Corresponding Author
Key Words: congenital heart disease, Eisenmenger syndrome, pulmonary arterial hypertension, pulmonary vascular disease, sotatercept
Despite major therapeutic advances in pulmonary arterial hypertension (PAH), Eisenmenger syndrome remains one of the most understudied and therapeutically challenging phenotypes within group 1 PAH.1,2 Especially patients with unrepaired congenital heart disease–associated PAH and Eisenmenger physiology have historically been excluded from pivotal randomized trials, leaving clinicians to extrapolate treatment strategies from idiopathic PAH populations despite substantial differences in pathophysiology, hematologic adaptation, and systemic oxygen delivery.1 Against this background, the report by Leung et al3 represents an important and timely contribution, offering one of the first real-world experiences with sotatercept in patients with Eisenmenger syndrome.
Why Eisenmenger Syndrome Remains Different
Beyond trial exclusion, Eisenmenger syndrome poses unique therapeutic dilemmas that make the introduction of sotatercept particularly intriguing. Chronic cyanosis, secondary erythrocytosis, platelet dysfunction, and complex shunt physiology raise understandable concerns regarding a therapy known to increase hemoglobin levels and alter platelet counts.1,4 In addition, pulmonary vascular disease in Eisenmenger syndrome is not merely an isolated pulmonary vasculopathy; it represents the culmination of lifelong hemodynamic stress, maladaptive vascular remodeling, and multisystem adaptation. Consequently, any disease-modifying therapy must be evaluated not only for conventional PAH endpoints, but also for its effects on oxygenation, systemic perfusion, hematologic balance, and right ventricular adaptation.
What Does This Case Series Teach Us?
In this context, the observations reported in the present case series are both reassuring and provocative.3 Among 6 patients with Eisenmenger syndrome receiving sotatercept on top of advanced background therapy, 5 remained on treatment with clinically meaningful improvements in exercise tolerance, dyspnea, oxygenation, and daily functional capacity. Importantly, no major bleeding events or treatment-limiting erythrocytosis were observed, despite longstanding concerns that sotatercept might exacerbate preexisting hematologic abnormalities in cyanotic congenital heart disease.3 Although 1 patient discontinued therapy because of thrombocytopenia, platelet counts recovered after treatment discontinuation.3
Perhaps the most compelling signal emerging from this report is the apparent improvement in systemic oxygenation across multiple patients.3 Several individuals demonstrated higher resting and exertional oxygen saturation following sotatercept initiation, alongside reductions in cyanosis and supplemental oxygen requirements.3 Although these observations remain anecdotal and uncontrolled, they raise an important mechanistic hypothesis: if sotatercept meaningfully reduces pulmonary vascular resistance through reverse remodeling, pulmonary blood flow may improve sufficiently to favorably influence shunt dynamics and systemic oxygen delivery. Such a possibility is particularly attractive in Eisenmenger syndrome, where therapeutic success is often limited less by pulmonary pressures alone and more by the consequences of chronic hypoxemia.1,2
Sotatercept: Beyond Vasodilation
Notably, the patients included in this series represented a severely advanced and heterogeneous population.3 Most were already receiving contemporary triple-combination therapy, including endothelin receptor antagonists, nitric oxide pathway agents, and prostacyclin-pathway therapies.3 Therefore, the observed clinical improvements occurred despite substantial baseline therapeutic optimization.
This raises the possibility that sotatercept may offer incremental biological effects distinct from conventional vasodilator therapy. Unlike traditional agents that primarily target vasoconstriction pathways, sotatercept addresses dysregulated proliferative signaling through restoration of the balance between ActRIIA/Smad2/3 and BMPRII/Smad1/5/8 pathways.5, 6, 7 For patients with Eisenmenger syndrome—whose pulmonary vasculopathy frequently resembles advanced obstructive vascular remodeling—this mechanistic distinction may prove especially relevant.
Figure 1 summarizes the proposed mechanistic rationale, potential therapeutic benefits, and unresolved clinical concerns associated with sotatercept therapy in Eisenmenger syndrome.
Figure 1.
Sotatercept May Represent a Novel Disease-Modifying Strategy in Eisenmenger Syndrome By Targeting Pulmonary Vascular Remodeling Beyond Conventional Vasodilation
Early real-world experience suggests potential improvements in oxygenation, exercise tolerance, and functional capacity, although careful hematologic monitoring and further prospective studies remain essential. 6MWD = 6-minute walk distance; CHD = congenital heart disease; PAH = pulmonary arterial hypertension; RV = right ventricular; SpO2, oxygen saturation; SuMILE = An Open-label, Randomized, Controlled Trial to Evaluate the Efficacy of Sotatercept Add-on Therapy Compared to Guideline-Directed Medical Therapy with Pulmonary Vasodilators for Pulmonary Arterial Hypertension Associated with Pulmonary Vasodilator-resistant, Unrepaired Congenital Shunts (ASD, VSD, PDA) Including Eisenmenger Syndrome; TGF = transforming growth factor.
Future Directions
Nevertheless, caution remains essential. Eisenmenger syndrome encompasses a remarkably heterogeneous spectrum, ranging from simple posttricuspid shunts to complex congenital anatomy with markedly different ventricular physiology and adaptive reserve.1,2 The optimal phenotype, timing, and monitoring strategy for sotatercept therapy therefore remain unknown. Moreover, this report is retrospective, single-center, and hypothesis-generating.3
The ongoing SuMILE (An Open-label, Randomized, Controlled Trial to Evaluate the Efficacy of Sotatercept Add-on Therapy Compared to Guideline-Directed Medical Therapy with Pulmonary Vasodilators for Pulmonary Arterial Hypertension Associated with Pulmonary Vasodilator-resistant, Unrepaired Congenital Shunts [ASD, VSD, PDA] Including Eisenmenger Syndrome) evaluating sotatercept in Eisenmenger syndrome and unrepaired shunt-associated PAH will therefore be critically important.8 Beyond traditional endpoints such as 6-minute walk distance or N-terminal pro–B-type natriuretic peptide, future studies should explore oxygenation profiles, exercise hemodynamics, right ventricular adaptation, erythrocytosis dynamics, and patient-reported quality of life.
Conclusions
For decades, Eisenmenger syndrome has remained a therapeutically marginalized population within PAH research. The emergence of sotatercept introduces the possibility that treatment strategies may evolve beyond cautious vasodilation toward true modification of pulmonary vascular biology. Although current evidence remains preliminary and hypothesis-generating, the experience reported by Leung et al3 provides an important early signal that carefully selected patients with Eisenmenger syndrome may benefit from this novel therapeutic approach. The ongoing SuMILE will now determine whether sotatercept can ultimately redefine the treatment landscape of congenital heart disease–associated PAH.
Funding Support and Author Disclosures
The author has reported that he has no relationships relevant to the contents of this paper to disclose.
Footnotes
The author attests they are in compliance with human studies committees and animal welfare regulations of the author’s institution and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Arvanitaki A., Gatzoulis M.A., Opotowsky A.R., et al. Eisenmenger syndrome: JACC state-of-the-art review. J Am Coll Cardiol. 2022;79(12):1183–1198. doi: 10.1016/j.jacc.2022.01.022. [DOI] [PubMed] [Google Scholar]
- 2.Banerjee R., Opotowsky A.R. Update on Eisenmenger syndrome—Review of pathophysiology and recent progress in risk assessment and management. Int J Cardiol Congenit Heart Dis. 2024;17 doi: 10.1016/j.ijcchd.2024.100520. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Leung G.P., Major E.C., Cason S.C., et al. Sotatercept in congenital heart disease-associated pulmonary arterial hypertension and Eisenmenger syndrome: first case series. JACC Case Rep. 2026;31(32):108814. doi: 10.1016/j.jaccas.2026.108814. [DOI] [PubMed] [Google Scholar]
- 4.Humbert M., Kovacs G., Hoeper M.M., et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023;61(1) doi: 10.1183/13993003.00879-2022. [DOI] [PubMed] [Google Scholar]
- 5.Hoeper M.M., Badesch D.B., Ghofrani H.A., et al. Phase 3 trial of sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388:1478–1490. doi: 10.1056/NEJMoa2213558. [DOI] [PubMed] [Google Scholar]
- 6.Humbert M., McLaughlin V., Gibs J.S.R., et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021;384(13):1204–1215. doi: 10.1056/NEJMoa2024277. [DOI] [PubMed] [Google Scholar]
- 7.Morrell N.W., Aldred M.A., Chung W.K., et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53(1) doi: 10.1183/13993003.01899-2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.A study of sotatercept for patients with Eisenmenger syndrome or unrepaired shunt-associated pulmonary arterial hypertension resistant to vasodilator therapy (SuMILE) https://clinicaltrials.gov/study/NCT07356778#contacts-and-locations