Abstract Body: Introduction: Children born with single ventricle heart disease often develop heart failure (SVHF), often requiring cardiac transplant. Explanted SV hearts have impaired mitochondrial bioenergetics and fatty acid oxidation (FAO). Sodium glucose transporter 2 inhibitors (SGLT2i) often alleviate symptoms in SVHF prompting us to study their mechanism. We tested if SGLT2i directly modulates pantothenate kinase (PANK) and if an increase in circulating ketones may benefit the SV heart. These ketones may provide an alternate energy source and regulate oxidative stress.
Hypothesis: Mitochondrial dysfunction associated with SVHF is improved by ketone supplementation and activation of PANK kinase.
Methods: Explanted SVHF heart right ventricle (RV) tissue was treated with the 3-hydroxybutyrate (3-OHB), long chain fatty acid (LCFA) Palmitate, or Glucose and Pyruvate (G/P) overnight, to assess substrate utilization. Mitochondrial function was measured via Oxygraph-2k. Primary rat ventricular myocytes were treated with SVHF or non-failing (NF) patient sera 72h, and supplemented with each substrate for 48h. Mitochondrial function was assessed via Seahorse XFe96. Tissue metabolomics and protein analysis were performed.
Results: Paired analysis of O₂ flux/unit tissue in SVHF +/- LCFA (N=4; 1 males, 3 Females) caused a significant decrease in Complex II activity and Maximal respiration. Respiration trended higher with 3-OHB, but hearts showed no effects of G/P or SCFA. In our in vitro model, 3-OHB increased oxygen consumption rate (OCR) in SVHF serum-treated cells. There was also a decrease in cardiac PANK1 and uncoupling protein (UCP2) protein levels in SVHF.
Conclusions: SVHF is characterized by impaired mitochondrial bioenergetics, involving downregulation of PANK1. Targeted treatments, such as SGLT2i and PANK activators, demonstrate potential by directly improving mitochondrial function. Additionally, SVHF hearts lose their capacity to efficiently oxidize LCFA, shifting to ketone oxidation as an alternative fuel source. Disease progression is further driven by oxidative stress linked to downregulated uncoupling proteins, which ketones may be able to mitigate.