Multidomain risk profiles and documented polyvascular involvement across atherosclerotic vascular beds

Atherosclerotic cardiovascular disease (ASCVD) manifests heterogeneously across coronary (CAD), cerebrovascular (CeVD), and peripheral artery (PAD) beds.

To evaluate sociodemographic, clinical, lifestyle, and genetic determinants of incident ASCVD, vascular bed localization, and subsequent documented polyvascular involvement.

We analyzed 468,266 UK Biobank participants free of ASCVD at baseline. Risk factor associations were examined using multivariable Cox models, machine learning-derived SHapley Additive Explanations (SHAP), multinomial logistic regression, and discrete-time multistate models of clinically documented ASCVD states.

Among participants (mean age 57 years, 56% female) followed for 13 years, 2.8% developed CAD, 1.9% CeVD, and 1.5% PAD. Risk domains showed distinct relative associations across vascular beds. PAD onset was most strongly associated with inflammation, metabolic dysfunction, and smoking, including hsCRP (HR per SD 1.22, 95% CI 1.19-1.26); CAD was more strongly associated with LDL-C (HR 1.24, 95% CI 1.21-1.26) and CAD polygenic risk score (PRS). CeVD showed overlapping features, with additional contribution from socioeconomic deprivation. Healthy sleep and physical activity were protective across outcomes. SHAP analyses yielded similar profiles. In multinomial models, inflammation, glycemic status, and smoking were enriched in non-CAD phenotypes, whereas LDL-C and CAD PRS were more specific to CAD. PAD was most frequently followed by subsequent documented polyvascular ASCVD and mortality. In multistate models, PRSs were primarily associated with early transitions from healthy to incident ASCVD or death, whereas later documented transitions and mortality after ASCVD were more strongly linked to clinical and lifestyle factors.

ASCVD shows distinct risk profiles across vascular beds and disease stages. Genetic factors were more strongly associated with early incident ASCVD, while clinical and lifestyle factors predominated in subsequent documented polyvascular involvement and later mortality.