We sincerely thank the authors for their thoughtful comments on our recent review.1 We appreciate their engagement with our work and their valuable contributions. Their observations regarding high-output physiology and bile acid (BA) dysregulation offer valuable perspectives that enrich our ongoing understanding of Fontan pathophysiology.
We agree that Fontan failure is not confined to cardiac dysfunction but represents a complex multisystem disease. In our article, we briefly highlighted this complexity by referring to a phenotype-based classification that includes this subset of patients (group III). In their original article, Book WM et al describe group III as a subgroup of Fontan patients with preserved systolic and diastolic function and either normal or high cardiac output with clear evidence of hepatic fibrosis and extracardiac manifestations. The authors highlight multisystem dysfunction as a potential contributor and refer to this group as the most challenging to manage despite “favorable hemodynamics.”2 This group reflects the very profile raised by the authors, and we welcome their insights into the mechanisms that may underlie this phenotype.
We also acknowledge and appreciate the authors’ focus on BA dysregulation as a potential mediator of Fontan-related pathophysiology. The authors’ work suggesting direct mitochondrial and inflammatory effects of BAs on the myocardium is compelling and aligns with evolving views that Fontan-associated liver disease may not merely be a consequence but also a contributor to cardiovascular dysfunction.3
The therapeutic implications of BA modulation, such as the potential benefits of ursodeoxycholic acid or BA sequestrants, are intriguing and warrant prospective investigation. Given the limited treatment options currently available for the failing Fontan patient, exploring these novel targets may lead to the development of disease-modifying therapies—an area of critical unmet need.
We thank the authors again for their important contribution and share their enthusiasm for advancing our collective understanding of Fontan pathophysiology and care.
Footnotes
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Khayyat I.M., Ordonez M.V., Marelli A., et al. Diagnosis of diastolic dysfunction in adults with failing Fontan circulation. JACC Adv. 2025;4(6_Part_1) doi: 10.1016/j.jacadv.2025.101758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Book W.M., Gerardin J., Saraf A., et al. Clinical phenotypes of fontan failure: implications for management. Congenit Heart Dis. 2016;11(4):296–308. doi: 10.1111/chd.12368. [DOI] [PubMed] [Google Scholar]
- 3.Guerrero-Chalela C.E., Therrien J., Grossman Y., et al. Severe fontan-associated liver disease and its association with mortality. J Am Heart Assoc. 2023;12(19) doi: 10.1161/JAHA.121.024034. [DOI] [PMC free article] [PubMed] [Google Scholar]