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

doi:10.1161/JAHA.120.021409

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 journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	e021409
Journal	Journal of the American Heart Association
Volume	10
Issue number	20
DOIs	https://doi.org/10.1161/JAHA.120.021409
State	Published - Oct 19 2021
Externally published	Yes

Keywords

Angiogenesis
Biomarkers
Children
Proteomics
Pulmonary vascular disease

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1161/JAHA.120.021409

Cite this

Daly, C. M., Griffiths, M., Simpson, C. E., Yang, J., Damico, R. L., Vaidya, R. D., Williams, M., Brandal, S., Jone, P. N., Polsen, C., Ivy, D. D., Austin, E. D., Nichols, W. C., Pauciulo, M. W., Lutz, K., Nies, M. K., Rosenzweig, E. B., Hirsch, R., Yung, D., & Everett, A. D. (2021). Angiostatic peptide, endostatin, predicts severity in pediatric congenital heart disease–associated pulmonary hypertension. Journal of the American Heart Association, 10(20), [e021409]. https://doi.org/10.1161/JAHA.120.021409

Daly, CM, Griffiths, M, Simpson, CE, Yang, J, Damico, RL, Vaidya, RD, Williams, M, Brandal, S, Jone, PN, Polsen, C, Ivy, DD, Austin, ED, Nichols, WC, Pauciulo, MW, Lutz, K, Nies, MK, Rosenzweig, EB, Hirsch, R, Yung, D & Everett, AD 2021, 'Angiostatic peptide, endostatin, predicts severity in pediatric congenital heart disease–associated pulmonary hypertension', Journal of the American Heart Association, vol. 10, no. 20, e021409. https://doi.org/10.1161/JAHA.120.021409

@article{370ec17cf72c45b3bea07ca88137997b,

title = "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.",

keywords = "Angiogenesis, Biomarkers, Children, Proteomics, Pulmonary vascular disease",

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

note = "Funding Information: This study was supported by National Institutes of Health/National Heart, Lung, and Blood Institute award R01HL135114 and R01HL150070 (A.D.E., M. N., J.Y., R.D., D.V., W.C.N., D.D.I and E.D.A.), R24HL105333 (W.C.N., M.W.P.), and K23HL153781 (C.E.S.). WCN and MWP are funded by HL105333. D.D.I. was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535 and the Jayden de Luca Foundation. M.G. was supported by the Pediatric Scientist Development Program. The Pediatric Scientist Development Program is supported by Award Number K12-HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. M.K.N was supported by The Matthew and Michael Wojciechowski Pulmonary Hypertension Pediatric Proof-of-Concept Grant (Dr Robyn J. Barst Pediatric PH Research and Mentoring Fund Grant). C.D. was supported by The Johns Hopkins School of Medicine Dean{\textquoteright}s Summer Research Funding. Funding Information: Serum/tissue samples provided by PHBI under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under a National Heart Lung and Blood Institute (NHLBI) R24 grant, #R24HL123767. Samples and/or Data from the National Biological Sample and Data Repository for PAH, which receives government support under an investigator-initiated grant (R24 HL105333) awarded by the NHLBI, were used in this study. We thank contributors, including the Pulmonary Hypertension Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Author Contributions: C.D., M.G., J.Y., D.V., and A.D.E planned the project, analyzed the data, and wrote the article; M.G., S.B., and J.Y. performed the experiments and interpreted the results; M.G., R.D., D.V., and J.Y. performed statistical analysis; M.K.N., C.E.S., R.D., D.I., E.D.A, W.C.N, M.W.P, K.L., E.B.R., R.H., D.Y., and A.D.E recruited subjects and performed research; all authors reviewed, revised, and approved the article for submission. D.D.I performed the catheterizations and collected the samples from CHCO. P.N.J. evaluated all echocardiograms from CHCO. Funding Information: Part of this work was presented as a virtual presentation at the American Heart Association?s Scientific Sessions, November 17, 2020.Serum/tissue samples provided by PHBI under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under a National Heart Lung and Blood Institute (NHLBI) R24 grant, #R24HL123767. Samples and/or Data from the National Biological Sample and Data Repository for PAH, which receives government support under an investigator-initiated grant (R24 HL105333) awarded by the NHLBI, were used in this study. We thank contributors, including the Pulmonary Hypertension Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Publisher Copyright: {\textcopyright} 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.",

year = "2021",

month = oct,

day = "19",

doi = "10.1161/JAHA.120.021409",

language = "English (US)",

volume = "10",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "Wiley-Blackwell",

number = "20",

}

TY - JOUR

T1 - Angiostatic peptide, endostatin, predicts severity in pediatric congenital heart disease–associated pulmonary hypertension

AU - Daly, Caroline M.

AU - Griffiths, Megan

AU - Simpson, Catherine E.

AU - Yang, Jun

AU - Damico, Rachel L.

AU - Vaidya, R. Dhananjay

AU - Williams, Monica

AU - Brandal, Stephanie

AU - Jone, Pei Ni

AU - Polsen, Cassandra

AU - Ivy, D. Dunbar

AU - Austin, Eric D.

AU - Nichols, William C.

AU - Pauciulo, Michael W.

AU - Lutz, Katie

AU - Nies, Melanie K.

AU - Rosenzweig, Erika B.

AU - Hirsch, Russel

AU - Yung, Delphine

AU - Everett, Allen D.

N1 - Funding Information: This study was supported by National Institutes of Health/National Heart, Lung, and Blood Institute award R01HL135114 and R01HL150070 (A.D.E., M. N., J.Y., R.D., D.V., W.C.N., D.D.I and E.D.A.), R24HL105333 (W.C.N., M.W.P.), and K23HL153781 (C.E.S.). WCN and MWP are funded by HL105333. D.D.I. was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535 and the Jayden de Luca Foundation. M.G. was supported by the Pediatric Scientist Development Program. The Pediatric Scientist Development Program is supported by Award Number K12-HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. M.K.N was supported by The Matthew and Michael Wojciechowski Pulmonary Hypertension Pediatric Proof-of-Concept Grant (Dr Robyn J. Barst Pediatric PH Research and Mentoring Fund Grant). C.D. was supported by The Johns Hopkins School of Medicine Dean’s Summer Research Funding. Funding Information: Serum/tissue samples provided by PHBI under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under a National Heart Lung and Blood Institute (NHLBI) R24 grant, #R24HL123767. Samples and/or Data from the National Biological Sample and Data Repository for PAH, which receives government support under an investigator-initiated grant (R24 HL105333) awarded by the NHLBI, were used in this study. We thank contributors, including the Pulmonary Hypertension Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Author Contributions: C.D., M.G., J.Y., D.V., and A.D.E planned the project, analyzed the data, and wrote the article; M.G., S.B., and J.Y. performed the experiments and interpreted the results; M.G., R.D., D.V., and J.Y. performed statistical analysis; M.K.N., C.E.S., R.D., D.I., E.D.A, W.C.N, M.W.P, K.L., E.B.R., R.H., D.Y., and A.D.E recruited subjects and performed research; all authors reviewed, revised, and approved the article for submission. D.D.I performed the catheterizations and collected the samples from CHCO. P.N.J. evaluated all echocardiograms from CHCO. Funding Information: Part of this work was presented as a virtual presentation at the American Heart Association?s Scientific Sessions, November 17, 2020.Serum/tissue samples provided by PHBI under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under a National Heart Lung and Blood Institute (NHLBI) R24 grant, #R24HL123767. Samples and/or Data from the National Biological Sample and Data Repository for PAH, which receives government support under an investigator-initiated grant (R24 HL105333) awarded by the NHLBI, were used in this study. We thank contributors, including the Pulmonary Hypertension Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Publisher Copyright: © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

PY - 2021/10/19

Y1 - 2021/10/19

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Biomarkers

KW - Children

KW - Proteomics

KW - Pulmonary vascular disease

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U2 - 10.1161/JAHA.120.021409

DO - 10.1161/JAHA.120.021409

M3 - Article

C2 - 34622662

AN - SCOPUS:85119303787

SN - 2047-9980

VL - 10

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 20

M1 - e021409

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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