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.