Abstract
Background: This study aimed to systematically investigate the association between serum branched-chain amino acids (BCAAs) and the risk of chronic rheumatic heart disease (RHD), as well as to explore potential mediating mechanisms through immune markers.
Methods: The data utilized in this prospective cohort study were derived from the UK Biobank. Serum BCAAs (leucine, isoleucine, and valine) were measured using metabolic profiling of nuclear magnetic resonance data. Chronic RHD cases were identified through hospital inpatient records and death registries. Multivariable Cox regression models were used to analyze the association between BCAAs and RHD risk. Causal mediation analysis was employed to investigate the mediated role of immune markers.
Results: A total of 273,595 participants were included, with 6051 (2.21%) participants developing chronic RHD. Each one-unit standard deviation increase in total BCAAs was associated with a 4.8% increased risk of RHD (hazard ratio (HR) = 1.048, 95% confidence interval (CI): 1.023-1.074). Among individual BCAAs, valine exhibited the strongest association (HR = 1.061, 95% CI: 1.035-1.088). Subgroup analyses revealed significantly stronger associations in participants aged <65 years compared to those aged ≥65 years (p for interaction = 0.032). Mediation analysis demonstrated that immune markers significantly mediated the BCAA-RHD association, with lymphocyte-to-C-reactive protein ratio accounting for 30.8% of the total effect.
Conclusions: Observational data suggest serum BCAAs correlate with increased RHD risk, especially in individuals aged <65 years; however, causation requires experimental verification. Immune markers significantly mediate the BCAA-RHD association, indicating that immunomodulatory pathways may be potential therapeutic targets. These findings provide novel insights into RHD pathogenesis and may inform risk stratification and prevention strategies.