{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T18:39:28Z","timestamp":1784745568512,"version":"3.55.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure\u2014a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175\/2248), which was comparable to the 6.6% (66\/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23\/159];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15\/53) and the validation cohort (11%; 13\/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)\u2013age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72\/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      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\/circheartfailure.125.014480","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:00:20Z","timestamp":1781859620000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Characterization of Unclassified Pulmonary Hypertension"],"prefix":"10.1161","volume":"19","clinical-trial-number":[{"clinical-trial-number":"nct02980887","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5322-0902","authenticated-orcid":true,"given":"Yogesh N.V.","family":"Reddy","sequence":"first","affiliation":[{"name":"The Department of Cardiovascular Medicine (Y.N.V.R., R.P.F., A.C.E., W.R.M., B.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-3978","authenticated-orcid":true,"given":"Robert P.","family":"Frantz","sequence":"additional","affiliation":[{"name":"The Department of Cardiovascular Medicine (Y.N.V.R., R.P.F., A.C.E., W.R.M., B.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8810-3631","authenticated-orcid":true,"given":"Alexander C.","family":"Egbe","sequence":"additional","affiliation":[{"name":"The Department of Cardiovascular Medicine (Y.N.V.R., R.P.F., A.C.E., W.R.M., B.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8864-8474","authenticated-orcid":true,"given":"William R.","family":"Miranda","sequence":"additional","affiliation":[{"name":"The Department of Cardiovascular Medicine (Y.N.V.R., R.P.F., A.C.E., W.R.M., B.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0147-4537","authenticated-orcid":true,"given":"Aneesh K.","family":"Asokan","sequence":"additional","affiliation":[{"name":"The Department of Cardiovascular Medicine (Y.N.V.R., R.P.F., A.C.E., W.R.M., B.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0601-4975","authenticated-orcid":true,"given":"Paul M.","family":"Hassoun","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD (P.M.H., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2755-5845","authenticated-orcid":true,"given":"Anna R.","family":"Hemnes","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (A.R.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5751-9415","authenticated-orcid":true,"given":"Evelyn","family":"Horn","sequence":"additional","affiliation":[{"name":"Perkin Heart Failure Center, Division of Cardiology, Weill Cornell Medicine, New York, NY (E.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-8882","authenticated-orcid":true,"given":"Jane A.","family":"Leopold","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (J.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Rischard","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Arizona, Tucson (F.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-214X","authenticated-orcid":true,"given":"Erika B.","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine, Columbia University, New York, NY (E.B.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8242-8339","authenticated-orcid":true,"given":"Nicholas S.","family":"Hill","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts Medical Center, Boston, MA (N.S.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-9065","authenticated-orcid":true,"given":"Serpil C.","family":"Erzurum","sequence":"additional","affiliation":[{"name":"Lerner Research Institute (S.C.E.), Cleveland Clinic, 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