Objective: To elucidate the bidirectional correlation of sarcopenia with coronary heart disease (CHD), as well as to investigate the mediating role of cardiometabolic factors and inflammatory biomarkers, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. Methods: Summary statistics were obtained from genome-wide association studies (GWAS). In our bidirectional two-sample MR, genetic variants associated with sarcopenia-related traits and CHD were instrumented for the estimation of bidirectional correlations. Besides, genetic variants associated with thirteen cardiometabolic factors and six inflammatory biomarkers were selected for further mediation analyses. To confirm the consistency of the results, several sensitivity analyses were carried out. Results: Genetically predicted higher appendicular lean mass (OR = 0.835, 95% CI: 0.790–0.882), left hand grip strength (OR = 0.703, 95% CI: 0.569–0.869), right hand grip strength (OR = 0.685, 95% CI: 0.555–0.844), and walking pace (OR = 0.321, 95% CI: 0.191–0.539) reduced CHD risk, while genetic predisposition to CHD did not affect any of the sarcopenia-related traits. Seven mediators were identified for the effects of appendicular lean mass on CHD, including waist-to-hip ratio, hip circumference, systolic blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and fasting insulin. The mediation proportion ranged from 10.23% for triglycerides to 35.08% for hip circumference. Hip circumference was found to mediate the relationships between both left (mediation proportion: 24.61%) and right-hand grip strength (24.14%) and CHD, and the link between walking pace and CHD was partially mediated by waist-to-hip ratio (31.15%) and body mass index (26.66%). Conclusion: Our results showed that higher appendicular lean mass, hand grip strength, and walking pace reduced CHD risk, but the causal relationship was not bidirectional. Several mediators were found to mediate the causal pathways between sarcopenia-related traits and CHD, and intervention of these factors may be helpful in terms of CHD prevention in sarcopenia patients.

Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg ^−/− mice were used. Expression of Areg was analyzed using western blotting, RT–qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP‐GFP‐LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3‐kinase/protein kinase B (PI3K‐Akt), mammalian target of rapamycin (mTOR) signaling pathways, V‐ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.

BACKGROUND: Tissue-specific regulatory T cells (Tregs) accumulate in the heart after myocardial infarction (MI) and play a vital role in limiting inflammation and promoting tissue repair. However, the developmental trajectory of heart Tregs and the molecular cues that guide their recruitment to the heart remain poorly understood, impeding therapeutic strategies that leverage Treg-mediated cardiac protection. METHODS: We used single-cell and bulk RNA sequencing in a murine MI model to delineate the differentiation trajectory of Tregs from mediastinal lymph nodes to the heart. Functional validation was performed using Treg-specific Ccr8 (CC motif chemokine receptor 8) knockout mice ( Ccr8 ^flox/flox Foxp3 ^Cre ), Ccl1 (CC motif chemokine ligand 1) knockout mice ( Ccl1 ^−/− ), macrophage-targeted Ccl1 knockdown mice, Ccl1 -overexpressing mice, and DEREG mice. The CCL1-CCR8 axis was evaluated in cardiac tissues and circulating blood from patients with MI. RESULTS: Single-cell RNA sequencing revealed a stepwise differentiation of mediastinal lymph node–derived naive Tregs into heart Tregs, marked by the progressive acquisition of CCR8 expression and reparative capacity. CCR8 ⁺ Tregs in the heart exhibited enhanced immunosuppressive and tissue-repair signatures. Treg-specific Ccr8 deletion led to reduced Treg accumulation and worsened cardiac function after MI, along with increased proinflammatory macrophage features and number of CD8 ⁺ T cells and natural killer cells. In addition, Tregs promoted a shift of macrophages toward an anti-inflammatory phenotype by secreting IL-1R2 (interleukin 1 receptor, type 2). We identified cardiac macrophages as the main source of CCL1, which was essential for CCR8 ⁺ Treg recruitment. Ccl1 deficiency or macrophage-specific Ccl1 knockdown impaired Treg infiltration and aggravated ventricular remodeling; Ccl1 overexpression promoted Treg recruitment and improved cardiac outcomes. Moreover, the cardioprotective effects of CCL1 were abolished in DEREG mice upon Treg depletion and Ccr8 ^flox/flox Foxp3 ^Cre mice, establishing a CCR8 ⁺ Treg-dependent mechanism. Furthermore, circulating CCR8 ⁺ Tregs and cardiac CCL1 were elevated in humans with MI, and the presence of CCR8 ⁺ Tregs and CCL1-expressing macrophages was confirmed in the hearts of patients with MI, suggesting important clinical relevance. CONCLUSIONS: Our findings reveal a 2-phase Treg specialization process and establish the CCL1-CCR8 axis as a crucial pathway for Treg recruitment and function in the infarcted heart. Therapeutic targeting of this axis may improve immune-regulated cardiac repair after MI.

CD4⁺ T‐cell counts are increased and activated in patients with chronic heart failure (CHF), whereas regulatory T‐cell (Treg) expansion is inhibited, probably due to aberrant T‐cell receptor (TCR) signaling. TCR signaling is affected by protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in autoimmune disorders, but whether PTPN22 influences TCR signaling in CHF remains unclear. This observational case–control study included 45 patients with CHF [18 patients with ischemic heart failure versus 27 patients with nonischemic heart failure (NIHF)] and 16 non‐CHF controls. We used flow cytometry to detect PTPN22 expression, tyrosine phosphorylation levels, zeta‐chain‐associated protein kinase, 70 kDa (ZAP‐70) inhibitory residue tyrosine 292 and 319 phosphorylation levels, and CD4⁺ T cell and Treg proportions. We conducted lentivirus‐mediated PTPN22 RNA silencing in isolated CD4⁺ T cells. PTPN22 expression increased in the CD4⁺ T cells of patients with CHF compared with that in controls. PTPN22 expression was positively correlated with left ventricular end‐diastolic diameter and type B natriuretic peptide but negatively correlated with left ventricular ejection fraction in the NIHF group. ZAP‐70 tyrosine 292 phosphorylation was decreased, which correlated positively with PTPN22 overexpression in patients with NIHF and promoted early TCR signaling. PTPN22 silencing induced Treg differentiation in CD4⁺ T cells from patients with CHF, which might account for the reduced frequency of peripheral Tregs in these patients. PTPN22 is a potent immunomodulator in CHF and might play an essential role in the development of CHF by promoting early TCR signaling and impairing Treg differentiation from CD4⁺ T cells.