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As NOTCH3 cleavage occurs constitutively in the lungs of individuals with IPAH, we investigated whether the NOTCH3 extracellular domain (NOTCH3-ECD) shed into serum could be used as a robust biomarker for IPAH. In three geographically distinct cohorts comprising 341 individuals with IPAH (267 women, 74 men) and 376 healthy individuals (278 women, 98 men), serum NOTCH3-ECD levels were significantly higher in individuals with IPAH (mean\u2009\u00b1\u2009s.d.: 19.9\u2009\u00b1\u20095.5\u2009ng\u2009ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) compared to controls (10.5\u2009\u00b1\u20091.9\u2009ng\u2009ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    ;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001), with consistent results among the three cohorts. NOTCH3-ECD levels correlated with mean right atrial pressure, pulmonary vascular resistance, mean pulmonary artery pressure, tricuspid regurgitant velocity, 6-min walk distance and the New York Heart Association class. The area under the receiver operating curve for diagnosis of IPAH, based on serum NOTCH3-ECD, was 0.96 (95% confidence interval, 0.95\u20130.98) with a 90% sensitivity and 93% specificity at a cutoff of 13.0\u2009ng\u2009ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    . The 3-year mortality risk for individuals with IPAH increased by 18% for each increase in 3\u2009ng\u2009ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    of NOTCH3-ECD above the diagnostic cutoff. The addition of serum NOTCH3-ECD levels improved the performance of prognostic calculators for PAH, including REVEAL 2.0, REVEAL 2.0 Lite and COMPERA 2.0. Moreover, serum NOTCH3-ECD levels predicted the presence of IPAH in treatment-naive individuals and correlated with disease progression over a follow-up of 6\u2009years. Measurement of serum NOTCH3-ECD can therefore provide a highly sensitive, specific and noninvasive test for predicting the presence, disease severity, progression and survival of individuals with IPAH.\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-04134-3","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T10:02:50Z","timestamp":1767952970000},"page":"306-317","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The NOTCH3 extracellular domain is a serum biomarker for pulmonary arterial hypertension"],"prefix":"10.1038","volume":"32","author":[{"given":"Moises","family":"Hernandez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0784-2679","authenticated-orcid":false,"given":"Nolan M.","family":"Winicki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0953-0150","authenticated-orcid":false,"given":"Cristian D.","family":"Puerta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7518-4668","authenticated-orcid":false,"given":"Swetha","family":"Lakshminarayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9172-9301","authenticated-orcid":false,"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Ramirez-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casandra E.","family":"Besse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Poch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason X.-J.","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Y.-J.","family":"Shyy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2145-4944","authenticated-orcid":false,"given":"Paul B.","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe G. 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