Byrd Carly E, Schramm Jennifer E, Yang Jun, Barnes Allan E, Griffiths Megan, Ambade Anjira S, Rosen Darin T, Cubero Salazar Ilton M, Simpson Catherine E, Tedford Ryan J, Hsu Steven, Vaidya Dhananjay, Kolb Todd M, Pauciulo Michael W, Nichols William C, Ivy David D, Austin Eric D, Hassoun Paul M, Damico Rachel L, Everett Allen D
Department of Pediatrics, Division of Neonatal-Perinatal Medicine Johns Hopkins University Baltimore Maryland USA.
Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Cardiac Critical Care Johns Hopkins University Baltimore Maryland USA.
Pulm Circ. 2025 Apr 1;15(2):e70067. doi: 10.1002/pul2.70067. eCollection 2025 Apr.
Cellular communication network 2 (CCN2) is a secreted matricellular protein associated with pulmonary arterial hypertension (PAH) but has not been studied relative to PAH severity, outcomes, or right ventricle (RV) structure and function in a large human cohort and preclinical animal model. This study assessed the associations between CCN2 and PAH severity, survival, hemodynamic measurements, and cardiovascular dysfunction. Serum CCN2 levels were compared in 2548 adults with PAH and 216 controls. CCN2 levels in PAH patients were compared to functional and hemodynamic measurements, and survival outcomes. RV-pulmonary artery coupling and RV morphology were also assessed in a small subset of patients via pressure-volume loops and cardiac magnetic resonance imaging. In a preclinical PAH model, plasma CCN2 levels were compared between ventricles with PAH progression. CCN2 mRNA levels in both ventricles in the preclinical model were measured to compare with morphologic histologic variables. CCN2 serum levels were significantly higher in PAH compared to controls ( < 0.0001). Higher CCN2 levels were associated with reduced RV contractility ( = 0.003). Higher CCN2 levels were associated with worse 6MWD ( = 0.035), and higher risk of mortality or transplant ( = 0.025). In the preclinical model, prepulmonary CCN2 plasma levels increased with the progression of disease. CCN2 mRNA levels in the RV were associated with decreased RV capillary density ( = 0.015) and increased RV fibrosis ( = 0.045). Though more investigation is needed, it appears that CCN2 plays a role in the development of PAH and potentially in RV maladaptation in PAH.
细胞通讯网络因子2（CCN2）是一种分泌型基质细胞蛋白，与肺动脉高压（PAH）相关，但尚未在大型人类队列和临床前动物模型中针对PAH严重程度、预后或右心室（RV）结构与功能进行研究。本研究评估了CCN2与PAH严重程度、生存率、血流动力学测量以及心血管功能障碍之间的关联。比较了2548例PAH成人患者和216例对照者的血清CCN2水平。将PAH患者的CCN2水平与功能和血流动力学测量结果以及生存预后进行比较。还通过压力-容积环和心脏磁共振成像对一小部分患者的右心室-肺动脉耦合和右心室形态进行了评估。在临床前PAH模型中，比较了随着PAH进展心室之间的血浆CCN2水平。测量了临床前模型中两个心室的CCN2 mRNA水平，以与形态学组织学变量进行比较。与对照组相比，PAH患者的CCN2血清水平显著更高（<0.0001）。较高的CCN2水平与右心室收缩力降低相关（=0.003）。较高的CCN2水平与较差的6分钟步行距离（6MWD）相关（=0.035），以及更高的死亡或移植风险（=0.025）。在临床前模型中，肺前血浆CCN2水平随疾病进展而升高。右心室中CCN2 mRNA水平与右心室毛细血管密度降低相关（=0.015），与右心室纤维化增加相关（=0.045）。尽管需要更多的研究，但似乎CCN2在PAH的发展中起作用，并且可能在PAH的右心室适应不良中起作用。
