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Review
. 2023 Feb 10;24(4):3534.
doi: 10.3390/ijms24043534.

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

Antonis S Manolis  1 , Theodora A Manolis  1 , Antonis A Manolis  2
Affiliations
Review

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

Antonis S Manolis et al. Int J Mol Sci. .

Abstract

The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40-70%) for ATP generation, followed mainly by glucose (20-30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4-15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

Keywords: acetoacetate; acetone; adenosine triphosphate; beta-hydroxybutyrate; cardiac energetics; cardiac metabolism; cardiovascular disease; fatty acid oxidation; heart failure; ketone bodies; myocardial infarction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The schema illustrates ketone body production and oxidation. Ketone bodies produced in the liver are released via the monocarboxylate transporter (MCT) 1/2 into the circulation and reach extrahepatic tissues, including the heart, where they can be utilized as energy sources. Ketone body oxidation in cardiac tissue involves beta-hydroxybutyrate dehydrogenase 1 (BDH1), bound to the inner mitochondrial membrane (MM), which converts beta-hydroxybutyrate (β-OHB) to acetoacetate. Acetoacetate can then be activated via succinyl-CoA:3-oxoacid-CoA transferase (SCOT) whereby a succinyl CoA is transferred to acetoacetate in order to form acetoacetyl CoA. Acetoacetyl CoA is subsequently cleaved to yield two acetyl CoA molecules which can then be oxidized in the tricarboxylic acid (Krebs) cycle. BDH1 = beta-hydroxybutyrate dehydrogenase; βOHB = beta-hydroxybutyrate; CoA = coenzyme A; CO2 = carbon dioxide; MCT = monocarboxylate transporter; MM = mitochondrial membrane; mThiolase = mitochondrial thiolase; NADH = nicotinamide adenine dinucleotide reduced; SCOT = succinyl-CoA:3-oxoacid-CoA transferase.
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