Highlights
- •Subclinical metabolic remodelling occurs early in the natural history of heart failure
- •Metabolic remodelling is characterized by an increased capacity to utilize ketone bodies, despite normal ketone body levels
- •Ketones utilization correlates with the degree of cardiac dysfunction and remodelling
- •Ketones myocardial utilization is uncoupled from use of other energetic substrates, without evidence of substrate competition
- •Ketone Ester drink is a feasible approach to achieve ketosis and should be tested as a potential therapeutic modality in HF
Abstract
Aims
Upregulation of ketone body (β-hydroxybutyrate, βHB) 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 25 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 βHB by 12.9-fold, revealing an increased
ability to utilize ketones in HFrEF as compared to controls (fractional extraction,
FE%: 52 vs 39%, p = 0.035). βHB FE% correlated directly with βHB myocardial delivery
(r = 0.90), LV mass (r = 0.56), LV diameter (r = 0.65) and inversely with LV EF (−0.59)
(all p < 0.05). βHB FE% positively correlated with lactate FE% (p < 0.01), but not
with FFA or glucose FE%, arguing against substrate competition.
Conclusions
Acute nutritional ketosis enhances βHB 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.
Graphical Abstract
Graphical Abstract
Abbreviations:
FFA (free fatty acids), KB (ketone bodies), KE (ketone ester), FE% (fractional extraction), βHB (β-hydroxybutyrate)Keywords
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Article info
Publication history
Published online: November 25, 2020
Accepted:
November 23,
2020
Received:
June 8,
2020
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
