The Prognostic Value of the Endothelial Activation and Stress Index in Stable Patients with Idiopathic Pulmonary Arterial Hypertension

Background: Endothelial dysfunction and chronic inflammation are central pathophysiological mechanisms in the development of idiopathic pulmonary arterial hypertension (IPAH). EASIX, the endothelial activation and stress index, is a simple and recently introduced score that captures endothelial activation and systemic stress. EASIX has been shown to be associated with several cardiovascular conditions. We investigated the relationship between EASIX and clinical outcomes in stable patients with IPAH. Methods: We retrospectively analyzed a total of 256 stable patients with IPAH in this single-center prevalent cohort. EASIX was calculated from lactate dehydrogenase, creatinine, and platelet count. The optimal cut-off of EASIX was derived by receiver operating characteristic (ROC) analysis in this cohort without external validation. Its association with all-cause mortality was assessed with ROC analysis, Kaplan–Meier estimates, and Cox regression models adjusted for age, sex, World Health Organization (WHO) functional class (WHO-FC), 6-min walking distance (6-MWD), and N-terminal pro B-type natriuretic peptide (NT-proBNP), and its incremental value with Harrell’s C-index. Results: Forty-one patients (16.0%) died during a median follow-up of 35 (interquartile range 21–46) months. In multivariable Cox regression analysis, EASIX was independently associated with all-cause mortality both as a continuous variable (Model 1; hazard ratio (HR) per 1-unit increase 1.528, 95% confidence interval (CI) 1.255–1.860; p < 0.001) and when dichotomized at ≥ 1.23 (Model 2; HR 3.989, 95% CI 1.962–8.111; p < 0.001). Adding EASIX to a model with WHO-FC, 6-MWD, and NT-proBNP changed Harrell’s C-index from 0.784 to 0.812 (likelihood-ratio test p < 0.001). The patients with higher EASIX had worse functional capacity, right ventricular function, and hemodynamics. WHO-FC III–IV and logNT-proBNP were also independently associated with all-cause mortality. Conclusions: In this single-center cohort of patients with IPAH, higher EASIX was associated with more advanced disease and was independently associated with long-term all-cause mortality. Its incremental value over established risk-stratification tools and the reproducibility of the data-derived cut-off require external validation.