Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic Predisposition on Coronary Artery Disease

Background Estimated pulse wave velocity (ePWV), a noninvasive marker of arterial stiffness, reflects vascular aging and has been associated with increased coronary artery disease (CAD) risk. However, the interplay between ePWV and genetic factors, including polygenic risk score (PRS) and apolipoprotein E genotypes, in determining CAD susceptibility remains unclear. Methods We analyzed data from the HRS (Health and Retirement Study), including 5856 participants (4741 White and 1115 Black individuals) without baseline CAD. ePWV was calculated, and genetic risk was assessed using PRS and apolipoprotein E genotyping. Cox proportional hazards models evaluated the associations between ePWV, genetic predisposition, and CAD incidence, with stratified analyses by race and sex. Mediation analyses explored underlying mechanisms. Results Elevated ePWV (≥10 m/s) was significantly associated with increased CAD risk (hazard ratio [HR], 1.50 [95% CI, 1.25–1.81], P <0.001). Among White participants, both high PRS and elevated ePWV independently predicted CAD, with a potential mitigating interaction effect. In Black participants, PRS was not significantly associated with CAD risk, whereas apolipoprotein E ε4 carriers with high ePWV exhibited a markedly increased risk (HR, 2.62 [95% CI 1.09–6.32], P =0.032). Sex‐stratified analyses indicated that White women with high PRS and high ePWV had a lower‐than‐expected CAD risk. Additionally, changes in total cholesterol and high‐density lipoprotein cholesterol mediated the association between ePWV and CAD. Conclusions Vascular aging and genetic predisposition interact in complex ways to influence CAD risk, with notable variations across racial and sex subgroups. These findings highlight the need for personalized prevention strategies incorporating both vascular health and genetic risk profiling.