Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis

Andriy O. Samokhin, Steven Hsu, Paul B. Yu, Aaron B. Waxman, George A. Alba, Bradley M. Wertheim, C. Danielle Hopkins, Frederick Bowman, Richard N. Channick, Ivana Nikolic, Mariana Faria-Urbina, Paul M. Hassoun, Jane A. Leopold, Ryan J. Tedford, Corey E. Ventetuolo, Peter J. Leary, Bradley A. Maron

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. METHODS: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010–2017): PAH (n = 139; female 82%, 58 [48–67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years). RESULTS: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease–PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = −0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = −0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant–free survival was 1.12 (95% confidence interval [CI], 1.02–1.22, p = 0.01) and 1.75 (95% CI, 1.12–2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. CONCLUSIONS: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

Original languageEnglish (US)
JournalJournal of Heart and Lung Transplantation
DOIs
StateAccepted/In press - Jan 1 2020

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Pulmonary Hypertension
Vascular Resistance
Connective Tissue Diseases
Biomarkers
Confidence Intervals
Hypertension
Ventricular Remodeling
Pulmonary Wedge Pressure
Brain Natriuretic Peptide
Arterioles
Proportional Hazards Models
Stroke Volume
Dyspnea
Referral and Consultation
Prospective Studies
Exercise
Lung
Survival

Keywords

  • biomarker
  • hemodynamics
  • mortality
  • NEDD9
  • pulmonary arterial hypertension
  • pulmonary vascular disease

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Circulating NEDD9 is increased in pulmonary arterial hypertension : A multicenter, retrospective analysis. / Samokhin, Andriy O.; Hsu, Steven; Yu, Paul B.; Waxman, Aaron B.; Alba, George A.; Wertheim, Bradley M.; Hopkins, C. Danielle; Bowman, Frederick; Channick, Richard N.; Nikolic, Ivana; Faria-Urbina, Mariana; Hassoun, Paul M.; Leopold, Jane A.; Tedford, Ryan J.; Ventetuolo, Corey E.; Leary, Peter J.; Maron, Bradley A.

In: Journal of Heart and Lung Transplantation, 01.01.2020.

Research output: Contribution to journalArticle

Samokhin, AO, Hsu, S, Yu, PB, Waxman, AB, Alba, GA, Wertheim, BM, Hopkins, CD, Bowman, F, Channick, RN, Nikolic, I, Faria-Urbina, M, Hassoun, PM, Leopold, JA, Tedford, RJ, Ventetuolo, CE, Leary, PJ & Maron, BA 2020, 'Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis', Journal of Heart and Lung Transplantation. https://doi.org/10.1016/j.healun.2019.12.002
Samokhin, Andriy O. ; Hsu, Steven ; Yu, Paul B. ; Waxman, Aaron B. ; Alba, George A. ; Wertheim, Bradley M. ; Hopkins, C. Danielle ; Bowman, Frederick ; Channick, Richard N. ; Nikolic, Ivana ; Faria-Urbina, Mariana ; Hassoun, Paul M. ; Leopold, Jane A. ; Tedford, Ryan J. ; Ventetuolo, Corey E. ; Leary, Peter J. ; Maron, Bradley A. / Circulating NEDD9 is increased in pulmonary arterial hypertension : A multicenter, retrospective analysis. In: Journal of Heart and Lung Transplantation. 2020.
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title = "Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis",
abstract = "BACKGROUND: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. METHODS: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010–2017): PAH (n = 139; female 82{\%}, 58 [48–67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56{\%}, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75{\%}, 54.2 ± 14.0 years). RESULTS: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease–PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = −0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = −0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant–free survival was 1.12 (95{\%} confidence interval [CI], 1.02–1.22, p = 0.01) and 1.75 (95{\%} CI, 1.12–2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. CONCLUSIONS: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.",
keywords = "biomarker, hemodynamics, mortality, NEDD9, pulmonary arterial hypertension, pulmonary vascular disease",
author = "Samokhin, {Andriy O.} and Steven Hsu and Yu, {Paul B.} and Waxman, {Aaron B.} and Alba, {George A.} and Wertheim, {Bradley M.} and Hopkins, {C. Danielle} and Frederick Bowman and Channick, {Richard N.} and Ivana Nikolic and Mariana Faria-Urbina and Hassoun, {Paul M.} and Leopold, {Jane A.} and Tedford, {Ryan J.} and Ventetuolo, {Corey E.} and Leary, {Peter J.} and Maron, {Bradley A.}",
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TY - JOUR

T1 - Circulating NEDD9 is increased in pulmonary arterial hypertension

T2 - A multicenter, retrospective analysis

AU - Samokhin, Andriy O.

AU - Hsu, Steven

AU - Yu, Paul B.

AU - Waxman, Aaron B.

AU - Alba, George A.

AU - Wertheim, Bradley M.

AU - Hopkins, C. Danielle

AU - Bowman, Frederick

AU - Channick, Richard N.

AU - Nikolic, Ivana

AU - Faria-Urbina, Mariana

AU - Hassoun, Paul M.

AU - Leopold, Jane A.

AU - Tedford, Ryan J.

AU - Ventetuolo, Corey E.

AU - Leary, Peter J.

AU - Maron, Bradley A.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - BACKGROUND: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. METHODS: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010–2017): PAH (n = 139; female 82%, 58 [48–67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years). RESULTS: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease–PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = −0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = −0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant–free survival was 1.12 (95% confidence interval [CI], 1.02–1.22, p = 0.01) and 1.75 (95% CI, 1.12–2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. CONCLUSIONS: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. METHODS: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010–2017): PAH (n = 139; female 82%, 58 [48–67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years). RESULTS: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease–PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = −0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = −0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant–free survival was 1.12 (95% confidence interval [CI], 1.02–1.22, p = 0.01) and 1.75 (95% CI, 1.12–2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. CONCLUSIONS: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

KW - biomarker

KW - hemodynamics

KW - mortality

KW - NEDD9

KW - pulmonary arterial hypertension

KW - pulmonary vascular disease

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DO - 10.1016/j.healun.2019.12.002

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JO - Journal of Heart and Lung Transplantation

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