Association of Limb Fat Distribution and Plasma Metabolites With the Risk of Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is a potentially life-threatening cardiovascular condition. However, the role of limb-specific fat distribution and related metabolic signatures in VTE remains unclear. OBJECTIVE: To assess associations of upper- and lower-limb fat distribution with VTE risk and evaluate whether circulating metabolites mediate these relationships. METHODS: This retrospective cohort study analyzed UK Biobank data, in which arm and leg fat mass was measured by bioelectrical impedance. Cox proportional hazards models and restricted cubic splines assessed its sex-specific associations with incident VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Least absolute shrinkage and selection operator regression identified metabolites related to the arm-to-leg fat mass percentage, followed by mediation analysis. RESULTS: Over a median follow-up of 13.6 years, 14,593 VTE events occurred among 458,651 participants. Higher arm-to-leg fat mass percentage was associated with increased VTE risk, with hazard ratios (HRs) of 1.81 (95% CI, 1.63-2.00) in women and 1.55 (95% CI, 1.47-1.64) in men when comparing the highest with lowest tertile. A total of 138 metabolites in women and 38 in men were associated with arm-to-leg fat distribution. In women, the metabolic signature mediated 15.2% (95% CI, 6.8-21.9) of the association between arm-to-leg fat and VTE, and 21.1% (95% CI, 12.8-28.4) of the corresponding association for PE; no significant mediation was observed in men. CONCLUSIONS: Upper-predominant peripheral fat distribution is associated with high risk of VTE. Sex-specific metabolic signatures partially mediate these associations in women, underscoring the importance of integrating limb fat distribution and metabolomics for improved VTE risk assessment.