Ketone treatment has favourable effects on cardiac energy metabolism in patients with chronic heart failure

Background In patients with heart failure with reduced ejection fraction (HFrEF), treatment with the ketone body 3-hydroxybutyrate (3-OHB) has demonstrated favorable hemodynamic cardiac effects. The cardiac mechanisms of action of 3-OHB remain unclear. Purpose To accurately quantify the effect of 3-OHB treatment on myocardial 3-OHB uptake, myocardial oxygen consumption, myocardial external efficiency, and myocardial perfusion both at trough levels and during acute hyperketonemia. Methods We enrolled twelve patients with HFrEF in this randomised, double-blind, placebo-controlled crossover study. In random order, patients received a 3-OHB ketone ester drink (25 g, four times daily) and an isocaloric placebo for two weeks, separated by a two-week washout period. At the end of each treatment period, patients underwent dynamic [11C]3-OHB and [11C]acetate high-sensitivity long-axial-field-of-view PET imaging to measure myocardial 3-OHB uptake, myocardial oxygen consumption, myocardial external efficiency, and myocardial blood flow. PET scans were performed at both trough levels and during acute hyperketonemia. Results All patients (mean LVEF 29±4%) completed the study. Myocardial external efficiency was 16.3±4.5% after ketone treatment and 13.9±4.2% after placebo treatment (pairwise difference of 1.1% (95% CI: 0.004 to 2.1; p=0.043). There was no difference between study arms with respect to myocardial blood flow (pairwise difference of -0.02 mL/min/g (95% CI: -0.07 to 0.02; p=0.3)), cardiac output (pairwise difference of 0.002 L/min (95% CI: -0.36 to 0.37; p=0.99)), MVO2 (pairwise difference of -0.5 mL/100 g/min (95% CI: -0.1-0.2; p=0.12)), and total cardiac work (pairwise difference of -0.04 J (95% CI: -4.4 to 4.3; p=0.98)). Compared with trough levels, acute hyperketonemia increased cardiac 3-OHB uptake 36-fold (p<0.001), and the contribution of 3-OHB to MVO2 increased 31-fold (p<0.001), i.e., approximately 80% of myocardial metabolism was derived from 3-OHB during ketosis. This was accompanied by increases from trough to hyperketonemia in myocardial blood flow (8%; p=0.02), myocardial oxygen consumption (27%; p<0.001), cardiac output (12%; p=0.007) and total work (12%; p=0.02). Conclusion Oral ketone treatment improved myocardial external efficiency in patients with HFrEF. This was paralleled by a marked metabolic flexibility to augment 3-OHB uptake and oxidation during acute hyperketonemia. This supports ketone-based interventions as a potential metabolic therapeutic strategy in heart failure.