Fatal pulmonary arterial hypertension in female Fischer 344 rats (1089.20)

Abstract

Background: Male Fischer 344 (F344) rats exposed to Sugen‐5416, hypoxia, and then normoxia (Su/Hx/Nx) develop severe pulmonary arterial hypertension that is accompanied by death within 8 weeks. The mechanism responsible for death in these animals is incompletely understood, although acute heart failure was suspected. Here, we test the hypothesis that development of pulmonary arterial hypertension is accompanied by decreased right ventricular perfusion, which corresponds with decreased right ventricular function and decreased cardiac output. Methods: Six female F344 rats were injected with Sugen‐5416 (20 mg/kg) followed by three weeks of hypoxia (10% normobaric oxygen) and then five weeks of normoxia (21% oxygen at sea level). Survival was plotted as a Kaplan‐Meier curve. Echocardiography was utilized to monitor the development and severity of pulmonary arterial hypertension. Microsphere analysis was used to assess coronary and microvascular perfusion in the right ventricle. Histology was used to determine right ventricular matrix deposition, and right ventricular hypertrophy was estimated using the Fulton index (RV/[LV+S]). Preliminary Results: Five of six female F344 PAH rats died within 5‐weeks following SU/Hx/Nx exposure. Echocardiography showed right ventricular dilation and septal encroachment on the left ventricle, as well as decreased cardiac output. RV/[LV+S] confirmed significant hypertrophy of the right ventricular wall. Microsphere analysis indicated a substantial decrease in right ventricular coronary and microvascular perfusion. Histological trichrome staining displayed increased extracellular matrix deposition surrounding coronary arteries and cardiac myocytes. Conclusion: Decreased coronary and microvascular perfusion, increased fibrosis of the hypertrophied right ventricle and decreased cardiac output contribute to maladaptive cardiac remodeling and death in female F344 rats with severe pulmonary arterial hypertension.Grant Funding Source: Sponsred by NIH