{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:00:22Z","timestamp":1787806822658,"version":"build-2784847793"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,10,19]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">Serum endostatin was measured in cross\u2010sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH\u2010CHD, N=185). Outcomes, assessed by regression and Kaplan\u2010Meier analysis, included hemodynamics, change in endostatin over time, and transplant\u2010free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH\u2010CHD. In APAH\u2010CHD, endostatin was associated with a shorter 6\u2010minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant\u2010free survival. Addition of endostatin to an NT\u2010proBNP (N\u2010terminal pro\u2010B\u2010type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Endostatin is associated with disease severity, disease improvement, and worse survival in APAH\u2010CHD. Endostatin with NT\u2010proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH\u2010CHD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.021409","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T09:11:20Z","timestamp":1633684280000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease\u2013Associated Pulmonary Hypertension"],"prefix":"10.1161","volume":"10","author":[{"given":"Caroline M.","family":"Daly","sequence":"first","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-9078","authenticated-orcid":false,"given":"Megan","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-1557","authenticated-orcid":false,"given":"Rachel L.","family":"Damico","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7164-1601","authenticated-orcid":false,"given":"R. Dhananjay","family":"Vaidya","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Critical Care Medicine Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Brandal","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Ni","family":"Jone","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Children's Hospital ColoradoUniversity of Colorado Aurora CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8665-1944","authenticated-orcid":false,"given":"Cassandra","family":"Polsen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Children's Hospital ColoradoUniversity of Colorado Aurora CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2541-3402","authenticated-orcid":false,"given":"D. Dunbar","family":"Ivy","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Children's Hospital ColoradoUniversity of Colorado Aurora CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric D.","family":"Austin","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology, and Pulmonary Medicine Department of Pediatrics Vanderbilt University Medical Center Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Pauciulo","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9554-7679","authenticated-orcid":false,"given":"Katie","family":"Lutz","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5453-425X","authenticated-orcid":false,"given":"Melanie K.","family":"Nies","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika B.","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics Columbia University New York City NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russel","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Yung","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics University of Washington Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5559-6708","authenticated-orcid":false,"given":"Allen D.","family":"Everett","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01916-2018"},{"key":"e_1_3_2_3_2","first-page":"169","article-title":"Pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome: current practice in pediatrics","volume":"67","author":"Frank DB","year":"2015","unstructured":"Frank DB, Hanna BD. Pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome: current practice in pediatrics. Minerva Pediatr. 2015;67:169\u2013185.","journal-title":"Minerva Pediatr"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccl.2016.04.002"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81848-6"},{"key":"e_1_3_2_6_2","unstructured":"The Genotype\u2010Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI . NHGRI NHLBI NIDA NIMH and NINDS. 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