Sotatercept Improves PAH Exercise Capacity Through Mechanisms Beyond the Lungs

Key Takeaways

• In adults with pulmonary arterial hypertension (PAH) treated with sotatercept for 24 weeks, peak-exercise pulmonary pressure relative to cardiac output, pulmonary vascular resistance, and right ventricular work all decreased.
• Resting hemoglobin rose without a significant change in red cell mass, in parallel with reduced plasma volume and decongestion.
• Resting cardiac output fell, while exercise cardiac output reserve and skeletal muscle oxygen extraction increased.

Sotatercept, an activin signaling inhibitor, improves exercise tolerance in PAH, but the physiologic basis of that benefit has not been fully defined. Effects on the pulmonary vasculature may not account for the full change, since blood volume, hemoglobin, cardiac output, and peripheral oxygen use each contribute to aerobic capacity.

Investigators conducted a prospective study of central, hematologic, and peripheral responses to sotatercept in 30 adults with PAH (mean age 49.3 years; 70% women) assessed before and after 24 weeks of treatment. Participants underwent blood volume quantification, supine invasive cardiopulmonary exercise testing with simultaneous echocardiography, single-leg exercise catheterization, and femoral venous blood sampling during exercise. Paired hemodynamic assessments spanned rest through peak exercise. The primary endpoint was the ratio of mean pulmonary artery pressure to cardiac output at peak exercise.

The primary endpoint decreased by 2.1 mm Hg/L/min (95% confidence interval [CI] −3.1 to −1.1; P = .0003). Pulmonary vascular resistance fell by 2.6 Wood units (95% CI −3.0 to −2.2), mean pulmonary artery pressure by 12.5 mm Hg (95% CI −13.8 to −11.2), and right ventricular work by 1.1 kg-m/min (95% CI −1.4 to −0.9). Right ventricle–pulmonary artery coupling improved across rest and exercise. NT-proBNP, right atrial pressure, and blood volume also declined.

Resting hemoglobin increased by 1.7 g/dL (95% CI 1.1–2.2), a change related to reduced plasma volume; red cell mass did not change significantly (P = .12). Resting cardiac output decreased by 0.58 L/min (95% CI −0.85 to −0.32), which appeared related to the hemoglobin increase. Cardiac output reserve with exercise increased by 0.74 L/min (95% CI 0.15–1.32) and correlated with peak oxygen consumption (r = 0.69). Single-leg exercise performance improved, and the arterial–femoral venous oxygen content difference widened by 1.1 mL/dL (95% CI 0.7–1.4), indicating greater skeletal muscle oxygen uptake.

The study was small, and each participant served as their own control; there was no placebo group. Links among decongestion, hemoconcentration, and exercise capacity are associations within this cohort, not causal estimates. The authors interpreted the lower resting cardiac output as consistent with higher hemoglobin and reduced right ventricular load rather than a sign of harm. That interpretation was not tested against clinical outcomes.

The authors concluded that sotatercept improves exercise tolerance through mechanisms beyond the pulmonary vasculature, including hemoconcentration, improved coupling, and enhanced cardiac output reserve that together increase oxygen delivery to skeletal muscle.