Sarcopenia-related traits and left ventricular ejection fraction: A bidirectional Mendelian randomization study

Objectives: Observational studies report a correlation between sarcopenia, an age-related decline in muscle mass and strength, and reduced left ventricular ejection fraction (LVEF), a key predictor of adverse cardiovascular events. However, whether this relationship is causal remains uncertain. This study aimed to investigate the bidirectional causal relationship between sarcopenia-related traits and LVEF using Mendelian randomization (MR). Methods: We conducted a two-sample, bidirectional MR study. Genetic variants associated with 3 sarcopenia-related traits—appendicular lean mass (ALM; n=450,243), low hand grip strength (n=256,523), and walking pace (n=459,915)—were obtained from the UK Biobank. Summary statistics for LVEF (n=32,532) were sourced from the GWAS Catalog. The primary analysis was performed using the inverse-variance weighted (IVW) method. We conducted extensive sensitivity analyses, including MR-Egger and MR-PRESSO, to assess horizontal pleiotropy. Results: Genetically predicted higher ALM was causally associated with a reduced risk of decreased LVEF (OR per 1-kg increase in ALM=0.684, 95% CI: 0.545–0.859; P =0.001). No significant causal associations were found for low hand grip strength (OR=0.763, 95% CI: 0.456–1.275; P =0.301) or walking pace (OR=0.363, 95% CI: 0.064–2.057; P =0.252) with LVEF. In the reverse MR analysis, there was no evidence of a causal effect of LVEF on any of the 3 sarcopenia-related traits. Conclusions: This study provides genetic evidence supporting a causal relationship between lower ALM, a key component of sarcopenia, and an increased risk of reduced LVEF. Our findings suggest that maintaining appendicular lean mass is a protective factor against cardiac dysfunction. Routine LVEF assessment in patients with low ALM could facilitate early detection of declining cardiac function.