Emerging therapeutic strategies for the failing Fontan circulation

Patients with Fontan circulation face progressive multisystem dysfunction driven by venous hypertension, lymphatic failure, and metabolic derangements. This state-of-the-art review synthesizes evidence across hemodynamic, lymphatic, pulmonary vascular, and metabolic domains to outline emerging therapies and a pragmatic care framework. We summarize data on exercise rehabilitation; pulmonary vasodilators; lymphatic imaging-guided interventions; metabolic modulation including bile acid sequestration and SGLT2 inhibition; arrhythmia prevention; mechanical circulatory support; and transplantation, including combined heart-liver strategies. Recognizing limitations of conventional randomized trials in this heterogeneous, small population, we propose adaptive, registry-embedded, and platform designs with harmonized phenotypes and core outcomes. This review aims to bridge mechanistic insight and clinical application, offering clinicians a concise roadmap and researchers a set of testable hypotheses to improve survival, function, and quality of life.