Causal Associations and Potential Mediating Factors Between Sarcopenia-related Traits and Heart Failure Risk: A Mendelian Randomization Study.
BACKGROUND 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 (GWASs). 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 walking pace (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 accounted for 32% of this effect, while time spent watching television accounted for 14%. Elevated appendicular lean mass 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.