What is the clinical evidence from this study?

Study design: Other. Population: Pulmonary hypertension in experimental left heart failure. Intervention: ActRIIA-Fc (sotatercept analog). Primary outcome: Cardiopulmonary structure and function.

February 23, 2023Open Access

Sotatercept analog improves cardiopulmonary remodeling and pulmonary hypertension in experimental left heart failure

Key Result

ActRIIA-Fc (sotatercept analog) broadly corrected cardiopulmonary structure and function and alleviated pulmonary hypertension in experimental models of left heart disease.

Structured PICO

Does ActRIIA-Fc improve cardiopulmonary remodeling and pulmonary hypertension in preclinical models of left heart failure?

Population

Preclinical models of left heart disease and pulmonary hypertension: Male C57BL/6 mice (10 weeks old) for TAC and MI models; male Balb/c mice (10 weeks old) for prolonged TAC model (PH-HFrEF); male obese ZSF1 rats (8 and 23 weeks old) and lean littermates for SU5416-induced PH-HFpEF model; human iPSC-derived cardiomyocytes; and human pulmonary artery smooth muscle cells (PASMCs).

Intervention

ActRIIA-Fc (murine RAP-011 10 mg/kg subcutaneous twice weekly in vivo; human ACE-011 in vitro).

Comparator

Vehicle (phosphate-buffered saline) or sham controls. Sildenafil (30 mg/kg oral twice daily) was used as an active comparator in the rat PH-HFpEF model.

Outcome

Cardiopulmonary structure, function, and hemodynamics (including right ventricular systolic pressure, pulmonary vascular remodeling, cardiac hypertrophy, and fibrosis).surrogate

ActRIIA-Fc (sotatercept analog) reverses pulmonary vascular remodeling and improves cardiopulmonary function in preclinical models of pulmonary hypertension due to left heart disease, supporting its clinical evaluation in PH-HFpEF.

Abstract

revealed that treatment with ActRIIA-Fc prevents an abnormal, glucose-induced, activin-mediated, migratory phenotype in human pulmonary artery smooth muscle cells, providing a mechanism by which ActRIIA-Fc could exert therapeutic effects in experimental PH-HFpEF with metabolic dysregulation. Our results demonstrate that ActRIIA-Fc broadly corrects cardiopulmonary structure and function in experimental PH-LHD, including models of PH-HFrEF and PH-HFpEF, leading to alleviation of PH under diverse pathophysiological conditions. These findings highlight the important pathogenic contributions of activin-class ligands in multiple forms of experimental PH and support ongoing clinical evaluation of human ActRIIA-Fc (sotatercept) in patients with PH-HFpEF.

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