Allostatic load and arterial and venous vascular events: findings from the Moli-sani Study

Background Allostatic load (AL) reflects cumulative multisystem biological dysregulation induced by chronic stress exposure, capturing chronic physiological burden. Whether AL predicts long-term risk across arterial and venous vascular outcomes remains unclear. This study examined the association between AL and cardiovascular disease (CVD) and venous thromboembolism (VTE) in a large population-based prospective cohort. Methods We analyzed 22,255 participants (aged ≥ 35 years; 53% women) free of CVD and VTE at baseline (2005-2010). Outcomes were fatal and non-fatal CVD, including 1447 events (1036 CHD, 235 ischemic stroke), and 108 unprovoked VTE during 13-year follow-up. AL was computed as the sum of standardized (z-score) biomarkers across cardiovascular (systolic/diastolic blood pressure, heart rate), inflammatory (C-reactive protein, fibrinogen, WBC, albumin, glycoprotein acetyls), metabolic (total/HDL-cholesterol, triglycerides, glucose, BMI, waist-to-hip ratio, insulin, lipoprotein(a), apolipoprotein B), respiratory (FEV1, FVC) and renal markers (creatinine, cystatin C). After inversion of protective biomarkers, these were equally summed into a global AL index: higher values indicate greater biological dysregulation. Cox proportional models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), across AL quartiles, adjusting for demographic, socioeconomic and lifestyle factors. Results Participants in the highest AL quartile, compared with the first, had increased hazard of CVD (HR 3.14; 95% CI 2.53-3.90), strongest for CHD (4.54; 3.45-5.98). Association with ischemic stroke was weaker (1.92; 1.15-3.20). Higher AL was also associated with higher hazard of VTE (2.25; 1.11-4.54). Conclusions Higher AL was associated with an excess hazard major arterial of major arterial events, particularly CHD, and also extended to unprovoked VTE. Cumulative multisystem biological dysregulation may represent an integrative marker for vascular risk stratification. Key messages • Cumulative multisystem biological dysregulation, captured by allostatic load, identifies individuals at higher risk of cerebro-cardiovascular disease and unprovoked venous thromboembolism. • Allostatic load supports vascular risk stratification beyond traditional arterial outcomes, highlighting a shared long-term vulnerability across arterial and venous disease.