Abstract 12533: Pulmonary Hypertension due to Left Atrium Stenosis Caused Intrapulmonary Venous Arterialization in Rats

Abstract

Introduction: Pulmonary hypertension (PH) due to left heart diseases (PH-LHD) is known as the most frequent cause of PH. Although pulmonary artery hypertension have been intensively investigated, the pathological mechanism and treatment of PH-LHD still remain unclear because of the lack of an adequate animal model of PH-LHD. Objective: The aim of this study was to investigate the pathophysiological characters of a novel rat model of PH-LHD caused by left atrium stenosis (LAS). Methods: Five-week-old male Sprague-Dawley rats were randomly divided into the two groups: the LAS and sham-operated control (SOC) groups. Through open heart surgery under anesthesia, LAS was generated by clipping the LA using HORIZON TM ligation clip (n=5). Thymectomy was only done in SOC group (n=5). Echocardiography was performed every 2 weeks after operation, and hemodynamic measurements and tissues were collected 10 weeks after operation. Results: Left ventricular (LV) inflow velocity measured by echocardiography was higher in LAS than in SOC group (2.2±0.2 and 1.1±0.03 m/s, p <0.01). Right ventricular (RV) pressure and RV pressure/LV pressure ratio were significantly increased in LAS than in SOC group (40.6±14.4 and 18.0±5.0 mmHg, p <0.01, 0.52±0.10 and 0.22±0.09, p <0.01, respectively). In addition, RV was weighted more in LAS than in SOC group (242±28 and 164±36 mg, p <0.01). Histological examination revealed that not only pulmonary arteriopathy with isolated medial hypertrophy, but also pulmonary venous arterialization in LAS group. Pulmonary venous media was significantly thickened in all of LAS rats when compared with that in SOC group. Furthermore, α-smooth muscle actin, ephrin-B2, and EphB4 (ephrin-B2 cognate receptor) were significantly increased in LAS group by immunohistological and real-time PCR analyses. Conclusions: We succeeded in establishing a novel, reliable rat model of PH-LHD by generating LAS for the first time in the world. Although PH was relatively mild, the PH-LHD model rats demonstrated the characteristic intrapulmonary venous arterialization and should be utilized to further investigate the mechanism of PH-LHD.