Sotatercept Improves Right Heart Mechanics Despite Reduced Myocardial Contractility in Pulmonary Arterial Hypertension - A Prospective Exercise Hemodynamic Study
Abstract
Background: The right ventricular (RV) response to pressure overload is a crucial determinant of outcomes in pulmonary arterial hypertension(PAH). Sotatercept improves clinical outcomes, but its effects on the RV have been inconsistent. We sought to evaluate the effects of sotatercept on load-independent measures of RV contractility, RV-PA coupling, and right heart deformation at rest and exertion in patients with PAH. Methods: In this prospective trial among participants with PAH recruited between July 2024 and May 2025, we performed simultaneous echocardiography and invasive pressure measurements during rest and exercise, to evaluate changes in RV contractility (end-systolic elastance [Ees]), afterload [PA elastance (Ea)], RV-PA coupling (ratio of arterial Ea to Ees), and right heart deformation including RV and right atrial(RA) strain, before and after 24 weeks of sotatercept using mixed models. Results: Among 30 participants (n=21, 70% female; mean age 49.3 years [SD 13.5]), sotatercept decreased PA Ea. These changes were associated with reduced RV contractility, pulmonary artery pulsatility index, and the maximal rate of RV pressure increase over time (dP/dtmax)(p<0.001 for all). The decrease in Ees was associated with decrease in PA Ea (r=+0.70[95% CI +0.44 to +0.85],p<0.0001) with preserved RV-PA coupling (mean difference +0.08[95% CI -0.11 to +0.26],p=0.42). Although systolic indices measured at the base of the RV (tricuspid annular plane systolic excursion and systolic velocity of the lateral tricuspid annulus) decreased after sotatercept, there was an increase in RV free wall-dependent systolic indices including resting and exercise RV free wall strain(FWS)(mean difference +6.2%[95% CI +4.5 to +7.8],p<0.0001) and fractional area change(p=0.0001). Beyond the RV, there was also improved RA filling and contractile performance across rest and exercise(p<0.0001 for all). Conclusions: Sotatercept decreases RV contractility in proportion to reduced afterload, while preserving the RV-PA coupling relationship. Despite decreased RV contractility, global measures of right heart performance such as RVFWS and RA strain improve, alongside redistribution of RV deformation from annular motion to free-wall shortening. These data suggest that sotatercept causes an energetically favorable reduction in resting RV contractility to match the lower afterload, which does not appear physiologically detrimental when considering the concurrent improvement in RV free-wall contractile mechanics and exertional right heart reserve. Clinical Trial Registration: NCT06409026 https://clinicaltrials.gov/study/NCT06409026