Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease–Associated Pulmonary Hypertension

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.

Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update

“…Of note, the Es levels decrease when patients display clinical and hemodynamic improvements. Furthermore, they correlate with responses to PAH-specific treatments [36]. Es is quite far from clinical use and is not widespread.…”

An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers

“…In PH pathophysiology: Es has been found to be elevated in PAH, particularly in IPAH ( 220 , 221 ), CTD-PAH ( 221 ) and CHD-PAH ( 222 ). In IPAH, elevated Es levels correlated with unfavorable hemodynamic alterations (higher mPAP and PVR, lower cardiac index and cardiac output), worse functional class, and reduced exercise tolerance ( 220 , 223 ).…”

“…Considering the case of SSc, Es appeared to predict the development of PAH in these patients ( 224 ). Thirdly, Daly et al investigated Es in CHD-PAH and found that, besides predicting worse hemodynamics and functional capacity, Es elevation was directly correlated to several echocardiographic alterations, predicting RV dysfunction; also, its levels lowered as patients showed clinical and hemodynamic improvement ( 222 ). Lastly, Es has been tested has a tool to predict clinical outcomes in IPAH, and CHD and CTD-PAH, in addition to tools that are currently validated [REVEAL, ESC/ERS ( 221 ), and NT-proBNP ( 222 )], and it was able to improve their performance in risk discrimination and mortality stratification.…”

COL18A1genotypic associations with endostatin levels and clinical features in pulmonary arterial hypertension: a quantitative trait association study

“…Decreased angiogenesis is a feature of pulmonary arterial hypertension (PAH) in animal models [ 3 ] and human subjects [ 4 ]. Our group has reported strong associations between circulating ES levels and haemodynamics and survival in PAH [ 5 – 7 ]. We have also reported that a missense variant in COL18A1 , which encodes ES, confers lower ES and longer survival, suggesting that variation within the gene contributes to circulating levels [ 5 ].…”