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Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease-Associated Pulmonary
Caroline M Daly1, Megan Griffiths2, Catherine E Simpson3
1Johns Hopkins University School of Medicine Baltimore MD.
Insights
Elevated endostatin levels correlate with increased pulmonary arterial hypertension (PAH) severity and poorer survival in children. Measuring endostatin, particularly with NT-proBNP, improves risk assessment for pediatric PAH patients.
Area of Science:
- Cardiology
- Pulmonology
- Biomarkers
Background:
- Endostatin, an angiogenic inhibitor, is linked to adverse outcomes in adult pulmonary arterial hypertension (PAH) and impaired lung growth in children.
- This study investigates the association between endostatin levels and disease severity in pediatric PAH.
Purpose of the Study:
- To assess the relationship between serum endostatin and disease severity in pediatric PAH.
- To evaluate endostatin as a prognostic marker for transplant-free survival in pediatric PAH.
- To explore the role of endostatin in adults with congenital heart disease-associated PAH (APAH-CHD).
Main Methods:
- Serum endostatin levels were measured in pediatric PAH patients, healthy controls, and controls with congenital heart disease (CHD).
- Longitudinal analysis tracked endostatin changes alongside hemodynamic parameters and survival outcomes.
- Endostatin secretion was examined in pulmonary artery cells.
Main Results:
- Endostatin levels were significantly higher in pediatric PAH and APAH-CHD groups compared to controls.
- In APAH-CHD, higher endostatin correlated with reduced 6-minute walk distance and increased right atrial pressure.
- Elevated endostatin predicted worse hemodynamics, including pulmonary artery pressure and right ventricular dysfunction, and was associated with decreased transplant-free survival.
- Combining endostatin with NT-proBNP enhanced risk stratification for adverse outcomes.
Conclusions:
- Endostatin is a significant biomarker associated with PAH severity, improvement, and survival in pediatric patients, especially those with APAH-CHD.
- Endostatin, particularly when used with NT-proBNP, improves the prediction of adverse outcomes in pediatric PAH.
- Elevated endostatin in PAH may be influenced by pulmonary artery flow and pressure, suggesting its potential as a noninvasive prognostic marker.
Abstract:
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.
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