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Abstract Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

Abstract Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82–0.84) and a balanced accuracy of 0.78 (95% CI 0.77–0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40–0.74). Quantitative PCR validated LEF1-AS1’s adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management.

Abstract Background Low relative fat free mass (FFM) is associated with a greater risk of chronic diseases and mortality. Unfortunately, FFM is currently not being measured regularly to allow for individuals therapy. Objective One reason why FFM is not being used may be related to additional equipment and resources, thus we aimed to identify easily accessible anthropometric markers related with FFM. Materials and methods We analyzed data of 1,593 individuals (784 women; 49.2%, age range 28–88 years) enrolled in the population-based Study of Health in Pomerania (SHIP-TREND 1). Forty-seven anthropometric markers were derived from a 3D optical body-scanner. FFM was assessed by bioelectrical impedance analysis (FFMBIA) or air displacement plethysmography (FFMADP). In sex-stratified linear regression models, FFM was regressed on anthropometric measurements adjusted for body height and age. Anthropometric markers were ranked according to the coefficient of determination (R2) derived from these regression models. Results Circumferences of high hip, belly, middle hip, waist and high waist showed the strongest inverse associations with FFM. These relations were stronger in females than in males. Associations of anthropometric markers with FFMAPD were greater compared to FFMBIA. Conclusion Anthropometric measures were more strongly associated with FFMADP compared to FFMBIA. Anthropometric markers like circumferences of the high or middle hip, belly or waist may be appropriate surrogates for FFM to aid in individualized therapy. Given that the identified markers are representative of visceral adipose tissue, the connection between whole body strength as surrogate for FFM and fat mass should be explored in more detail.

Abstract Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

Abstract Background To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen. Study design This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed. Statistical analysis plan N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0–10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients’ global assessment of treatment success are secondary outcomes. Discussion The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals. Trial registration ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered).

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

Abstract Recently, the parameter internal work (IW) has been introduced as change in oxygen uptake (VO2) between resting and unloading workload in cardiopulmonary exercise testing (CPET). The proportional IW (PIW) was defined as IW divided by VO2 at peak exercise. A second option is to calculate the PIW based on the workload [PIW (Watt)] by considering the aerobic efficiency. The aim of our study was to investigate whether IW and PIW differ between patients with and without pulmonary hypertension and healthy controls. Our study population consisted of 580 patients and 354 healthy controls derived from the Study of Health in Pomerania. The PIW was slightly lower in patients (14.2%) than in healthy controls (14.9%; p = 0.030), but the PIW (Watt) was higher in patients (18.0%) than in the healthy controls (15.9%; p = 0.001). Such a difference was also observed, when considering only the submaximal workload up to the VAT (19.8% in patients and 15.1% in healthy controls; p

Abstract Background Recent studies have highlighted the role of low-grade systemic inflammation in linking periodontitis to cardiovascular disease (CVD) outcomes, but many aspects remain unclear. This study examines the independent and reciprocal associations of periodontitis and low-grade systemic inflammation with all-cause and CVD mortality in a large-scale cohort. Methods A total of 3047 participants from the prospective, population-based Study of Health in Pomerania (SHIP-START) were followed for a period of 13.0 ± 2.4 years. For the association between various inflammation/periodontitis measures and mortality, hazard ratios (HRs) were obtained from covariate-adjusted Cox proportional hazards models. Interactions were analysed in joint models: on the multiplicative scale, HRs were reported and on the additive scale, relative excess risks due to interaction (RERI) were calculated. Subject and variable-specific interval records were used to account for time-varying exposures and covariates. Results During the observation period, 380 (12.5%) individuals died from CVD (n = 125) or other causes (n = 255). All markers of periodontitis and inflammation showed apparent associations with all-cause mortality (HRs per SD-increase: mean PPD: 1.068 (95% confidence interval (CI): 0.988–1.155), mean CAL: 1.205 (95% CI: 1.097–1.323), missing teeth: 1.180 (95% CI: 1.065–1.307), periodontitis score: 1.394 (95% CI: 1.202–1.616), leukocytes: 1.264 (95% CI: 1.163–1.374), fibrinogen: 1.120 (95% CI: 1.030–1.218), CRP: 1.231 (95% CI: 1.109–1.366), inflammation score: 1.358 (95% CI: 1.210–1.523)). For CVD mortality, all PPD related variables showed significant associations. Interaction modelling revealed some variation with respect to mortality type and exposure combinations. On the additive scale, RERIs for periodontitis score and inflammation score implied 18.9% and 27.8% excess mortality risk for all-cause and CVD mortality, respectively. On the multiplicative scale, the HRs for interaction were marginal. Conclusions Both periodontitis and inflammation were significantly associated with all-cause mortality and CVD mortality. On the additive scale, a substantial excess risk was observed due to the interaction of periodontitis and inflammation, suggesting that the greatest treatment benefit may be achieved in patients with both periodontitis and high systemic inflammation. As periodontal therapy has been reported to also reduce systemic inflammation, the possibility of a reduction in CVD mortality risk by anti-inflammatory treatments, including periodontal interventions, seems worthy of further investigation.

Abstract Telemedicine has been shown to improve the outcome of heart failure (HF) patients in addition to medical and device therapy. We investigate the effectiveness of a comprehensive telehealth programme in patients with recent hospitalisation for HF on subsequent HF hospitalisations and mortality compared to usual care in a real-world setting. The telehealth programme consists of daily remote telemonitoring of HF signs/symptoms and regular individualised telecoaching sessions. Between January 2018 and September 2020, 119,715 patients of a German health insurer were hospitalised for HF and were eligible for participation in the programme. Finally, 6065 HF patients at high risk for re-hospitalisation were enroled. Participants were retrospectively compared to a propensity score matched usual care group (n = 6065). Median follow-up was 442 days (IQR 309–681). Data from the health insurer was used to evaluate outcomes. After one year, the number of hospitalisations for HF (17.9 vs. 21.8 per 100 patient years, p

Abstract Background Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen. Methods This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients’ global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed. Discussion This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care. Trial registration ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680

Background: The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population. Materials & methods: Cross-sectional data from 1,106 individuals aged 30–90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers. Results: Spleen volume was positively associated with RBC (β = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin (β = 0.05; 95% CI = 0.01 to 0.09) but inversely with platelet count (β = −16.3; 95% CI = –20.5 to −12.1) and WBC (β = −0.25; 95% CI = −0.37 to −0.14). Furthermore, spleen volume showed inverse associations with total cholesterol (β = −0.17; 95% CI = −0.24 to −0.09), HDL-C (β = −0.08; 95% CI = −0.10 to −0.05), and LDL-C (β = −0.12; 95% CI = −0.17 to −0.06). There was no significant association of spleen volume with triglycerides. Conclusion: Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population.

Abstract Arterial hypertension is considered a risk factor for the development of heart failure. Here we investigate cross-sectional associations of systolic and diastolic blood pressure with subtle functional and morphological changes of left ventricular echocardiographic parameters representing early dysfunction in three representative German population-based studies. We assessed 26,719 individuals without symptomatic heart failure from the Hamburg City Health Study (HCHS, n = 7396, derivation cohort), the Gutenberg Health Study (GHS, 14,715, validation cohort) and the Study of Health in Pomerania (SHIP, 4608, validation cohort). Multivariable linear regression analyses with systolic and diastolic blood pressure as continuous exposure variables were adjusted for common cardiovascular risk factors and antihypertensive medication. Both systolic and diastolic blood pressure were consistently associated with measures of left ventricular hypertrophy (β per standard deviation (SD) for LV mass (g) and systolic blood pressure: 5.09 (p

Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Abstract Background and aims Prevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters. Methods We utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models. Results APRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile. Conclusion Our findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.

Dilated cardiomyopathy (DCM) is characterized by reduced left ventricular ejection fraction (LVEF) and left or biventricular dilatation. We evaluated sex-specific associations of circulating proteins and metabolites with structural and functional heart parameters in DCM. Plasma samples (297 men, 71 women) were analyzed for proteins using Olink assays (targeted analysis) or LC-MS/MS (untargeted analysis), and for metabolites using LC MS/MS (Biocrates AbsoluteIDQ p180 Kit). Associations of proteins (n = 571) or metabolites (n = 163) with LVEF, measured left ventricular end diastolic diameter (LVEDDmeasured), and the dilation percentage of LVEDD from the norm (LVEDDacc. to HENRY) were examined in combined and sex-specific regression models. To disclose protein–metabolite relations, correlation analyses were performed. Associations between proteins, metabolites and LVEF were restricted to men, while associations with LVEDD were absent in both sexes. Significant metabolites were validated in a second independent DCM cohort (93 men). Integrative analyses demonstrated close relations between altered proteins and metabolites involved in lipid metabolism, inflammation, and endothelial dysfunction with declining LVEF, with kynurenine as the most prominent finding. In DCM, the loss of cardiac function was reflected by circulating proteins and metabolites with sex-specific differences. Our integrative approach demonstrated that concurrently assessing specific proteins and metabolites might help us to gain insights into the alterations associated with DCM.

Abstract Background Metabolic Syndrome (MetS) is characterized by risk factors such as abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, and hyperglycemia, which contribute to the development of cardiovascular disease and type 2 diabetes. Here, we aim to identify candidate metabolite biomarkers of MetS and its associated risk factors to better understand the complex interplay of underlying signaling pathways. Methods We quantified serum samples of the KORA F4 study participants (N = 2815) and analyzed 121 metabolites. Multiple regression models adjusted for clinical and lifestyle covariates were used to identify metabolites that were Bonferroni significantly associated with MetS. These findings were replicated in the SHIP-TREND-0 study (N = 988) and further analyzed for the association of replicated metabolites with the five components of MetS. Database-driven networks of the identified metabolites and their interacting enzymes were also constructed. Results We identified and replicated 56 MetS-specific metabolites: 13 were positively associated (e.g., Val, Leu/Ile, Phe, and Tyr), and 43 were negatively associated (e.g., Gly, Ser, and 40 lipids). Moreover, the majority (89%) and minority (23%) of MetS-specific metabolites were associated with low HDL-C and hypertension, respectively. One lipid, lysoPC a C18:2, was negatively associated with MetS and all of its five components, indicating that individuals with MetS and each of the risk factors had lower concentrations of lysoPC a C18:2 compared to corresponding controls. Our metabolic networks elucidated these observations by revealing impaired catabolism of branched-chain and aromatic amino acids, as well as accelerated Gly catabolism. Conclusion Our identified candidate metabolite biomarkers are associated with the pathophysiology of MetS and its risk factors. They could facilitate the development of therapeutic strategies to prevent type 2 diabetes and cardiovascular disease. For instance, elevated levels of lysoPC a C18:2 may protect MetS and its five risk components. More in-depth studies are necessary to determine the mechanism of key metabolites in the MetS pathophysiology.

Abstract Background Multimedia multi-device measurement platforms may make the assessment of prevention-related medical variables with a focus on cardiovascular outcomes more attractive and time-efficient. The aim of the studies was to evaluate the reliability (Study 1) and the measurement agreement with a cohort study (Study 2) of selected measures of such a device, the Preventiometer. Methods In Study 1 (N = 75), we conducted repeated measurements in two Preventiometers for four examinations (blood pressure measurement, pulse oximetry, body fat measurement, and spirometry) to analyze their agreement and derive (retest-)reliability estimates. In Study 2 (N = 150), we compared somatometry, blood pressure, pulse oximetry, body fat, and spirometry measurements in the Preventiometer with corresponding measurements used in the population-based Study of Health in Pomerania (SHIP) to evaluate measurement agreement. Results Intraclass correlations coefficients (ICCs) ranged from .84 to .99 for all examinations in Study 1. Whereas bias was not an issue for most examinations in Study 2, limits of agreement for most examinations were very large compared to results of similar method comparison studies. Conclusion We observed a high retest-reliability of the assessed clinical examinations in the Preventiometer. Some disagreements between Preventiometer and SHIP examinations can be attributed to procedural differences in the examinations. Methodological and technical improvements are recommended before using the Preventiometer in population-based research.

Abstract Homoarginine (hArg) is a non-essential cationic amino acid which inhibits hepatic alkaline phosphatases to exert inhibitory effects on bile secretion by targeting intrahepatic biliary epithelium. We analyzed (1) the relationship between hArg and liver biomarkers in two large population-based studies and (2) the impact of hArg supplementation on liver biomarkers. We assessed the relationship between alanine transaminase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatases (AP), albumin, total bilirubin, cholinesterase, Quick’s value, liver fat, and Model for End-stage Liver Disease (MELD) and hArg in appropriately adjusted linear regression models. We analyzed the effect of L-hArg supplemention (125 mg L-hArg daily for 4 weeks) on these liver biomarkers. We included 7638 individuals (men: 3705; premenopausal women: 1866, postmenopausal women: 2067). We found positive associations for hArg and ALT (β 0.38 µkatal/L 95% confidence interval (CI): 0.29; 0.48), AST (β 0.29 µkatal/L 95% CI 0.17; 0.41), GGT (β 0.033 µkatal/L 95% CI 0.014; 0.053), Fib-4 score (β 0.08 95% CI 0.03; 0.13), liver fat content (β 0.016% 95% CI 0.006; 0.026), albumin (β 0.030 g/L 95% CI 0.019; 0.040), and cholinesterase (β 0.003 µkatal/L 95% CI 0.002; 0.004) in males. In premenopausal women hArg was positively related with liver fat content (β 0.047% 95%CI 0.013; 0.080) and inversely with albumin (β − 0.057 g/L 95% CI − 0.073; − 0.041). In postmenopausal women hARG was positively associated with AST (β 0.26 µkatal/L 95% CI 0.11; 0.42). hArg supplementation did not affect liver biomarkers. We summarize that hArg may be a marker of liver dysfunction and should be explored further.

Abstract Background Long periods of uninterrupted sitting, i.e., sedentary bouts, and their relationship with adverse health outcomes have moved into focus of public health recommendations. However, evidence on associations between sedentary bouts and adiposity markers is limited. Our aim was to investigate associations of the daily number of sedentary bouts with waist circumference (WC) and body mass index (BMI) in a sample of middle-aged to older adults. Methods In this cross-sectional study, data were collected from three different studies that took place in the area of Greifswald, Northern Germany, between 2012 and 2018. In total, 460 adults from the general population aged 40 to 75 years and without known cardiovascular disease wore tri-axial accelerometers (ActiGraph Model GT3X+, Pensacola, FL) on the hip for seven consecutive days. A wear time of ≥ 10 h on ≥ 4 days was required for analyses. WC (cm) and BMI (kg m− 2) were measured in a standardized way. Separate multilevel mixed-effects linear regression analyses were used to investigate associations of sedentary bouts (1 to 10 min, >10 to 30 min, and >30 min) with WC and BMI. Models were adjusted for potential confounders including sex, age, school education, employment, current smoking, season of data collection, and composition of accelerometer-based time use. Results Participants (66% females) were on average 57.1 (standard deviation, SD 8.5) years old and 36% had a school education >10 years. The mean number of sedentary bouts per day was 95.1 (SD 25.0) for 1-to-10-minute bouts, 13.3 (SD 3.4) for >10-to-30-minute bouts and 3.5 (SD 1.9) for >30-minute bouts. Mean WC was 91.1 cm (SD 12.3) and mean BMI was 26.9 kg m− 2 (SD 3.8). The daily number of 1-to-10-minute bouts was inversely associated with BMI (b = -0.027; p = 0.047) and the daily number of >30-minute bouts was positively associated with WC (b = 0.330; p = 0.001). All other associations were not statistically significant. Conclusion The findings provide some evidence on favourable associations of short sedentary bouts as well as unfavourable associations of long sedentary bouts with adiposity markers. Our results may contribute to a growing body of literature that can help to define public health recommendations for interrupting prolonged sedentary periods. Trial registration Study 1: German Clinical Trials Register (DRKS00010996); study 2: ClinicalTrials.gov (NCT02990039); study 3: ClinicalTrials.gov (NCT03539237).

Objective: Thyroid dysfunction is associated with relevant disturbances in glucose metabolism. Moreover, thyroid function undergoes important changes with ageing. The objective of this study was to investigate the association of thyroid function with insulin resistance with particular consideration of possible age-related effect modifications. Design: A sample of 4193 participants from two independent epidemiological studies, the Study of Health in Pomerania-TREND-0 and the Berlin Aging Study II, was included in this cross-sectional analysis. Methods: Insulin resistance was estimated by homeostasis model of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI). Associations of thyroid biomarkers (thyroid-stimulating hormone, free thyroxine, and free triiodothyronine (fT3)) with parameters of glucose metabolism were analysed by regression models adjusted for age, sex, smoking status, and study site. Results: A higher fT3 was significantly associated with higher fasting g lucose and higher fasting and 2-h postload insulin levels, a higher HOMA-IR, and lower ISI. A higher fT3 was also associated with a higher risk for impaired fasting glucose (RR 1.09, 95 CI 1.02; 1.18; P = 0.017). Many of these associations between thyroid markers and parameters of glucose metabolism were significant in young and middle-aged participants but not in older individuals. Conclusions: The main finding of this study was a consistent association of fT3 with almost all markers of insulin resistance. However, this effect s eems to be wearing off in higher age highlighting a potential age-related modification of the interaction between thyroid function and glucose metabolism. Further studies are needed to clarify causal relationships.

Life-threatening toxic shock syndrome is often caused by the superantigen toxic shock syndrome toxin-1 (TSST-1) produced by Staphylococcus aureus. A well-known risk factor is the lack of neutralizing antibodies. To identify determinants of the anti-TSST-1 antibody response, we examined 976 participants of the German population-based epidemiological Study of Health in Pomerania (SHIP-TREND-0). We measured anti-TSST-1 antibody levels, analyzed the colonization with TSST-1-encoding S. aureus strains, and performed a genome-wide association analysis of genetic risk factors. TSST-1-specific serum IgG levels varied over a range of 4.2 logs and were elevated by a factor of 12.3 upon nasal colonization with TSST-1-encoding S. aureus. Moreover, the anti-TSST-1 antibody levels were strongly associated with HLA class II gene loci. HLA-DRB1*03:01 and HLA-DQB1*02:01 were positively, and HLA-DRB1*01:01 as well as HLA-DQB1*05:01 negatively associated with the anti-TSST-1 antibody levels. Thus, both toxin exposure and HLA alleles affect the human antibody response to TSST-1.

BackgroundThe COVID-19 pandemic has spurred large-scale, interinstitutional research efforts. To enable these efforts, researchers must agree on data set definitions that not only cover all elements relevant to the respective medical specialty but also are syntactically and semantically interoperable. Therefore, the German Corona Consensus (GECCO) data set was developed as a harmonized, interoperable collection of the most relevant data elements for COVID-19–related patient research. As the GECCO data set is a compact core data set comprising data across all medical fields, the focused research within particular medical domains demands the definition of extension modules that include data elements that are the most relevant to the research performed in those individual medical specialties. ObjectiveWe aimed to (1) specify a workflow for the development of interoperable data set definitions that involves close collaboration between medical experts and information scientists and (2) apply the workflow to develop data set definitions that include data elements that are the most relevant to COVID-19–related patient research regarding immunization, pediatrics, and cardiology. MethodsWe developed a workflow to create data set definitions that were (1) content-wise as relevant as possible to a specific field of study and (2) universally usable across computer systems, institutions, and countries (ie, interoperable). We then gathered medical experts from 3 specialties—infectious diseases (with a focus on immunization), pediatrics, and cardiology—to select data elements that were the most relevant to COVID-19–related patient research in the respective specialty. We mapped the data elements to international standardized vocabularies and created data exchange specifications, using Health Level Seven International (HL7) Fast Healthcare Interoperability Resources (FHIR). All steps were performed in close interdisciplinary collaboration with medical domain experts and medical information specialists. Profiles and vocabulary mappings were syntactically and semantically validated in a 2-stage process. ResultsWe created GECCO extension modules for the immunization, pediatrics, and cardiology domains according to pandemic-related requests. The data elements included in each module were selected, according to the developed consensus-based workflow, by medical experts from these specialties to ensure that the contents aligned with their research needs. We defined data set specifications for 48 immunization, 150 pediatrics, and 52 cardiology data elements that complement the GECCO core data set. We created and published implementation guides, example implementations, and data set annotations for each extension module. ConclusionsThe GECCO extension modules, which contain data elements that are the most relevant to COVID-19–related patient research on infectious diseases (with a focus on immunization), pediatrics, and cardiology, were defined in an interdisciplinary, iterative, consensus-based workflow that may serve as a blueprint for developing further data set definitions. The GECCO extension modules provide standardized and harmonized definitions of specialty-related data sets that can help enable interinstitutional and cross-country COVID-19 research in these specialties.

Abstract Aims Low cardiorespiratory fitness (CRF) is associated with greater mortality and morbidity. Galectin‐3 (Gal‐3) is a prognostic biomarker for fibrosis and heart failure. Gal‐3 is also associated with a greater risk for cardiovascular mortality. Whether CRF is related with Gal‐3 is unclear. The objective of this study was to assess the sex‐specific associations of CRF and Gal‐3 levels in the general population. Methods Gal‐3 concentrations were determined using a sandwich enzyme immunoassay in the population‐based Study of Health in Pomerania (SHIP‐TREND‐0). Sex‐stratified linear regression models adjusted for age, current smoking status, and renal function were used. Individuals with left ventricular ejection fraction (LVEF) 99th percentile) were excluded. Results A total of n = 1515 participants with a median age of 49 (IQR: 39–60 years, 48% males) were included. In men, a 1 L/min greater VO2peak was significantly related to 0.50 ng/mL (95% CI −0.8068 to −0.1938, P

Objective: Aging, physical inactivity, and chronic disease can decrease strength and muscle mass and affect mobility and autonomy in older adults. This study aimed to analyze the prevalence and associated factors of low physical functional performance among older adults in the city of Pomerode, in southern Brazil. Methods: This is a cross-sectional population-based study with data on 733 older adults from the Study of Health in Pomerode – SHIP-Brazil. Low functional physical performance was defined as handgrip strength ≤ 32 kg for men or ≤ 20 kg for women and/or a Timed Up and Go test ≥ 11 seconds for men or ≥ 13 seconds for women. Associations were analysed by multiple logistic regression. Results: The prevalence of low physical functional performance was 43.7% (42.2% among women and 45.5% among men). Low physical functional performance was associated with the 70-79 years age group (odds ratio [OR] = 2.07) and insufficient physical activity (OR = 2.73) in men, and with the 70-79 years age group (OR = 2.09) and multimorbidity (OR = 1.87) in women. In general, older age, insufficient physical activity, and multimorbidity were associated with low physical functional performance in older adults. Conclusion: Our findings suggest that while insufficient physical activity is crucial for physical functional performance in older men, multimorbidity appears to be crucial for older women.

Abstract The assessment of cardiorespiratory fitness (CRF) is an important tool for prognosis evaluation of cardiovascular events. The gold standard to measure CRF is cardiopulmonary exercise testing (CPET) to determine peak oxygen uptake (VO2peak). However, CPET is not only time consuming but also expensive and is therefore not widely applicable in daily practice. The aim of our study was to analyze, whether and which anthropometric markers derived from a 3D body scanner were related to VO2peak in a general population-based study. We analyzed data (SHIP-START-3) from 3D body scanner and CPET of 1035 subjects (529 women; 51.1%, age range 36–93). A total of 164 anthropometric markers were detected with the 3D body scanner VITUS Smart XXL using the software AnthroScan Professional. Anthropometric measurements were standardized and associated with CRF by sex-stratified linear regression models adjusted for age and height. Anthropometric markers were ranked according to the − log- p values derived from these regression models. In men a greater left and right thigh-knee-ratio, a longer forearm-fingertip length, a greater left thigh circumference and greater left upper arm circumference were most strongly associated with a higher VO2peak. In women a greater left and right thigh circumference, left calf circumference, thigh thickness and right calf circumference were most strongly associated with a higher VO2peak. The detected VO2peak-related anthropometric markers could be helpful in assessing CRF in clinical routine. Commonly used anthropometric markers, e.g. waist and hip circumference, were not among the markers associated with VO2peak.

Abstract This is the first study to analyze the association of accelerometer-measured patterns of habitual physical activity (PA) and sedentary behavior (SB) with serum BDNF in individuals with coronary heart disease. A total of 30 individuals (M = 69.5 years; 80% men) participated in this pre-post study that aimed to test a multi-behavioral intervention. All participants underwent standardized measurement of anthropometric variables, blood collection, self-administered survey, and accelerometer-based measurement of PA and SB over seven days. Serum BDNF concentrations were measured using enzyme-linked immunosorbent assay kit. We applied separate multiple linear regression analysis to estimate the associations of baseline SB pattern measures, light and moderate-to-vigorous PA with serum BDNF (n = 29). Participants spent 508.7 ± 76.5 min/d in SB, 258.5 ± 71.2 min/d in light PA, and 21.2 ± 15.2 min/d in moderate-to-vigorous PA. Per day, individuals had 15.5 ± 3.2 numbers of 10-to-30 min bouts of SB (average length: 22.2 ± 2.1 min) and 3.4 ± 1.2 numbers of > 30 min bouts of SB (average length: 43.8 ± 2.4 min). Regression analysis revealed no significant associations between any of the accelerometer-based measures and serum BDNF. The findings of this study did not reveal an association of accelerometer-measured PA and SB pattern variables with serum BDNF in individuals with coronary heart disease. In addition, our data revealed a considerable variation of PA and SB which should be considered in future studies.

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.

Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.

IntroductionHeart rate variability (HRV), defined as the variability of consecutive heart beats, is an important biomarker for dysregulations of the autonomic nervous system (ANS) and is associated with the development, course, and outcome of a variety of mental and physical health problems. While guidelines recommend using 5 min electrocardiograms (ECG), recent studies showed that 10 s might be sufficient for deriving vagal-mediated HRV. However, the validity and applicability of this approach for risk prediction in epidemiological studies is currently unclear to be used.MethodsThis study evaluates vagal-mediated HRV with ultra-short HRV (usHRV) based on 10 s multichannel ECG recordings of N = 4,245 and N = 2,392 participants of the Study of Health in Pomerania (SHIP) from two waves of the SHIP-TREND cohort, additionally divided into a healthy and health-impaired subgroup. Association of usHRV with HRV derived from long-term ECG recordings (polysomnography: 5 min before falling asleep [N = 1,041]; orthostatic testing: 5 min of rest before probing an orthostatic reaction [N = 1,676]) and their validity with respect to demographic variables and depressive symptoms were investigated.ResultsHigh correlations (r = .52–.75) were revealed between usHRV and HRV. While controlling for covariates, usHRV was the strongest predictor for HRV. Furthermore, the associations of usHRV and HRV with age, sex, obesity, and depressive symptoms were similar.ConclusionThis study provides evidence that usHRV derived from 10 s ECG might function as a proxy of vagal-mediated HRV with similar characteristics. This allows the investigation of ANS dysregulation with ECGs that are routinely performed in epidemiological studies to identify protective and risk factors for various mental and physical health problems.

The amino acids arginine (Arg), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are related to nitric oxide (NO) metabolism and potential markers of two different disease entities: cardiovascular disease such as atherosclerosis and systemic inflammation in critically ill patients with sepsis. Although very different in their pathophysiological genesis, both entities involve the functional integrity of blood vessels. In this context, large population-based data associating NO metabolites with proinflammatory markers, e.g., white blood cell count (WBC), high-sensitivity C-reactive protein (hsCRP), and fibrinogen, or cytokines are sparse. We investigated the association of Arg, ADMA and SDMA with WBC, hsCRP, and fibrinogen in 3556 participants of the Study of Health in Pomerania (SHIP)-TREND study. Furthermore, in a subcohort of 456 subjects, 31 inflammatory markers and cytokines were analyzed. We identified Arg and SDMA to be positively associated with hsCRP (β coefficient 0.010, standard error (SE) 0.002 and 0.298, 0.137, respectively) as well as fibrinogen (β 5.23 × 10−3, SE 4.75 × 10−4 and 0.083, 0.031, respectively). ADMA was not associated with WBC, hsCRP, or fibrinogen. Furthermore, in the subcohort, Arg was inversely related to a proliferation-inducing ligand (APRIL). SDMA was positively associated with osteocalcin, tumor necrosis factor receptor 1 and 2, and soluble cluster of differentiation 30. Our findings provide new insights into the involvement of Arg, ADMA, and SDMA in subclinical inflammation in the general population.

Abstract Aims Available upper reference levels (URLs) in older adults for N‐terminal pro brain natriuretic peptide (NT‐proBNP), an established biomarker for heart failure, are mainly based on small samples. We aimed to identify NT‐proBNP URL in a population‐based reference sample of individuals aged ≥65 years. Methods and results We analysed established NT‐proBNP predictors using quantile regression among 2459 participants of two‐independent population‐based cohorts located in Germany, the Activity and Function in the Elderly Study (ActiFE, n = 1450) and the Study of Health in Pomerania (SHIP‐TREND‐0, n = 1009). Based on predictors a reference population of 441 subjects (ActiFE, n = 227; SHIP‐TREND‐0, n = 214) without history of diabetes, cardiovascular, or pulmonary diseases and with systolic blood pressure (BP) 125 ng/L in 165 participants (37.4%), with NT‐proBNP URL (97.5% quantiles) equal to 663, 824, 592, and 697 ng/L in men, and 343, 463, 2641, 1276 ng/L in women for ages 65–69, 70–74, 75–79, and 80+ years, respectively. In the secondary analysis with a LVEF ≥50 and no diastolic dysfunction (35 men and 62 women) NT‐proBNP levels >125 ng/L were still observed in 38 (39.2%) participants. Conclusions This reference sample of apparently healthy asymptomatic older adults showed an age‐related increment of NT‐proBNP levels with URL markedly higher than the European Society of Cardiology recommended cut‐off of 125 ng/L for the diagnosis of heart failure in ambulatory settings. Identifying URL in those ≥80 years remains complex. Our results attempt to provide a frame for the further investigation of age‐specific NT‐proBNP cut‐offs in older adults. Considering the demographic changes, further evaluation of NT‐proBNP URL in larger samples of older adults followed by the validation of age‐specific cut‐off values for the identification of heart failure in those 65 years or older are urgently needed.

Introduction Antares is a pulse wave analysis (PWA) algorithm designed to allow a non-invasive estimation of central (aortic) blood pressure (cBP) using automated oscillometric blood pressure (BP) devices. Diabetes may affect elastic and muscular arteries differently, resulting in disparate pulse wave characteristics in central and peripheral arteries, which may limit the accuracy of PWA devices. The aim of our study was to evaluate the accuracy of Antares for estimating cBP as compared with invasively measured cBP in patients with type 2 diabetes.Research design and methods In this study, consecutive patients undergoing elective coronary angiography were recruited between November 2017 and September 2020. In 119 patients with type 2 diabetes, cBP was measured invasively and simultaneously determined non-invasively using the custo screen 400 device with the integrated Antares algorithm.Results The mean difference between the estimated and invasively measured cBP was 1.2±6.3 mmHg for central systolic BP (cSBP), 1.0±4.3 mmHg for central mean arterial pressure (cMAP) and 3.6±5.7 mmHg for central diastolic BP (cDBP). High correlations were found between estimated cBP and invasively measured cBP (cSBP: r=0.916; cMAP: r=0.882; cDBP: r=0.791; all p

Abstract Small animal models are frequently used to improve our understanding of the molecular and biological signaling pathways underlying the beneficial effects of physical activity and exercise. Unfortunately, when running wheels are employed, mice and rats are often kept single-housed to determine the individual running distance of each animal. However, social isolation can be stressful for rodents, and may alter an individual’s propensity for or response to exercise. For example, increased stress from single housing may significantly affect the results when investigating systemic metabolic responses to exercise. We have combined two already available and well-established systems, a radiotelemetry system and a running wheel, to determine spontaneous cage activity (SCA) as well as voluntary exercise (VE) levels of the individual animal in group-housed rodents. Further, we developed a simple software tool which allows monitoring and analyzing the data. Specifically, the radiotelemetry-system utilizes radio-frequency identification via a small, implanted chip to determine the location of each animal. Since, in addition to the animals’ position, also the location of the running wheel in the cage is known, the conclusion of which animal is exercising can be drawn. The developed software enables a fast and reliable assignment of the VE data to the individual animal and a simple analysis of the data collected. Hence, our combined method may be used to investigate the beneficial effects of physical activity, as well as the impact of therapeutic interventions on animal behavior in group-housed rodents.

Abstract The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20–79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: − 0.02 [95% CI − 0.04, − 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke.

Abstract Aims Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). It is known that AF impairs the diagnostic accuracy of NT‐proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT‐proBNP for HF and AF in stable outpatients with cardiovascular risk factors. Methods and results Data were obtained from the DIAST‐CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population‐based cohorts using the same inclusion/exclusion criteria: LIFE‐Adult (n = 2869), SHIP (n = 2013), and SHIP‐TREND (n = 2408). Serum levels of NT‐proBNP were taken once at baseline. The DIAST‐CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT‐proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT‐proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver‐operating characteristic curves of NT‐proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79–0.88]) and for HF with EF 50% was significantly lower (0.61 [0.56–0.65]) than for AF (P = 0.001). During follow‐up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT‐proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75–0.83]) than of newly diagnosed HF (0.59 [0.55–0.63]; P 50% is very limited.

High serum thyroid-stimulating hormone (TSH) levels have previously been associated with a low estimated glomerular filtration rate (eGFR), but studies associating thyroid hormone levels with albuminuria revealed inconsistent results. We used cross-sectional data from 7933 individuals aged 20 to 93 years of the Berlin Aging Study II and the Study of Health in Pomerania to associate serum TSH, fT3, and fT4 levels with eGFR and albuminuria. In multivariable analyses adjusted for confounding, we found inverse non-linear associations of serum TSH levels with eGFR, while serum fT3 levels showed a positive association with eGFR. High as well as low serum fT4 levels were associated with a lower eGFR. Age but not sex modified the association between thyroid hormone levels and eGFR. The inverse associations between serum TSH levels and eGFR were strongest in the youngest age groups, while the positive associations between serum fT3 levels and eGFR were strongest in older individuals. No significant associations between thyroid hormone levels and albuminuria were found. Our results indicate that hypothyroidism might be associated with a reduced kidney function. Thyroid function might be more tightly related to the eGFR than to albuminuria in the general population.

Abstract Aims We assessed the outcome of hospitalized coronavirus disease 2019 (COVID‐19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. Methods and results International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID‐19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF‐COVICAV). The primary endpoint was in‐hospital mortality. Of 1974 patients hospitalized with COVID‐19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62–81] years, 58% male), with HF being present in 256 [20%] patients. Overall in‐hospital mortality was 25% (n = 323/1282 deaths). In‐hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non‐HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44–2.59], P

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Abstract 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

Abstract Aims Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences. Methods and results We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF‐related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF‐related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; −29%), while the total number of HF‐related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in‐hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population). Conclusions Heart failure remains the most common cause of hospitalization and in‐hospital death throughout Germany. The increase in HF‐related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures.

Abstract 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

Post-COVID-19 syndrome (PCS) has been described as ‘the pandemic after the pandemic’ with more than 65 million people worldwide being affected. The enormous range of symptoms makes both diagnosis complex and treatment difficult. In a post-COVID rehabilitation outpatient clinic, 184 patients, mostly non-hospitalized, received a comprehensive, interdisciplinary diagnostic assessment with fixed follow-up appointments. At baseline, three in four patients reported more than 10 symptoms, the most frequent symptoms were fatigue (84.9%), decreased physical capacity (83.0%), tiredness (81.1%), poor concentration (73.6%), sleeping problems (66.7%) and shortness of breath (67.3%). Abnormalities were found in the mean values of scores for fatigue (FAS = 34.3), cognition (MoCA = 25.5), psychological alterations (anxiety, depression, post-traumatic stress disorder), limitation of lung function (CAT) and severity scores for PCS (PCFS, MCRS). Clinical abnormalities were found in elevated values of heart rate, breathing rate at rest, blood pressure and NT-proBNP levels. As the frequency of the described symptoms decreases only slowly but most often significantly over the course, it is important to monitor the patients over a longer period of time. Many of them suffer from an immense symptom burden, often without pre-existing clinical correlates. Our results show a clear association with objectifiable assessments and tests as well as pronounced symptoms.

Abstract The aim of our study was to investigate the association of hepatic steatosis derived from quantitative ultrasound and magnetic resonance imaging (MRI) with prediabetes in a large population-based study conducted in Northeast Germany. Hepatic steatosis was assessed through transabdominal ultrasound and quantitative MRI. For analysis we included 1622 subjects with MRI who participated in an oral glucose tolerance test and reported no known type 2 diabetes mellitus (T2DM). We classified participants as proposed by the American Diabetes Association: isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT), and undiagnosed T2DM. Regression models were adjusted for age, sex body mass index and alcohol consumption. We observed positive associations of hepatic steatosis with glycated hemoglobin, fasting glucose and insulin, 2-h glucose and insulin, as well as homeostasis model assessment-insulin resistance index. Similarly, individuals having hepatic steatosis as defined by MRI had a higher relative risk ratio (RR) to be in the prediabetes groups i-IFG (RR = 1.6; 95% confidence interval (CI) 1.2; 2.2), i-IGT (RR = 3.3, 95% CI 2.0; 5.6) and IFG + IGT (RR = 2.5, 95% CI 1.6; 3.9) or to have undiagnosed T2DM (RR = 4.8, 95% CI 2.6; 9.0). All associations were attenuated when defining hepatic steatosis by ultrasound. Hepatic steatosis is associated with prediabetes and undiagnosed T2DM in the general population. Quantitative liver MRI revealed stronger associations with prediabetes and undiagnosed T2DM compared to ultrasound, which indicates the higher sensitivity and specificity of MRI to determine hepatic steatosis.

Abstract Previous studies on the association between thyroid function and body composition are conflicting and showed strong differences across age groups. Our aim was to clarify age-specific associations of serum thyroid-stimulating hormone (TSH) levels with markers of body composition including body mass index (BMI), waist circumference, fat mass (FM), fat-free mass (FFM) and body cell mass (BCM). We used data from two independent population-based cohorts within the framework of the Study of Health in Pomerania. The study population included 5656 individuals aged 20 to 90 years. Markers of body composition were measured by bioelectrical impedance analysis. Serum TSH levels were significantly positively associated with BMI (β = 0.16; 95% confidence interval [CI]: 0.06 to 0.27), waist circumference (β = 0.35; 95% CI: 0.08 to 0.62) and FM (β = 0.32; 95% CI: 0.12 to 0.52), but not with FFM and BCM. Interaction analysis revealed positive associations of serum TSH levels with BMI, waist circumference, FM, FFM and BCM in individuals older than 60 years, while no such associations were observed in younger individuals. We demonstrated that lower serum TSH levels were accompanied with lower values of BMI, waist circumference, FM, FFM, and BCM in the elderly, while no such associations were observed in younger individuals.

(1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe’s overall aim is to optimize diagnostics and therapy in PCS patients.