Does the Ketogenic Diet Benefit Patients With Heart Failure?

Kim L. Ho, BSc; John R. Ussher, PhD; Gary D. Lopaschuk, PhD

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January 13, 2021

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The ketogenic ("keto") diet, originally developed in the 1920s as an alternative treatment for pediatric epilepsy, remains a therapeutic strategy for a variety of conditions, including neurodegenerative diseases, diabetes, nonalcoholic fatty liver disease, cancer, and, most notably, weight loss. However, conflicting study results fuel the ongoing debate regarding the role of the ketogenic diet in patients with heart failure (HF). Is the ketogenic diet beneficial in HF in the long term, and how does it affect cardiovascular risk factors? Here's a look at the current research.

Ketones and the Failing Heart

The daily caloric intake for people on the ketogenic diet is, approximately, 70%-80% from fats, 10%-20% from proteins, and 5%-10% from carbohydrates. Reducing carbohydrate intake while increasing fat intake results in a metabolic shift in the body called ketosis. In this state, blood ketone levels are increased due to the restriction of carbohydrates, decreased circulating insulin (and consequently, decreased insulin-mediated inhibition of lipolysis and ketogenesis), and a subsequent increase in the mobilization of adipose tissue fatty acids, which are used by the liver for ketogenesis.

Ketones can be utilized by the heart as an energy source in an unregulated manner, raising the question of whether it is possible to increase energy production in cardiac metabolic scenarios such as HF. Studies on patients with advanced HF have shown an increased adaptive reliance of the failing heart on ketones as an alternative energy source. Findings from the EMPA-REG OUTCOME trial, which looked at the effects of empagliflozin on morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD), led to the hypothesis that higher levels of circulating ketones increase cardiac ketone oxidation and may contribute to improved cardiovascular outcomes. Furthermore, a crossover design study, in which patients with heart failure with reduced ejection fraction (HFrEF) were intravenously infused with either the ketone, beta-hydroxybutyrate, or placebo, demonstrated that increases in circulating ketone levels increased cardiac output by 40% in participants who received beta-hydroxybutyrate. Therefore, the capacity of the heart to oxidize ketones appears to be beneficial in patients with HF.

What About Cardiovascular Risk?

The American Heart Association's dietary guidelines for cardiovascular disease recommend limiting intake of saturated and trans fat, decreasing sodium, and consuming a variety of fruits and vegetables, whole grains, poultry, and fish. These dietary recommendations contradict the high-fat/low-carb ketogenic diet because fruits and many vegetables are high in carbohydrates. While mono- and polyunsaturated fats may be beneficial in a heart failure setting, many ketogenic diet meal plans result in the consumption of a variety of both saturated and unsaturated fats. Therefore, careful planning to decrease saturated fat consumption and increase unsaturated fat intake is necessary if the ketogenic diet is to be implemented in a heart failure setting.

Studies looking at CVD risks of high-fat, low-carbohydrate diets have shown mixed results. For example, a meta-analysis of 11 randomized controlled trials found that ketogenic diets promoted greater weight loss than low-fat diets, but they also increased low-density lipoprotein cholesterol (LDL-C). In contrast to these findings, multiple studies have reported improvement of CVD risk factors with no adverse effects on lipid profiles in men, women, and adolescents who followed a low-fat diet. Yet, a meta-analysis by Nordmann and colleagues comparing low-fat and low-carbohydrate diets found that ketogenic diets improved triglyceride and high-density lipoprotein cholesterol values but worsened LDL-C. These contradictory findings are probably due to differences between the types of ketogenic diets used (eg. type of fat) and how each study was modeled (eg, variations in specific daily caloric intake, macronutrient composition, and duration). More clinical studies are necessary to determine the impact of a ketogenic diet on CVD risk factors.

What We Do and Don't Know

While we know that increased ketone metabolism is adaptive in HFrEF, whether ketogenic diets can confer these benefits remains unclear. Findings from a crossover study of 16 healthy participants assigned to a ketogenic or control diet demonstrated a decreased cardiac phosphocreatine-to-adenosine triphosphate ratio in patients on the ketogenic diet; these findings signify an impaired energy production that is similar to that seen in patients with HF. When considering heart failure with preserved ejection fraction (HFpEF), because metabolic inflammation is becoming recognized as the crux of HFpEF pathophysiology and the ketogenic diet exhibits anti-inflammatory properties, the latter may be beneficial in HFpEF. However, whether the ketogenic diet can confer the same benefits in HF as does the direct administration of ketones remains to be determined.

Overall, assessment of the ketogenic diet's long-term effects on cardiac function in the setting of HF are limited. In fact, most studies to date have evaluated only short-term effects of a ketogenic diet in patients without HF or other cardiovascular risk factors. Moreover, because ketogenic diets vary by recommendation (eg, amount of daily protein intake), there is no general consensus on cardiovascular implications, treatment duration, and mode of implementation. On the basis of current evidence, future high-quality clinical trials that assess the long-term effects of the ketogenic diet in the setting of HFrEF and HFpEF are needed.

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