Abstract 4360112: Ketones as an Optimal Substrate in Single Ventricle Heart Disease

Introduction: Heart failure (HF) is a common morbidity in children with single ventricle heart disease (SVHD). Unfortunately, there are no proven treatments for SVHD associated HF. After birth, the myocardium shifts substrate use from glucose oxidation to fatty acid oxidation (FAO), which becomes responsible for 40-60% of all the ATP produced. Previous publications from our group have shown mitochondrial dysfunction and impaired FAO in the failing hearts of patients with SVHD. An alternative source of mitochondrial fuel such as ketone bodies, could improve mitochondrial function and represents a novel therapeutic target for SVHD HF. Hypothesis: Ketone body supplementation can improve mitochondrial function in SVHD hearts. Methods: SVHD hearts were collected in the operating room at the time of transplantation. Freshly explanted tissue was treated with the ketone 3-hydroxybutyrate (3-OHB), the long chain fatty acid (LCFA) palmitate or Glucose and Pyruvate (G/P) overnight, to assess its ability to utilize each of these substrates. Mitochondrial function was measured via Oxygraph-2k with the sequential addition of multiple substrates, which allows for a stepwise assessment of electron transport chain components [ADP/Glutamate for Complex I (CI); Succinate for Complex II (CII), CCCP for Maximal Respiration (MR)]. Results: Paired analysis of O 2 flux/unit tissue (pmol/(s*unit)) in SVHD +/- 3-OHB, LCFA, and G/P was performed (N=4; 2 males, 2 Females, Mean age = 9.25). 3-OHB treatment resulted in significant improvement in CI (Mean + SEM; 34.8 + 8.0, P=0.04), CII (31.6 + 9.2, P=0.04) and MR (34.8 + 8.0, P=0.020) when compared to the G/P treatment. Importantly, LCFA decreased mitochondrial function. Conclusions: Mitochondrial function in SVHD myocardium is improved by ex vivo treatment with ketone bodies, whereas treatment with LCFA decreased mitochondrial function. This study highlights the ketolytic potential of SVHD failing hearts, as well as their inability to effectively utilize fatty acids for fuel. Further studies will be carried out to better understand the mechanisms behind ketone utilization and their signaling role in the failing myocardium.