Alterations of myocardial ketone metabolism in heart failure with preserved ejection fraction (HFpEF)
Abstract
INTRODUCTION: Cardiac energy metabolism is disrupted in heart failure with preserved ejection fraction (HFpEF), as characterized by a switch from glucose oxidation towards fatty acid oxidation. However, although oxidation of ketones is an important source of ATP it remains unclear how the heart oxidizes ketones in HFpEF. It is also unclear whether elevating ketone supply to the heart can improve cardiac energetics and/or provide functional benefit for the hearts in HFpEF.
AIMS: The present study investigated the effects of increasing ketone supply to the heart via ketone supplementation or SGLT2 inhibitor treatment in a mouse model of HFpEF.
METHODS: HFpEF was induced in 13-month-old C57BL/6N female mice with 60% high-fat diet and L-NAME (0.5 g/L/day in the drinking water) for 6 weeks. In parallel, two other groups of mice were maintained on the HFpEF protocol while also receiving either a ketone ester supplement (1-3 butanediol 1 g/kg/day) or SGLT2 inhibitor (empagliflozin 10 mg/kg/day) for 6 weeks. Control mice were fed with regular low-fat diet and regular drinking water. Hearts of the mice were excised and perfused in the isolated working mode aerobically with 5-mM glucose, 0.8-mM palmitate, 100-μU/mL insulin, with either low (0.6 mM) or high (1 mM) levels of β-hydroxybutyrate. Metabolic rates of the hearts were measured with radiolabelled [U-14C] glucose, [9,10-3H] palmitate and [3-14C] β-hydroxybutyrate.
RESULTS: In HFpEF mouse hearts, glucose oxidation was…
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