Abstract Body (Do not enter title and authors here): Introduction: Children with severe forms of congenital heart disease (CHD), such as single ventricle CHD (SV), are surviving into adulthood. Heart failure (HF) is a common morbidity for patients with SV, but there are no evidence-based treatments. SGLT2-inhibitors (SGLT2i) are approved for the treatment of HF in adults and are being increasingly used in patients with a Fontan despite the absence of safety and efficacy data. The mechanism of SGLT2i in HF is unknown. We have demonstrated that failing SV explanted hearts have decreased mitochondrial function as measured by an Oroboros oxygraphy-2k and that ex vivo supplementation with ketone bodies (beta-hydroxybutyrate, B-OHB) improves mitochondrial function. One proposed mechanism of SGLT2i efficacy in HF is that they promote ketone body production by the liver providing an alternate fuel source for cardiac mitochondria.

Hypothesis: Treatment of exercise-limited patients with a Fontan with SGLT2i will result in increased circulating B-OHB.

Methods: This is a 6-month observational prospective multicenter pragmatic study. Inclusion criteria: SV Fontan, age 10 – 40 years, ability to perform an exercise test, max VO₂ < 70% predicted. Exclusion criteria: current treatment with an SGLT2i, prior discontinuation of SGLT2i for adverse event, pregnancy, diabetes. Participants will be enrolled and stratified by intent to treat with SGLT2i, goal enrollment of 55 per cohort (Figure). Type of SGLT2i, dosing, and decision to treat are at the discretion of the treating cardiologist. Primary outcome is change in circulating B-OHB between enrollment and 6-months and adverse events will be documented.

Results: Between Feb and May 2025, 20 Fontan participants were enrolled (14 male, 5 female, 1 unknown); median age 19y (IQR 15-21y); race=18 White, 1 Asian, 1 American Indian/Alaska native; ethnicity=5 Hispanic, 15 Not Hispanic; insurance type=11 private, 7 Federal, 2 unknown; SGLT2i Cohort=7 and No SGLT2i Cohort=13. The median NT-proBNP level at enrollment is 114.5pg/ml (IQR 44.6-247). Mean B-OHB level at enrollment is 0.18±0.15mM/L (normal<0.4). One participant was removed from the study due to missing B-OHB data. Interim results for these 19 participants will be available at the time of presentation.

Conclusions: This is the first prospective study of SGLT2i in children and young adults with CHD. The results could inform the use of SGLT2i and serve as the basis to perform a larger efficacy trial in this population.