Key result
Elevated serum endostatin was associated with worse disease severity, hemodynamics, and transplant-free survival in congenital heart disease-associated pulmonary arterial hypertension.
Why the study?
Endostatin is associated with worse PAH outcomes in adults and poor lung growth in children, but whether it is associated with disease severity and outcomes in pediatric PAH was unknown.
Is serum endostatin associated with disease severity and transplant-free survival in pediatric and adult congenital heart disease-associated pulmonary hypertension?
Cohort (n=478)
Is serum endostatin associated with disease severity and transplant-free survival in pediatric and adult congenital heart disease-associated pulmonary hypertension?
Serum endostatin is a promising noninvasive prognostic biomarker that, when combined with NT-proBNP, improves risk stratification in congenital heart disease-associated pulmonary hypertension.
Should not yet change practice in CHD-PAH; leaves open prospective validation of endostatin with NT-proBNP for risk stratification.
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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Daly et al. (2021) conducted a cohort in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension (n=478). Serum endostatin vs. Healthy controls and controls with CHD was evaluated on Hemodynamics, change in endostatin over time, and transplant-free survival. Elevated serum endostatin was associated with worse disease severity, hemodynamics, and transplant-free survival in congenital heart disease-associated pulmonary arterial hypertension.
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