Longitudinal Endothelial Activation and Stress Index (EASIX) trajectories and mortality risk in chronic heart failure

BACKGROUND: The Endothelial Activation and Stress Index (EASIX) is a routinely available marker of endothelial activation and systemic stress. Although baseline EASIX predicts mortality in chronic heart failure, its long-term longitudinal behavior and prognostic relevance during follow-up remain insufficiently characterized. AIM: To assess whether serial EASIX measurements identify clinically relevant risk trajectories and improve dynamic mortality risk stratification in chronic heart failure. METHODS: We analyzed 1924 patients with chronic heart failure from the Heidelberg chronic heart failure outpatient registry with at least two available EASIX measurements. The main landmark transition analysis included 1789 patients with valid first-to-second transition assignment, follow-up after the second EASIX measurement, and complete covariate data for the adjusted Cox model. Patients were categorized into early EASIX transition groups using the median baseline log2(EASIX) threshold applied to the first and second measurements. Survival analyses were landmarked at the second EASIX measurement. Associations with all-cause mortality were assessed using multivariable Cox regression, patient-specific EASIX slopes derived from linear mixed-effects models, and time-updated Cox models. RESULTS: In the full longitudinal cohort, 330 deaths occurred. In the adjusted landmark transition cohort, patients rising from low to high EASIX had markedly increased subsequent mortality compared with stable low patients (adjusted HR 2.33, 95% CI 1.57-3.46; p < 0.001), as did patients with persistently high EASIX (adjusted HR 1.88, 95% CI 1.35-2.62; p < 0.001). Mortality after the second EASIX measurement was lowest in stable low patients and highest in patients rising to high or remaining persistently high. Each 0.10 log2(EASIX) units/year increase in EASIX slope was associated with higher mortality risk (HR 1.43, 95% CI 1.22-1.67; p < 0.001), and time-updated log2(EASIX) remained independently prognostic. CONCLUSIONS: Serial EASIX assessment captures dynamic systemic risk in chronic heart failure. Rising or persistently elevated EASIX identifies patients at increased mortality risk and may provide a practical, low-cost tool for longitudinal risk stratification.