Endotypes of Vascular Health Predict Transplantation‐Free Survival in Pulmonary Hypertension

BACKGROUND: The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. METHODS: We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC-PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation-free survival across the new PH clusters. We quantify metabolites of the arginine-nitric oxide pathway and D-dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. RESULTS: Clustering analysis identify 3 clear clusters in CC-PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation-free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D-dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. CONCLUSIONS: We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.