Sotatercept in Pulmonary Arterial Hypertension

BACKGROUND: Sotatercept is an activin ligand trap that markedly improves exercise tolerance in patients with pulmonary arterial hypertension (PAH). OBJECTIVES: The aim of this study was to determine the mechanisms of these functional benefits. METHODS: The effects of 24-week sotatercept treatment on central and peripheral determinants of aerobic capacity, hemodynamic status, cardiovascular function, and oxygen transport in patients with PAH were comprehensively evaluated. Participants underwent blood volume quantification, supine invasive cardiopulmonary exercise testing with simultaneous echocardiography, single-leg exercise catheterization, and exercise femoral venous blood sampling. Participants underwent 7 paired hemodynamic assessments before and after sotatercept (rest, nitric oxide, passive leg raise, 20-W exercise, peak exercise, repeat baseline, and single-leg exercise). RESULTS: Among 30 participants (mean age 49.3 ± 13.5 years, 70% women), sotatercept improved the primary endpoint of peak exercise mean pulmonary artery (PA)/cardiac output (CO) (-2.1 mm Hg/L/min; 95% CI: -3.1 to -1.1 mm Hg/L/min; P = 0.0003). Sotatercept reduced pulmonary vascular resistance (-2.6 WU; 95% CI: -3.0 to -2.2 WU; P < 0.0001), mean PA pressure (-12.5 mm Hg; 95% CI: -13.8 to -11.2 mm Hg; P < 0.0001), and right ventricular (RV) work (-1.1 kg-m/min; 95% CI: -1.4 to -0.9 kg-m/min; P < 0.0001) and improved RV-PA coupling across rest and exercise. Sotatercept reduced systemic congestion, evidenced by decreases in N-terminal pro-B-type natriuretic peptide (P < 0.0001), right atrial pressure (P = 0.04), and blood volume (P < 0.0001). Increases in resting hemoglobin were observed (1.7 g/dL; 95% CI: +1.1 to +2.2 g/dL; P < 0.0001) that were related to reduction in plasma volume (P < 0.0001), as there was no effect on red cell mass (P = 0.12). A decrease in resting CO was observed with sotatercept (-0.58 L/min; 95% CI: -0.85 to -0.32 L/min; P < 0.0001), which appeared to be related to the increase in hemoglobin. Despite lower resting CO, CO reserve with exercise was enhanced (+0.74 L/min; 95% CI: +0.15 to +1.32 L/min; P = 0.015), which was associated with improved aerobic capacity (peak oxygen consumption; r = +0.69; 95% CI: +0.43 to +0.84; P < 0.0001). Single-leg exercise performance also improved after sotatercept. Sotatercept increased both convective oxygen delivery with exertion (P = 0.002; interaction P = 0.018) and peripheral oxygen uptake in skeletal muscle, as evidenced by an increase in arterial-femoral venous O CONCLUSIONS: Sotatercept improves exercise tolerance in patients with PAH through multiple, previously unappreciated mechanisms beyond the pulmonary vasculature, including increased hemoglobin (driven in part by systemic decongestion with hemoconcentration), which along with enhanced RV-PA coupling and CO reserve increases skeletal muscle O