Abstract 18362: Cardiac-targeted Therapy With Cardiotrophin-1 Rescues Defective Right Ventricular Adaptation in Severe Pulmonary Arterial Hypertension in Fischer Rats

Abstract

Introduction: In patients with pulmonary arterial hypertension (PAH), right ventricular (RV) dysfunction is one of the strongest predictors of poor prognosis. Therapies targeting RV failure could lead to significant improvement in exercise tolerance and survival in patients with severe PAH. Cardiotrophin-1 (CT-1) is a member of the IL-6 cytokine family that promotes physiological cardiac hypertrophy and cardiomyocyte survival. Hypothesis: We hypothesized that RV-specific therapy using CT-1 therapy will improve RV adaptation to PAH. Methods: PAH was induced by a single subcutaneous injection of SU5416 (SU; 20 mg/kg) followed by exposure to chronic hypoxia (CH; 10% O2) for 3 weeks. On day 22 post SU, human recombinant cardiotrophin-1 (CT-1, Fate Therapeutics) (6 ug/kg/hr) or vehicle (PBS) was administered via subcutaneously implanted mini-osmotic pumps until end-study at 7 weeks. Echocardiography (Vevo 2100, VisualSonics) was performed weekly starting at baseline (day 21). Results: We observed a ~5-fold reduction in expression of endogenous CT-1 mRNA in the RV of rats treated with SU5416+hypoxia compared to healthy controls. Administration of CT-1 to Fischer rats with PAH had no significant effect on pulmonary hemodynamics (pulmonary acceleration time, RVSP), nor RV/LV+S. At 6 weeks post SU, CT-1 significantly reduced RV dilatation (end diastolic RV/LV internal diameter) (p<0.001), improved RV function (cardiac output, RV fractional area change, p<0.05) (Figure 1), which was associated with an increase in RV capillary density (p<0.05) and a 2-fold improvement in survival (31 vs 12%). Conclusions: Targeted cardiac therapy with CT-1 therapy improved RV adaptation in the SU/CH model of severe PAH without altering pulmonary hemodynamics, which in part was mediated by enhancing RV myocardial angiogenesis. These findings support the development of RV-targeted therapeutics for patients with severe PAH and RV failure.