David J. Goldberg

BACKGROUND: Survival after Fontan palliation for single ventricle heart disease has improved substantially, yet the long-term trajectory remains poorly defined. The Fontan Outcomes Network, a learning health network of 38 congenital heart centers in the United States and Canada, was established to address this gap. We report baseline characteristics and early findings from the first 1121 participants enrolled in this prospective clinical registry. METHODS: We performed a cross-sectional analysis of individuals who had undergone Fontan palliation enrolled in the Fontan Outcomes Network from August 2022 through August 2024. Demographic, clinical, imaging, procedural, and medication data were analyzed descriptively, overall and by age group (<12, 12 to <18, and ≥18 years). RESULTS: A total of 1121 participants were enrolled (mean age, 16.3±10.2 years; 471 [42%] female). Hypoplastic left heart syndrome (n=431 [38.5%]) and right ventricular–dominant anatomy (n=615 [54.9%]) were the most common primary cardiac diagnoses, especially in younger age groups. Extracardiac conduit was the most frequent Fontan type (n=749 [66.8%]). Typical Fontan-related adverse events were noted in 59% of cases (n=662), including chylous pleural effusions (n=108 [9.6%]), Fontan thrombosis (n=79 [7.1%]), and nonperioperative stroke (n=73 [6.5%]). A history of arrhythmia was present in 41.3% of patients (n=463) overall, increasing with age. Acquired comorbidities were present in 57.5% of patients (n=645), including asthma (n=132 [12%]) and sleep apnea (n=103 [9%]), with burden increasing by age. Antithrombotic medication use was nearly universal. Use of other medications varied widely by age, and included β-blockers, angiotensin-converting enzyme inhibitors, and pulmonary vasodilators. A clinical diagnosis of an anxiety disorder was present in 34.1% of patients (n=382), including 48.1% of adults (n=194 of 403), and antidepressants were prescribed in 11.8% of patients (n=132), including 23.6% of adults (n=95 of 403), highlighting the mental health needs of this population. CONCLUSIONS: The Fontan Outcomes Network includes one of the largest prospective, multi-institutional data sets of patients with Fontan circulation. These initial findings demonstrate the potential for a collaborative learning health network to advance research and quality improvement for this rare disease population.

Introduction: Pediatric plastic bronchitis (PB) is a rare complication of surgically palliated congenital heart disease (CHD). Fibrin casts obstruct airways and can cause respiratory distress. There are no therapeutics approved by the United States Food and Drug Administration to treat PB, but inhaled tissue plasminogen activator (tPA) has been anecdotally used to relieve symptoms. We conducted a phase II open‐label clinical trial to test the safety of inhaled tPA in pediatric PB.Methods: Patients with an acute exacerbation of PB requiring hospitalization were enrolled to test the safety of an inhaled tPA regimen (5 mg every 6 h). The primary end point was to assess the safety and tolerability of repeated doses of nebulized, inhaled tPA in pediatric patients with acute PB. Safety parameters consisted of clinical laboratories to assess bleeding, which were measured prior to, during, and after tPA treatment. To benchmark efficacy using spirometry and oxygen saturation, children with Fontan‐palliated CHD without a history of PB, with and without protein losing enteropathy (PLE), and healthy children were enrolled in a control arm that did not receive tPA.Results: Of the 10 patients with PB screened for enrollment, eight qualified for immediate treatment with inhaled tPA. A total of 29 non‐PB participants (PLE, n = 8 [10–18 yo]; CHD, n = 9 [8–17 yo]; and healthy, n = 12 [7–16 yo]) were enrolled. There were no differences in pretreatment clinical blood laboratory values of hemostasis and those during and after treatment with the study drug (primary safety outcome). However, there were four episodes of self‐limiting epistaxis related to the study drug. Inhaled tPA statistically improved oxygen saturation although this was moderate and likely not clinically significant; inhaled tPA did not alter spirometry values.Conclusion: In this small, phase II study, repeated doses of inhaled tPA in patients with an acute exacerbation of PB did not result in disrupted systemic coagulation or hematological homeostasis or serious bleeding. However, patients should be monitored for localized bleeding. Larger, randomized trials are needed to provide more comprehensive assessments of bleeding risk and to further assess efficacy.Trial Registration: ClinicalTrials.gov identifier: NCT02315898

Background: In the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (V o ₂ ) at peak exercise. This disparate response may be explained by the physiologic challenge of improving peak V o ₂ in participants with near‐normal baseline exercise performance. Methods: Participants were divided into subgroups by baseline predicted peak V o ₂ (2 2 2 improved significantly after 6 months of udenafil treatment, when compared with placebo (0.23±4.17 mL/kg per min versus −0.90±3.74 mL/kg per min; P =0.021). Secondary outcome measures, including V o ₂ at ventilatory anaerobic threshold ( P =0.023), work at ventilatory anaerobic threshold ( P =0.032), and the myocardial performance index ( P =0.007) were all significantly improved as well. A significant interaction was found between exercise subgroups and response to udenafil for peak V o ₂ ( P =0.036) but not for other outcomes. Conclusions: In this post hoc subgroup analysis, after exclusion of patients with Fontan circulation with near‐normal baseline peak V o ₂ , a positive treatment effect of udenafil was identified for the primary outcome of peak V o ₂ . The interaction between baseline peak V o ₂ and treatment may have influenced the outcome of the FUEL trial. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT0274115.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network’s Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO₂) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO₂ declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO₂ tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO₂ at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO₂ at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO₂ at VAT was better preserved than peak VO₂ across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.