Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure

INTRODUCTION The ability of the right ventricle (RV) to adapt to increased afterload is the major determinant of survival in patients with pulmonary hypertension. In this study, we explored the effect of genetic background on RV adaptation and survival in a rat model of severe pulmonary arterial hypertension (PAH). METHODS AND RESULTS PH was induced by a single injection of SU5416 (SU) in age-matched Sprague-Dawley (SD) or Fischer rats, followed by a 3-week exposure to chronic hypoxia (SUHx). SD and Fischer rats exhibited similar elevations in RV systolic pressure, number of occlusive pulmonary vascular lesions and RV hypertrophy (RV/LV+S) in response to SUHx. However, no Fischer rats survived until 7-weeks compared to complete survival for SD rats. This high early mortality of Fischer rats was associated with significantly greater RV dilatation and reduced ejection fraction, cardiac output and exercise capacity at 4-weeks post-SU. Moreover, microarray analysis revealed that over 300 genes were uniquely regulated in the RV in the severe PAH model in the Fischer compared to SD rats, mainly related to angiogenesis and vascular homeostasis, fatty acid metabolism, and innate immunity. A focused PCR array confirmed down-regulation of angiogenic genes in the Fischer compared to SD RV. Furthermore, Fischer rats demonstrated significantly lower RV capillary density compared to SD rats in response to SUHx. CONCLUSIONS Fischer rats are prone to develop RV failure in response to increased afterload. Moreover, the high mortality in the SUHx model of severe PAH was caused by a failure of RV adaptation associated with lack of adequate microvascular angiogenesis, together with exaggerated metabolic and immunological responses in the hypertrophied RV.