Heart Stress, Frailty and Mortality Risk in two prospective cohorts

Importance Frailty is a multisystem syndrome that reflects age-related physiological decline, underscoring the need for more biologically informed risk stratification within frailty assessments. Frailty and heart stress (HS) are individually associated with increased mortality risk, but their combined effects remain practically unexplored. Objective To evaluate whether the combined exposure to frailty and HS is associated with an increased risk of mortality. Design, Setting, and Participants This prospective cohort study used data from the US National Health and Nutrition Examination Survey (NHANES) and the Health and Retirement Study (HRS). Participants with complete data on frailty and HS were included. Analyses was performed between May 2025 and October 2025. Exposure Frailty was assessed using three frailty indices (FI) based on self-reported items (FI-Self-report), blood biomarkers (FI-Lab), and their combination (FI-Combined). HS was defined by age-adjusted elevation in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Participants were estimate into four groups according to baseline frailty and HS status. Main Outcomes and Measures The primary outcome was all-cause mortality. Cox proportional hazard models were employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results A total of 12,252 participants from NHANES (mean age 49.91 years, 52.18% female), and 9,488 participants from HRS (mean age 69.16 years, 58.97% female) were included. Compared with those having neither frailty nor HS, participants with frailty and/or HS showed significantly elevated mortality risk in both cohorts, with HRs ranging from 1.81 to 5.54. The highest mortality risk was observed in participant with both frailty and HS, the HRs were 3.58 (95% CI: 3.20-4.01) for FI Self Report, 3.43 (95% CI: 3.04-3.86) for FI Lab, and 4.15 (95% CI: 3.70-4.67) for FI Combined in NHANES; the corresponding HRs were 5.02 (95% CI: 4.38-5.76), 4.73 (95% CI: 4.13-5.41), and 5.54 (95% CI: 4.84-6.35) in HRS, respectively. Conclusions and Relevance Co-occurrence of frailty and HS is common, and jointly associated with increased mortality risk in the general population. These findings support integrating HS into frailty assessments to improve mortality risk stratification and guide targeted interventions. Key Points Question: Is the combination of frailty and heart stress (HS) associated with increased mortality risk? Findings: In this prospective cohort study including 12,252 participants from the US National Health and Nutrition Examination Survey (NHANES) and 9,488 participants from the Health and Retirement Study (HRS), participants with frailty and/or HS exhibited higher risk of all-cause mortality. The greatest mortality risk was found among participant with both frailty and HS. Meaning: These findings indicate that co-occurrence of frailty and HS is associated with increased mortality risk, supporting integration of HS into frailty assessment for risk stratification and intervention.