Ketones and the Heart: Metabolic Principles and Therapeutic Implications

Abstract

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

Keywords: 3-hydroxybutyric acid; acetoacetate; diet, ketogenic; fatty acid oxidation; heart failure; hypertrophy; ketone bodies.

Figure 1.. Hepatic ketogenesis and cardiac ketolysis.

Pathways of hepatic mitochondrial ketogenesis and cardiac mitochondrial oxidation of the ketone bodies acetoacetate (AcAc) and D-ß-hydroxybutyrate (ßOHB). CoA, coenzyme A; TCA, tricarboxylic acid; HMGCS2, 3-hydroxymethylglutaryl-CoA synthase 2; HMG-CoA, 3-hydroxyglutaryl-CoA; HMGCL, 3-hydroxymethylglutaryl-CoA lyase; BDH1, D-ß-hydroxybutyrate dehydrogenase 1; SCOT, succinyl-CoA:3-oxoacid-CoA transferase; NAD, nicotinamide adenine dinucleotide; Lys, lysine; Leu, leucine; CS, citrate synthase; ETC, electron transport chain.

Figure 2.. Enhanced cardiac ketone utilization in the failing heart.

Schematic of organ-organ cross talk during heart failure mediating enhanced hepatic ketogenesis and cardiac ketolysis in the setting of diminished fatty acid oxidation. The precise mechanism(s) through which the failing heart induces ketogenesis is unknown, represented as Factor ? in the schematic. Similarly, the precise regulation of cardiac ketolysis and its relationship to non-ketone substrate oxidation is yet to be determined.

Figure 3.. Potential mechanisms of ketone-mediated cardioprotection.

The ketone bodies acetoacetate (AcAc), D-ß-hydroxybutyrate (D-ßOHB), and L-ß-hydroxybutyrate (L-ßOHB), depicted in center, have pleiotropic effects that act directly on the heart and systemically. A subset or combination of these mechanisms underlie the salutary effects of ketone administration in the setting of heart failure. ATP, adenosine triphosphate; HDAC, histone deacetylase; SIRT, sirtuin; Ac, acetyl; Bhb, beta-hydroxybutyrate; Ca²⁺, calcium; MvO₂, myocardial oxygen consumption.

Figure 4.. Ketone therapeutic strategies.

Methods and considerations for inducing therapeutic ketosis. This figure was created with Biorender.com.