Rebuttal from Manoja K. Brahma, Adam R. Wende and Kyle S. McCommis.

Abstract

Drs Karwi and Lopaschuk have provided compelling evidence of the potential for ketone bodies to provide an extra source of ATP for the heart. The foundation of our opposing views most likely stems from comparing analyses of the acute effects of ketone bodies in predominantly ex vivo studies to that which occurs in vivo with more chronic ketosis. Likewise, we must all be more prudent when comparing cardiac metabolic adaptations to physiological ketosis to those observed with ‘pure’ ketosis as occurs with consumption of ketone esters or salts, or ketone infusion. In physiological states of ketosis such as fasting or consumption of a low-carbohydrate, high-fat ketogenic diet, hearts preferentially downregulate ketolytic enzymes, decreasing ketone oxidation and enhancing fatty acid oxidation (Wentz et al. 2010; McCommis et al. 2020). This downregulation of ketolytic enzymes also occurs in the hearts of diabetic mice, or in hearts overexpressing glucose transporter 4 with enhanced glucose uptake and utilization (Brahma et al. 2020). However, cardiac ketone metabolism may be directly enhanced if delivery of lipids or glucose is not concurrently elevated. Recent studies suggest that ketone ester supplementation enhanced cardiac ketone uptake in humans (Monzo et al. 2020), and ketone ester-enriched diets increased the expression of ketolytic enzymes in the rat heart (Yurista et al. 2020). These studies imply that elevated ketone extraction is associated with increased oxidation, but neither of these studies directly measured oxidation. We agree that ketone utilization appears to be more important in failing hearts. Failing hearts from humans and rodent models display enhanced expression of the ketolytic enzymes β-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA:3-oxoacid CoA transferase (SCOT) and have been shown to extract more ketones than non-failing hearts (Aubert et al. 2016; Bedi et al. 2016; Horton et al. 2019; Monzo et al. 2020; Murashige et al. 2020). Also, cardiac-specific deletion of BDH1 or SCOT in mice exacerbates cardiac dysfunction and remodelling when challenged by pressure overload (Schugar et al. 2014; Horton et al. 2019). But these knockout mouse models provide perhaps the most significant evidence that ketone body metabolism is not critical for normal hearts, as deletion of BDH1 or SCOT does not directly induce cardiac dysfunction, and these hearts can even normally adapt to physiological ketosis (Schugar et al. 2014; Horton et al. 2019). To conclude, further investigation is needed to better understand the importance of ketone body metabolism in heart failure, as well as in response to ketosis as a potential therapy for heart failure. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘Last Word’. Please email your comment, including a title and a declaration of interest, to [email protected]. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. All authors conceived, wrote, and edited this manuscript. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. A.R.W. is supported by NIH R01 HL133011. K.S.M. is supported by NIH R00 HL136658.