A plasma proteomic frailty signature for cardiovascular risk stratification: A multi-cohort study

Background Frailty predicts adverse health outcomes, but its relationship with cardiovascular disease (CVD) requires further validation across diverse populations. The value of a circulating protein signature for cardiovascular risk assessment remains uncertain. Methods We examined frailty–CVD associations in the XiDu2017 cohort ( n = 4323) and UK Biobank (UKB; n = 84,276) using logistic and Cox regression, respectively. XiDu longitudinal analyses included 844 participants without baseline CVD. In the UKB proteomic subset, a 20-protein frailty (PF) score was compared with clinical frailty and a model of conventional cardiovascular risk factors. Results Each higher frailty category was associated with prevalent CVD in XiDu (adjusted odds ratio, 1.120; 95% confidence interval [CI], 1.004–1.251). In UKB, frail participants had a higher CVD hazard than robust participants (adjusted hazard ratio, 1.38; 95% CI, 1.28–1.48). For heart failure, the 5-year area under the curve (AUC) was 0.756 for PF and 0.595 for clinical frailty. Adding PF to conventional risk factors increased the optimism-corrected heart failure AUC by 0.113 (95% CI, 0.077–0.142). Conclusions Clinical frailty was associated with cardiovascular outcomes in both cohorts. PF showed incremental discrimination for selected outcomes, particularly heart failure. External validation and evaluation of clinical utility are needed before clinical application.