Beyond vasodilation: sotatercept and the remodeling hypothesis in hfpef-associated pulmonary hypertension

Pulmonary hypertension complicating heart failure with preserved ejection fraction (HFpEF), particularly the combined post- and pre-capillary form (CpcPH), has lacked any mechanism-specific therapy, as repeated trials of pulmonary vasodilators have failed or caused harm. This mini-review highlights findings from the Phase 2 CADENCE study evaluating sotatercept, an activin signaling inhibitor that targets vascular remodeling rather than vascular tone. Sotatercept met its primary endpoint by reducing pulmonary vascular resistance at 24 weeks and produced concordant improvements in mean pulmonary artery pressure, wedge pressure, 6-minute walk distance, NYHA class, and NT-proBNP, without the compensatory rise in left-sided filling pressure that characterizes vasodilator therapy. Notably, the lower 0.3 mg/kg dose appeared to outperform the 0.7 mg/kg dose across several hemodynamic and functional endpoints while offering a more favorable safety profile. These findings position sotatercept as the first non-vasodilatory, potentially disease-modifying option for advanced HFpEF-associated pulmonary hypertension, and a confirmatory Phase 3 trial is warranted to determine whether this hemodynamic benefit translates into durable clinical outcomes.