Sotatercept May Reach Beyond Pulmonary Hypertension Into Heart Failure and Transplant Care

A drug developed to treat pulmonary arterial hypertension is now being proposed as a candidate therapy for some of the most difficult patients in cardiology: those with advanced heart failure, mechanical heart pumps, and heart transplantation. In an opinion article published in Frontiers in Transplantation, a team of Greek and American cardiologists argues that sotatercept, a first-in-class activin-signaling inhibitor, may deserve systematic investigation across the entire advanced heart failure and transplant continuum. The argument is deliberately narrow. The authors are not suggesting that sotatercept should become a general heart failure drug. Instead, they identify a specific pulmonary vascular phenotype, characterized by persistently elevated pulmonary vascular resistance and a struggling right ventricle, in which the biology of this agent could plausibly help.

Sotatercept works in a fundamentally different way from older pulmonary hypertension therapies. Conventional drugs augment the nitric oxide, endothelin, or prostacyclin pathways to relax blood vessels. Sotatercept instead acts as a ligand trap, binding selected activin and growth differentiation factor ligands and thereby rebalancing pro-proliferative and anti-proliferative signaling within the transforming growth factor-beta superfamily. In pulmonary arterial hypertension, where excessive proliferation of cells in the pulmonary vessel walls drives disease, this rebalancing improves exercise capacity, functional class, pulmonary hemodynamics, and clinical outcomes when added to background therapy. The question raised by the new article is whether the same biology matters in conditions where pulmonary vascular remodeling arises secondary to left-sided heart disease rather than as a primary process.

The clinical foundation for this hypothesis comes from a series of landmark trials in pulmonary arterial hypertension. In the phase 2 PULSAR trial, sotatercept added to established therapy reduced pulmonary vascular resistance and improved six-minute walk distance. The phase 3 STELLAR trial then demonstrated a clinically meaningful improvement in exercise capacity, together with reductions in pulmonary vascular resistance and N-terminal pro-B-type natriuretic peptide, better functional class, and lower risk of clinical worsening. In the ZENITH trial, sotatercept reduced the composite of death, lung transplantation, or hospitalization for worsening disease in high-risk patients, with event rates of 17.4 percent compared with 54.7 percent in the placebo group, a hazard ratio of 0.24. Similarly, the HYPERION trial showed that sotatercept cut clinical worsening within the first year after diagnosis from 36.9 percent to 10.6 percent. A meta-analysis of four randomized trials involving 889 patients reported a 77 percent lower risk of clinical worsening or death.

Detailed analysis of STELLAR indicated that the fall in pulmonary vascular resistance was driven predominantly by a reduction in pulmonary artery pressure and was accompanied by reverse right-heart remodeling and improved right ventricular function. Emerging observations suggest the response may begin even earlier than structural reverse remodeling alone would predict. Continuous invasive pressure monitoring in five treated patients showed a rapid decline in right ventricular pressure and improvement in right ventricle-pulmonary artery interaction after the first dose, although that sample was extremely small and nonrandomized. In a separate cardiovascular magnetic resonance cohort of 18 intermediate-high-risk patients, right ventricular end-diastolic and end-systolic volumes decreased by 34 and 27 milliliters respectively, while right ventricular ejection fraction rose by five percentage points over approximately 24 weeks. Notably, that imaging study also reported new or enlarging pericardial effusions in five of the 18 patients, a finding that requires confirmation but foreshadows safety questions discussed later.

The strongest evidence beyond pulmonary arterial hypertension comes from CADENCE, a phase 2 randomized trial in combined post- and precapillary pulmonary hypertension associated with heart failure with preserved ejection fraction. Among 164 participants with a median baseline pulmonary vascular resistance of 5.2 Wood units, sotatercept reduced resistance at 24 weeks compared with placebo, with placebo-adjusted estimates of minus 1.02 Wood units at a dose of 0.3 milligrams per kilogram and minus 0.75 Wood units at 0.7 milligrams per kilogram. Both doses lowered mean pulmonary artery pressure by approximately 9 millimeters of mercury. The lower dose also reduced pulmonary artery wedge pressure by roughly 3 millimeters of mercury and increased six-minute walk distance by 20.3 meters relative to placebo. This matters because vasodilator drugs developed for pulmonary arterial hypertension have frequently been neutral or harmful in this group 2 population.

CADENCE is significant for a further technical reason: pulmonary vascular resistance fell despite a reduction in resting cardiac output, while pulmonary artery wedge pressure, right atrial pressure, left atrial volume, natriuretic peptide levels, pulmonary arterial compliance, and indices of right ventricle-pulmonary artery coupling generally moved favorably. The lower dose appeared at least as effective as the higher one, suggesting that more intense ligand trapping does not necessarily produce greater benefit. Commentator Milton Packer has interpreted the results through the adipokine hypothesis of heart failure with preserved ejection fraction, in which activin A derived from dysfunctional epicardial adipose tissue promotes both myocardial fibrosis and pulmonary vascular disease. That framework would elegantly explain simultaneous improvement in vascular resistance, left atrial volume, and filling pressures, but the authors caution it remains an interpretation rather than a demonstrated human mechanism. The narrower message is that hemodynamically confirmed combined pulmonary hypertension may define a treatable pulmonary vascular phenotype within heart failure with preserved ejection fraction.

Extension to heart failure with reduced ejection fraction is far more speculative, since no clinical study has yet evaluated sotatercept in that population. In advanced disease, pulmonary hypertension initially reflects elevated left atrial and pulmonary venous pressure, but sustained exposure can produce endothelial dysfunction, inflammation, fibrosis, and arterial and venous remodeling that generate a precapillary component and rising resistance. This transition carries prognostic weight because the right ventricle then faces increased afterload alongside reduced coronary perfusion reserve. The authors stress that sotatercept should not be considered while congestion remains inadequately treated, since increasing transpulmonary flow across an unprepared left ventricle could worsen pulmonary venous pressure, as pulmonary-selective vasodilators have done in left-heart disease. The rational population would instead consist of patients on optimized guideline-directed therapy who show reproducible combined pulmonary hypertension, disproportionate resistance elevation, and right ventricular uncoupling after decongestion, and any use should currently be confined to properly designed clinical studies.

Left ventricular assist devices offer a particularly informative testing ground. Pump implantation unloads the left ventricle and often reduces wedge pressure, pulmonary artery pressure, and resistance, yet pulmonary vascular disease does not regress uniformly. Some patients retain elevated resistance despite adequate unloading, while others develop early or late right ventricular failure as increased venous return, septal shift, intrinsic dysfunction, and residual afterload exceed right ventricular reserve. Experience with phosphodiesterase-5 inhibitors supports the general premise that pharmacological modulation of the pulmonary circulation after implantation may influence outcomes: an analysis of 13,772 continuous-flow device recipients linked post-implant use of these inhibitors to fewer thrombotic events and lower mortality at the cost of more gastrointestinal bleeding, and a study of 7,229 centrifugal-flow recipients found lower mortality and ischemic stroke with unchanged pump thrombosis. These observational associations require randomized confirmation. The testable sotatercept hypothesis is more specific: after pump speed, volume status, valvular disease, arrhythmias, and conventional right-ventricular therapy are optimized, could the drug reduce persistent resistance, improve coupling, prevent late right ventricular failure, or convert a patient from transplant ineligibility to candidacy?

Transplantation adds two further arenas. Elevated, insufficiently reversible pulmonary vascular resistance remains a major barrier to heart transplantation because an unconditioned donor right ventricle may fail when exposed to high afterload, and sotatercept could be investigated as a bridge-to-candidacy strategy once adequate left-sided unloading has been documented. The post-transplant setting is even more speculative but clinically compelling. A 2026 conference case described a 43-year-old woman who developed severe right ventricular failure after heart transplantation, with recurrent resistance of 5 Wood units, dependence on vasopressors and inhaled nitric oxide, and limited response to sildenafil because of systemic hypotension. After a single dose of sotatercept at 0.3 milligrams per kilogram, vasopressors and inhaled therapy were discontinued within one week, right ventricular function improved, and the patient was discharged. The authors are explicit that this single, uncontrolled case cannot establish efficacy, since concomitant therapies and natural postoperative recovery are major confounders, but it illustrates why a strategy that does not rely on systemic vasodilation could be attractive when high resistance drives post-transplant right ventricular failure.

Safety, the authors insist, may differ across the continuum and must be treated as co-primary in any early trial. In the meta-analysis of four randomized pulmonary arterial hypertension trials, total bleeding occurred in 37.9 percent of sotatercept patients versus 18.7 percent on placebo, epistaxis in 26.7 versus 5.4 percent, telangiectasia in 19.8 versus 6.4 percent, increased hemoglobin in 10.0 versus 0.7 percent, and thrombocytopenia in 8.9 versus 4.0 percent. In device recipients, erythrocytosis could theoretically increase blood viscosity even as it enhances oxygen delivery, while thrombocytopenia and vascular lesions could amplify bleeding, and no current evidence defines the net hemocompatibility effect during continuous-flow support. Transplant recipients may carry cytopenias, renal impairment, infection risk, and antithrombotic therapy that alter tolerability, and interactions with immunosuppression, wound healing, and allograft biology remain unknown. The proposed path forward is deliberately staged: a mechanistic study in stable patients with confirmed wedge-pressure control but persistent resistance elevation, potentially including a device-supported stratum; then a bridge-to-candidacy trial with blinded transplant-committee assessment; and only later observational or compassionate-use evaluation after transplantation. The next step, the authors conclude, is not therapeutic extrapolation but disciplined, phenotype-enriched trials.

Subject of Research: Investigating sotatercept, an activin-pathway ligand trap, as a therapy for pulmonary vascular remodeling across advanced heart failure, LVAD support, and heart transplantation

Article Title: Beyond pulmonary arterial hypertension: sotatercept across the advanced heart failure and transplant continuum

Article References: Xanthopoulos, A., Kourek, C., Magouliotis, D. E., Triposkiadis, F., & Briasoulis, A. (2026). Beyond pulmonary arterial hypertension: sotatercept across the advanced heart failure and transplant continuum. Frontiers in Transplantation, 5, Article 1966659. https://doi.org/10.3389/frtra.2026.1966659

Image Credits: AI Generated

DOI: 10.3389/frtra.2026.1966659

Keywords: sotatercept, pulmonary arterial hypertension, pulmonary vascular resistance, heart failure, HFpEF, right ventricular function, left ventricular assist device, heart transplantation, CADENCE trial, activin signaling, pulmonary hypertension, reverse remodeling