PubMed2026
INTRODUCTION: In this two-sample, two-step Mendelian randomization (MR) study, we aimed to elucidate the causal associations between sarcopenia-related characteristics and heart failure (HF) risk, and to identify the factors mediating these associations, with a particular focus on the mediating roles of obesity and sedentary habits. METHODS: Genetic instruments for appendicular lean mass (ALM), hand grip strength (HGS), walking pace (WP), and potential mediators were extracted from genome-wide association studies. Inverse-variance weighting (IVW) was used as the primary analytical method, supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses including Cochran's Q test and MR-Egger intercept method were performed to assess heterogeneity and pleiotropy. Bidirectional MR was conducted to exclude reverse causation. RESULTS: IVW revealed that a faster genetically predicted WP was associated with lower HF risk (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.33-0.60, p = 5.806 × 10-7). The mediation analysis indicated that body mass index (BMI) accounted for 32% of this effect, while time spent watching television accounted for 14%. Elevated ALM showed a slight but significant positive association with HF risk (OR 1.06, 95% CI 1.03-1.09, p = 5.437 × 10-4). However, multivariable MR adjusting for BMI completely attenuated this association (p = 0.693), suggesting ALM reflects overall body composition rather than isolated muscle mass. No significant associations were found between HGS and HF. Bidirectional MR showed no robust reverse effects. CONCLUSIONS: These findings suggest that genetically predicted increased WP exerts beneficial effects against HF, partially mediated by obesity and sedentary habits. Targeting weight management and anti-sedentary interventions may mitigate HF risk in individuals with sarcopenia-related characteristics.