Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis.,The Journal of Heart and Lung Transplantation

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Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis.
The Journal of Heart and Lung Transplantation ( IF 6.4 ) Pub Date : 2019-12-31 , DOI: 10.1016/j.healun.2019.12.002
Andriy O Samokhin ₁ , Steven Hsu ₂ , Paul B Yu ₃ , Aaron B Waxman ₄ , George A Alba ₅ , Bradley M Wertheim ₄ , C Danielle Hopkins ₂ , Frederick Bowman ₁ , Richard N Channick ₅ , Ivana Nikolic ₆ , Mariana Faria-Urbina ₄ , Paul M Hassoun ₇ , Jane A Leopold ₃ , Ryan J Tedford ₈ , Corey E Ventetuolo ₉ , Peter J Leary ₁₀ , Bradley A Maron ₃

Affiliation

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Pulmonary and Critical Care Medicine.
Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
Division of Pulmonary, Critical Care & Sleep Medicine, Departments of Medicine and Health Services, Policy and Practice, Brown University, Providence, Rhode Island.
Division of Pulmonary, Critical Care & Sleep Medicine, University of Washington, Seattle, Washington.

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.

中文翻译：

肺动脉高压中循环NEDD9升高：一项多中心，回顾性分析。

背景技术肺动脉高压（PAH）是一种高度致病的疾病，其特征在于肺血管阻力（PVR）升高和致病性右心室重塑。在纤维化的PAH小动脉中，前转移蛋白NEDD9的内皮表达增加，而NEDD9的抑制作用会降低实验性PAH中的PVR。我们假设循环NEDD9在PAH中增加，并告知患者的临床情况。方法回顾性分析5个转诊中心（2010-2017）的242例患者的临床数据和血浆样本：PAH（n = 139;女性82％，58 [48-67]岁），非PAH肺动脉高压（PH）（ n = 54；女性56％，63.4±12.2岁）和呼吸困难非PH对照（n = 36；女性75％，54.2±14.0岁）。结果与对照组相比，NEDD9的PAH增加了1.82倍（p <0.0001）。特发性PAH（ρ= 0.42，p <0.0001，n = 54），结缔组织疾病（CTD）-PAH（ρ= 0.53，p <0.0001，n = 53）和先天性心脏病-PAH中NEDD9升高与PVR相关（ρ= 0.68，p <0.0001，n = 10）。在CTD-PAH中，NEDD9与6分钟的步行距离相关（ρ= -0.35，p = 0.028，n = 39）。与PAH生物标志物N端脑利钠肽前体（n = 38）相反，NEDD9与运动肺动脉楔形压成反比，与右心室射血分数成反比（ρ= -0.41，p = 0.006，n = 45 ）。每1 ng / ml的无肺移植存活调整风险比为1.12（95％置信区间[CI]，1.02-1.22，p = 0.01）和1.75（95％CI，1.12-2.73，p = 0.01），通过Cox比例风险模型，血浆NEDD9分别增加5 ng / ml。结论在PAH中，血浆NEDD9升高并且与关键的预后变量相关。包括硬终点在内的前瞻性研究有必要验证NEDD9是一种新颖的PAH生物标记物。

更新日期：2020-03-19

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