{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T16:59:25Z","timestamp":1785257965018,"version":"3.55.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC\u2010PH (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\u2010free survival across the new PH clusters. We quantify metabolites of the arginine\u2010nitric oxide pathway and D\u2010dimer 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Clustering analysis identify 3 clear clusters in\n                      <jats:styled-content style=\"fixed-case\" toggle=\"no\">CC<\/jats:styled-content>\n                      \u2010\n                      <jats:styled-content style=\"fixed-case\" toggle=\"no\">PH<\/jats:styled-content>\n                      that are validated in\n                      <jats:styled-content style=\"fixed-case\" toggle=\"no\">PVDOMICS<\/jats:styled-content>\n                      and outperform conventional classifications in predicting transplantation\u2010free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D\u2010dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">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.<\/jats:p>\n                    <jats:p xml:lang=\"en\">\n                      REGISTRATION: URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifier: NCT02980887.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.048795","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:53:28Z","timestamp":1784285608000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Endotypes of Vascular Health Predict Transplantation\u2010Free Survival in Pulmonary Hypertension"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4800-8928","authenticated-orcid":false,"given":"Samar","family":"Farha","sequence":"first","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-7639","authenticated-orcid":false,"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"Duke University","place":["Durham, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoying","family":"Chen","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2403-8268","authenticated-orcid":false,"given":"John","family":"Barnard","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1918-9002","authenticated-orcid":false,"given":"Suzy","family":"Comhair","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-2599","authenticated-orcid":false,"given":"Gustavo","family":"Heresi","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Parambil","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2321-9545","authenticated-orcid":false,"given":"Adriano","family":"Tonelli","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8876-5045","authenticated-orcid":false,"given":"Gerald","family":"Beck","sequence":"additional","affiliation":[{"name":"Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-214X","authenticated-orcid":false,"given":"Erika","family":"Berman\u2010Rosenzweig","sequence":"additional","affiliation":[{"name":"New York Medical College","place":["Valhalla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8410-4429","authenticated-orcid":false,"given":"Hilary","family":"DuBrock","sequence":"additional","affiliation":[{"name":"Mayo Clinic","place":["Rochester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-6757","authenticated-orcid":false,"given":"J. 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