Endothelial Activation Stress Index and risk of all-cause and cardiovascular mortality in early-stage cardio-renal-metabolic syndrome: A nationwide retrospective cohort study

Endothelial dysfunction plays a central role in the pathophysiology of cardiovascular, renal, and metabolic diseases. The Endothelial Activation Stress Index (EASIX) has emerged as a promising prognostic marker in endothelial-related disorders. This study aimed to evaluate the association between EASIX and the risks of all-cause and cardiovascular mortality in individuals with cardio-renal-metabolic (CKM) syndrome stages 0 to 3. Data were obtained from the National Health and Nutrition Examination Survey 2005 to 2010 and 2015 to 2018 cycles. A total of 7046 participants with CKM stages 0 to 3 were included. EASIX was calculated as lactate dehydrogenase × creatinine/platelet count. The primary outcome was cardiovascular mortality, and the secondary outcome was all-cause mortality, ascertained through linkage to the National Death Index. The optimal cutoff value of EASIX was determined using maximally selected rank statistics. Associations were assessed using survey-weighted Cox proportional hazards models, restricted cubic splines, and subgroup analyses. Predictive performance was evaluated using time-dependent receiver operating characteristic curves. Mediation analysis and competing risk models were also performed. Higher EASIX (≥0.64) was significantly associated with increased risks of cardiovascular mortality (adjusted hazard ratio = 1.65, 95% confidence interval = 1.11-2.46) and all-cause mortality (adjusted hazard ratio = 1.45, 95% confidence interval = 1.16-1.81). Restricted cubic spline analysis revealed a significant nonlinear relationship between EASIX and mortality (P < .001). Kaplan-Meier curves showed lower survival probabilities in the high-EASIX group (log-rank P < .0001). The association remained consistent across subgroups. EASIX demonstrated good predictive performance for 1-, 3-, and 5-year mortality. Mediation analysis indicated that chronic kidney disease accounted for approximately 30% to 35% of the observed associations. Competing risk analysis confirmed the independent association between EASIX and cardiovascular mortality. EASIX is a simple and robust predictor of all-cause and cardiovascular mortality in patients with CKM stages 0 to 3, and may facilitate early risk stratification and personalized management.