Association of fat-to-muscle mass ratio with incident coronary artery disease and the potential role of metabolic signatures

The fat-to-muscle mass ratio (FMR) reflects the balance between metabolic burden and capacity. However, the associations of total and regional FMR with incident coronary artery disease (CAD) and their underlying metabolic mechanisms remain unclear. We included 398,435 UK Biobank participants free of baseline cardiovascular disease, diabetes, or lipid-lowering therapy. Total and regional (trunk, arm, leg) FMR were quantified via bioelectrical impedance analysis. Participants were stratified by sex and classified based on FMR thresholds derived from restricted cubic splines and BMI categories. Primary outcome was incident CAD, defined as myocardial infarction, coronary revascularization, or CAD mortality. Metabolic signatures were constructed using elastic net regression on 251 NMR metabolites. During a median follow-up of 12.61 years, 10,740 incident CAD cases were documented. Higher total and regional FMR were significantly associated with increased CAD risk in both sexes. Leg FMR exhibited the strongest independent association; after mutual adjustment for BMI, it remained a significant predictor in both women (HR: 3.672, 95% CI 1.958–6.887) and men (HR: 2.682, 95% CI 1.682–4.275), whereas associations for other FMR types were attenuated. Mediation analysis suggested that metabolic signatures partially accounted for the association between FMR and CAD, explaining over 70% of the statistical effect. Furthermore, adding leg FMR to standard risk factors significantly improved risk reclassification (NRI: 0.142 for women, 0.081 for men; both p value < 0.001). Elevated FMR, particularly leg FMR, is strongly associated with higher CAD risk independent of BMI. These findings suggest that altered body composition may reflect underlying metabolic dysregulations, and assessing leg FMR could provide additive value for risk reclassification, particularly in women.