Cardiac Output and Oxygen Delivery Responses to Sotatercept in Pulmonary Arterial Hypertension

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Abstract
Sotatercept, a first‐in‐class activin signaling inhibitor, improves pulmonary vascular hemodynamics and clinical outcomes in pulmonary arterial hypertension (PAH). However, despite reductions in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), cardiac output (CO) does not generally increase, and some patients experience a decline in CO, a finding of unclear clinical significance. We sought to characterize the heterogeneity of CO responses to sotatercept in PAH and to determine whether incorporating oxygen delivery (DO 2 ) provides additional insight into the physiological significance of these changes. We retrospectively analyzed PAH patients who underwent right heart catheterization before and during sotatercept therapy (median 7.3 months, IQR 4.8, 9.3). Hemodynamic, echocardiographic, hematologic, and clinical parameters were collected, including functional class, 6‐min walk distance (6MWD) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). Patients were dichotomized by CO response (decreased vs. maintained), and DO 2 was calculated at each catheterization. A total of 56 patients were included. While most demonstrated reductions in PVR and mPAP, 63% experienced decreased CO. Improvements in 6MWD and NT‐proBNP were similar between groups, and hemoglobin increased comparably. However, among patients with decreased CO, 63% had a concomitant decline in DO 2 accompanied by worsening 6MWD and a reduced NT‐proBNP response. In this real‐world cohort, over half of sotatercept‐treated PAH patients experienced reduced CO despite overall hemodynamic and clinical improvement. Concomitant reductions in DO 2 identify a subgroup with worse functional outcomes. These findings suggest that DO 2 adds additional information beyond CO alone when assessing the physiological response to sotatercept.

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