Ketone bodies may have therapeutic benefits for patients with cardiovascular disease (CVD), regardless of the method used to increase their presence in the heart, a new review suggests.

The authors looked at the current body of experimental and clinical research on the potential role of ketone bodies in improving CVD and found that increasing circulating ketone levels might offer protective benefits in affected patients.

A ketogenic diet, which consists of a very low-carbohydrate and high-fat intake, is a popular way to induce ketosis; however, administration of exogenous ketones might be a viable and superior alternative to the diet as a means of elevating circulating ketone bodies, they suggest.

“Despite their negative clinical stigma, ketones serve several critical roles in the cardiovascular response to (metabolic) stress,” senior author B. Daan Westenbrink, MD, PhD, cardiologist and translational scientist, University Medical Center, Groningen (UMCG), Netherlands, told theheart.org | Medscape Cardiology.

“Accordingly, ketone-based therapy may emerge as a novel nutraceutical strategy for the treatment of a variety of cardiovascular diseases,” he said.

The review was published online February 23 in the Journal of the American College of Cardiology.

“Sophisticated” Role

“We recently discovered that the beneficial effects of new heart failure drugs, the SGLT2 [sodium glucose co-transporter 2] inhibitors, rely on ketone bodies and, in addition, we and others showed that exogenous ketones can improve cardiac function in heart failure,” Westenbrink explained.

This realization led to a clinical trial in which Westenbrink and colleagues are testing the effects of exogenous ketones on exercise performance in patients with heart failure.

“While working on these projects, we soon realized that the role of ketones in cardiovascular pathophysiology was much more sophisticated than merely serving as efficient fuel and, in addition, we realized that there are multiple ways to increase circulating ketone levels that should be considered,” he said.

The intention of this review was to “summarize the current literature from animal and human studies, which we hope will serve to facilitate further studies to explore the benefits of ketones as therapeutic agents in CVD.”

Most people are aware that circulating ketone levels can be increased through fasting or a ketogenic diet, “but our review draws attention to other means of increasing ketones using exogenous ketones or ketone precursors that are more practical for nutraceutical purposes,” he said.

Beyond Efficient Fuel

The authors also reviewed the mechanisms of ketone metabolism, including ketogenesis and ketolysis, as well as cardiac metabolism in the normal heart and in CVD.

Ketogenesis involves reactions that lead to the formation of the ketone bodies acetoacetate (AcAc), β-hydroxybutyrate (βOHB), and acetone.

Reduced insulin-to-glucagon ratio, such as that induced by fasting, mobilizes fatty acids, which are then converted into ketone bodies by the liver. In turn, they are transferred to peripheral tissues, where they then undergo “terminal oxidation.”

Ketones provide “ancillary fuels” for numerous organs during prolonged fasting, severe carbohydrate restriction, or after periods of very intense exercise, the authors say. In fact, Westenbrink noted that under “extreme conditions, ketone bodies may account for roughly 5% to 20% of total energy expenditure of the body.”

Cardiac diseases are associated with loss of metabolic flexibility, he said, and even in the early stages of structural heart diseases, “substrate utilization switches from fatty acids to glucose utilization,” thereby reducing oxidative metabolism. The reduced capacity to utilize fatty acids “sets the stage for myocardial energy starvation, contributing to the pathogenesis of HF.”

As heart failure progresses, the heart seems to “reprogram metabolism to increased reliance on ketone bodies as a fuel source,” the authors suggest, with increased circulating ketone concentrations and cardiac ketone utilization.

But “ketones are not merely efficient fuels that recharge the failing heart,” Westenbrink commented. “They also pose pleiotropic effects on the cardiovascular system, including improvements in oxidative stress, endothelial function, inflammation, and gene transcription blood pressure, to name just a few.”

Keto Diet “Not Promising”

The authors discuss methods to induce ketosis, including the popular diet, prolonged exercise, or fasting for more than 24 hours.

“Despite their widespread use, the effect of ketogenic diets on cardiovascular risk factors is not that well described and is rather inconsistent,” Westenbrink commented.

Moreover, “considering the cumbersome nature of the ketogenic diet, associated with the uncertainties related to its effects on cardiovascular risk, we do not consider this a very promising way to induce ketosis,” he said.

Additional methods for achieving ketosis include the ingestion of ketone precursors or the oral administration of exogenous sources of ketones (e.g., ketone salts or ketone esters).

“Ketones can also be infused intravenously,” Westenbrink added, noting that several new classes of drugs, such as the SGLT2 inhibitors, “can increase ketone levels or ketone utilization and may exert their effects, at least in part, via ketones.”

Further Research Needed

Commenting on the study for theheart.org | Medscape Cardiology, Christophe Kosinski, MD, endocrinologist, Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Switzerland, called the ketogenic diets “trendy and attractive, though restrictive — a point not often highlighted in the nonmedical mass media,” and they are also “difficult to adhere to in the long term and expensive (regarding both money and time).”

Nevertheless, if the ketogenic diet is “done properly, metabolic results are positive, with induced weight loss and improved diabetes control in patients with type 2 diabetes,” said Kosinski, who was not involved with the review.

The alternatives to the ketogenic diet for inducing ketosis presented in the review “are very interesting, and perhaps more accessible and more easily used in the daily practice, compared to a ketogenic diet.”

Kosinski added, “Now that the role and benefits of ketones have been assessed, further studies should focus on the applicability of this supplementation in a practical way.”

The UMCG, which employs Westenbrink and several coauthors, has received research grants and/or fees from Abbott, AstraZeneca, Bristol Myers Squibb, Novartis, Novo Nordisk, and Roche. Westenbrink is supported by the Netherlands Organisation for Scientific Research and the Netherlands Heart Foundation. The other authors’ disclosures are listed on the original paper. Kosinski declares no relevant financial relationships.

J Am Coll Cardiol. Published online February 23, 2021. Full text

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