Unraveling the Mechanism Behind the Ketogenic Diet-Mediated Reversal of Heart Failure in Mice
Authors: Foulks Zachary , Pyles Kelly , Weinheimer Carla , Kovacs Atilla , McCommis Kyle 
Published: May 2024

It has become clear that heart failure involves a host of metabolic alterations, and nutritional or pharmacologic modulation of cardiac metabolism can improve heart failure. We previously studied the role of the mitochondrial pyruvate carrier (MPC) in heart failure, and observed that pyruvate transport into the mitochondria of cardiac myocytes was critical for maintenance of normal cardiac size and function. However, we were also able to prevent or reverse heart failure in cardiac-specific MPC2−/− (cs-MPC2−/−) mice by feeding a low carbohydrate, high fat “ketogenic” diet. Intriguingly, while ketosis was associated with this reversal in heart failure, it was observed that cardiac ketone body oxidation enzymes were downregulated in these hearts, and direct administration of ketone bodies without altering dietary fat did not improve heart failure. The objective of this current study was to define whether ketone body oxidation was necessary for improving heart failure with a ketogenic diet. Wildtype mice were subjected to combined transverse aortic constriction and apical myocardial infarction (TAC-MI) to induce heart failure, were imaged by echocardiography two weeks later and randomized to either low fat control or ketogenic diet for an additional two weeks before repeat echocardiography and euthanasia. Cardiac size and function was also assessed in cs-MPC2−/− mice, mice with cardiac deletion of betahydroxybutyrate dehydrogenase 1 (cs-BDH1−/−, the first enzyme in ketone body oxidation), and cs-MPC2/BDH1−/− double KO mice. Mice were aged to 16 weeks, when MPC−/− hearts have developed dilated cardiomyopathy, and then fed either low fat control or ketogenic diet for 3 weeks before echocardiography and euthanasia. Of the WT mice subjected to TAC-MI, being fed a LF control diet led to further cardiac remodeling and worsened contractile function. However, ketogenic diet feeding completely prevented the progression of cardiac remodeling. cs-BDH1−/− hearts maintained normal size and function, suggesting that lack of ketone oxidation has no overt effect on cardiac function or remodeling. However, as previously reported, cs-MPC2−/− hearts developed dilated cardiomyopathy, which was not significantly altered by combined deletion of BDH1. Switching cs-MPC2−/− or cs-MPC2/BDH1−/− mice to a ketogenic diet was able to significantly reverse the heart failure, suggesting that enhanced ketone oxidation is not the mechanism for improved heart failure. Gene expression from these hearts suggests that ketogenic diet suppresses ketolytic gene expression and enhances expression of fat oxidation genes. Altogether, these findings suggest that improving heart failure with a ketogenic diet is due to stimulation of cardiac fat oxidation and not ketone body metabolism. Project was funded by NIH R00 HL136658 and SLU institutional funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.