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.

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Publication Details

Journal
Journal of the American Heart Association
Published
2026-07-17
DOI
https://doi.org/10.1161/jaha.125.048795
Citations
1
Primary Topic
Pulmonary Hypertension Research and Treatments
Type
article
Field-Weighted Citation Impact
7.89
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article

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

Hilary M. DuBrock, Gustavo A. Heresi, J. Emanuel Finet, Suzy Comhair et al.
1 citations
Journal of the American Heart Association
Pulmonary Hypertension Research and Treatments
7.89
article

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

Hilary M. DuBrock, Gustavo A. Heresi, J. Emanuel Finet, Suzy Comhair, Paul M. Hassoun, Serpil C. Erzurum, John Barnard, Adriano R. Tonelli, Ruoying Chen, W.H. Wilson Tang, Christine Jellis, Catherine E. Simpson, Evelyn M. Horn, Samar Farha, Mitchell A. Olman, Anna R. Hemnes, Jane A. Leopold, Nicholas S. Hill, Bo Hu, Raed A. Dweik, Robert P. Frantz, Margaret Park, Gabriele Grünig, Erika B. Rosenzweig, Gerald J. Beck, the PVDOMICS Study Group, Joseph Parambil, Franz P. Rischard
article en
1 citations

Abstract

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.

Journal of the American Heart Association
Brigham and Women's Hospital (US), Tufts Medical Center (US), Cleveland Clinic (US), University of Arizona (US), Duke University (US), New York Medical College (US), Cornell University (US), WinnMed (US), Johns Hopkins Hospital (US), New York University (US), Vanderbilt University Medical Center (US)
Good health and well-being
Openalex Percentile: Top 2%
Pulmonary Hypertension Research and Treatments
7.89
DOIOpen Access PDFOpenAlex
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