviewed

Long-chain n-3 PUFA from fish and exercise capacity are associated with CVD risk. Fish, especially large and old predatory fish, may contain Hg, which may attenuate the inverse association of long-chain n-3 PUFA with CVD. However, the associations of long-chain n-3 PUFA or Hg exposure with exercise capacity are not well known. We aimed to evaluate the associations of serum long-chain n-3 PUFA EPA, docosapentaenoic acid (DPA) and DHA and hair Hg with exercise cardiac power (ECP, a ratio of VO2max:maximal systolic blood pressure (SBP) during an exercise test), a measure for exercise capacity. For this, data from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were analysed cross-sectionally in order to determine the associations between serum long-chain n-3 PUFA, hair Hg and ECP in 1672 men without CVD, aged 42–60 years. After multivariate adjustments, serum total long-chain n-3 PUFA concentration was associated with higher ECP and VO2max (P trend across quartiles=0·04 and P trend=0·02, respectively), but not with maximal SBP (P trend=0·69). Associations were generally similar when EPA, DPA and DHA were evaluated individually. Hair Hg was not associated with ECP, VO2max or maximal SBP. However, the associations of total long-chain n-3 PUFA (P interaction=0·03) and EPA (P interaction=0·02) with higher VO2max were stronger among men with lower hair Hg. Higher serum long-chain n-3 PUFA concentration, mainly a marker for fish consumption in this study population, was associated with higher ECP and VO2max in middle-aged men from eastern Finland., published version, peerReviewed

BACKGROUND The role of n-6 (ω-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations. OBJECTIVES We investigated the associations of serum n-6 PUFAs and activities of enzymes involved in PUFA metabolism, Δ5 desaturase (D5D) and Δ6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations. DESIGN The study included 2189 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y and free of T2D at baseline in 1984-1989. T2D was assessed by self-administered questionnaires, by fasting and 2-h oral-glucose-tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline, and by record linkage to the hospital discharge registry and the reimbursement register on diabetes medication expenses. Multivariate-adjusted Cox proportional hazards regression models were used to analyze associations. RESULTS During the average follow-up of 19.3 y, 417 men developed T2D. Those with higher estimated D5D activity (extreme-quartile HR: 0.55; 95% CI: 0.41, 0.74; P-trend < 0.001) and higher concentrations of total n-6 PUFAs (HR: 0.54; 95% CI: 0.41, 0.73; P-trend < 0.001), linoleic acid (LA; HR: 0.52; 95% CI: 0.39, 0.70; P-trend < 0.001), and arachidonic acid (AA; HR: 0.62; 95% CI: 0.46, 0.85; P-trend = 0.007) had a lower risk and those with higher concentrations of γ-linolenic acid (GLA; HR: 1.28; 95% CI: 0.98, 1.68; P = 0.021) and dihomo-γ-linolenic acid (DGLA; HR: 1.38; 95% CI: 1.04, 1.84; P-trend = 0.005) and higher D6D activity had a higher (HR: 1.50; 95% CI: 1.14, 1.97; P-trend < 0.001) multivariate-adjusted risk of T2D. Zinc mainly modified the association with GLA on T2D risk, with a higher risk observed among those with serum zinc concentrations above the median (P-interaction = 0.04). CONCLUSIONS Higher serum total n-6 PUFA, LA, and AA concentrations and estimated D5D activity were associated with a lower risk of incident T2D, and higher GLA and DGLA concentrations and estimated D6D activity were associated with a higher risk. In addition, a higher serum zinc concentration modified the association of GLA on the risk of T2D.

Fish intake and the long-chain omega-3 polyunsaturated fatty acids (PUFAs) in fish have been suggested to lower the risk of cognitive decline. We assessed whether serum long-chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are associated with performance on neuropsychological tests in an older population and whether exposure to methylmercury, mainly from fish, or apolipoprotein-E4 (Apo-E4) phenotype can modify the associations.A total of 768 participants from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were included. Cognitive function was measured using five neuropsychological tests: the Trail Making Test, the Verbal Fluency Test, the Selective Reminding Test, the Visual Reproduction Test and the Mini Mental State Exam. Multivariate-adjusted analysis of covariance and linear regression were used to analyze the cross-sectional associations.We found statistically significant associations between serum EPA+DPA+DHA and better performance in the Trail Making Test and the Verbal Fluency Test. The individual associations with EPA and DHA were similar with the findings with EPA+DPA+DHA, although the associations with DHA were stronger. No associations were observed with serum DPA. Pubic hair mercury content was associated only with a worse performance in the Trail Making Test, and mercury had only little impact on the associations between the serum PUFAs and cognitive performance. Apo-E4 phenotype did not modify the associations with PUFAs or mercury.Higher serum long-chain omega-3 PUFA concentrations were associated with better performance on neuropsychological tests of frontal lobe functioning in older men and women. Mercury exposure or Apo-E4 phenotype had little impact on cognitive performance.

Objectives Little is known about the role of cardiorespiratory fitness (CRF) and leisure-time physical activity (LTPA) with the risk of lung cancer. Previous research shows that maintaining a sufficient amount of physical activity may have a protective effect against cancer. The aim of this study is to examine the associations of CRF, LTPA and lung cancer among middle-aged Finnish men. Design Prospective cohort study. Methods In a population-based cohort study of 2305 men from Eastern Finland with no history of cancer at baseline. CRF and LTPA data was collected at baseline, 73 cases of lung cancer occurred during an average follow-up of 20-years. Results In a multivariate adjusted model, every 3.8 mL/kg/min (1 SD) increase of CRF was related to a 31% decrease in lung cancer risk across all VO2max quartiles. Furthermore, a 2.8-fold (95% CI 1.14–7.22, p = 0.024) increased risk of lung cancer among men in the lowest quartile (≤20.3 mL/kg/min) of CRF as compared those in the highest quartile (>35.1 mL/kg/min). In a multivariate adjusted model LTPA was not associated to lung cancer. Conclusions In middle-aged men with no history of lung cancer, increasing levels of CRF serves as a protective factor against lung cancer. Increasing CRF may reduce the risk of lung cancer. Furthermore, CRF is a better predictor of lung cancer than LTPA.

Fatty liver disease (FLD) has been identified as constituting cardiometabolic risk. However, evidence on the association of fatty liver index (FLI) with cardiovascular disease (CVD) is largely cross-sectional, with limited evidence on the predictability of incident CVD, and specifically, acute myocardial infarction (AMI). Therefore, we aimed to investigate the prospective associations between fatty liver as estimated by FLI and incident CVD, and specifically AMI, in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort.Our patients were 1205 middle-aged men free of CVD at baseline. The associations of baseline FLI with incident CVD and incident AMI were analyzed using multivariable-adjusted Cox regression models.During a median follow-up of 17 years, a total of 690 incident cases of CVD and 269 cases of AMI were recorded through Finnish registries. For incident CVD, for the high (FLI≥60) versus the low (≤30) FLI category, the hazard ratio (HR) was 1.77 [95% confidence interval (CI): 1.46-2.14] in the minimally adjusted model. With increasing adjustment, the association was attenuated progressively. In the most adjusted model, the HR was 1.41 (95% CI: 1.10-1.79). For incident AMI, for the high FLI category, the HR was 1.65 (95% CI: 1.22-2.23) in the minimally adjusted model, but in most comprehensive models when we included metabolic factors, the HR was not significant (HR=1.136, 95% CI: 0.777-1.662).FLI can predict incident CVD. However, the predictability of AMI using FLI is subject to interactions of metabolic factors. Individuals with FLI in the moderate to high category should be evaluated and monitored for subclinical or overt cardiovascular (including coronary) disease.

Background: Animal and plant protein intakes have indicated opposite associations with cardiovascular mortality risk. Whether dietary proteins are associated with risk of heart failure (HF) is unclear. Thus, we examined the associations of proteins from different food sources with risk of HF. Methods and Results: The study included 2441 men aged 42 to 60 years at the baseline examinations in 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Protein intakes at baseline were assessed with 4-day dietary records. Data on incident HF cases were obtained from national registers. HF risk according to protein intake was estimated by Cox proportional hazard ratios. During the mean follow-up of 22.2 years, 334 incident HF cases occurred. Higher intake of total protein indicated a trend toward increased risk of HF (multivariable-adjusted hazard ratio in the highest versus lowest quartile=1.33; 95% confidence interval: 0.95–1.85; P -trend=0.05). The associations between specific types and sources of protein with incident HF were consistent with this overall finding although not all associations reached statistical significance. For example, the hazard ratio in the highest versus lowest quartile was 1.43 (95% confidence interval: 1.00–2.03; P -trend=0.07) for total animal protein and 1.17 (95% confidence interval: 0.72–1.91; P -trend=0.35) for total plant protein. Conclusions: In middle-aged men, higher protein intake was marginally associated with increased risk of HF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03221127

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals. The PROG-IMT project, which includes this publication, has been funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, www.dfg.de) under the grants DFG Lo 1569/2-1 and DFG Lo 1569/2-3, received by MWL. The DFG had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Simon Thompson is supported by the British heart Foundation (CH/12/2/29428). Some of the contributing studies were funded by different parties, as listed in the acknowledgement section. Here, too, the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Low concentrations of serum 25-hydroxyvitamin D [25(OH)D] have been postulated to associate with an increased prevalence of depression. As there are a limited number of publications on this issue, we examined the association between serum 25(OH)D and depression in a general middle-aged or older population. A population-based cross-sectional study. A total of 1602 men and women from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland, aged 53-73 y in 1998-2001, were analysed. Depressive symptoms were assessed with the DSM-III depression scale, and those individuals who had scores over 4 (range 0-12) or had reported undergoing current antidepressant therapy, were considered as suffering from depression. Associations were estimated in serum 25(OH)D tertiles using logistic regression. Among the participants, 183 subjects (11.4%) were considered to have depression. The mean age of the subjects was 62.6 years (SD 6.4, range 53.4- 73.8 years). The mean serum 25(OH)D concentration was 43.8 nmol/L (SD 17.7, range 8.5-112.8 nmol/L), concentrations

BACKGROUND The prevalence of type 2 diabetes (T2D) is increasing around the world. Eggs are a major source of cholesterol, which has been associated with elevated blood glucose and an increased risk of T2D. However, there are limited and conflicting data from prospective population studies on the association between egg consumption and risk of T2D. OBJECTIVE We investigated the association between egg consumption and risk of incident T2D in middle-aged and older men from eastern Finland. DESIGN The study included 2332 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Dietary intakes were assessed with 4-d food records at baseline. Incident T2D was assessed by self-administered questionnaires; by fasting and 2-h oral-glucose-tolerance-test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline; and by record linkage to a hospital discharge registry and reimbursement register of diabetes medication expenses. Cox proportional hazards regression analyses were used to estimate associations with the risk of incident T2D. Associations with the metabolic risk markers at baseline and at the 4-y examinations were analyzed by ANCOVA. RESULTS During an average follow-up of 19.3 y, 432 men developed T2D. After adjustment for potential confounders, those in the highest compared with the lowest egg intake quartile had a 38% (95% CI: 18%, 53%; P-trend across quartiles

Background 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. Methods 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. Results 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). Conclusions 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. Copyright © 2014 John Wiley & Sons, Ltd.

Independently, cardiorespiratory fitness (CRF), C-reactive protein (CRP), and leukocyte count have been shown to predict cancer death. Little is known about the joint impact of CRF and prediagnostic markers of inflammation, particularly leukocyte count and CRP, and their prognostic value with cancer death. The aim of this study was to explore the association between prediagnostic inflammatory markers and CRF with cancer mortality. A population-based cohort of 2270 men from Eastern Finland with no cancer history at baseline participated in the study. CRP, leukocyte count, and CRF data were among the measures collected at baseline. Blood leukocyte count was measured with a cell counter, and serum CRP concentrations were measured using an immunometric assay. The highest value or plateau of directly measured oxygen consumption by a respiratory gas analyzer during an incremental exercise test to exhaustion was used to describe CRF. Over an average follow-up of 22 years, 272 cases of cancer mortality occurred. In a multivariate model, the joint impact of high leukocyte count (>5.40 × 109 /L) and low CRF (VO2 max 30.08 mL kg-1 min-1 ). The joint impact of CRP and CRF shared no association with cancer mortality in a multivariate model. The joint impact of high leukocyte count and low CRF increases risk for cancer death, suggesting it is a better predictor of cancer death compared to the joint impact of CRP and CRF.