Abstract Body: Introduction: There is considerable confusion as to what changes in cardiac energy metabolism occur in heart failure with preserved ejection fraction (HFpEF). In HFpEF mice hearts, we found a marked decrease in cardiac glucose oxidation, which is accompanied by an increase in fatty acid oxidation. Ketones have been proposed as an extra source of fuel for the failing, heart, although it remains unclear if ketones may adversely affect glucose and fatty acid oxidation.
Methods: 13-month-old C57BL/6N female mice were administered a 60% high-fat diet and L-NAME (0.5g/L/day) for 6 weeks to induce HFpEF. 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 significantly decreased with a parallel increase in fatty acid oxidation. As a result, the HFpEF hearts showed overall preserved ATP production rates (79 ± 12 vs. to 106 ± 13 μmol^.g dry wt^-1.min^-1 control vs. HFpEF). Increasing β-hydroxybutyrate levels from 0.6 mM to 1 mM resulted in a rise in ketone oxidation rates in HFpEF hearts (from 692 ± 47 to 952 ± 90 nmol^.g dry wt^-1.min^-1). Interestingly, this increase in ketone oxidation did not further compromise the rates of glucose oxidation in HFpEF hearts, but actually increased glucose oxidation rates (from 95 ± 13 to 190 ± 17 nmol^.g dry wt^-1.min^-1), and had minor effects on fatty acid oxidation rates (from 796 ± 123 to 678 ± 92 nmol^.g dry wt^-1.min^-1). This resulted in an increase in the contribution of ketone and glucose oxidation to ATP production from 15 % to 28 % in HFpEF hearts.
Conclusion: In HFpEF mice hearts overall ATP production is not impaired, but rather the heart switches from glucose oxidation to fatty acid oxidation as the main source of ATP production. Increasing ketone supply to the heart increases ketone oxidation and results in a favourable shift in ATP production in HFpEF.