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

Background: 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. Methods: 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 (109/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. Results: 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. Conclusions: 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.