Effect of Activin Type II Receptor Signaling in Patients With HFpEF and Pulmonary Hypertension: A Critical Analysis of Biological Mechanisms and Clinical Trials

The totality of evidence indicates that the mechanisms underlying the increase in pulmonary vascular resistance in patients with combined postcapillary and precapillary pulmonary hypertension (CpcPH) associated with heart failure with preserved ejection fraction (HFpEF) differ meaningfully from those responsible for the increase in pulmonary vascular resistance in patients with pulmonary arterial hypertension. CpcPH-HFpEF is a complex disorder involving the pulmonary veins, left atrium, and pulmonary arterioles, but recent evidence has highlighted a potentially central role for pulmonary venous and left atrial (LA) dysfunction. Epicardial adipose tissue occupies anatomical proximity to both structures, allowing derivative secretory products to influence their structure and function. The most well-characterized proinflammatory adipokine released from an expanded epicardial fat mass is activin A, which causes fibrosis and cardiomyocyte stiffness and senescence in underlying tissues by signaling through activin type II receptor signal transduction. Such signaling regulates pulmonary venular responses to mechanical stretch, and circulating activin A is elevated in patients with HFpEF who have enlarged LA chambers, pulmonary venous hypertension and increased pulmonary vascular resistance. The adipokine hypothesis of HFpEF identified activin A and activin type II receptor signaling as key adipokine mediators in the pathogenesis of HFpEF. Experimentally, activin A signaling promotes the development of both atrial myopathy and HFpEF, and activin type II receptor ligand traps alleviate HFpEF and ameliorate both the pulmonary vascular and left heart abnormalities in experimental models in which CpcPH-HFpEF is induced by obesity. These collective observations led to the prospective hypothesis that adipokine modulation by sotatercept would mediate benefits on the left heart in patients with CpcPH-HFpEF. These expectations were validated when the CADENCE trial showed that sotatercept decreased both pulmonary artery wedge pressures and left atrial volume index in patients with CpcPH-HFpEF, which are effects that could not explained by a decrease in pulmonary vascular resistance. Activin A released from an expanded epicardial adipose tissue promotes both pulmonary venous and left atrial remodeling and fibrosis in vivo, which (in turn) are effects that can be attenuated by an activin A decoy. The efficacy of sotatercept to slow the progression of CpcPH-HFpEF is now being tested in a phase III outcomes trial.