Endothelial stress as reflected by EASIX predicts cardiovascular morbidity and mortality: Insights from a nationally representative cohort

Endothelial dysfunction (ED) is a key pathophysiological mechanism in cardiovascular diseases (CVD). The Endothelial Activation and Stress Index (EASIX), derived from routine laboratory markers, has been proposed as a surrogate indicator of endothelial stress. However, its relevance to CVD burden and long-term outcomes in the general population remains uncertain. We analyzed data from 38,713 adults aged ≥20 years enrolled in the U.S. National Health and Nutrition Examination Survey (NHANES, 1999–2018), representing approximately 1.7 billion individuals after weighting. EASIX was calculated as [LDH (U/L) × creatinine (mg/dL)] / platelet count (10 9 /L) and log₂-transformed. Weighted logistic regression assessed the association between EASIX and CVD prevalence, while weighted Cox models examined its relationship with all-cause (ACM) and cardiovascular mortality (CVM). Restricted cubic spline analyses evaluated potential nonlinear trends, and subgroup analyses tested effect modification. Among 38,713 participants, 4131 had CVD. Higher EASIX values were independently associated with greater CVD prevalence (adjusted OR = 1.43, 95% CI: 1.34–1.53). Each log₂ increase in EASIX corresponded to higher risks of ACM (HR = 1.39, 95% CI: 1.28–1.51) and CVM (HR = 1.54, 95% CI: 1.38–1.72). Individuals in the top EASIX quartile exhibited more than double the mortality risks compared with those in the lowest quartile. Associations were nonlinear and consistent across most subgroups. EASIX demonstrated independent, nonlinear associations with both CVD prevalence and long-term mortality. These findings highlight EASIX as a practical, cost-efficient biomarker for cardiovascular risk stratification in population settings. • EASIX independently predicts cardiovascular disease prevalence in U.S. adults. • Elevated EASIX levels are linked to higher all-cause and cardiovascular mortality. • Nonlinear associations highlight EASIX's dynamic role in vascular pathophysiology. • Results remained robust after multivariable adjustment and across key subgroups. • EASIX may serve as a simple, accessible biomarker for cardiovascular risk assessment.