Background: The relationship between triglyceride-glucose (TyG) index, an emerging marker of insulin resistance, and the risk of incident heart failure (HF) was unclear. This study thus aimed to investigate this relationship. Methods: Subjects without prevalent cardiovascular diseases from the prospective Kailuan cohort (recruited during 2006–2007) and a retrospective cohort of family medicine patients from Hong Kong (recruited during 2000–2003) were followed up until December 31st, 2019 for the outcome of incident HF. Separate adjusted hazard ratios (aHRs) summarizing the relationship between TyG index and HF risk in the two cohorts were combined using a random-effect meta-analysis. Additionally, a two-sample Mendelian randomization (MR) of published genome-wide association study data was performed to assess the causality of observed associations. Results: In total, 95,996 and 19,345 subjects from the Kailuan and Hong Kong cohorts were analyzed, respectively, with 2,726 cases of incident HF in the former and 1,709 in the latter. Subjects in the highest quartile of TyG index had the highest risk of incident HF in both cohorts (Kailuan: aHR 1.23 (95% confidence interval: 1.09–1.39), P_Trend <0.001; Hong Kong: aHR 1.21 (1.04–1.40), P_Trend =0.007; both compared with the lowest quartile). Meta-analysis showed similar results (highest versus lowest quartile: HR 1.22 (1.11–1.34), P < 0.001). Findings from MR analysis, which included 47,309 cases and 930,014 controls, supported a causal relationship between higher TyG index and increased risk of HF (odds ratio 1.27 (1.15–1.40), P < 0.001). Conclusion: A higher TyG index is an independent and causal risk factor for incident HF in the general population. Clinical Trial Registration: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-TNRC-11,001,489.

Cardiac fibrosis is a primary phenotype of cardiac remodeling that contributes to cardiac dysfunction and heart failure. The expansion and activation of CD4+ T cells in the heart has been identified to facilitate pathological cardiac remodeling and dysfunction; however, the underlying mechanisms remained not well clarified. Herein, we found that exosomes derived from activated CD4+ T cells (CD4-activated Exos) evoked pro-fibrotic effects of cardiac fibroblasts, and their delivery into the heart aggravated cardiac fibrosis and dysfunction post-infarction. Mechanistically, miR-142-3p that was enriched in CD4-activated Exos recapitulated the pro-fibrotic effects of CD4-activated Exos in cardiac fibroblasts, and vice versa. Furthermore, miR-142-3p directly targeted and inhibited the expression of Adenomatous Polyposis Coli (APC), a negative WNT signaling pathway regulator, contributing to the activation of WNT signaling pathway and cardiac fibroblast activation. Thus, CD4-activated Exos promote post-ischemic cardiac fibrosis through exosomal miR-142-3p-WNT signaling cascade-mediated activation of myofibroblasts. Targeting miR-142-3p in CD4-activated Exos may hold promise for treating cardiac remodeling post-MI.

This study investigated whether pretreatment with puerarin could alleviate myocardial ischemia/reperfusion (I/R) injury in a cardiomyocyte oxygen–glucose deprivation and reoxygenation (OGD/R) model and in a mouse I/R injury model. For in vitro experiments, H9C2 cells were divided into control, erastin, OGD/R, OGD/R + puerarin, and OGD/R + ferrostatin (Fer)-1 groups. Parameters related to ferroptosis included levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), ATP, reactive oxygen species (ROS), glutathione (GSH), prostaglandin endoperoxide synthase (Ptgs) 2 mRNA, glutathione peroxidase (GPX) 4 protein and iron. In H9C2 cells, puerarin or Fer-1 pretreatment reduced ferroptosis, as indicated by decreased ROS and increased GSH, ATP levels. In vivo, wild-type mice were randomly divided into sham, I/R + vehicle, I/R + puerarin, and IR + Fer-1 groups. The I/R model was established by 30 min of left anterior descending artery occlusion followed by 24 h of reperfusion. Pretreatment with puerarin or Fer-1 significantly reduced infarct size in I/R mice, and decreased the activities of Myeloperoxidase (MPO) and cardiac enzymes such as creatine kinase MB isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) compared to those in the vehicle-treated group. Puerarin also reduced the production of MDA and 4-HNE, reduced the mRNA expression of Ptgs2 mRNA, and increased GPX4 protein expression. These results showed that puerarin exerted protective effects against myocardial I/R injury by inhibiting ferroptosis and inflammation, and therefore may have therapeutic potential for treatment of acute myocardial infarction.