Abstract 14397: Sotatercept Analog RAP-011 Inhibits Right Ventricular Remodeling and Restores Function in a Mouse Model of Pressure Overload

Abstract

IIntroduction: Right ventricular (RV) failure is the primary cause of death in patients with pulmonary arterial hypertension (PAH). Beneficial effects of sotatercept - an activin receptor type IIA-Fc fusion protein that traps activins and growth differentiation factors - have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We have reported that therapeutic treatment with sotatercept analog RAP-011 reverses RV remodeling and function in rats with severe angio-obliterative PAH, providing benefits on top of standard care. Hypothesis: To determine whether RAP-011 exerts a direct cardioprotective effect in a mouse model of pressure overload-induced RV failure. Methods: RV failure was induced in male C57BL/6 mice by pulmonary artery banding (PAB). RAP-011 or vehicle were administered subcutaneously twice weekly for 3 weeks beginning one day post surgery. RV remodeling and function were assessed by echocardiography and RV pressure measured by catheterization. RV fibrosis was assessed by Masson’s trichrome staining. Results: PAB caused RV hypertrophy and increased RV wall thickness in comparison to sham surgery. RAP-011 treatment markedly attenuated these PAB-induced changes (by 72% and 41%, respectively; P < 0.0001). PAB significantly reduced tricuspid annular plane systolic excursion (0.68 ± 0.03 vs. 0.98 ± 0.03 mm), which was partially restored by RAP-011 (0.84 ± 0.04 mm; P < 0.01). In addition, the PAB-induced increase in myocardial performance index was reversed by RAP-011 (1.86 vs. 1.48, P < 0.0001). RAP-011 attenuated PAB-induced RV developed pressure (by 82%, P < 0.0001) and partially normalized peak rates of RV pressure change (+dP/dt max and -dP/dt min , P < 0.05). RAP-011 also reduced the extent of PAB-induced RV fibrosis (19.5% vs. 10.5%, P < 0.001). Conclusions: Consistent with our previous findings in a rat model of severe angio-obliterative PAH, RAP-011 treatment reduces RV remodeling and improves function in a PAB model, thus implicating direct cardioprotective actions of RAP-011 as an important component of its therapeutic effects in severe experimental PAH.