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It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations. Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95% CI: 0.98-1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95% CI: 1.12-1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95% CI: 0.76-0.89) and CVD mortality (hazard ratio: 0.64, 95% CI: 0.57-0.72). The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.

Declining participation rates in health examination surveys may impair the representativeness of surveys and introduce bias into the comparison of results between population groups if participation rates differ between them. Changes in the characteristics of non-participants over time may also limit comparability with earlier surveys. We studied the association of socio-economic position with participation, and its changes over the past 25 years. Occupational class and educational level are used as indicators of socio-economic position. Data from six cross-sectional FINRISK surveys conducted between 1987 and 2012 in Finland were linked to national administrative registers, which allowed investigation of the differences between survey participants and non-participants. Our results show that individuals with low occupational class or low level of education were less likely to participate than individuals with high occupational class or high level of education. Participation rates decreased in all subgroups of the population but the decline was fastest among those with low level of education. The differences in participation rates must be taken into account to avoid biased estimates because socio-economic position has also been shown to be strongly related to health, health behaviour and biological risk factors. Particular attention should be paid to the recruitment of the less-educated population groups.

Growth differentiation factor-15 (GDF-15), Cystatin C and C-reactive protein (CRP) have been discussed as biomarkers for prediction of cardiac diseases. The aim of this study was to investigate the predictive value of single and repeated measurements of GDF-15 compared to Cystatin C and CRP for incidence of heart failure (HF) and death due to coronary heart disease (CHD) in the general population. Levels of GDF-15, CRP and Cystatin C were determined in three repeated measurements collected 5 years apart in the DAN-MONICA (Danish-Multinational MONitoring of trends and determinants in Cardiovascular disease) cohort (participants at baseline n = 3785). Cox regression models adjusted for cardiovascular risk factors revealed significantly increased hazard ratios (HR) for GDF-15 for incident HF 1.36 (HR per interquartile range (IQR) increase, 95% confidence interval (CI): 1.16; 1.59) and for death from CHD 1.51 (HR per IQR increase, 95% CI: 1.31, 1.75) (both with p<0.001). Joint modeling of time-to-event and longitudinal GDF-15 over a median 27-year follow-up period showed that the marker evolution was positively associated with death of CHD (HR per IQR increase 3.02 95% CI: (2.26, 4.04), p < 0.001) and HF (HR per IQR increase 2.12 95% CI: (1.54, 2.92), p<0.001). However using Cox models with follow-up time starting at the time of the third examination, serial measurement of GDF-15, modeled as changes between the measurements, did not improve prediction over that of the most recent measurement. GDF-15 is a promising biomarker for prediction of HF and death due to CHD in the general population, which may provide prognostic information to already established clinical biomarkers. Repeated measurements of GDF-15 displayed only a slight improvement in the prediction of these endpoints compared to a single measurement.

Background Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts. Methods The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts ( n  = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts ( n  = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality. Results The overall prevalence of CKD stage 3–5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts. Conclusion CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value.

To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS). Using 36 cohorts from the MORGAM-Project with baseline between 1982-1997, 69094 men and women aged 19-78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5. The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19-39 years to 60-78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P=0.01/P=0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05). In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.

Background Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A 1c (HbA 1c ) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA 1c with cardiovascular outcomes in the general population. Methods Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA 1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). Results Kaplan–Meier curves showed higher event rates with increasing HbA 1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA 1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02–1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03–1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02–1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA 1c . The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA 1c levels (HR 1.12; 95% CI 1.01–1.25, p = 0.04) and HR 1.10; 95% CI 1.01–1.20, p = 0.02) respectively. HbA 1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. Conclusions HbA 1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA 1c levels and outcomes. Elevated HbA 1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA 1c levels in the overall population.

Background Accurate blood pressure measurements are needed in clinical practice, intervention studies and health examination surveys. Blood pressure measurements are sensitive: their accuracy can be affected by measurement environment, behaviour of the subject, measurement procedures, devices used for the measurement and the observer. To minimize errors in blood pressure measurement, a standardized measurement protocol is needed. Methods The European Health Examination Survey (EHES) Pilot project was conducted in 2009–2012. A pilot health examination survey was conducted in 12 countries using a standardized protocol. The measurement protocols used in each survey, training provided for the measurers, measurement data, and observations during site visits were collected and evaluated to assess the level of standardization. Results The EHES measurement protocol for blood pressure was followed accurately in all 12 pilot surveys. Most of the surveys succeeded in organizing a quiet and comfortable measurement environment, and staff instructed survey participants appropriately before examination visits. In all surveys, blood pressure was measured three times, from the right arm in a sitting posture. The biggest variation was in the device used for the blood pressure measurement. Conclusions It is possible to reach a high level of standardization for blood pressure measurements across countries and over time. A detailed, standardized measurement protocol, and adequate training and monitoring during the fieldwork and centrally organized quality assessment of the data are needed. The recent EU regulation banning the sale of mercury sphygmomanometer in European Union Member States has set new challenges for the standardization of measurement devices since the validity of oscillometric measurements is device-specific and performance of aneroid devices depends very much on calibration.

The prevalence of diabetes is increasing in all industrialized countries and its prevention has become a public health priority. However, the predictors of diabetes risk are insufficiently understood. We evaluated, whether 31 novel biomarkers could help to predict the risk of incident diabetes. The biomarkers were evaluated primarily in the FINRISK97 cohort (n = 7,827; 417 cases of clinically incident diabetes during the follow-up). The findings were replicated in the Health 2000 cohort (n = 4,977; 179 cases of clinically incident diabetes during the follow-up). We used Cox proportional hazards models to calculate the relative risk of diabetes, after adjusting for the classic risk factors, separately for each biomarker. Next, we assessed the discriminatory ability of single biomarkers using receiver operating characteristic curves and C-statistics, integrated discrimination improvement (IDI) and net reclassification improvement (NRI). Finally, we derived a biomarker score in the FINRISK97 cohort and validated it in the Health 2000 cohort. A score consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per one standard deviation increase 1.88, p = 2.8 e-5). It also improved discrimination of the model (IDI = 0.0149, p<0.0001) and reclassification of diabetes risk (NRI = 11.8%, p = 0.006). Gender-specific analyses suggested that the best score differed between men and women. Among men, the best results were obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1 receptor antagonist, which gave an NRI of 25.4% (p<0.0001). Among women, the best score included adiponectin, apolipoprotein B, C-reactive protein and insulin. It gave an NRI of 13.6% (p = 0.041). We identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors. This gives new insights into the pathogenesis of diabetes and may help with targeting prevention and treatment.

Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca 2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

BackgroundThe main aim was to examine age-specific risk factor associations with incident atrial fibrillation (AF) and their attributable fraction in a large European cohort. Additionally, we aimed to examine risk of stroke and mortality in relation to new-onset AF across age.MethodsWe used individual-level data (n=66 951, 49.1% men, age range 40–98 years at baseline) from five European cohorts of the MOnica Risk, Genetics, Archiving and Monograph Consortium. The participants were followed for incident AF for up to 10 years and the association with modifiable risk factors from the baseline examinations (body mass index (BMI), hypertension, diabetes, daily smoking, alcohol consumption and history of stroke and myocardial infarction (MI)) was examined. Additionally, the participants were followed up for incident stroke and all-cause mortality after new-onset AF.ResultsAF incidence increased from 0.9 per 1000 person-years at baseline age 40–49 years, to 17.7 at baseline age ≥70 years. Multivariable-adjusted Cox models showed that higher BMI, hypertension, high alcohol consumption and a history of stroke or MI were associated with increased risk of AF across age groups (p<0.05). Between 30% and 40% of the AF risk could be attributed to BMI, hypertension and a history of stroke or MI. New-onset AF was associated with a twofold increase in risk of stroke and death at ages≥70 years (p≤0.001).ConclusionIn this large European cohort aged 40 years and above, risk of AF was largely attributed to BMI, high alcohol consumption and a history MI or stroke from middle age. Thus, preventive measures for AF should target risk factors such as obesity and hypertension from early age and continue throughout life.