This study aimed to identify microbial signatures that contribute to the shared etiologies between chronic heart failure (CHF), type 2 diabetes, and chronic kidney disease. The serum levels of 151 microbial metabolites were measured in 260 individuals from the Risk Evaluation and Management of heart failure cohort, and it was found that those metabolites varied by an order of 10 5 fold. Out of 96 metabolites associated with the three cardiometabolic diseases, most were validated in two geographically independent cohorts. In all three cohorts, 16 metabolites including imidazole propionate (ImP) consistently showed significant differences. Notably, baseline ImP levels were three times higher in the Chinese compared with the Swedish cohorts and increased by 1.1-1.6 fold with each additional CHF comorbidity in the Chinese population. Cellular experiments further supported a causal link between ImP and distinct CHF relevant phenotypes. Additionally, key microbial metabolite-based risk scores were superior in CHF prognosis than the traditional Framingham or Get with the Guidelines-Heart Failure risk scores. Interactive visualization of these specific metabolite-disease links is available on our omics data server (https://omicsdata.org/Apps/REM-HF/).

Background Insulin resistance is an overlapping risk factor for both heart and breast cancer, while its interaction with cardiotoxicity in breast cancer (BC) patients is not clear. This study investigated the impact of insulin resistance on cardiac remodeling in patients with human epidermal growth factor receptor 2 (HER2)-positive BC during and after trastuzumab therapy in real-world clinical practice. Methods HER2-positive BC patients who received trastuzumab treatment between December 2012 and December 2017 were reviewed and 441 patients with baseline metabolic indices and serial echocardiographic measurements (baseline, 6, 12, and 18 months) after trastuzumab therapy initiation were included. Repeated measurement analysis of variance was used to evaluate temporal trends in multiparameter echocardiography. Linear mixed model was applied to further evaluate the role of insulin resistance in forementioned changes. Correlation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) levels to changes in echocardiography parameters was explored. Results Of 441 patients (mean age 54 ± 10 [SD] years), 61.8% received anthracycline-based chemotherapy, 33.5% received left-sided radiotherapy, 46% received endocrine therapy. No symptomatic cardiac dysfunction was observed over the therapy course. A total of 19 (4.3%) participants experienced asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), and the peak onset time was 12 months after the initiation of trastuzumab. Albeit relatively low CTRCD incidence, cardiac geometry remodeling, especially left atrial (LA) dilation over therapy was notable and was more severe in high HOMA-IR and TyG level groups (P < 0.01). Noteworthy, a partial reversibility of cardiac remodeling was observed with treatment cessation. Additionally, HOMA-IR level positively correlated to changes in LA diameter from baseline to 12 months (r = 0.178, P = 0.003). No significant association (all P > 0.10) was detected between HOMA-IR or TyG level and dynamic left ventricular parameter evaluation. Multivariate linear regression analysis demonstrated that higher HOMA-IR level was an independent determinant for LA enlargement in BC patients during anti-HER2 targeted therapy course after adjusting for confounding risk factors (P = 0.006). Conclusion Insulin resistance was associated with left atrial adverse remodeling (LAAR) in HER2-positive BC patients that received standard trastuzumab therapy, indicating that insulin resistance could be a supplementation to baseline cardiovascular risk stratification proforma for HER2-targeted antitumor therapies.

Background Catestatin has been reported as a pleiotropic cardioprotective peptide. Heart failure with preserved ejection fraction (HFpEF) was considered a heterogeneous syndrome with a complex cause. We sought to investigate the role of catestatin in HFpEF and diastolic dysfunction. METHODS AND RESULTS Administration of recombinant catestatin (1.5 mg/kg/d) improved diastolic dysfunction and left ventricular chamber stiffness in transverse aortic constriction mice with deoxycorticosterone acetate pellet implantation, as reflected by Doppler tissue imaging and pressure‐volume loop catheter. Less cardiac hypertrophy and myocardial fibrosis was observed, and transcriptomic analysis revealed downregulation of mitochondrial electron transport chain components after catestatin treatment. Catestatin reversed mitochondrial structural and respiratory chain component abnormality, decreased mitochondrial proton leak, and reactive oxygen species generation in myocardium. Excessive oxidative stress induced by Ru360 abolished catestatin treatment effects on HFpEF‐like cardiomyocytes in vitro, indicating the beneficial role of catestatin in HFpEF as a mitochondrial ETC modulator. The serum concentration of catestatin was tested among 81 patients with HFpEF and 76 non–heart failure controls. Compared with control subjects, serum catestatin concentration was higher in patients with HFpEF and positively correlated with E velocity to mitral annular e′ velocity ratio, indicating a feedback compensation role of catestatin in HFpEF. Conclusions Catestatin protects against diastolic dysfunction in HFpEF through attenuating mitochondrial electron transport chain–derived reactive oxygen species generation. Serum catestatin concentration is elevated in patients with HFpEF, probably as a relatively insufficient but self‐compensatory mechanism.