Phenotypic age acceleration and all-cause and cardiovascular mortality among U.S. adults at risk for heart failure

Objective: To examine the associations of phenotypic age acceleration (PAA) with all-cause and cardiovascular mortality among U.S. adults at risk for heart failure. Methods: We analyzed 19,665 participants aged ≥20 years at risk for heart failure from the National Health and Nutrition Examination Survey (NHANES) 1999–2010 and 2015–2018. PAA was defined as the residual from regressing phenotypic age on chronological age. Kaplan-Meier analysis, weighted Cox regression, Fine-Gray competing-risk models, and restricted cubic spline analyses were used to evaluate these associations. Results: Compared with the lowest quartile, participants in the highest quartile of PAA had higher risks of all-cause mortality (HR, 2.63; 95% CI, 2.31–2.98) and cardiovascular mortality (HR, 2.55; 95% CI, 2.00–3.25). Restricted cubic spline analysis showed a nonlinear association between PAA and all-cause mortality (P for nonlinearity = 0.005), with a threshold at PAA = −8.26, whereas the association with cardiovascular mortality was linear (P for nonlinearity = 0.881). In competing-risk analysis, the highest PAA quartile remained significantly associated with increased cardiovascular mortality (SHR, 1.39; 95% CI, 1.15–1.68). Conclusion: Higher PAA was significantly associated with increased risks of all-cause and cardiovascular mortality among adults at risk for heart failure, suggesting that PAA may be a potential marker of mortality risk.