Trends in Endocrinology & Metabolism
ReviewKetone bodies for the failing heart: fuels that can fix the engine?
Introduction
Heart failure (HF) is a major global health problem that is reaching epidemic proportions [1., 2., 3.]. According to American Heart Association, more than 6 million adults in the United States are living with HF [4]. Despite the large range of pharmacological and device-based therapies available to treat HF, morbidity and mortality remain high [5., 6., 7.]; thus, new treatment strategies are urgently needed. Because of its high energy consumption and limited ability to store ATP, the heart is highly dependent on a continuous supply and efficient oxidation of exogenous substrates. In patients with HF, metabolic roadblocks in fatty acid (FA) and glucose metabolism occur, which reduce the myocardial capacity to generate ATP [8,9]. This results in myocardial energy deficiency, and the failing heart is often likened to an ‘engine out of fuel’ [10]. Ketone bodies have long been recognized as an efficient metabolic substrate as they have higher phosphate-to-oxygen ratio than FAs (2.5 for ketone bodies vs 2.3 for FAs) and release more free energy per two-carbon moiety than glucose [11,12]; with the heart being one of the largest energy-consuming organs in the body, ketone bodies could be advantageous metabolic substrates for patients with HF.
Section snippets
Metabolic regulation of ketone metabolism: ketogenesis and ketolysis
In a fed state, few ketone bodies are present in the circulation. During fasting, a reduced insulin-to-glucagon ratio fosters the mobilization of FAs from peripheral stores to be converted into ketone bodies by the liver through a series of enzymatic steps. Ketones are then transferred from the liver, which cannot oxidize ketones by itself, to peripheral tissues where they generate ATP within mitochondria. This physiological mechanism provides an alternative fuel for multiple organs, including
Fuels for the failing heart
In the regular fed state, the contribution of ketone bodies to the cardiac energy provision in the healthy heart is modest. This contribution can, however, dramatically increase when hearts are exposed to higher ketone concentrations. A recent study in the working mouse heart model demonstrated that in the presence of normal concentrations of carbohydrates and FAs, ketone bodies become the predominant cardiac fuel source for the heart at βOHB concentrations above 2.0 mM [62]. A recent study in
Therapeutic ketosis in heart failure: what we know so far
In Table 1, we summarize evidence from animals and human studies evaluating cardiac effects of therapeutic ketosis in a dedicated HF setting. The pros and cons from each method to induce ketosis have been discussed and reviewed elsewhere [20].
Sodium–glucose co-transporter 2 inhibitors
SGLT2is gained basic and clinical research attention due to their cardiovascular benefits in HF regardless of the patient’s glycemic status [90,91]. It has been postulated that the mechanism underlying the cardiovascular benefits of SGLT2is could include ketogenesis [92]. Studies from us and from others have indicated that oral administration of SGLT2is empagliflozin in small and large animal models of HFrEF improved systolic function, increased circulating ketone levels, associated with
Concluding remarks and future perspectives
Our understanding of cardiac metabolism has advanced greatly in the last years and in particular, ketone bodies have emerged as an important substrate with additional pleiotropic effects that may treat and restore cardiac function of the failing heart. Limited data in animals and humans suggest that ketone bodies may be beneficial for HF patients regardless of the method used to increase the ketone delivery to the heart. Nevertheless, the results should be interpreted cautiously, as the
Acknowledgments
R.A.d.B is supported by grants from the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, Grant No. 2017-21; CVON RED-CVD, Grant No. 2017-11; CVON PREDICT2, Grant No. 2018-30; and CVON DOUBLE DOSE, Grant No. 2020B005), by a grant from the leDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN)], and by a grant from the European Research Council (Grant No. ERC CoG 818715, SECRETE-HF). B.D.W is supported by The Netherlands Organization for Scientific Research (NWO VENI, Grant
Declaration of interests
The UMCG, which employs Drs de Boer and Westenbrink, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. Dr de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche.
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