Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure?

It is increasingly recognized that metabolic remodeling is integral to heart failure (HF) development and progression.1,2 In particular, impairments in the ability of cardiac mitochondria to oxidize fatty acids have been noted, along with an increase in glycolysis that is uncoupled from glucose oxidation.3,4 This overall reduction in the myocardial oxidative capacity is purported to be the root cause of energy deficiency in the failing heart. Although past research has focused primarily on myocardial use of glucose and fatty acids, the heart is an omnivore and capable of oxidizing other substrates such as lactate, ketone bodies, and amino acids. The current understanding of the contribution of lactate, ketone bodies, and amino acids to cardiac metabolism is limited, particularly in the setting of HF. In this issue of Circulation , 2 independent studies provide new insights into the reliance of the failing heart on ketone bodies for energy supply. Proteomics analysis in mouse models of HF by Aubert et al5 and metabolomics analysis of end-stage human failing hearts by Bedi et al6 demonstrate strong and concordant evidence of increased ketone oxidation in the failing heart.$\backslash$n$\backslash$nArticles, see p 698 and 706 $\backslash$n$\backslash$nKetone bodies, that is, acetoacetate, β-hydroxybutyrate (βOHB), and acetone (in low abundance), are produced in the liver and used in peripheral tissues as an energy source when glucose is not readily available because of either a limited exogenous supply or impaired insulin signaling or when fatty acids are in surplus, which occurs in marked activation of lipolysis. On entering the cell, they rapidly form acetyl CoA via a series of reactions catalyzed by βOHB dehydrogenase (BDH1), succinyl-CoA:3-oxoacid-CoA transferase (SCOT), and mitochondrial acetyl-CoA acetyltransferase 1 (also known as thiolase), as shown in the Figure. All enzymes are present in the heart, and \ldots