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

JOURNAL OF HEART AND LUNG TRANSPLANTATION

卷:39

Article

Samokhin, Andriy O.^1,2  Hsu, Steven³  Yu, Paul B.^1,2,4  Waxman, Aaron B.^1,2,5  Alba, George A.⁶  Wertheim, Bradley M.^1,2,5  Hopkins, C. Danielle³  Bowman, Frederick^1,2  Channick, Richard N.⁶  Nikolic, Ivana⁷  Faria-Urbina, Mariana^1,2,5  Hassoun, Paul M.⁸  Leopold, Jane A.^1,2,4  Tedford, Ryan J.⁹  Ventetuolo, Corey E.¹⁰  Leary, Peter J.¹¹  Maron, Bradley A.^1,2,4 

[1] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[2] Harvard Med Sch, 77 Ave Louis Pasteur,New Res Bldg,Room 0630-N, Boston, MA 02115 USA

[3] Johns Hopkins Sch Med, Dept Med, Div Cardiol, Baltimore, MD USA

[4] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA

[6] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[8] Johns Hopkins Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD USA

[9] Med Univ South Carolina, Dept Med, Div Cardiol, Charleston, SC 29425 USA

[10] Brown Univ, Dept Med & Hlth Serv, Div Pulm Policy & Practice, Providence, RI 02912 USA

[11] Univ Washington, Div Pulm Crit Care & Sleep Med, Seattle, WA 98195 USA

关键词: pulmonary arterial hypertension;    NEDD9;    biomarker;    hemodynamics;    mortality;    pulmonary vascular disease;   

DOI  :  10.1016/j.healun.2019.12.002

来源: Elsevier

【 摘 要 】

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 (rho = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (rho = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (rho = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (rho = -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 (rho = -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. (C) Published by Elsevier Inc.

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