Sotatercept, an activin ligand trap, has been shown to improve exercise tolerance in pulmonary arterial hypertension (PAH). A mechanistic study published in the Journal of the American College of Cardiology investigated the physiological mechanisms underlying these functional benefits after 24 weeks of treatment. 

Thirty participants with PAH (mean age 49.3 ± 13.5 years; 70% women) underwent comprehensive physiological assessments before and after treatment. Evaluations included blood volume quantification, invasive cardiopulmonary exercise testing with simultaneous echocardiography, single-leg exercise catheterization, and femoral venous blood sampling during exercise. Seven paired hemodynamic measurements were performed across different physiological states, including rest, nitric oxide administration, passive leg raise, 20-watt exercise, peak exercise, re-baseline, and single-leg exercise.

Sotatercept improved the primary endpoint of peak exercise mean pulmonary artery pressure to cardiac output slope (−2.1 mmHg/L/min; 95% CI −3.1 to −1.1; p=0.0003). Pulmonary vascular resistance decreased by 2.6 Wood units (95% CI −3.0 to −2.2; p<0.0001), and mean pulmonary artery pressure declined by 12.5 mmHg (95% CI −13.8 to −11.2; p<0.0001). Right ventricular work was reduced (−1.1 kg-m/min; p<0.0001), while right ventricular–pulmonary artery coupling improved during rest and exercise. Markers of systemic congestion declined, including N-terminal pro-B-type natriuretic peptide, right atrial pressure, and blood volume. Hemoglobin increased by 1.7 g/dL, related to reduction in plasma volume without a significant change in red cell mass.

Sotatercept enhanced exercise cardiac output reserve and increased convective oxygen delivery and skeletal muscle oxygen extraction during exertion.

These physiological changes were associated with improved aerobic capacity and exercise performance. Findings indicate that sotatercept influences multiple mechanisms contributing to exercise tolerance in PAH.