Advances in Cardiovascular Pharmacotherapy. XI: Sotatercept in Pulmonary Arterial Hypertension.

Sotatercept is a groundbreaking new treatment for pulmonary arterial hypertension (PAH). The disease-modifying drug is a recombinant fusion protein that consists of the extracellular domain of the activin receptor 2A linked to the Fc fragment of human immunoglobulin G1. Sotatercept potently traps activins and growth differentiation factors to inhibit transforming growth factor-beta (TGF-β) signaling through its activin receptor 2A/2B pathway, thereby restoring the neutral balance between pro-proliferative and antiproliferative signaling in PAH and causing a striking reversal of the disease's pathologic consequences. This article had the following objectives: (1) describe the parallel TGF-β signaling pathways and their opposing effects on pulmonary artery endothelial and smooth muscle cell quiescence and proliferation; (2) discuss the mechanisms by which sotatercept differentially affects TGF-β signaling to inhibit and reverse aberrant vascular proliferation and facilitate cellular quiescence; (3) review the preclinical evidence indicating that sotatercept has favorable actions in experimental models of PAH; (4) examine the findings of major clinical trials and their substudies demonstrating that sotatercept exerts temporally durable benefits on pulmonary and right ventricular hemodynamics, clinical symptoms, exercise tolerance, quality of life, and mortality in patients with long-standing, high-risk, and newly identified PAH; (5) assess recent findings indicating that sotatercept produces salutary actions in patients with precapillary and postcapillary pulmonary hypertension resulting from heart failure with preserved ejection fraction; and lastly, (6) comment on the adverse effects of sotatercept and its potential anesthetic implications.