Multidimensional Aging Trajectories Preceding Cardiovascular Events

Whether declines in functional aging markers precede cardiovascular (CVD) events is unclear.

To determine 14-year trajectories of frailty, intrinsic capacity (IC), and physical health-related quality of life (HRQOL) preceding CVD events in later life and to compare these with matched CVD-free controls.

This was a case-control study nested within the Aspirin in Reducing Events in the Elderly (ASPREE) cohort. Participants were aged 70 years and older (≥65 years for US racial and ethnic minoritized groups) with no prior CVD event, dementia, or significant physical disability and were recruited in Australia and the US between March 2010 and December 2014. Four controls were matched to each CVD case by age (±1 year), sex, and education. Participants were followed up prospectively until December 2024. Data were analyzed between January and May 2026.

The 64-item Frailty Index (FI), Fried phenotype frailty, IC (comprising cognitive, locomotor, vitality, and psychological domains), and 12-item short form physical HRQOL were assessed annually.

CVD events were adjudicated by expert clinical panels. Linear mixed-effects models were used to compare the trajectories between cases and controls.

This study included 12 015 participants (2403 cases and 9612 controls) with a mean (SD) age of 76.4 (4.7) years; 6190 were male (52%). Compared with matched controls, individuals who went on to experience a CVD event had consistently worse profiles up to a decade beforehand, including higher frailty, lower IC, and poorer physical HRQOL. These differences widened markedly in the 5 years preceding the event. Cases showed faster deterioration over time, with greater increases in frailty (FI, β = 0.78; 95% CI, 0.66-0.91; Fried, β = 0.05; 95% CI, 0.03-0.07), and steeper declines in IC (β = -0.34; 95% CI, -0.44 to -0.24) and physical HRQOL (β = -0.55; 95% CI, -0.70 to -0.40). Patterns were broadly similar across components of the CVD composite, with the exception that divergence occurred earlier for heart failure and fatal coronary heart disease (≥10 years before the event) than for myocardial infarction or stroke.

Results of this nested case-control study show that declines in functional aging markers were prominent before clinically apparent CVD, suggesting that they may represent the culmination of progressive multisystem aging and indicating a prolonged window of opportunity for closer clinical evaluation and early intervention.