ABSTRACT Physical activity (PA) is key to improve the prognosis of patients with chronic coronary syndrome (CCS). This study investigated changes in movement behaviors (MB), obesity markers, cardiorespiratory fitness (VO2peak), cardiometabolic risk (CMR), and brain‐derived neurotrophic factor (BDNF) and whether changes in MB are associated with VO2peak, CMR, and BDNF from baseline to 9 months after a 12‐week exercise intervention. In total, 35 CCS patients (M = 69.5 ± 6.4 years; 82.9% men) underwent a group‐based intervention; including two 1‐h exercise sessions per week Data was collected on anthropometrics, blood samples, cardiopulmonary exercise testing, and 7‐day accelerometry at baseline, 3‐month, and 12‐month follow‐up. Absolute changes were examined using paired t‐tests. Mixed‐effects linear regression models were applied to investigate associations of MB with VO2peak, CMR, and BDNF over time. Intra‐class correlations were calculated to estimate within‐person variability. From baseline to 3‐month follow‐up, light PA (23.7 min/d ± 10.9) increased and body mass index (−0.3 kg/m2 ± 1.2), glucose (−0.8 mmol/L ± 0.3), and diastolic blood pressure (−2.7 mmHg ± 1.3) decreased. From baseline to 12‐month follow‐up, there were no changes in any marker. Regression models revealed no associations between any measure of habitual movement behaviors and VO2peak, CMR, and BDNF over time. To conclude, short‐term but no long‐term changes in MB and cardiovascular health markers were observed among CCS patients after a 12‐week exercise intervention. Modeling the associations between MB and VO2peak, CMR, and BDNF over time revealed considerable within‐person variability in the data, which should be considered in future research. Trial Registration NCT06178263, Retrospectively registered (20/12/2023)

Objective: Sphingosine-1-phosphate (S1P) is a versatile immunomodulatory lipid mediator that affects both immune and cardiovascular health. S1P has been linked to thyroid health, for example, by affecting inflammatory reactions found in Graves’ disease. In our study, we explored associations of S1P with thyroid markers obtained from laboratory tests (thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4)) and ultrasound examination. Methods: We quantified S1P by LC–MS/MS in participants from the population-based ‘Study of Health in Pomerania’ conducted in Northeast Germany. Serum levels of TSH, fT3, and fT4 were measured using chemiluminescent immunoassays. Thyroid volume, thyroid nodules, and echogenic patterns were assessed by ultrasonography. Cross-sectional associations between serum S1P and thyroid biomarkers were evaluated using multivariable linear regression models adjusted for confounding. Results: The total study population consisted of 4,034 participants (51.6% women aged 20–84 years). A 1 μmol/L higher S1P level was associated with a 0.17 mIU/L lower TSH level (95% confidence interval (CI): −0.32; −0.04) and a 0.52 pmol/L (0.42; 0.63) higher fT3 level. These associations persisted after excluding individuals with high or low serum TSH levels and those taking thyroid medication. S1P levels were not significantly associated with serum fT4 levels. Higher S1P levels were associated with a larger thyroid volume, the presence of thyroid nodules, and a hypoechogenic thyroid pattern. Conclusion: Circulating S1P is inversely associated with TSH and positively associated with fT3, suggesting a potential modulatory role of S1P in thyroid function.

BACKGROUND:In cardiovascular magnetic resonance (CMR), myocardial native T1 mapping enables quantitative, non-invasive tissue characterization and is sensitive to subclinical changes in myocardial structure and composition. However, data on the association between cardiometabolic risk and myocardial alterations are still limited. We therefore investigated how age, sex, and cardiometabolic risk factors are associated with myocardial T1 as a potential imaging marker of myocardial target-organ involvement in a population-based analysis within the German National Cohort (NAKO). METHODS:This cross-sectional study included 29,573 prospectively enrolled participants who underwent midventricular T1 mapping using 3.0T CMR along with deep clinical phenotyping. After artificial intelligence-assisted myocardial segmentation, a subset of 9,162 outlier cases was subjected to manual quality control according to clinical evaluation standards. Cardiometabolic risk factors were identified through self-reported, physician-diagnosed medical history, clinical chemistry, and blood pressure measurements. Associations with myocardial T1 were evaluated using multiple linear regression models adjusted for age, sex, heart rate, imaging site, and comorbidities. RESULTS:After quality control, 27,794 participants (12,401 [44.6%] women; 20-75 years) were included. Mean T1 was overall higher in women (1,231 ± 33 ms) than in men (1,209 ± 34 ms), with differences progressively declining with age. The sex difference was confirmed in a healthy subcohort (n = 3,910), whilst age interaction was less pronounced. In adjusted analyses, T1 was significantly higher in individuals with diabetes, kidney disease, and current smoking. Conversely, hyperlipidaemia was significantly associated with lower T1. Associations with hypertension showed strongly sex-specific patterns: women had lower T1 values, while T1 increased with hypertension severity in men. CONCLUSIONS:Myocardial native T1 varies by sex and age and shows distinct sex-specific associations with major cardiometabolic risk factors, supporting its role as a sensitive imaging marker of subtle myocardial alterations. Unexpectedly lower T1 times in participants with hyperlipidaemia suggest a potential direct effect of blood lipids on the heart, which warrants further investigation.

Aims:Effective heart failure (HF) prevention requires early identification of high-risk individuals, yet population-wide stratification remains difficult. We evaluated whether deep learning using single-lead (lead I) electrocardiograms (ECGs), obtainable from medical systems and wearables, enables population-scale risk assessment. We developed AI-HF to estimate incident clinical HF risk using UK Biobank (UKB) data, validating in the prospective SHIP-START and SHIP-TREND cohorts. Methods and results:The analysis included 31 740 UKB participants (median age 64, 5.2 year follow-up, 243 events), 3025 SHIP-START participants (age 50, 15 year follow-up, 166 events), and 1342 SHIP-TREND participants (age 51, 9 year follow-up, 84 events). Participants with prevalent HF were excluded. Performance was evaluated at a harmonized 5-year prediction horizon. C-indices for incident clinical HF were 0.693 [95% confidence interval (CI) 0.654-0.732] in UKB, 0.715 (0.652-0.777) in SHIP-START, and 0.791 (0.749-0.833) in SHIP-TREND. Hazard ratios per standard deviation increase in AI-HF output were 1.67 (1.56-1.79), 1.43 (1.25-1.65), and 1.46 (1.34-1.59), respectively (all P < 0.001). Adding biometric variables improved discrimination modestly (C-indices: 0.714, 0.718, and 0.77). Conclusion:Across cohorts, AI-HF identified individuals at elevated 5-year incident clinical HF risk using single-lead ECGs. Given the ubiquity of wearables, this method may enable population-scale assessment to support targeted prevention and early intervention.

CONTEXT:Magnesium deficiency may contribute to subclinical cardiac changes, particularly metabolic diastolic cardiomyopathy. OBJECTIVE:To investigate the association between magnesium depletion, metabolic syndrome (MetS), and magnetic resonance imaging (MRI)-derived cardiac alterations in a population-based sample. METHODS:We cross-sectionally analyzed participants (N = 9568) from the baseline examination of the German National Cohort who underwent whole-body MRI. Associations of serum magnesium and magnesium depletion score (MDS) with MetS and cardiac alterations were assessed using multivariable logistic and linear regression, respectively. Two-sample Mendelian Randomization was performed to evaluate the potential causal relationship between serum magnesium and MRI-derived cardiac parameters. RESULTS:Our analysis revealed no correlation between serum magnesium and MDS (Spearman's rho = 0.065; P < .001). A 1-SD increase in serum magnesium was associated with lower MetS prevalence (odds ratio, 0.93 [95% CI, 0.88-0.99]) and reduced left and right ventricular systolic and diastolic volumes. Higher MDS, indicating magnesium deficiency, was linked to increased MetS prevalence (OR per 1 unit, 1.32 [95% CI, 1.23-1.41]) and its individual components. Furthermore, higher MDS was associated with increased left ventricular remodeling index (estimate, 0.012 g/mL [95% CI, 0.008-0.017]) and decreased left ventricular end-diastolic volume (estimate, -1.132 mL/m2 [95% CI, -1.538 to -0.727]), indicating concentric hypertrophy. Two-sample Mendelian Randomization suggested no causal relationship between serum magnesium and MRI-derived cardiac markers. CONCLUSION:Magnesium depletion may serve as an early indicator of cardiac impairment. However, Mendelian Randomization results do not support a causal role of serum magnesium on cardiac structure and morphology.

BACKGROUND:This study investigated the cross-sectional association between periodontal status and left ventricular (LV) geometry and function, an early and prognostically relevant marker of cardiovascular disease. METHODS:Data were drawn from two population-based cohorts in the Study of Health in Pomerania (SHIP): SHIP-START-2 (N = 2333) and SHIP-TREND-0 (N = 4420). Periodontal status (half mouth protocol) was assessed by bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), and the number of missing teeth. Periodontitis was classified using a modified version of the 2018 framework based exclusively on clinical measurements without radiographic data. LV geometry and function were assessed using echocardiography and analyzed using adjusted regression models. RESULTS:Mean PD, CAL, and the number of missing teeth were positively associated with LV volumes and mass (end-diastolic volume (PD: β = 0.44; 95%CI: 0.13-0.74; CAL: β = 0.21; 95%CI: 0.07-0.36; teeth: β = 0.06; 95%CI: 0.03-0.09), end-systolic volume (PD: β = 0.21; 95%CI: 0.05-0.37; CAL: β = 0.12; 95%CI: 0.05-0.20; teeth: β = 0.03; 95%CI: 0.02-0.05), and LV mass (PD: β = 1.31; 95%CI: 0.58-2.03; CAL: β = 0.52; 95%CI: 0.18-0.86; teeth: β = 0.17; 95%CI: 0.10-0.24)), increasing across periodontitis stages (p < 0.05). Stage IV was associated with a reduced ejection fraction (β = -1.28; 95%CI: -2.45 to -0.12), though other functional markers were not significant. CONCLUSION:Periodontitis markers were linked to cardiac remodeling, notably increased LV volume and mass. The findings support integrating periodontal assessment and treatment into cardiovascular risk evaluation. Although statistically significant, effect sizes were small and clinical relevance remains uncertain. Further research is needed to clarify the clinical implications.

Exercise training is recommended in coronary heart disease (CHD) and type 2 diabetes (T2DM) patients alike; however, uncertainty remains on the influence of exercise intensity and duration in older patients with both entities. To address this, we performed a secondary analysis including 201 patients (67.9 ± 8.2 years; 84.1% men) from the LeIKD trial (NCT038359), which introduced 6 months of home-based telemedicine-supported exercise intervention in patients with CHD and T2DM. We assessed the relationships between exercise duration and intensity with change in peak oxygen uptake (V̇O2peak) (simple and multiple regression analyses, α = 0.05). V̇O2peak increased by 0.42 mL/kg/min per hour of endurance exercise/week (95% CI: 0.17-0.66, p = 0.001). Exercise intensity was not significantly associated with the change in V̇O2peak (p = 0.10). In a subgroup of patients with high adherence (≥ 66.7% of prescribed total duration and meeting prescribed exercise duration in ≥ 50% of weeks of intervention), a 10% increase in exercise intensity (mean % heart rate reserve (HRR)) was associated with an increase in V̇O2peak of 0.26 mL/kg/min (95% CI: 0.00-0.52; p = 0.05). Longer training duration within the initial 2 weeks of intervention was significantly associated with high adherence over 6 months (increased likelihood per 10 min/week: OR of 1.09 [95% CI: 1.05-1.14], p < 0.001). Therefore, exercise duration but not intensity influences changes in V̇O2peak during exercise intervention in a high-risk population of older patients with CHD and T2DM. In patients with high adherence to exercise duration, higher exercise intensity led to an additional increase in V̇O2peak. Training duration within the first 2 weeks was an important predictor of long-term adherence. Trial Registration: https://www.clinicaltrials.gov: Identifier: NCT038359.

Background Circulating cellular communication network factor 1 (CCN1) improves risk stratification in patients with acute coronary syndrome. We here investigated the association of CCN1 with all-cause mortality in patients with dilated cardiomyopathy (DCM). Methods Patients with a primary diagnosis of DCM, defined as LVEF <45% and increased LVEDD (LVEDD >117%), were included in a derivation (SFB/TR19 Greifswald) and a validation (IKARUS Marburg) cohort. Exclusion criteria comprised primary valvular diseases, acute myocarditis, active infectious diseases, pulmonary diseases, cancer, chronic alcoholism, and heart failure of other origins. CCN1 levels were determined in serum from study inclusion using an enzyme-linked immunosorbent assay. An adjusted multivariable Cox regression model was used to assess the association (hazard ratios) between tertiles of CCN1 concentration and all-cause mortality. Results In the SFB/TR19 cohort and [IKARUS cohort], respectively a total of 283 [236] predominantly male (78% [75%]) DCM patients with a median age of 56 [51] years with a severely reduced LVEF (31% [30%]), increased LVEDD (67.0 [67.0]), and normal eGFR (90.9 [83.6] ml/min) were analyzed. During a median follow-up of 10.6 [14.9] years, a total of 107 (37%) [100 (42%)] patients died. Patients in the highest CCN1 tertile had a significantly higher mortality risk than those in the lower tertile (p = 0.007 [p = 0.004]). In both cohorts, CCN1 remained associated (1.92; 95% CI: 1.14–3.24; p = 0.014 [1.69; 1.00–2.85; p = 0.049]) in adjusted multivariable Cox regression models. Conclusion CCN1 is associated with all-cause mortality in DCM patients, warranting further research into the underlying pathophysiology.

Aims Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular disease. We previously compared supervised machine learning techniques to classify cardiac magnetic resonance (CMR)-derived LVH using electrocardiogram (ECG) and clinical variables in 37 534 UK Biobank participants, obtaining an area under the receiving operating curve (AUROC) of 0.85, but with limited specificity and requiring external validation. In this study, we develop a deep learning (DL) model to improve classification with external evaluation in the Study of Health in Pomerania (SHIP).Methods and results We analysed 12-lead ECGs of 48 835 participants from the UK Biobank imaging study. The dataset was split into a training set (70%), validation set (15%), and test set (15%) for performance evaluation. The model architecture was a fully convolutional network, for which the input was the participants' median ECG and clinical variables and the predicted indexed left ventricular mass (iLVM) as the output. A subsequent logistic regression model was used to recalibrate iLVM predictions. In UK Biobank, 717 (1.5%) participants had CMR-derived LVH and the AUROC for the DL model was 0.97. The ECG components most predictive of LVH were the QRS complex and ventricular rate. The DL model outperformed our supervised algorithms, previous DL modelling efforts and clinical ECG benchmarks. There was modest generalizability of the DL model to 1423 participants in SHIP (AUROC 0.78), with differences in clinical profile, ECG acquisition, and CMR labelling as important factors.Conclusion Our findings support the feasibility of scalable DL-based screening tools for the prediction of LVH from the ECG, whilst highlighting the need for model development using larger datasets with greater diversity to ensure generalizability.

Abstract Background Left ventricular (LV) remodeling is associated with impaired cardiac function and future cardiovascular disease (CVD). Current remodeling definitions use broad categorizations based on hypertrophy and mean wall thickness. Cardiac magnetic resonance (CMR) imaging provides detailed characterization of regional myocardial wall properties, which may enhance sex-specific cardiovascular disease (CVD) risk stratification. Objectives We aimed to identify detailed LV remodeling patterns, their associations with CVD risk, and their clinical predictors. Methods LV wall thickness data were obtained by CMR in three independent population-based cohorts (SHIP-TREND-0, n=931; SHIP-START-2, n=490; KORA-FF4, n=368). Sex-specific remodeling patterns were identified by k-means clustering and associated with established CVD risk scores and incident morbidity and all-cause mortality. Bootstrapped multinomial regression with LASSO regularization was used to select relevant clinical predictors of remodeling patterns. Results The sample comprised 991 men (mean age 52.9 years, prevalent CVD 7.8%) and 798 women (52.5 years, 2%). Four remodeling clusters were found for men and women, respectively. For a subset of these clusters, significant associations with an increased CVD risk were found, e.g. in women, the high-risk cluster was associated with a 10.6 (95% confidence interval: 8.9, 12.3) percentage point increase in the 10-year Framingham Risk Score. Associations were independent of blood pressure and myocardial mass. Only in women, associations were also independent of average wall thickness and LV concentricity. Variable selection identified distinct clinical predictors of remodeling patterns. Conclusion Particularly in women, regional LV wall thickness patterns detect unfavorable cardiac remodeling and might improve CVD risk stratification beyond existing strategies. Automated implementation during image acquisition and integration with shape-based models may facilitate clinical application. Graphical Abstract

SARS-CoV-2 infection affects multiple immune mechanisms and leads to severe COVID-19 and death, in part related to infection-induced or pre-existing autoantibodies. Here, we describe severe COVID-19 to associate with autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) and progranulin (PGRN), endogenous antagonists of IL-1 and TNF signaling, respectively. These autoantibodies coincide with hyperphosphorylation of IL-1Ra (Thr111) or PGRN (Ser81), form immune complexes independent of phosphorylation, reduce antigen plasma levels, and permit enhanced IL-1 and TNF signaling. Using phage-display selected Fabs specific for hyperphosphorylated isoforms, we track phospho-antigens and autoantibodies in a German national pandemic network cohort. Most seropositive patients show both autoantibodies. Levels peak at baseline and decline over 12 months, with phospho-antigens decreasing before autoantibodies. Seropositivity associates with hyperinflammation and cytokine profiles. Importantly, signaling by key inflammatory cytokines induce IL-1Ra and PGRN hyperphosphorylation in healthy monocytes, but require up to 1000-fold higher doses than in monocytes from previously seropositive severe COVID-19 survivors.

Epidemiological population studies may include cardiac magnetic resonance (CMR)-derived phenotyping and large-scale genotyping, providing unprecedented level of detail to investigate novel gene-lifestyle-disease interactions. The systematic review presents high-level summaries and critically appraises contemporary challenges and biobank opportunities. The authors identified 17 relevant biobanks by searching "CMR," "genome" and "population study" on MEDLINE, EMBASE, and Web of Science 2025. Collectively, studies recruited ∼1 million participants with stored blood samples for extensive genomic analyses, of whom >180,000 have or will undergo CMR. Use of expansive personal data must safeguard participant confidentiality, encourage technological standardization, and champion inclusivity and sustainability. Application of genotypic and imaging-derived phenotypic information will be readily translatable to clinical practice through investigation of, among others, new therapeutic targets and highly sensitive and specific biomarkers. Imaging biobanks are accessible to researchers by application. This systematic review should inspire greater use and cross-collaboration and facilitate powerful discoveries in more heterogeneous population samples.

Background The postmenopausal period is associated with a more adverse cardiometabolic risk factor profile as well as unfavourable cardiac remodelling patterns. However, it remains unclear whether and how the associations between risk factors and cardiac remodelling differ before and after menopause and in the corresponding age groups in men. Methods We used cross-sectional data from the baseline examination of the population-based German National Cohort (NAKO, age range 19-74 years). Cardiovascular resonance imaging (CMR) was performed on 3T MRI, and morphofunctional data of both ventricles were derived from standard short-axis cine balanced steady-state free precession. Associations between cardiometabolic risk factors and cardiac parameters were evaluated using adjusted multivariable linear regression, stratified by menopausal status in women and age group (<50 / ≥50 years) in men. Results The final sample comprised 20,152 participants (40% women; mean age 47±12 years) from the NAKO MRI subsample. Cardiometabolic risk factor profiles differed across the stratified groups, with higher systolic blood pressure and less favourable lipid profiles in older participants. Ventricular volumes declined and concentric remodelling increased with age in both sexes, with a steeper age-related pattern observed in women than in men. Higher BMI in women was associated with higher left ventricular concentricity index (LVCI) in postmenopausal than in premenopausal women (0.097 vs. 0.047; p for difference = 0.016). Associations between triglycerides and ventricular volumes were strongest in premenopausal women and significantly stronger than in men younger than 50 years (e.g., right ventricular end-diastolic volume (RVEDV): -0.173 vs. -0.064, p for difference < 0.001). Sleep problems were more strongly associated with cardiac parameters in men, with significant sex differences in older men compared with postmenopausal women (e.g. left ventricular end-diastolic volume (LVEDV): -0.105 vs. 0.043, p for difference = 0.023). Conclusions Less favourable cardiac remodelling observed in postmenopausal women appeared to be associated with a higher burden of cardiometabolic risk factors rather than stronger associations between these risk factors and cardiac structure. Several associations showed sex- and age-specific patterns, including Body Mass Index (BMI), triglyceride levels, and sleep problems. These findings highlight the importance of controlling cardiometabolic risk factors across adulthood, and raising awareness for sex-specific differences. ### Competing Interest Statement FB: Unrestricted research grant from Siemens Healthineers; FB, CLS: Honoraria from the speaker's bureaus of Bayer Healthcare and Siemens Healthineers; PMF: Honoraria from the speaker's bureaus of CSL Behring. All other authors declare no competing interest. ### Funding Statement The NAKO is funded by the Federal Ministry of Education and Research (BMBF) (project funding reference numbers: 01ER1301A/B/C, 01ER1511D, 01ER1801A/B/C/D and 01ER2301A/B/C), federal states of Germany and the Helmholtz Association, the participating universities, and the institutes of the Leibniz Association. This project received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - project no. 428224476 / SPP 2177. We thank all participants who took part in the NAKO study and the staff of this research initiative. PMF has received the Kaltenbach Scholarship from the German Heart Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received ethical approval from the Ethics Committee of the Medical Faculty of Freiburg University, Germany (No. 20-1107). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Access to and use of NAKO (German National Cohort) data and biosamples can be obtained via an electronic application portal (https://transfer.nako.de/transfer/index).

BACKGROUND:Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. METHODS:In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were estimated per individual and categorised into quintiles, with the highest and lowest quintiles defined as increasing and decreasing, respectively, and the rest as stable. Patterns of thyroid function change were identified based on combined TSH and FT4 evolution. We used cohort-stratified Cox models to assess associations between changing patterns and all-cause mortality. This study is registered with PROSPERO, CRD42023408086. FINDINGS:In this IPD analysis, we analysed data collected between Jan 1, 2011, and Oct 13, 2022, from 31 cohorts across Europe (n=19), the USA (n=5), Asia (n=3), Brazil (n=2), and Australia (n=2; 137 488 participants; 68 322 [49·7%] were female and 69 166 [50·3%] were male; median age 60 years [range 18-106]). Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and with lower TSH in iodine-insufficient regions. Longitudinal analyses showed that TSH increased with increasing age regardless of iodine status. The overall increase in TSH from age 18 years to 100 years was 0·61 mIU/L (0·52 SD) for female participants and 0·99 mIU/L (0·76) for male participants from iodine-sufficient regions. Greater variability in population distribution and longitudinal TSH changes was observed in adults aged 65 years or older. Higher FT4 with older age was suggested cross-sectionally, but longitudinally FT4 increased in iodine-sufficient regions and decreased in iodine-insufficient regions. Compared with stable thyroid function, all changing patterns were associated with increased all-cause mortality: hazard ratios of 1·80 (95% CI 1·57-2·06) for increasing TSH with stable or decreasing FT4; 2·45 (2·01-2·97) for increasing TSH and increasing FT4; 2·45 (1·99-3·01) for decreasing TSH with decreasing FT4; and 1·94 (1·68-2·24) for decreasing TSH with stable or increasing FT4. INTERPRETATION:Ageing-related changes in thyroid function varied by sex and iodine status. Most individuals had stable thyroid function during ageing with a slight increase in TSH, although older adults displayed greater variability. Patterns of changing thyroid function were associated with an increased all-cause mortality risk, warranting further exploration of the underlying mechanisms and clinical management. FUNDING:None.

BACKGROUND/OBJECTIVES:Associations between adiponectin and chemerin with the most clinically established lipid parameters for assessing cardiovascular risk - LDL-cholesterol, HDL-cholesterol, and triglycerides-are well documented. Since lipoproteins are heterogeneous with respect to size, density, and chemical composition, the examination of their subclasses could help to elucidate the complex interactions between adipokines and lipid metabolism. SUBJECTS/METHODS:Lipoprotein subclasses were quantified by nuclear magnetic resonance spectroscopy in samples from 3199 participants of the Study of Health in Pomerania (SHIP-TREND-0). Associations between adiponectin/chemerin and lipoprotein subclasses were analyzed using appropriately adjusted linear regression models. RESULTS:The analyses revealed a wide range of statistically significant associations between adiponectin/chemerin and lipoprotein subclasses, that were primarily in opposite directions. Higher adiponectin concentrations were, for example, related to a lower particle number and a lower cholesterol, phospholipid and triglyceride content in atherogenic small, dense LDL-particles, while positive associations were observed for chemerin. CONCLUSIONS:Our highly consistent results demonstrate that high adiponectin was associated with a favorable, anti-atherogenic lipoprotein profile, whereas the opposite was observed for chemerin. Whether these cross-sectional associations reflect causal mechanisms or alternatively, shared underlying metabolic processes, must be clarified by experimental and longitudinal research.

The relationship between childhood maltreatment (CM) and obesity is nuanced, and recent evidence suggests stronger associations between CM and obesity-related traits in females compared to males. This study aims to validate and extend these findings in a large sample from the German National Cohort (NAKO). The NAKO is a population-based cohort study including 204,744 adults. For the present analyses, 151,143 individuals (74,596 female) were included. CM was assessed using the Childhood Trauma Screener (CTS). From the CTS, an overall severity score (CTS sum score), a cumulative CM score (number of CM subtypes with at least moderate severity), and five CTS subtypes were considered as exposures. Obesity-related traits included anthropometric (height, weight, body mass index [BMI], waist circumference [WC]) and body fat markers (relative fat mass [rFM], subcutaneous [SAT], visceral adipose tissue [VAT]). Sex-stratified linear and logistic regression models were adjusted for age, education, and examination center to associate CTS-based scores with obesity-related traits. Associations of the CTS sum score with weight, BMI, WC, rFM, and SAT were stronger in females compared to males, while similar associations were observed for VAT. In both sexes, most obesity-related traits exhibited dose-response relationships with increasing numbers of CM subtypes. Compared to unexposed females, females with exposure to ≥3 CM subtypes had a higher risk for obesity (i.e., BMI ≥ 30 kg/m2; OR = 1.56; 95% CI: 1.43, 1.71) and high WC (i.e., WC ≥ 88 cm; OR = 1.39; 95% CI: 1.29, 1.50). In males, exposure to ≥3 CM subtypes was also associated with increased obesity risk (OR = 1.51; 95% CI: 1.32, 1.72) and high WC (i.e., WC ≥ 102 cm; OR = 1.31; 95% CI: 1.18, 1.44). Physical and emotional abuse exhibited the strongest average associations and were associated with the most outcomes. Associations of CM exposure with adult anthropometric and body fat markers are stronger in females compared to males.

Aims:Angiotensin II (AngII) causes hypertension and vascular inflammation and is essential in neurohumoral activation promoting the development of heart failure. The role of the adaptor protein myeloid factor of differentiation 88 (MyD88) driving this pathology remains incompletely understood. Methods and results:Male C57BL/6JMyD88-/-, LysMCre/wtMyD88LSL/LSL, LysMCre/wt, TLR2-/-, TLR4-/-, TLR7-/-, and TLR9-/- mice were investigated (1 mg/AngIIkg/d for 7 days). Additionally, we performed biodata analyses from a population-based cohort study and human protein network interactome analyses to understand the role of MyD88 in hypertension. MyD88 deficiency attenuated AngII-induced hypertension and endothelial dysfunction in conductance and resistance vessels, surpassing the effect of single TLR deficiencies. Vascular mRNA expression levels of vcam-1, nos2, nox2, cd62L, cd68, ccl2, il12, and il1b and accumulation of CD11b+Ly6Chi inflammatory monocytes and interferon-g+ NK cells were significantly dampened in MyD88-/-. Vascular protection was conferred by MyD88 deficiency in bone marrow-derived cells. Re-expression of MyD88 in LysMCre/wtMyD88LSL/LSL mice restored AngII-induced pathology, revealing that myeloid cells drive vascular dysfunction in a MyD88-dependent manner. Computational analyses of the human protein interactome demonstrated that MyD88 expression significantly associates with proteins encoded by genetic loci associated with blood pressure traits in multiple GWAS. In hypertensive individuals of the Gutenberg Health Study, monocytic MyD88 mRNA expression was associated with prevalent heart failure and all-cause mortality after a median follow-up of 16.5 years. Conclusion:MyD88 promotes AngII-induced vascular dysfunction and arterial hypertension and might serve as both an inflammatory diagnostic marker and a drug target to tackle the risk of death and incident heart failure in hypertensive patients.