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.

Ketones with a twist: Tipping the heart's hat to fat

“…This is not a shortcoming of the experimental design but rather due to the fact that there are currently no ketone tracer methods available to evaluate ketone oxidation by imaging techniques. It is highly likely that during the ketogenic diet period, ketones were oxidized at the expense of fatty acids, because the heart has a high capacity for oxidizing ketones and the rate of myocardial ketone oxidation is dependent largely on circulating ketone concentration [1]. Based on the relative stoichiometry of fatty acid and ketone oxidation, one would expect a lower oxygen consumption when the heart is fueled by ketones rather than fatty acids.…”

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Ketones are readily oxidized by the heart and may have a beneficial effect on cardiac function because they produce energy more efficiently (at lower oxygen cost per ATP) than fatty acids [1]. In this issue of Obe-

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Effect of dietary carbohydrate restriction on cardiometabolic function in type 2 diabetes: weight loss and beyond

“…It is also possible that the degree of carbohydrate restriction and the extent of ketogenesis are important for the effects of low-carbohydrate diets on heart structure and function [46]. Ketone bodies have vasodilatory properties, improve cardiac perfusion, and are a major alternative fuel source for the failing heart, which has a limited capacity to utilized glucose and fatty acids for energy production [47]. Evidence from clinical and preclinical studies suggests that ketone bodies influence a variety of cellular processes, including gene transcription, inflammation and oxidative stress, endothelial function, and cardiac remodeling, which could have beneficial cardiovascular effects [48].…”

Ketone Bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity

“…Ketone bodies, metabolites that are primarily synthesized by the liver, regulate diverse biological functions ranging from energy homeostasis, inflammation, and epigenetic regulation (5). In LVF preclinical models and patients with LVF, ketone levels are elevated and correlate with HF severity (6). This response is widely believed to be compensatory as ketogenic interventions improve cardiac function in rodent LVF and ketone infusion acutely increases cardiac output in LVF patients (6).…”

“…In LVF preclinical models and patients with LVF, ketone levels are elevated and correlate with HF severity (6). This response is widely believed to be compensatory as ketogenic interventions improve cardiac function in rodent LVF and ketone infusion acutely increases cardiac output in LVF patients (6). Additionally, the ketone body β-hydroxybutyrate (βOHB) suppresses nucleotidebinding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activity (7), a pathway recently implicated in PAHmediated RVF (8).…”