Declines in physical function were measurable years before cardiovascular events among older adults, according to a nested case-control study published September 23, 2026, in JAMA Cardiology. Researchers analyzed 12,015 people from the Aspirin in Reducing Events in the Elderly (ASPREE) cohort, including 2,403 who subsequently experienced cardiovascular disease and 9,612 matched controls, and found that frailty and other markers diverged as much as a decade before some events.
Functional differences appeared years before cardiovascular disease became clinically apparent
The researchers examined participants enrolled in ASPREE between March 2010 and December 2014 and followed through December 2024. Eligible adults were generally at least 70 years old, although some US participants could enroll at 65. None had a history of overt cardiovascular disease (CVD), dementia, or significant physical disability at enrollment.
Within this cohort, the investigators identified 2,403 people who subsequently had an adjudicated CVD event, then matched four event-free controls to each case by age, sex, education and observation time. The resulting 12,015-person analytic sample had a mean enrollment age of 76.4 years; 52% were men.
Those who eventually developed CVD had consistently higher frailty and lower intrinsic capacity and physical health-related quality-of-life scores than controls. The differences were visible up to a decade before the event in some comparisons, and widened markedly during the five preceding years.
The timing depended on the eventual diagnosis. Divergence appeared at least 10 years before heart failure and fatal coronary heart disease in the modeled trajectories, whereas differences generally became evident later before myocardial infarction or stroke. These are patterns observed across groups, not a countdown to a cardiovascular event for an individual patient.
Annual assessments captured frailty, walking ability and perceived physical health
The investigators used a 64-item Frailty Index incorporating diseases, function, cognitive and psychosocial indicators, together with a modified Fried frailty measure covering shrinking, weakness, exhaustion, slowness and low physical activity. Higher scores represent greater frailty.
They also assessed modified intrinsic capacity, drawing on cognition, locomotion, vitality and psychological well-being. Measurements included usual walking speed over three meters and standardized cognitive tests. A 12-item survey assessed physical health-related quality of life, reflecting the participant’s perceived ability to function.
These instruments capture overlapping but distinct dimensions of aging. Frailty expresses accumulated health deficits, intrinsic capacity summarizes abilities across physiological domains, and quality of life captures how physical limitations are experienced. Their agreement makes the observed association harder to dismiss as an artifact of any single questionnaire.
At baseline, the group who subsequently developed CVD had a mean Frailty Index score of 13.1 versus 11.2 among controls. Modified intrinsic capacity averaged 49.5 versus 50.6, and physical quality-of-life scores averaged 46.9 versus 48.6. None of these differences establishes a clinically validated threshold for diagnosing occult heart disease.
Reduced functional reserve may reflect several biological processes
One possible explanation is that cardiovascular disease develops gradually before a heart attack, stroke or heart-failure diagnosis becomes apparent. Less effective circulation or declining physiological reserve may impair stamina and everyday mobility well before an event is recognized.
However, the study cannot demonstrate that those mechanisms produced the decline. Muscle aging, other chronic conditions, neurologic disease, physical inactivity, nutrition and medication effects can also reduce functional performance. Frailty is a multisystem characteristic rather than a cardiovascular-specific symptom.
This distinction is relevant to related research on silent atherosclerosis, immune regulation in atherosclerosis, and whole grains and cardiovascular risk factors. Each examines a different dimension of heart health. The functional trajectories in this study should not be treated as direct evidence of arterial plaque or a basis for diagnosing coronary disease.
Changes in trajectory persisted in several sensitivity analyses
Repeated annual scores allowed the researchers to estimate how each outcome changed with time before an event. They used longitudinal mixed-effects models and compared the event group with matched controls. Patterns persisted in additional analyses accounting for aspirin assignment, physical activity, existing chronic conditions and an estimated cardiovascular risk score at enrollment.
Results were also examined after excluding those who died from noncardiovascular causes. Broad consistency strengthens confidence that the measured association is real, but statistical adjustment cannot eliminate unmeasured differences between participants. Moreover, aspirin was randomized in the original ASPREE trial, not functional screening or interventions prompted by declining function.
What the evidence cannot yet answer
This was an observational analysis of prospectively followed participants. It cannot establish whether early functional deterioration contributes causally to CVD, reflects previously unrecognized cardiovascular problems, or arises from processes that also increase cardiovascular risk.
The sample was relatively healthy at entry by design, and approximately 94% of the analyzed participants identified as White. That limits how confidently the results can be applied to more diverse populations, adults under 65, or people already living with major disability. The intrinsic-capacity measure omitted the sensory domain of the World Health Organization framework, and some measures shared components such as gait speed and grip strength. Self-reported health may also be affected by perception and reporting differences.
The study did not measure the sensitivity, specificity or clinical usefulness of an individual functional screening threshold. It did not show that acting on changes in these scores prevents cardiovascular events, or that they improve risk predictions beyond blood pressure, cholesterol, diabetes and other established factors. A decline in the ability to climb stairs is not proof of silent heart disease.
Long-term changes in daily function deserve clinical attention
The findings suggest that tracking physical health over time might complement conventional cardiovascular assessment in older adults. The authors discuss repeated physical health-related quality-of-life questionnaires as a potentially feasible starting point for busy clinical settings, although prospective studies are needed to test such an approach.
For patients and clinicians, the practical distinction is between a concerning change and a diagnosis. New or progressively worsening difficulty with walking, stairs or routine tasks should be assessed in its broader medical context. The cause may be cardiovascular, musculoskeletal, neurologic or another condition, and the appropriate evaluation depends on symptoms and history.
Researchers conclude that progressive functional decline may indicate a prolonged opportunity for closer assessment before clinically evident cardiovascular disease. Whether systematic monitoring of these patterns ultimately improves outcomes remains unanswered.
References
- Phyo AZZ, Wu Z, Tonkin AM, et al. Multidimensional Aging Trajectories Preceding Cardiovascular Events. JAMA Cardiology. Published online September 23, 2026. DOI: 10.1001/jamacardio.2026.3597.