Ketone treatment has favourable effects on cardiac energy metabolism in patients with chronic heart failure
N Abild Jespersen, K B H Berg-Hansen, H V Vase, M J A Andersen, B R N Nielsen, J C N Cosedis, N M Moeller, D W Westenbrink, L T Tolbod, L G Gormsen, H W WiggersAbstract
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.