Angiostatic peptide, endostatin, predicts severity in pediatric congenital heart disease–associated pulmonary hypertension

Caroline M. Daly, Megan Griffiths, Catherine E. Simpson, Jun Yang, Rachel L. Damico, R. Dhananjay Vaidya, Monica Williams, Stephanie Brandal, Pei Ni Jone, Cassandra Polsen, D. Dunbar Ivy, Eric D. Austin, William C. Nichols, Michael W. Pauciulo, Katie Lutz, Melanie K. Nies, Erika B. Rosenzweig, Russel Hirsch, Delphine Yung, Allen D. Everett

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


BACKGROUND: 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. METHODS AND RESULTS: Serum endostatin was measured in cross-sectional (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-CHD, N=185). Outcomes, assessed by regression and Kaplan-Meier analysis, included hemodynamics, change in endostatin over time, and transplant-free 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-CHD. In APAH-CHD, endostatin was associated with a shorter 6-minute 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-free survival. Addition of endostatin to an NT-proBNP (N-terminal pro-B-type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells. CONCLUSIONS: Endostatin is associated with disease severity, disease improvement, and worse survival in APAH-CHD. Endostatin with NT-proBNP 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-CHD.

Original languageEnglish (US)
Article numbere021409
JournalJournal of the American Heart Association
Issue number20
StatePublished - Oct 19 2021
Externally publishedYes


  • Angiogenesis
  • Biomarkers
  • Children
  • Proteomics
  • Pulmonary vascular disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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