Abstract 11209: KER-012, a Novel Modified ActrII Ligand Trap, Attenuated Cardiac Pathology in a Pulmonary Arterial Banding Model of Right Ventricle Overload

Abstract

Pulmonary arterial hypertension (PAH) is a debilitating disorder, characterized by right ventricle (RV) pressure overload, cardiac hypertrophy, and progressive RV dysfunction. PAH is associated with unbalanced TGFß signaling, favoring signaling of SMAD2/3 and opposing SMAD1/5/9. The result is an increase in vascular proliferation and disruption of vascular homeostasis. KER-012 is a modified ActRII ligand trap designed to inhibit ligands that signal through SMAD2/3 to promote restoration of vascular homeostasis. To investigate the cardio-protective effects of RKER-012, a research version of KER-012, we evaluated the effect of treatment in a pulmonary arterial banding (PAB) model. In this study, 8-week-old, male C57BL/6 mice underwent sham or PAB surgery to increase RV pressure and induce cardiac remodeling. The sham cohort received vehicle (VEH) treatment and PAB mice received either vehicle (VEH) or 10 mg/kg RKER-012 twice weekly for 3 weeks. Relative to sham mice, all PAB mice had elevated pulmonary arterial pressures on day 1 (all ps<0.0001) that persisted until day 21 (all ps<0.01), indicating that the PAB procedure was effective. VEH PAB mice also exhibited diminished cardiac function, including increased end systolic pressure volume relationship (ESPVR; +79.3%; p<0.001) and increased myocardial performance index (MPI; +45.6%; p<0.0001) compared to Sham VEH. Additionally, VEH PAB mice had markers of cardiac remodeling, including increased Fulton Indices (+54.8%; p<0.0001), increased RV free wall thickness (RVFWT; +95.8%; p<0.0001) and increased cardiac fibrotic tissue (+529.9%; p<0.0001). In contrast, RKER-012 treatment was cardioprotective and prevented changes in cardiac function and tissue remodeling. In treated mice, there was a trend for decreased ESPVR (-14.2%), decreased MPI (-13.2%, p<0.01), decreased Fulton Index (-13.5%; p<0.01), and decreased RVFWT (-22.9%; p<0.0001) compared to VEH PAB. Treated mice also had reduced cardiac fibrotic tissue (-38.9%, p<0.01). Taken together, these data provide evidence that KER-012 has the potential to reduce cardiac remodeling and improve cardiac performance in pathologies involving constricted pulmonary arterial blood flow and could provide benefit in diseases such as PAH.