ABSTRACT
AIMS: Upregulation of ketone body (ß-hydroxybutyrate, ßHB) utilization has been documented in human end-stage heart failure (HF), but is unclear if this is due to intrinsic cardiac metabolic remodeling or a HF-related catabolic state. This study sought to evaluate the maximal ketone body utilization capacity and its determinants in controls and in patients with moderate HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: 19 HFrEF patients and 9 controls underwent sampling from the arterial circulation (A) and coronary sinus (CS) to measure transmyocardial extraction of energy-providing substrates and oxygen. In a separate experiment, measurements were performed 80-min after oral administration of 25â¯g of ketone ester (KE, (R)-3-hydroxybutyl(R)-3-hydroxybutyrate) drink in 11 HFrEF and 6 control subjects. There were no statistically significant differences in fasting substrate levels and fractional extractions between HF and controls. Administration of KE increased ßHB by 12.9-fold, revealing an increased ability to utilize ketones in HFrEF as compared to controls (fractional extraction, FE%: 52 vs 39%, pâ¯=â¯0.035). ßHB FE% correlated directly with ßHB myocardial delivery (râ¯=â¯0.90), LV mass (râ¯=â¯0.56), LV diameter (râ¯=â¯0.65) and inversely with LV EF (-0.59) (all pâ¯<â¯0.05). ßHB FE% positively correlated with lactate FE% (pâ¯<â¯0.01), but not with FFA or glucose FE%, arguing against substrate competition. CONCLUSIONS: Acute nutritional ketosis enhances ßHB extraction in patients with HFrEF compared to controls, and this enhancement correlates with degree of cardiac dysfunction and remodeling. Data suggest that subclinical metabolic remodeling occurs early in HF progression. Further studies are needed to determine whether exogenous ketones may have a potential therapeutic role.
