Tanja Zeller

BACKGROUND: Stratification of stroke risk remains challenging, but metabolomic profiling offers the potential to detect new biomarkers and to improve early risk assessment of incident stroke. The objective of this study was to evaluate the association between circulating metabolites and the incidence of stroke in a case-cohort study conducted across several large population-based European cohorts. METHODS: Following the case-cohort design, a subset of 10 299 individuals, including all individuals with incident stroke, was selected from the original cohort of >70 000 individuals. The case-cohort design used a random subsample of the selected population cohorts, supplemented with cases not sampled in this random subcohort. A total of 141 circulating metabolites were measured from serum samples of the selected individuals, and associations of these metabolites with risk of incident stroke were estimated and compared with those of classic risk factors (sex, age at examination, systolic blood pressure, total cholesterol, body mass index, diabetes, daily smoking status, and antihypertensive treatment). Associations with time to stroke were assessed using weighted Cox proportional hazards models adjusted for the classic risk factors. Hazard ratios (HRs) for the log-transformed metabolites were reported per 1 SD increase. RESULTS: Of the 70 195 individuals in the original cohort, 1516 (2.2%) experienced incident strokes during a median follow-up time of 8.9 years (interquartile range, 4.4–14.7). Median age was 56.8 years (interquartile range, 49.5–62.4), and 39.5% were women. Six of the 141 metabolites (2 diacyl-phosphatidylcholines, 2 lyso-phosphatidylcholines, 1 hydroxysphingomyelin, and glutamic acid) remained significantly associated with incident stroke after correction for multiple comparisons (adjusted HRs [95% CIs] per SD: lyso-phosphatidylcholines a C18:2 HR, 0.88 [95% CI, 0.82–0.93], lyso-phosphatidylcholines a C17:0 HR, 0.88 [95% CI, 0.83–0.94], hydroxysphingomyelin C14:1 HR, 0.90 [95% CI, 0.85–0.94], diacyl-phosphatidylcholines C34:1 HR, 1.10 [95% CI 1.05–1.16], diacyl-phosphatidylcholines C32:1 HR, 1.14 [95% CI, 1.08–1.21], glutamic acid HR, 1.23 [95% CI 1.11–1.37]). The strengths of these associations were similar to those for classic cardiovascular risk factors (C statistics for 10-year prediction ranging from 0.782 to 0.785 for metabolites compared with 0.781 to 0.792 for classic cardiovascular risk factors). CONCLUSIONS: Among 10 299 individuals from the general European population, we identified 6 metabolites from 4 different metabolite classes that were associated with future risk of stroke. The application of specific circulating metabolites may improve early stroke risk prediction before the onset of potentially irreversible cerebrovascular pathological processes.

Aims/hypothesis Environmental exposures have been adversely associated with the risk of diabetes but their role in the remission and progression of prediabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]), especially different phenotypes, is poorly understood. This study aimed to investigate the relationship between environmental exposures and remission or progression of prediabetes phenotypes. Methods Data were derived from the KORA (Cooperative Health Research in the Region of Augsburg) cohort in Southern Germany (2006–2022). Glucose tolerance status was defined according to the 1999/2006 WHO criteria. We included annual values of particulate matter (PM), light at night (LAN), normalised difference vegetation index (NDVI), imperviousness (IMP) and air temperature variation (T_sd). We fitted complementary log–log regression models for associations between IQR changes in exposures and the incidence of prediabetes phenotypes (isolated impaired fasting glucose [iIFG], isolated impaired glucose tolerance [iIGT], or their combination [IFG+IGT]), remission to normal glucose tolerance (NGT) or progression to type 2 diabetes. We also applied Quantile g-computation regression models for joint association analysis. Results During the follow-up, 370/1618 participants developed prediabetes (124 iIFG, 199 iIGT and 47 IFG+IGT). Among participants with prediabetes, 136/367 (without medication) regressed to NGT and 133/420 progressed to type 2 diabetes. We observed consistent associations of air pollutants and the built environment with iIGT or IFG+IGT. For example, an IQR increase in PM_2.5 (aerodynamic diameter ≤2.5 μm) showed an HR of 1.89 (95% CI 1.07, 3.31) for the risk of IFG+IGT and 1.59 (95% CI 1.03, 2.46) with a decrease in NDVI. Co-exposure to environmental mixtures (higher air pollution, T_sd, IMP and LAN, and lower NDVI) was associated with increased risks of iIFG, iIGT and IFG+IGT. Additionally, lower NDVI (HR 0.52 [95% CI 0.28, 0.96]), higher LAN (HR 0.22 [95% CI 0.08, 0.62]) and higher IMP were associated with reduced remission of iIFG but we found no statistically significant associations with the progression to type 2 diabetes. Conclusions/interpretation The findings indicate potential heterogeneity in environmental exposures and prediabetes phenotypes. Specifically, they are associated with increased incidence of IGT and decreased remission of iIFG. Graphical Abstract

Background: Early rhythm control reduces cardiovascular events in patients with atrial fibrillation (AF) and cardiovascular comorbidities. Whether this effect is consistent across severities of different AF-associated conditions is not known. Methods: In the EAST-AFNET 4 biomolecule study (n=1,586; median age 70 years; 45% women), 14 circulating biomarkers reflecting inflammation, fibrosis, ageing, cardiac strain, and myocardial damage were quantified. Log-transformed, winsorized biomarkers were analysed in quintiles to detect non-linear associations and as continuous parameters. Cox proportional hazards models evaluated associations with the primary outcome (cardiovascular death, stroke, or unplanned hospitalization for heart failure or acute coronary syndrome) and the safety outcome (death, stroke, or major bleeding) of the trial, including interaction terms for biomarkers and randomized treatment (early rhythm control [ERC] vs usual care). [UC]). Two independent cohorts, BBC-AF resembling UC and a TRUST snapshot resembling ERC were combined for external replication. All tests were exploratory. Results: ERC reduced the primary outcome consistently across biomarker concentrations. No signal for treatment interaction was observed for 13 of 14 biomarkers for the primary outcome. For BMP10, a nominal interaction was observed in categorical analyses, suggesting an attenuated treatment effect of ERC in patients in the lowest BMP10 quintile. No interaction was detected for continuous parameters. Similar patterns were observed in exploratory analyses of the replication cohort. Conclusions: Early rhythm control therapy is effective across patients with different severities of conditions associated with atrial fibrillation as quantified by biomolecule concentrations. A potentially attenuated effect of ERC with low BMP10 concentrations warrants further research.

Aims: Biomarkers have the potential to improve risk prediction beyond clinical characteristics. We examined the association of four emerging cardiovascular biomarkers [angiopoietin 2 (Angpt2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), insulin-like growth factor binding protein 7 (IGFBP7)] in comparison with N-terminal pro B-type natriuretic peptide (NT-proBNP) across the disease course of atrial fibrillation (AF). Methods and results: We enrolled patients from a prospective cohort of patients at risk of AF or with manifest arrhythmia. The circulating vascular biomarkers were quantified using high-throughput, high-precision precommercial assays (Roche Diagnostics). A combined endpoint comprised: stroke, transient ischaemic attack (TIA), myocardial infarction, incident coronary heart disease, heart failure, and all-cause mortality. Of the total n = 1047 individuals, n = 527 had prevalent AF, and n = 507 were free of AF at baseline. Median follow-up was 42 months. A total of n = 66 individuals died; the combined endpoint occurred in n = 198 individuals. All five biomarkers were significantly associated with the incidence of AF, both in multistate analysis (MSA) and Cox regression, although the association with FGF23 was only significant in the age- and sex-adjusted Cox model. AF recurrence was significantly associated with all biomarkers, most strongly with NT-proBNP. In prevalent AF, NT-proBNP, FGF23, and IGFBP7 were associated with the combined endpoint and all-cause mortality, and Angpt2 was associated with all-cause mortality. NT-proBNP showed the strongest association for all-cause mortality, and IGFBP7 for the combined endpoint in prevalent AF. In incident AF the association with the combined outcome was statistically significant for NT-proBNP in multivariable-adjusted models. All-cause mortality in individuals with incident AF was associated with NT-proBNP, Angpt2, FGF23, and IGFBP7 both in the MSA and Cox model. Conclusion: All novel biomarkers Angpt2, BMP10, FGF23, and IGFBP7 showed predictive value for incident and recurrent AF. Individual biomarkers showed distinct strengths in prediction of outcomes across the disease spectrum of AF.

Previous research suggests that the use of snus, a smokeless tobacco product, is associated with increased all-cause and cardiovascular mortality, but the underlying mechanisms are unknown. We aimed to evaluate the associations of snus use with biomarkers of cardiometabolic importance: high-sensitivity C-reactive protein (hs-CRP), 25-hydroxyvitamin D (25(OH)D) and calculated free testosterone (cfT). We performed cross-sectional analyses within the population-based Northern Sweden MONICA-study. The study sample consisted of 6 158 never-smoking men and women (of whom 21 and 3.3% were current snus users, respectively), examined between 1990 and 2014. Harmonized analyses on biomarkers were conducted 2016 to 2018. We evaluated the relationships between snus use and biomarker concentrations using linear and logistic regression. Snus use, compared to never-use, was associated with lower hs-CRP (exp(β_ln) 0.88, 95% CI 0.81; 0.96) and 25(OH)D-concentrations (β - 1.01, 95% CI -1.70; -0.33) in mixed-sex analyses. Among men, snus use was also associated with higher cfT-concentrations (exp(β_ln) 1.04, 95% CI 1.01; 1.07). Former snus users had no significant differences in biomarker concentrations. Snus users have lower concentrations of 25(OH)D and hs-CRP, irrespective of sex, while male users have higher cfT-concentrations. These findings may in part contribute to the previously observed increased mortality among snus users.

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.

Aims: Optimal outcomes for patients with cardiac arrhythmias can be achieved through multimodal therapy including lifestyle support, medication, and interventions. Planning of these therapy concepts requires a detailed understanding of phenotypes, responses to therapies, and outcomes. Objective: The prospective Long-term Outcome and Predictors for Recurrence after Medical and Interventional Treatment of Arrhythmias at the University Heart Center Hamburg (TRUST) combines deep phenotypic, procedural, and follow-up information in a contemporary cohort of patients with cardiac arrhythmias. Methods and results: TRUST is an investigator-initiated, prospective, cohort study enrolling consecutive patients at the UHZ Hamburg. Comprehensive baseline work-up, imaging, and biobanking at baseline is combined with follow-up using a combination of in-person visits, online questionnaires, and remote rhythm-monitoring. Enrolment started in March 2021 and is ongoing. This paper describes the design and the clinical characteristics of the first 1500 enrolled patients with verified baseline datasets (562 women (37%), median age 64 (IQR 55, 74) years). Overall, 1077/1500 patients (71%) were seen for atrial fibrillation, 161/1500 (11%) for ventricular tachycardia and premature ventricular complexes, 239/1500 (16%) for supraventricular tachycardia, and 23/1500 (2%) patients for other reasons. Ablations, rhythm surgery, or invasive procedures were performed in 1363/1500 (91%) within 1 month after inclusion. Conclusion: This snapshot of the first 1500 patients enrolled in TRUST illustrates current characteristics and comorbidity burden in patients undergoing arrhythmia treatment. This rich data set will provide information on treatment patterns, detailed phenotypes, and follow-up, offering insights into the natural progression and treatment responses of arrhythmias in routine care.