Abstract
Older adults with established cardiovascular diseases (CVD) are at elevated risk of heart failure (HF). Frailty, a hallmark of multi-system aging, may contribute to HF development through inflammation. However, population-based evidence remains scarce. Leveraging data from 49,530 CVD patients in the UK Biobank, frailty was measured by five components: weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. We employed Cox regression models to assess the association between frailty and incident HF, and conducted mediation analyses to evaluate mediating roles of 15 inflammatory markers in this association. Furthermore, we constructed a polygenic risk score (PRS) for HF risk based on the Global Biobank Meta-analysis Initiative (N = 1,020,441), and evaluated the joint association and interaction between frailty and PRS in relation to incident HF. During a median follow-up of 13.3 years, 6293 participants developed HF. Compared to robust individuals, pre-frail (hazard ratio (HR) = 1.31 [95% CI: 1.23-1.40]) or frail (HR = 1.80 [1.64-1.98]) participants had a higher risk of HF, and the potential causality was suggested by Mendelian randomization. Such relationship was partially mediated by inflammatory markers, including interleukin-6, tumor necrosis factor-α, and C-reactive protein. Moreover, individuals with both frailty and high PRS had the greatest risk of HF (HR = 4.35 [3.74-5.06]), with a relative excess risk due to interaction of 1.39, accounting for 32% of total risk. Frailty interacts with PRS to enhance risk stratification of HF. Inflammation may mediate the frailty-HF association, suggesting the potential of anti-inflammatory interventions to mitigate HF risk in frail CVD patients.Graphical Abstract