Noly Pierre-Emmanuel, Guihaire Julien, Coblence Matthieu, Dorfmüller Peter, Fadel Elie, Mercier Olaf
Surgical Research Lab, Marie Lannelongue Hospital.
Surgical Research Lab, Marie Lannelongue Hospital; Thoracic and Cardiovascular Surgery, University Hospital of Rennes;
J Vis Exp. 2015 Nov 4(105):e53133. doi: 10.3791/53133.
An original piglet model of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) associated with chronic Right Ventricular (RV) dysfunction is described. Pulmonary Hypertension (PH) was induced in 3-week-old piglets by a progressive obstruction of the pulmonary vascular bed. A ligation of the left Pulmonary Artery (PA) was performed first through a mini-thoracotomy. Second, weekly embolizations of the right lower pulmonary lobe were done under fluoroscopic guidance with n-butyl-2-cyanoacrylate during 5 weeks. Mean Pulmonary Arterial Pressure (mPAP) measured by ritght heart catheterism, increased progressively, as well as Right Atrial pressure and Pulmonary Vascular Resistances (PVR) after 5 weeks compared to sham animals. Right Ventricular (RV) structural and functional remodeling were assessed by transthoracic echocardiography (RV diameters, RV wall thickness, RV systolic function). RV elastance and RV-pulmonary coupling were assessed by Pressure-Volume Loops (PVL) analysis with conductance method. Histologic study of the lung and the right ventricle were also performed. Molecular analyses on RV fresh tissues could be performed through repeated transcutaneous endomyocardial biopsies. Pulmonary microvascular disease in obstructed and unobstructed territories was studied from lung biopsies using molecular analyses and pathology. Furthermore, the reliability and the reproducibility was associated with a range of PH severity in animals. Most aspects of the human CTEPH disease were reproduced in this model, which allows new perspectives for the understanding of the underlying mechanisms (mitochondria, inflammation) and new therapeutic approaches (targeted, cellular or gene therapies) of the overloaded right ventricle but also pulmonary microvascular disease.
本文描述了一种与慢性右心室（RV）功能障碍相关的慢性血栓栓塞性肺动脉高压（CTEPH）的原始仔猪模型。通过逐步阻塞肺血管床，在3周龄仔猪中诱导肺动脉高压（PH）。首先通过小型开胸手术结扎左肺动脉（PA）。其次，在5周内，在透视引导下每周使用正丁基-2-氰基丙烯酸酯对右下肺叶进行栓塞。与假手术动物相比，5周后通过右心导管测量的平均肺动脉压（mPAP）以及右心房压力和肺血管阻力（PVR）逐渐升高。通过经胸超声心动图（RV直径、RV壁厚度、RV收缩功能）评估右心室（RV）的结构和功能重塑。通过电导法压力-容积环（PVL）分析评估RV弹性和RV-肺耦合。还对肺和右心室进行了组织学研究。可以通过重复经皮心内膜活检对RV新鲜组织进行分子分析。使用分子分析和病理学方法，从肺活检研究阻塞和未阻塞区域的肺微血管疾病。此外，该模型的可靠性和可重复性与动物中一系列PH严重程度相关。该模型再现了人类CTEPH疾病的大多数方面，这为理解潜在机制（线粒体、炎症）以及针对右心室过载和肺微血管疾病的新治疗方法（靶向、细胞或基因治疗）提供了新的视角。
