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Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Background Inflammatory processes have been implicated in the development of chronic kidney disease (CKD). We investigated the association of a large panel of inflammatory biomarkers reflecting aspects of immunity with kidney function and CKD incidence. Methods We used data from two independent population-based studies, KORA F4 (discovery, n = 1110, mean age 70.3 years, 48.7% male) and ESTHER (replication, n = 1672, mean age 61.9 years, 43.6% male). Serum levels of biomarkers were measured using proximity extension assay technology. The association of biomarkers with estimated glomerular filtration rate (eGFR) at baseline and with incident CKD was investigated using linear and logistic regression models adjusted for cardiorenal risk factors. Independent results from prospective analyses of both studies were pooled. The significance level was corrected for multiple testing by false-discovery rate (PFDR Results In the KORA F4 discovery study, 52 of 71 inflammatory biomarkers were inversely associated with eGFR based on serum creatinine. Top biomarkers included CD40, TNFRSF9 and IL10RB. Forty-two of these 52 biomarkers were replicated in the ESTHER study. Nine of the 42 biomarkers were associated with incident CKD independent of cardiorenal risk factors in the meta-analysis of the KORA (n = 142, mean follow-up 6.5 years) and ESTHER (n = 103, mean follow-up 8 years) studies. Pathway analysis revealed the involvement of inflammatory and immunomodulatory processes reflecting cross-communication of innate and adaptive immune cells. Conclusions Novel and known biomarkers of inflammation were reproducibly associated with kidney function. Future studies should investigate their clinical utility and underlying molecular mechanisms in independent cohorts.

BACKGROUND: The coexistence of low muscle mass and high fat mass, two interrelated conditions strongly associated with declining health status, has been characterized by only a few protein biomarkers. High-throughput proteomics enable concurrent measurement of numerous proteins, facilitating the discovery of potentially new biomarkers. METHODS: Data derived from the prospective population-based Cooperative Health Research in the Region of Augsburg S4/FF4 cohort study (median follow-up time: 13.5years) included 1478 participants (756 men and 722 women) aged 55-74years in the cross-sectional and 608 participants (315 men and 293 women) in the longitudinal analysis. Appendicular skeletal muscle mass (ASMM) and body fat mass index (BFMI) were determined through bioelectrical impedance analysis at baseline and follow-up. At baseline, 233 plasma proteins were measured using proximity extension assay. We implemented boosting with stability selection to enable false positives-controlled variable selection to identify new protein biomarkers of low muscle mass, high fat mass, and their combination. We evaluated prediction models developed based on group least absolute shrinkage and selection operator (lasso) with 100× bootstrapping by cross-validated area under the curve (AUC) to investigate if proteins increase the prediction accuracy on top of classical risk factors. RESULTS: In the cross-sectional analysis, we identified kallikrein-6, C-C motif chemokine 28 (CCL28), and tissue factor pathway inhibitor as previously unknown biomarkers for muscle mass [association with low ASMM: odds ratio (OR) per 1-SD increase in log2 normalized protein expression values (95% confidence interval (CI)): 1.63 (1.37-1.95), 1.31 (1.14-1.51), 1.24 (1.06-1.45), respectively] and serine protease 27 for fat mass [association with high BFMI: OR (95% CI): 0.73 (0.61-0.86)]. CCL28 and metalloproteinase inhibitor 4 (TIMP4) constituted new biomarkers for the combination of low muscle and high fat mass [association with low ASMM combined with high BFMI: OR (95% CI): 1.32 (1.08-1.61), 1.28 (1.03-1.59), respectively]. Including protein biomarkers selected in ≥90% of group lasso bootstrap iterations on top of classical risk factors improved the performance of models predicting low ASMM, high BFMI, and their combination [delta AUC (95% CI): 0.16 (0.13-0.20), 0.22 (0.18-0.25), 0.12 (0.08-0.17), respectively]. In the longitudinal analysis, N-terminal prohormone brain natriuretic peptide (NT-proBNP) was the only protein selected for loss in ASMM and loss in ASMM combined with gain in BFMI over 14years [OR (95% CI): 1.40 (1.10-1.77), 1.60 (1.15-2.24), respectively]. CONCLUSIONS: Proteomic profiling revealed CCL28 and TIMP4 as new biomarkers of low muscle mass combined with high fat mass and NT-proBNP as a key biomarker of loss in muscle mass combined with gain in fat mass. Proteomics enable us to accelerate biomarker discoveries in muscle research.

Background The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. Methods Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. Results Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71–0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = − 0.12, Wald-p = 3.63e−13), apolipoprotein B (APOB) (Wald-Ratio = − 0.09, Wald-p = 2.54e−04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e−04). Conclusions Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.

Background Little is known about the associations between cardiovascular risk factors (CRF) and disc degeneration (DD). Purpose To evaluate the potential association between CRFs and intervertebral DD in a population-based sample. Methods A total of 400 participants from the community-based KORA-study were assessed in terms of CRFs, specifically obesity, hypertension, diabetes, elevated LDL-c, low HDL-c, elevated triglycerides, smoking status, and alcohol consumption. The patients additionally underwent whole-body magnetic resonance imaging (MRI) using T2-weighted single-shot fast-spin-echo and T1 dual-echo gradient-echo Dixon pulse sequences. Thoracic and lumbar DD were assessed using the Pfirrmann score and for the presence of disc bulging/protrusion. Cross-sectional associations between CRFs and MR-based Pfirrmann score were then analyzed. Results A total of 385 individuals (58.2% men; mean age 56.3 ± 9.2 years) were included. Prevalence of DD was 76.4%. Older age (β = 0.18; 95% CI 0.12–0.25; P Conclusion A significant independent association exists between age, BMI, and intervertebral DD. In contrast, there is no significant association between cardiovascular risk factors and DD. Providing strong evidence that the pathologic process undergirding DD is mechanical, rather than microvascular, in nature.

Background Diabetes mellitus is an established risk factor for cardiovascular diseases. Even impaired levels of glucose and insulin might harm organ function prior to diabetes onset. Whether serum glucose or insulin plays a direct role in cardiac dysfunction or lung volume reduction remains unclear. The aim was to investigate the relationship between glucose and insulin with the right ventricle and lung volumes within KORA-MRI FF4 study. Methods From the KORA-MRI FF4 cohort study 337 subjects (mean age 55.7 ± 9.1 years; 43% women) underwent a whole-body 3T MRI scan. Cardiac parameters derived from a cine-steady-state free precession sequence using cvi42. MRI-based lung volumes derived semi-automatically using an in-house algorithm. Fasting serum glucose, fasting insulin levels, and HOMA index were calculated in all study subjects. Linear regression analyses were performed to assess the relationships between glucose and insulin levels with right ventricle volumes and lung volumes adjusted for age, sex, BMI, and cardiovascular risk factors. Results In univariate and multivariate-adjusted models, high serum insulin was inversely associated with end-diastolic volume (β = −12.43, P < 0.001), end-systolic volume (β = −7.12, P < 0.001), stroke volume (β = −5.32, P < 0.001), but not with ejection fraction. The association remained significant after additional adjustment for lung volumes. Similarly, serum insulin was inversely associated with lung volume (β = −0.15, P = 0.04). Sensitivity analysis confirmed results after excluding subjects with known diabetes. Conclusions Serum insulin was inversely associated with right ventricle function and lung volumes in subjects from the general population free of cardiovascular disease, suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E−04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).

Mental health research opportunities in the MONICA-KORA study Goal: Initially, part of the worldwide MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Project of the World Health Organization (WHO), the project was pursued 1996 as KORA (Cooperative Health Research in the Region Augsburg) Study, which now substantially expands the former focus on cardiovascular medicine. Major research questions within the mental health focus emphasize the prognostic impact of psychosocial stress on the incidence of somatic endpoints and the gender-driven crosstalk of psycho-neuro- immunological conditions with somatic diseases. Methods: Three independent representative population-based MONICA/KORA surveys (S1 to S3) starting in 1984/85 and performed in 5-years intervals, constitute the backbone of the psychosocial MONICA sub study. An extensive set of psychosocial baseline data captured in the S1 to S3 surveys are available for a total of approximately 13000 participants in the age range of 25 to 75 years. Here, data allow estimates of work-stress conditions, social isolation, social network, life satisfaction and the Type A Behavior Pattern. The Follow-up studies (F3, F4, FFF4) allow for prospective, time-dependent analyses. In the follow-up (F) surveys, psychosomatic research was strengthened with the inclusion of standardized assessments of depression, anxiety, Type D personality and (in F4) for Posttraumatic Stress Disorder (PTSD), psychosocial stress and life satisfaction. Combined analyses with genetic, epigenetic and metabolomic datasets are feasible. Results: The initial S1 to S3 surveys provided psychosocial baseline data for approximately 13000 participants in the age range of 25 to75 years. The Follow-up studies (F3, F4, FFF4) each included approximately 3000 participants with validated datasets with a median of 9 to 15 years of follow-up period from baseline. An increasing number of co-operations dealing with sophisticated basic research tools are currently ongoing. Conclusions: Prospective assessments of psychosocial stress conditions on the onset of somatic disease conditions and research on the interaction with autonomic, endocrine and inflammatory pathways result in new insights of established disease conditions and may contribute as a game-changer in the current disease understanding.

Purpose Diet is one of the most important modifiable risk factors for the development of type 2 diabetes. Here, we aim to identify dietary patterns and to investigate their association with prediabetes, undetected diabetes and prevalent diabetes. Methods The present study included 1305 participants of the cross-sectional population-based KORA FF4 study. Oral glucose tolerance test (OGTT) measurements together with a physician-confirmed diagnosis allowed for an accurate categorization of the participants according to their glucose tolerance status into normal glucose tolerance (n = 698), prediabetes (n = 459), undetected diabetes (n = 49), and prevalent diabetes (n = 99). Dietary patterns were identified through principal component analysis followed by hierarchical clustering. The association between dietary patterns and glucose tolerance status was investigated using multinomial logistic regression models. Results A Prudent pattern, characterized by high consumption of vegetables, fruits, wholegrains and dairy products, and a Western pattern, characterized by high consumption of red and processed meat, alcoholic beverages, refined grains and sugar-sweetened beverages, were identified. Participants following the Western pattern had significantly higher chances of having prediabetes (odds ratio [OR] 1.92; 95% confidence interval [CI] 1.35, 2.73), undetected diabetes (OR 10.12; 95% CI 4.19, 24.43) or prevalent diabetes (OR 3.51; 95% CI 1.85, 6.67), compared to participants following the Prudent pattern. Conclusion To our knowledge, the present study is one of the few investigating the association between dietary patterns and prediabetes or undetected diabetes. The use of a reference group exclusively including participants with normal glucose tolerance might explain the strong associations observed in our study. These results suggest a very important role of dietary habits in the prevention of prediabetes and type 2 diabetes.

Since family history of diabetes is a very strong risk factor for type 2 diabetes, which is one of the most important risk factors for cardiovascular disease (CVD), it might be also useful to assess the risk for CVD. Therefore, we aimed to investigate the relationship between a familial (parents and siblings) history of diabetes and the risk of incident CVD. Data from four prospective German cohort studies were used: EPIC-Potsdam study (n = 26,054), CARLA study (n = 1,079), SHIP study (n = 3,974), and KORA study (n = 15,777). A multivariable-adjusted Cox regression was performed to estimate associations between familial histories of diabetes, myocardial infarction or stroke and the risk of CVD in each cohort; combined hazard ratios (HRMeta) were derived by conducting a meta-analysis. The history of diabetes in first-degree relatives was not related to the development of CVD (HRMeta 0.99; 95% CI 0.88–1.10). Results were similar for the single outcomes myocardial infarction (MI) (HRMeta 1.07; 95% CI 0.92–1.23) and stroke (HRMeta 1.00; 95% CI 0.86–1.16). In contrast, parental history of MI and stroke were associated with an increased CVD risk. Our study indicates that diabetes in the family might not be a relevant risk factor for the incidence of CVD. However, the study confirmed the relationship between a parental history of MI or stroke and the onset of CVD.

The correlation between physical inactivity, thoracolumbar disc degeneration, and back pain remains unclear.This study investigated the relationship between short- and long-term physical inactivity and degenerative changes of the thoracic and lumbar spine in a southern German cohort from the general population over a time period of 14 years.This study was designed as a cross-sectional case-control study, nested in a prospective cohort from the "Cooperative Health Research in the Region of Augsburg/Kooperative Gesundheitsforschung in der Region Augsburg" (KORA) study.All participants in the population-based KORA study were assessed using a physical activity questionnaire to establish a baseline in 1999-2001 (exam 1), within an initial follow up questionnaire in 2006-2008 (exam 2), and a second follow-up questionnaire between 2013 and 2014 (exam 3). A subsample of this group (400 subjects) underwent full body MR scan performed on a 3T magnetic resonance imaging scanner current with exam 3.Data regarding physical inactivity over a time period of 14 years and back pain, and quantification of thoracic and lumbar disc degeneration on magnetic resonance imaging.Quantification of thoracic and lumbar disc degeneration was performed using the Pfirrmann score. Physical activity was grouped as no physical activity, irregularly for 1 hour, regularly for 1 hour, or regularly for ≥2 hours. This was used to calculate another variable "physical inactivity," with the options of irregular activity ≤1 hour per week or regularly ≥1 hour. Physical labor, walking, and cycling activity were additionally investigated. Correlations between physical inactivity measurements and thoracic and lumbar disc degeneration were analyzed via linear regression models adjusted for age, sex, BMI, hypertension, diabetes, and back pain.In total, 385 individuals (mean age: 56 years, SD ± 9.19; 58.2% male) were included in this study. Mean summed Pfirrmann score was 2.41 (SD ± 4.19) in the thoracic and 1.78 (SD ± 1.81) in the lumbar spine. The level of current exercise in our cohort varied with 113 (29.4%) subjects exercising regularly ≥2 hours per week, 118 (30.7%) regularly 1 hour per week, 57 (14%) irregularly for about 1 hour per week, and 97 (25.2%) stated not to exercise at exam 3. Disc degeneration was more apparent in those with irregular activity1 hour compared to those with regular activity of ≥1 hour and more per week (p.01) and in those with no activity compared to those with regular activity of ≥2 (p.001) measured using exam 3. Less physical activity over a time period of 14 years correlated with an increase of disc degeneration of the thoracic and lumbar spine after adjustment for age, sex, BMI, hypertension and diabetes mellitus (p.05). There was no statistically significant association between physical labor, walking activity, or cycling activity with disc degeneration. Additionally, no significant correlations between degree of disc degeneration (p=.990), degree of physical inactivity (p=.158), and back pain were observed.Degree of physical inactivity as measured over a time period of 14 years demonstrated a strong correlation with disc degeneration of the thoracic and lumbar spine.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)—mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions—were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)—mapping respectively to SERINC2, CHST12, and an intergenic region—were associated with increased mortality risk. DNA methylation at each site predicted 5%¬¬–15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

Background Hypertension remains a significant modifiable risk factor for cardiovascular diseases and a major determinant of morbidity and mortality. We aimed to describe sex-stratified age-standardized estimates of prevalence, awareness, treatment and control of hypertension, and their associated factors in older adults. Methods The KORA-Age1 is a population-based cross-sectional survey carried out in 2008/2009 on individuals aged 65–94 years in Augsburg region, Germany. Blood pressure measurements were available for 1052 out of 1079 persons who participated in the physical examination. Factors associated with prevalence, awareness and control of hypertension were investigated by multivariable logistic regression. Results The overall prevalence of hypertension (≥140/90 mmHg) was 73.8% [95% confidence interval (CI), 69.3–77.9], representing 74.8% (95% CI, 68.4–80.2) in men and 73.5% (95% CI, 66.8–79.3) in women. Among those with hypertension, 80.2% (95% CI, 75.3–84.4) were aware of their hypertensive condition and 74.4% (95% CI, 69.2–79.1) were on treatment for hypertension. Among those aware of their hypertension status, 92.8% (95% CI, 88.8–95.6) were on treatment and 53.7% (95% CI, 47.0–60.1) had their blood pressure controlled. Hypertension was more frequent in individuals who were older, obese, or had diabetes. Higher education attainment or presence of comorbidities was associated with higher level of hypertension awareness. Individuals taking three antihypertensive drug classes were more likely to have controlled hypertension compared with those taking one antihypertensive drug class, odds ratio (OR), 1.85 (95% CI, 1.14–2.99). Conclusion Our findings identified high prevalence of hypertension and relevant health gaps on awareness, treatment and suboptimal control of hypertension in older adults in Germany. Screening for hypertension should especially target older adults with low educational attainment and ‘healthy’ elderly with less contact to physicians.

Die korperliche Aktivitat stellt ein komplexes Verhalten dar, dessen valide und reliable Erfassung in gros angelegten populationsbasierten Studien mit besonderen Herausforderungen einhergeht. In der bundesweiten NAKO Gesundheitsstudie liegen zur Halbzeit der Basiserhebung die Daten zur korperlichen Aktivitat fur 100.000 Teilnehmende vor. Beschreibung der Erfassung der korperlichen Aktivitat und Prasentation erster deskriptiver Ergebnisse. Das multimodale Erhebungskonzept bestand aus zwei Fragebogen, dem Questionnaire on Annual Physical Activity Pattern (QUAP) und dem Global Physical Activity Questionnaire (GPAQ), einem computerbasierten Erinnerungsprotokoll der vergangenen 24 h (cpar24) und einer 7‑Tage-Akzelerometrie (Actigraph GT3X/+; Fa. ActiGraph, Pensacola, FL, USA). Fur die einzelnen Erhebungsmodule lagen auswertbare Datensatze in unterschiedlicher Zahl vor (QUAP: n = 16.372; GPAQ: n = 90.900; cpar24: n = 23.989; Akzelerometrie: n = 35.218). Die Analysen der einzelnen Module ergaben unterschiedliche Durchschnittswerte fur die moderate oder intensive korperliche Gesamtaktivitat der Teilnehmenden: Bei Frauen wurden 75–216 min/Tag gemessen, bei Mannern 73–224 min/Tag. Personen der Altersgruppe 20–39 Jahre verbrachten 66–200 min/Tag in moderater oder intensiver korperlicher Gesamtaktivitat, wahrend Personen der Altersgruppe 40–69 Jahre 78–244 min/Tag aufwendeten. Erste modulubergreifende Analysen der korperlichen Aktivitat in der NAKO zeigen den Nutzen komplementar eingesetzter Erhebungsmethoden. Die umfangreichen Daten stellen eine wertvolle Ressource fur die Charakterisierung der Zusammenhange zwischen korperlicher Aktivitat und Krankheitspravention dar, die in der Zukunft erfolgen soll.

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Background Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. Results By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61–0.66 in the external validation datasets. Conclusions The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.

Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the “Effects of low-level air pollution: A study in Europe” (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO 2), particulate matter with diameter 2.5), black carbon (BC), warm-season ozone (O 3), and eight elemental components of PM 2.5 (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO 2 (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 μg/m 3), PM 2.5 (1.12, 0.92-1.36 per 5 μg/m 3), and BC (1.15, 1.00-1.33 per 0.5 10 −5/m) and liver cancer incidence. Associations with NO 2 and BC persisted in two-pollutant models with PM 2.5. Most components of PM 2.5 were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM 2.5 or NO 2. Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.

Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.

Type 2 diabetes mellitus (T2D) is one of the most prevalent diseases in the world and presents a major health and economic burden, a notable proportion of which could be alleviated with improved early prediction and intervention. While standard risk factors including age, obesity, and hypertension have shown good predictive performance, we show that the use of CpG DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Whilst previous studies have been largely constrained by linear assumptions and the use of CpGs one-at-the-time, we have adopted a more flexible approach based on a range of linear and tree-ensemble models for classification and time-to-event prediction. Using the Generation Scotland cohort (n=9,537) our best performing model (Area Under the Curve (AUC)=0.880, Precision Recall AUC (PRAUC)=0.539, McFaddens R2=0.316) used a LASSO Cox proportional-hazards predictor and showed notable improvement in onset prediction, above and beyond standard risk factors (AUC=0.860, PRAUC=0.444 R2=0.261). Replication of the main finding was observed in an external test dataset (the German-based KORA study, p=3.7x10-4). Tree-ensemble methods provided comparable performance and future improvements to these models are discussed. Finally, we introduce MethylPipeR, an R package with accompanying user interface, for systematic and reproducible development of complex trait and incident disease predictors. While MethylPipeR was applied to incident T2D prediction with DNA methylation in our experiments, the package is designed for generalised development of predictive models and is applicable to a wide range of omics data and target traits.

Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898).The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 × 10−7, odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 × 10−6, OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 × 10−6, OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 × 10−5. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4).Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy.These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Background Glycated haemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment; however, its role in predicting cardiovascular outcomes in the general population remains uncertain. Purpose The additional use of glycated haemoglobin A1c (HbA1c) as a biomarker might highlight subjects of the general population with an increased risk for cardiovascular outcomes with cardiovascular disease, cardiovascular mortality or overall-mortality. Methods Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analysed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular diseases (CVD), and overall mortality in the study population, in non-diabetic (N=32,477), and diabetic participants (N=3,703). Results Kaplan-Meier curves showed higher event rates with increasing continuous log-transformed HbA1c levels. Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) log-transformed divided by interquartile range and the examined outcomes, with a hazard ratio (HR) of 1.12 (95% confidence interval (CI): 1.04–1.20, p=0.0019) for cardiovascular mortality, 1.10 (95% CI: 1.04–1.16, p An increased risk of CVD was observed in subjects without diabetes with increased HbA1c levels (HR 1.09; 95% CI: 1.01–1.16, p=0.021). An HbA1c cut-off value of 39.89 mmol/mol (5.8%), 36.62 mmol/mol (5.5%), and 38.80 mmol/mol (5.7%) for cardiovascular mortality, CVD, and overall mortality, respectively, was determined for selecting individuals at an increased risk. Conclusion HbA1c was demonstrated to be an independent prognostic biomarker for all investigated outcomes in the general European population. An approximately linear relationship was observed between an increase of HbA1c levels and the outcomes. Elevated HbA1c levels were also associated with the outcomes in participants without diabetes (i.e. HbA1c levels Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Seventh Framework ProgrammeEuropean Union FP 7 project CHANCES Kaplan-Meier curves for the outcomesPenalised cubic splines HbA1c/time event

Background The number of people using long-term care (LTC) is increasing steadily, hence, demand for adequate services is rising. The purpose of this exploratory study was to identify relevant gender-linked determinants for utilization of LTC in community-dwelling older adults. Methods We examined 4077 females (52.7%) and males ≥ 65 years old (range: 65–97 years) between 2011/12 (t1) and 2016 (t2). Data originated from the population-based Cooperative Health Research in the Region of Augsburg (KORA)-Age study in southern Germany. A descriptive analysis assessed the amount of LTC used. Cross-sectional generalized estimating equation logistic models identified determinants for utilization of (in)formal LTC. Determinants for transition to LTC between t1 and t2 were examined using a longitudinal logistic regression model. Potential determinants were chosen according to Andersen's Behavioral Model of Health Services Use. Results At t2, 820 (20.1%) were LTC users with 527 (64.3%) being female. The average amount of informal LTC was higher in males, whereas the amount of formal LTC was higher in females. In both genders, higher age, multimorbidity, and disability were associated with utilization of and transition to LTC. Living alone was significantly associated with utilization of LTC in both genders, but its effect was two times stronger in males. Thus, it is considered the essential gender-linked determinant. Conclusions Gender-linked determinants must be considered when establishing demand-oriented policies. Future health programs should specifically target older individuals, especially males, living alone to improve their capabilities in activities of daily living to allow them to remain living longer and independently within community settings.

Background Compared to individuals without type 2 diabetes mellitus, the relative increase in cardiovascular mortality is much higher in women than in men in individuals with type 2 diabetes mellitus. Methods We evaluated data from 7443 individuals (3792 women, 50.9%), aged 20 to 81 years, from two independent population-based investigations, SHIP-0 and MONICA/KORA S3. We analyzed the longitudinal sex-specific associations of lipoprotein(a) with cardiovascular mortality in individuals with and without type 2 diabetes mellitus using Cox regression. Results During a median follow-up of 20.5 years (136,802 person-years), 657 participants (404 men and 253 women) died of cardiovascular causes. Among individuals without type 2 diabetes mellitus, men had a significantly higher risk for cardiovascular mortality compared to women in unadjusted model and after adjustment. On the other hand, in participants with type 2 diabetes mellitus, the risk for cardiovascular mortality was not different between men and women in the unadjusted model and after adjustment for age, body mass index, low-density lipoprotein-cholesterol, fasting status and study sample (SHIP-0, MONICA/KORA S3). Further adjustment for lipoprotein(a) concentrations had no impact on the hazard ratio (HR) for cardiovascular mortality comparing men versus women in individuals without type 2 diabetes mellitus [HR: 1.94; 95% confidence interval (CI) 1.63 to 2.32; p Conclusions Women are described to have a stronger relative increase in cardiovascular mortality than men when comparing individuals with and without type 2 diabetes mellitus. Higher lipoprotein(a) concentrations in women with type 2 diabetes mellitus than in men with type 2 diabetes mellitus might partially explain this finding.

Background Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) 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 HbA1c with cardiovascular outcomes in the general population. Methods Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c 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 HbA1c levels (log-rank-test: p 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 HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c 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. HbA1c 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 HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

To improve ambient air quality during the 2008 Summer Olympic and Paralympic Games, the Chinese Government and Beijing’s municipal government implemented comprehensive emission control policies in Beijing and its neighboring regions before and during this period. The goal of this study was to investigate the association between particulate air pollution and cause-specific respiratory mortality before, during and after the period of the Olympic Games. Further, we wanted to assess whether changes in pollutant concentrations were linked to changes in respiratory mortality. We obtained daily data on mortality due to respiratory diseases (coded as J00-J99 according to the International Classification of Diseases and Related Health Problems 10th revision [ICD10]) and pneumonia (ICD10: J12–18), meteorology, particulate matter less than 10 µm or 2.5 μm in diameter (PM10, PM2.5) and particle number size distribution from official monitoring networks and sites located on the Peking University campus between May 20 and December 1, 2008. We assessed the effects of particulate air pollution on daily respiratory mortality using confounder-adjusted Quasi-Poisson regression models. Furthermore, we estimated air pollution effects for three periods—before (May 20 to July 20, 2008), during (August 1 to September 20, 2008) and after (October 1 to December 1, 2008)—by including interaction terms in the models. We found associations between different particle metrics and respiratory and pneumonia mortality, with more pronounced effects in smaller particle size ranges. For example, an interquartile range increase of 7,958 particles/cm3 in ultrafine particles (particles

OBJECTIVES: Glycosylation of immunoglobulin G (IgG) is an important regulator of the immune system and has been implicated in prevalent hypertension.The aim of this study is to investigate whether the IgG glycome begins to change prior to hypertension diagnosis by analysing the IgG glycome composition in a large population-based female cohort with two independent replication samples. METHODS: We included 989 unrelated cases with incident hypertension and 1628 controls from the TwinsUK cohort (mean follow-up time of 6.3 years) with IgG measured at baseline by ultra-performance liquid chromatography and longitudinal BP measurement available. We replicated our findings in 106 individuals from the 10 001 Dalmatians and 729 from KORA S4. Cox regression mixed models were applied to identify changes in glycan traits preincident hypertension, after adjusting for age, mean arterial pressure, BMI, family relatedness and multiple testing (FDR

Educational inequalities in mortality have been observed for decades, however the underlying biological mechanisms are not well known. We assessed the mediating role of altered aging of immune cells functioning captured by DNA methylation changes in blood (known as epigenetic clocks) in educational associated all-cause mortality. Data were from eight prospective population-based cohort studies, representing 13,021 participants. We found educational inequalities in mortality were larger for men than for women, estimated by hazard differences and ratios. Epigenetic clocks explained approximately 50% of educational inequalities in mortality for men, while the proportion was small for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the WHO risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.

Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)—being lower in samples with late or incomplete penetrance—thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.

BackgroundLong-term exposure to ambient air pollution has been linked to childhood-onset asthma, although evidence is still insufficient. Within the multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we examined the associations of long-term exposures to particulate matter with a diameter 2.5), nitrogen dioxide (NO2) and black carbon (BC) with asthma incidence in adults.MethodsWe pooled data from three cohorts in Denmark and Sweden with information on asthma hospital diagnoses. The average concentrations of air pollutants in 2010 were modelled by hybrid land-use regression models at participants’ baseline residential addresses. Associations of air pollution exposures with asthma incidence were explored with Cox proportional hazard models, adjusting for potential confounders.ResultsOf 98 326 participants, 1965 developed asthma during a mean follow-up of 16.6 years. We observed associations in fully adjusted models with hazard ratios of 1.22 (95% CI 1.04–1.43) per 5 μg·m−3 for PM2.5, 1.17 (95% CI 1.10–1.25) per 10 µg·m−3 for NO2 and 1.15 (95% CI 1.08–1.23) per 0.5×10−5 m−1 for BC. Hazard ratios were larger in cohort subsets with exposure levels below the European Union and US limit values and possibly World Health Organization guidelines for PM2.5 and NO2. NO2 and BC estimates remained unchanged in two-pollutant models with PM2.5, whereas PM2.5 estimates were attenuated to unity. The concentration–response curves showed no evidence of a threshold.ConclusionsLong-term exposure to air pollution, especially from fossil fuel combustion sources such as motorised traffic, was associated with adult-onset asthma, even at levels below the current limit values.

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65–90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts (n = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) (n = 82, 10.8%) (p = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus., publishedVersion

Resettlers are a large migrant group of more than 2 million people in Germany who migrated mainly from the former Soviet Union to Germany after 1989. We sought to compare the distribution of the major risk factors for cardiovascular disease (CVD) and to investigate the overall genetic differences in a study population which consisted of resettlers and native (autochthone) Germans. This was a joint analysis of two cohort studies which were performed in the region of Augsburg, Bavaria, Germany, with 3363 native Germans and 363 resettlers. Data from questionnaires and physical examinations were used to compare the risk factors for cardiovascular diseases between the resettlers and native Germans. A population-based genome-wide association analysis was performed in order to identify the genetic differences between the two groups. The distribution of the major risk factors for CVD differed between the two groups. The resettlers lead a less active lifestyle. While female resettlers smoked less than their German counterparts, the men showed similar smoking behavior. SNPs from three genes (BTNL2, DGKB, TGFBR3) indicated a difference in the two populations. In other studies, these genes have been shown to be associated with CVD, rheumatoid arthritis and osteoporosis, respectively.

Objective Metabolic syndrome and obesity are risk factors for chronic kidney disease. However, early kidney alterations may escape diagnosis in these conditions due to glomerular hyperfiltration. Uromodulin, a glycoprotein exclusively synthesized in tubular cells of the thick ascending limb of Henle's loop, is a novel tissue-specific biomarker for kidney function. In contrast to the commonly used markers creatinine and cystatin C, serum uromodulin does not primarily depend on glomerular filtration. We hypothesized that serum uromodulin is a marker for metabolic syndrome and related components. Design The analyses included 1088 participants of the population-based KORA F4 study aged 62–81 years. Metabolic syndrome was present in 554 participants. After a mean follow-up time of 6.5 years, 621 participants were reevaluated, of which 92 had developed incident metabolic syndrome. Methods The association of serum uromodulin with metabolic syndrome and its components were assessed using multivariable logistic regression models. Results Serum uromodulin was inversely associated with metabolic syndrome after adjustment for sex, age, estimated glomerular filtration rate, physical activity, smoking, alcohol consumption and high-sensitivity C-reactive protein (OR 0.65; 95% CI 0.56–0.76 per standard deviation uromodulin; P Conclusions Serum uromodulin is independently associated with prevalent, but not with incident metabolic syndrome. Low serum uromodulin may indicate a decreased renal reserve in the metabolic syndrome.

Background: Associations between several persistent organic pollutants (POPs) and type 2 diabetes have been found in humans, but the relationship has rarely been investigated in the general population. The current nested case-control study examined internal exposure to polychlorinated biphenyls (PCB) and pesticides and the incidence of type 2 diabetes among participants of two population-based German cohort studies. Methods: We retrospectively selected 132 incident cases of type 2 diabetes and 264 age- and sex-matched controls from the CARdiovascular Living and Aging in Halle (CARLA) study (2002–2006, East Germany) and the Cooperative Health Research in the Region of Augsburg (KORA) study (1999–2001, South Germany) based on diabetes status at follow-up examinations in 2007–2010 and 2006–08, respectively (60% male, mean age 63 and 54 years). We assessed the association between baseline POP concentrations and incident diabetes by conditional logistic regression adjusted for cohort, BMI, cholesterol, alcohol, smoking, physical activity, and parental diabetes. Additionally, we examined effect modification by sex, obesity, parental diabetes and cohort. Results: In both cohorts, diabetes cases showed a higher BMI, a higher frequency of parental diabetes, and higher levels of POPs. We observed an increased chance for incident diabetes for PCB-138 and PCB-153 with an odds ratio (OR) of 1.50 (95%CI: 1.07–2.11) and 1.53 (1.15–2.04) per interquartile range increase in the respective POP. In addition, explorative results suggested higher OR for women and non-obese participants. Conclusions: Our results add to the evidence on diabetogenic effects of POPs in the general population, and warrant both policies to prevent human exposure to POPs and additional research on the adverse effects of more complex chemical mixtures. Keywords: Type 2 diabetes, Incidence, Environmental contaminates, Case-control study, Epidemiology

Objective:The origin of malnutrition in older age is multifactorial and risk factors may vary according to health and living situation. The present study aimed to identify setting-specific risk profiles of malnutrition in older adults and to investigate the association of the number of individual risk factors with malnutrition.Design:Data of four cross-sectional studies were harmonized and uniformly analysed. Malnutrition was defined as BMI < 20 kg/m2 and/or weight loss of >3 kg in the previous 3–6 months. Associations between factors of six domains (demographics, health, mental function, physical function, dietary intake-related problems, dietary behaviour), the number of individual risk factors and malnutrition were analysed using logistic regression.Setting:Community (CD), geriatric day hospital (GDH), home care (HC), nursing home (NH).Participants:CD older adults (n 1073), GDH patients (n 180), HC receivers (n 335) and NH residents (n 197), all ≥65 years.Results:Malnutrition prevalence was lower in CD (11 %) than in the other settings (16–19 %). In the CD sample, poor appetite, difficulties with eating, respiratory and gastrointestinal diseases were associated with malnutrition; in GDH patients, poor appetite and respiratory diseases; in HC receivers, younger age, poor appetite and nausea; and in NH residents, older age and mobility limitations. In all settings the likelihood of malnutrition increased with the number of potential individual risk factors.Conclusions:The study indicates a varying relevance of certain risk factors of malnutrition in different settings. However, the relationship of the number of individual risk factors with malnutrition in all settings implies comprehensive approaches to identify persons at risk of malnutrition early.

Accurate prediction of relevant outcomes is important for targeting therapies and to support health economic evaluations of healthcare interventions in patients with diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) risk equations are some of the most frequently used risk equations. This study aims to analyze the calibration and discrimination of the updated UKPDS risk equations as implemented in the UKPDS Outcomes Model 2 (UKPDS-OM2) for predicting cardiovascular (CV) events and death in patients with type 2 diabetes mellitus (T2DM) from population-based German samples. Analyses are based on data of 456 individuals diagnosed with T2DM who participated in two population-based studies in southern Germany (KORA (Cooperative Health Research in the Region of Augsburg)-A: 1997/1998, n = 178; KORA-S4: 1999–2001, n = 278). We compared the participants’ 10-year observed incidence of mortality, CV mortality, myocardial infarction (MI), and stroke with the predicted event rate of the UKPDS-OM2. The model’s calibration was evaluated by Greenwood–Nam–D’Agostino tests and discrimination was evaluated by C-statistics. Of the 456 participants with T2DM (mean age 65 years, mean diabetes duration 8 years, 56% male), over the 10-year follow-up time 129 died (61 due to CV events), 64 experienced an MI, and 46 a stroke. The UKPDS-OM2 significantly over-predicted mortality and CV mortality by 25% and 28%, respectively (Greenwood–Nam–D’Agostino tests: p

Background: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes.Methods: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation–validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days.Results: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set.Conclusions: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.)

Purpose Inter-individual metabolic differences may be a reason for previously inconsistent results in diet–diabetes associations. We aimed to investigate associations between dietary intake and diabetes for metabolically homogeneous subgroups (‘metabotypes’) in a large cross-sectional study. Methods We used data of 1517 adults aged 38–87 years from the German population-based KORA FF4 study (2013/2014). Dietary intake was estimated based on the combination of a food frequency questionnaire and multiple 24-h food lists. Glucose tolerance status was classified based on an oral glucose tolerance test in participants without a previous diabetes diagnosis using American Diabetes Association criteria. Logistic regression was applied to examine the associations between dietary intake and diabetes for two distinct metabotypes, which were identified based on 16 biochemical and anthropometric parameters. Results A low intake of fruits and a high intake of total meat, processed meat and sugar-sweetened beverages (SSB) were significantly associated with diabetes in the total study population. Stratified by metabotype, associations with diabetes remained significant for intake of total meat (OR 1.67, 95% CI 1.04–2.67) and processed meat (OR 2.23, 95% CI 1.24–4.04) in the metabotypes with rather favorable metabolic characteristics, and for intake of fruits (OR 0.83, 95% CI 0.68–0.99) and SSB (OR:1.21, 95% CI 1.09–1.35) in the more unfavorable metabotype. However, only the association between SSB intake and diabetes differed significantly by metabotype (p value for interaction = 0.01). Conclusions Our findings suggest an influence of metabolic characteristics on diet–diabetes associations, which may help to explain inconsistent previous results. The causality of the observed associations needs to be confirmed in prospective and intervention studies. Electronic supplementary material The online version of this article (10.1007/s00394-019-01988-5) contains supplementary material, which is available to authorized users.

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01–1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02–1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82–1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00–1.42]; third quartile: 1.35 [1.14–1.59]; fourth quartile: 1.38 [1.07–1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Objectives: An inverse relationship between education and cardiovascular risk has been described, however, the combined association of education, income, and neighborhood socioeconomic status with macrovascular disease is less clear. The aim of this study was to evaluate the association of educational level, equivalent household income and area deprivation with macrovascular disease in Germany.Methods: Cross-sectional data from two representative German population-based studies, SHIP-TREND (n = 3,731) and KORA-F4 (n = 2,870), were analyzed. Multivariable logistic regression models were applied to estimate odds ratios and 95% confidence intervals for the association between socioeconomic determinants and macrovascular disease (defined as self-reported myocardial infarction or stroke).Results: The study showed a higher odds of prevalent macrovascular disease in men with low and middle educational level compared to men with high education. Area deprivation and equivalent income were not related to myocardial infarction or stroke in any of the models.Conclusion: Educational level, but not income or area deprivation, is significantly related to the macrovascular disease in men. Effective prevention of macrovascular disease should therefore start with investing in individual education.

Upon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to increased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI. Supplementary Information The online version contains supplementary material available at 10.1007/s00395-021-00864-w.

Subclinical effects of coffee consumption (CC) with regard to metabolic, cardiac, and neurological complications were evaluated using a whole-body magnetic resonance imaging (MRI) protocol. A blended approach was used to estimate habitual CC in a population-based study cohort without a history of cardiovascular disease. Associations of CC with MRI markers of gray matter volume, white matter hyperintensities, cerebral microhemorrhages, total and visceral adipose tissue (VAT), hepatic proton density fat fraction, early/late diastolic filling rate, end-diastolic/-systolic and stroke volume, ejection fraction, peak ejection rate, and myocardial mass were evaluated by linear regression. In our analysis with 132 women and 168 men, CC was positively associated with MR-based cardiac function parameters including late diastolic filling rate, stroke volume (p &lt, 0.01 each), and ejection fraction (p &lt, 0.05) when adjusting for age, sex, smoking, hypertension, diabetes, Low-density lipoprotein (LDL), triglycerides, cholesterol, and alcohol consumption. CC was inversely associated with VAT independent of demographic variables and cardiovascular risk factors (p &lt, 0.05), but this association did not remain significant after additional adjustment for alcohol consumption. CC was not significantly associated with potential neurodegeneration. We found a significant positive and independent association between CC and MRI-based systolic and diastolic cardiac function. CC was also inversely associated with VAT but not independent of alcohol consumption.

ObjectiveTo determine the association between circulating interleukin-6 (IL-6) levels and risk of incident ischemic stroke in the general population.MethodsFollowing the PRISMA guidelines, we systematically searched the literature for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effect meta-analyses and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS).ResultsWe identified 11 studies (n=27,411 individuals; 2,669 incident stroke cases) meeting our eligibility criteria. Overall, quality of the included studies was high (median 8 out of 9 NOS points). In meta-analyses, 1-standard deviation increment in circulating IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.ConclusionsHigher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

Prior studies examined association between short-term mortality and certain changes in the admission ECG in acute myocardial infarction (AMI). Nevertheless, little is known about possible differences between patients with diabetes and without diabetes in this regard. So the aim of the study was to investigate the association between 28-day case fatality according to certain ECG changes comparing AMI cases with and without diabetes from the general population. From 2000 until 2017 a total of 9756 AMI cases was prospectively recorded in the study Area of Augsburg, Germany. Each case was assigned to one of the following groups according to admission ECG: ‘ST-elevation’, ‘ST-depression’, ‘only T-negativity’, ‘predominantly bundle branch block’, ‘unspecific changes’ and ‘normal ECG’ (the last two were put together for regression analyses). Multivariable adjusted logistic regression models were calculated to compare 28-day case-fatality between the ECG groups for the total sample and separately for diabetes and non-diabetes cases. For the non-diabetes group, the parsimonious logistic regression model revealed significantly better 28-day-outcome for the ‘normal ECG / unspecific changes’ group (OR: 0.47 [0.29–0.76]) compared to the reference group (STEMI). Contrary, in AMI cases with diabetes the category ‘normal ECG / unspecific changes’ was not significantly associated with lower short-term mortality (OR: 0.87 [0.49–1.54]). Neither of the other ECG groups was significantly associated with 28-day-mortality in the parsimonious logistic regression models. Consequently, the absence of AMI-typical changes in the admission ECG predicts favorable short-term mortality only in non-diabetic cases, but not so in patients with diabetes.

Aim. Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and Results. We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs – leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions. Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. Translational perspectives. Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.