Joint association of early vascular aging and frailty with major adverse cardiovascular events: a Chinese community-based cohort study

Background Early vascular aging (EVA) and frailty represent two distinct phenotypes of accelerated biological aging. While both are associated with cardiovascular (CV) risk, their interrelationship and joint impact on long-term outcomes in the general population remain unclear. Purpose This study aims to evaluate the association between EVA and frailty, and to determine their independent and combined predictive value for major adverse cardiovascular events (MACE). Methods 8,233 participants without CV disease were analyzed from a Chinese community-based cohort. Vascular age was calculated using a multivariable regression model including brachial-ankle pulse wave velocity and traditional risk factors. ΔAge was defined as the residual obtained from a linear regression of vascular age on chronological age. EVA was defined as ΔAge >80th percentile. Frailty status was assessed using a 31-item deficit-accumulation Frailty Index (FI), with frailty defined as FI ≥0.21. Participants were stratified into four groups: Non-Frail+Non-EVA, Non-Frail+EVA, Frail+Non-EVA, and Frail+EVA. The endpoint was MACE, comprising cardiovascular mortality, non-fatal stroke, and non-fatal myocardial infarction. Kaplan-Meier curve, Cox proportional hazard models, subgroup and interaction analyses, and reclassification analyses (C-statistic, NRI, IDI) were performed. Results The mean age was 56.6 ± 8.9 years, and and 64.6% of participants were female. Over a median follow-up of 9.86 years, 826 (10.0%) participants experienced MACE. There was a weak positive correlation between FI and ΔAge (Pearson r=0.139, P<0.001). Kaplan-Meier curves showed significant differences in MACE risk across groups (Log-rank P<0.001), with the Frail+EVA group having the highest risk. After adjusting for age, sex, and China-PAR CV risk score, both EVA alone (HR 1.59, 95% CI 1.18–2.15) and Frailty alone (HR 1.76, 95% CI 1.46–2.12) were associated with an increased risk of MACE compared to the Non-Frail+Non-EVA group. Notably, the combined Frail+EVA group conferred the highest risk (HR 2.13, 95% CI 1.71–2.66). Interaction analyses revealed no significant interaction on either the multiplicative (P=0.119) or additive scale (RERI -0.22, 95% CI -0.79 to 0.35). Consistent associations were observed across subgroups stratified by age, sex, obesity, comorbidities, and medications (all P for interaction >0.05). Adding both FI and ΔAge to the baseline China-PAR CV risk prediction model significantly improved risk discrimination (C-statistic increase 0.008, P=0.002) and reclassification (NRI 12.8%, P<0.001; IDI 0.41%, P=0.008). Conclusion EVA and frailty are distinct aging phenotypes that confer independent and additive risks for MACE. The coexistence of both conditions identifies a high-risk “double-hit” phenotype. Assessing both vascular health and frailty status provides significant incremental value for CV risk stratification in the community-based population.