The Fontan procedure has rewritten the natural history of many children with congenital heart disease and univentricular physiology. However, long-term survival is limited by the development of haemodynamic and multisystem failure, leading to high morbidity and mortality. Absence of a subpulmonary ventricular pump, chronically elevated central venous pressure, and reduced cardiac output, along with lymphatic dysfunction and progressive multiorgan involvement, define the clinical course of many patients with the Fontan procedure, resulting in the heterogeneous clinical entity of Fontan failure. This review provides a comprehensive overview of the pathophysiological mechanisms underlying Fontan failure and a critical analysis of the currently available advanced therapeutic options. Particular attention is paid to the current frontiers of mechanical circulatory support. Although the presence of a total cavopulmonary connection may represent an anatomical limitation, ventricular assist devices have gained attention both as a bridge to transplantation and, in selected cases, as a long-term strategy. Nonetheless, despite the high surgical complexity, heart transplantation currently represents the only definitive option for this patient population. Optimizing clinical outcomes in Fontan failure represents one of the most challenging frontiers in congenital heart disease. Achieving significant advances will require accurate risk stratification, timely transition to advanced therapies, and coordinated multidisciplinary collaboration.

Background and Objective: Heart failure (HF) is a major cause of morbidity in adults with congenital heart disease (ACHD), who may also have limited access to transplant. Intermittent levosimendan administration has shown benefit in advanced HF due to acquired heart disease, but currently, there are no data on ACHD. We aimed to evaluate the effects of this treatment in ACHD patients with advanced heart failure, focusing on both clinical status and objective outcome measures. Materials and Methods: We conducted a single-center retrospective analysis of ACHD patients aged >18 years with advanced HF who received ≥ three intermittent levosimendan infusions (either 12.5 mg once monthly or 6.25 mg every two weeks over a 6 h infusion) between March 2020 and January 2025 at a tertiary ACHD center. Clinical outcomes during follow-up were compared with those in the year preceding treatment. Primary endpoints included safety and HF-related adverse events, particularly HF hospitalizations. Secondary endpoints included changes in New York Heart Association (NYHA) class, nt-pro-B-natriuretic peptide (nt-proBNP) values, and ventricular systolic function assessed by echocardiography. Results: Twelve patients (median age 44.6 years, 25% female) were included, with heterogeneous congenital diagnoses and advanced HF. Five patients had a systemic right ventricle (sRV) and one had a single ventricle with previous Fontan palliation. During a median follow-up of 1.3 years, intermittent levosimendan was well-tolerated, with no treatment-limiting adverse events. Two patients (16%) required hospitalization for HF during follow-up compared with 8 (66%) in the year preceding treatment. The incidence of HF hospitalizations decreased from 0.83 to 0.20 events per person-year during follow-up (p = 0.03), although findings should be interpreted cautiously given the small sample size and retrospective design. NYHA functional class improved significantly (p = 0.005). While no significant changes were observed in NT-proBNP or left ventricular ejection fraction, patients with a systemic right ventricle (sRV) showed an increase in right ventricular fractional area change (27 ± 7.4% to 30.6 ± 7%, p = 0.02); however, this observation should be regarded as exploratory given the limited sample size. Two deaths occurred, consistent with the severity of the underlying disease and not directly attributable to levosimendan and the Fontan patient received a successful heart and liver transplant. Conclusions: In a small, real-world cohort of ACHD and advanced HF, intermittent levosimendan administration was safe and associated with improved symptoms, reduced HF hospitalizations, and signals of enhanced systemic right ventricular function. These hypothesis-generating findings may help inform future multicenter studies in ACHD patients with advanced HF, suggesting a potential role for intermittent levosimendan in selected patients, while highlighting the need for prospective, adequately powered studies to confirm its efficacy and better define optimal patient selection.

Background: Heart failure (HF) is a major cause of morbidity in adults with congenital heart disease (ACHD), who may also have limited access to transplant. Intermittent levosimendan has shown benefit in advanced HF due to acquired heart disease, but currently there are no data in ACHD. Methods: We conducted a retrospective analysis of ACHD patients aged >18 years with advanced HF who received ≥3 intermittent levosimendan infusions between March 2020 and January 2026 at a tertiary ACHD centre. Clinical outcomes during follow-up were compared with those in the year preceding treatment. Primary endpoints included safety and HF-related adverse events, particularly HF hospitalizations. Secondary endpoints included changes in New York Heart Association (NYHA) class, NT-proBNP levels, and ventricular systolic function assessed by echocardiography. Results: Twelve patients (median age 44.6 years, 25% female) were included, with heterogeneous congenital diagnoses and advanced HF. Five patients had a systemic right ventricle (sRV) and one had a single ventricle with previous Fontan palliation. During a median follow-up of 1.3 years, intermittent levosimendan was generally well tolerated, with no treatment-limiting adverse events. HF hospitalization incidence significantly decreased from 0.83 events/person-year before treatment to 0.20 events/person-year during follow-up (p=0.03). NYHA functional class improved significantly (p=0.005). While no significant changes were observed in NT-proBNP or left ventricular ejection fraction, patients with an sRV demonstrated a significant improvement in right ventricular fractional area change (27±7.4% to 30.6±7%, p=0.02). Two deaths occurred, consistent with the severity of underlying disease and not directly attributable to levosimendan. Conclusions: In this real-world cohort of ACHD patients with advanced HF, intermittent levosimendan administration was safe and associated with improved symptoms, reduced HF hospitalizations, and enhanced systemic right ventricular function. These findings support the potential role of intermittent levosimendan as a therapeutic option in selected ACHD patients and underscore the need for prospective, adequately powered studies to confirm efficacy and define optimal patient selection.