Over the past decade, there has been significant interest in the role of ketone bodies (KBs) both within and outside the medical arena because of their reported beneficial effects in the heart. In a fed state, circulating KB (mainly acetone, acetoacetate, β-hydroxybutyrate) concentrations are low and elevation of KBs occurs during prolonged fasting or when consuming a ketogenic diet or ketone supplements (eg, 1,3-butanediol, medium-chain triglyceride, ketone salts, ketone ester). Ketogenesis, a metabolic pathway that produces KBs, can also be augmented by lipolytic hormones (eg, glucagon, cortisol, and catecholamines) through their actions on adipocytes, which yields more release of free fatty acids to be used in the ketogenic pathway. 

The heart is generally recognized as a “metabolic omnivore” with the ability to oxidize different energy substrates to generate adenosine triphosphate and shift from one fuel source to another, depending on metabolic demand, neurohormonal status, and substrate availability. Accumulating evidence suggests that metabolic perturbations contribute to the progression of heart failure (HF), and the failing heart reprograms energy metabolism towards increased KB use. Likewise, increasing delivery of readily processed fuels in the form of KBs (through supplementation or other means) results in augmented myocardial ketone oxidation and/or enhanced ventricular function. These findings can be explained by the expected role of KBs as “energy-efficient” substrates and potentially by pleiotropic effects of KBs in the heart.  Increased ketogenesis with sodium-glucose co-transporter inhibitors is considered a possible mechanism that contributes to their cardiovascular benefits. 

KBs require lower amounts of oxygen per molecule of adenosine triphosphate generated than that of fatty acid oxidation, and therefore, may provide supplemental fuel for the failing heart to overcome bioenergetic insufficiency, although the efficiency is not higher than glucose. The debate over whether KBs represent a significant contributor to overall cardiac bioenergetics is still ongoing. A recent study demonstrated that KBs contribute to approximately 6% of total cardiac adenosine triphosphate production in healthy subjects and that this percentage can increase 3-fold in the failing heart. The uptake of ketones in HF with a preserved (HFpEF) and reduced (HFrEF) ejection fraction at least, in part, depends on circulating concentrations of KBs. 

Myocardial infarction (MI) remains the most common cause of HFrEF, and cardiac metabolic changes occurring during ischemia likely contribute to HF development.  Although previous studies of KBs have focused mainly on HF, their role in MI is unclear. In this issue of the Journal, de Koning et al explore changes in KBs in the setting of ischemia/reperfusion. Their study was conducted in 369 patients without diabetes who presented with ST-segment elevation myocardial infarction (STEMI) and who were enrolled in a prospective, single-center, double-blind, randomized placebo-controlled trial of early metformin treatment after STEMI called the GIPS-III (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction [GIPS-III]: a Randomized Controlled Trial; NCT01217307) trial. First, the investigators sought to determine the longitudinal changes in circulating ketone concentrations. Using nuclear magnetic resonance spectroscopy, circulating KBs were measured at presentation, 24 hours after primary percutaneous coronary intervention, and 4 months after STEMI presentation. The investigators discovered that the patients had elevated total KBs at presentation, which remained elevated at 24 hours after percutaneous coronary intervention. Moreover, plasma KBs concentration at admission were not correlated with culprit vessel location or the ischemic time window. Although there were no non-STEMI, healthy, or disease control subjects included, KBs levels were compared with the concentrations at 4-month follow-up. Next, the investigators evaluated functional outcomes, namely, MI size and left ventricular ejection fraction (LVEF) using cardiac magnetic resonance at 4 months for associations. Elevated total KBs and β-hydroxybutyrate concentrations at 24 hours after percutaneous coronary intervention were independently associated with both larger infarct size and lower LVEFs.

These findings form an essential basis for our understanding of the role of KBs in ischemia/reperfusion. Increased circulating ketone concentrations and/or myocardial ketone oxidation that were associated with poor functional outcome were also reported in other clinical contexts, including HFrEF, HFpEF, diabetes, and arrhythmogenic cardiomyopathy. Previous studies discovered that acute myocardial ischemia and infarction immediately induced catecholamine release, and catecholamine excess was recognized as an important mechanism in the progression of HF and cardiomyopathy. Because catecholamines exert lipolytic activity on adipocytes, catecholamine surge may contribute to increased KB concentrations. In HF, increases in inflammatory cytokines and natriuretic peptides may also stimulate ketogenesis. Taken together, these observations suggest a ketogenic shift is a common cardiac response to stress (Figure 1). In addition, increased KB concentrations may serve as biomarkers that are associated with disease severity at least in some contexts. Although the current study was designed to reveal associations and did not test the functional effects of KBs after STEMI, there are multiple reasons to believe modulating cardiac ketone oxidation by increasing KBs availability could have therapeutic benefits in STEMI. These include the well-documented and substantial changes that occur in cardiac energy metabolism during ischemia, the supplemental metabolic substrate and potential pleiotropic cardiac effects of KBs, and the positive impact of circulating KB levels on cardiac ketone oxidation rates.

Ketogenic Shift Is a Universal Cardiac Response to Stress

When different cardiac stressors exist (eg, in myocardial ischemia and/or infarction, heart failure), the heart will release neurohormones (eg, catecholamines), cytokines, and natriuretic peptides, which can act synergistically, inducing lipolysis on adipocytes and result in increased ketogenesis.

The investigators are to be praised for performing meticulous collection, analyses, and interpretation of the data, as well measurement of KB concentrations in fed subjects without diabetes to avoid the confounding effects of diabetes and overnight fasting. However, as acknowledged by the investigators, this study was limited by a low prevalence left ventricular dysfunction and relatively small infarcts; therefore, it might not generalizable to a broader population. Future research with larger sample sizes and an appropriate control group could fruitfully validate the kinds of conclusions that can be drawn from this study. Furthermore, incorporation of direct measurement of cardiac arterio-venous KB gradients into future studies would enable assessment of human KB use and production in STEMI, providing additional insights into the mechanisms underlying dynamic regulation of this important metabolic pathway in STEMI.

Recent work such as the current study by de Koning et al has heightened scientific interest in KBs and their potential cardiac benefits. Although the appeal of enhancing KBs as a therapeutic approach is understandable, additional rigorous preclinical and clinical studies will be required to test this therapeutic hypothesis and determine the mechanisms contributing to any benefits observed. Ongoing clinical trials have the potential to provide new data addressing these important questions and could shed considerable light on the role of KBs in cardiovascular disease and their potential as therapeutic targets.

This article is reproduced from JACC journals.

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