Reddy YNV; Department of Cardiovascular Medicine, Mayo Clinic, USA
Frantz RP; Miranda WR; Harada T; Kazui S; Borlaug BA

Comment by Dr Older
Sotatercept is available in Australia but NOT subsidised on PBS

Journal of the American College of Cardiology. 88(4):415-432, 2026 Jul 28.

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
O2 content difference across phases (+1.1 mL/dL; 95% CI: +0.7 to +1.4
mL/dL; P < 0.0001).

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 O2 delivery. The
increased O2 delivered occurs despite decreased RV work, with functional
benefits further enhanced by augmented skeletal muscle O2 use.
(Sotatercept on Central Cardiopulmonary Performance and Peripheral Oxygen
Transport During Exercise in Pulmonary Arterial Hypertension;