Ketone Ester for Heart Failure

(KEHeart Trial)

Overseen By Jessica Lee

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Cleveland Clinic

Disqualifiers: Claustrophobia, Implanted device

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The study is aimed to phenotype with cardiac MRI the physiological effects of ketone esters on the heart. Patients with heart failure will be recruited and given ketone esters or placebo in a randomized fashion. Cardiac MRI will be performed at baseline and after 12weeks follow up.

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications.

What evidence supports the effectiveness of the treatment Ketone Ester for heart failure?

Research suggests that ketone esters can improve heart function in heart failure by providing an alternative energy source for the heart and reducing harmful inflammation and oxidative stress. Studies in animals and some human data indicate that increasing ketone levels may help the heart work better, especially in heart failure with reduced ejection fraction (a condition where the heart doesn't pump blood as well as it should). ^{1 2 3 4 5}

Is ketone ester safe for human consumption?

Research shows that ketone esters are generally safe and well-tolerated in healthy adults, with no significant changes in vital signs or lab tests. Some mild side effects like nausea and gastrointestinal discomfort were reported, but these were not common. ^{2 3 6 7 8}

How is the ketone ester treatment different from other heart failure treatments?

Ketone ester treatment is unique because it provides an alternative energy source for the heart by increasing ketone body utilization, which can improve heart function and reduce damage in heart failure, unlike traditional treatments that focus on hormonal and blood flow issues. ^{2 3 5 9 10}

Eligibility Criteria

This trial is for heart failure patients with an ejection fraction (EF) less than 40%. It's not suitable for individuals who don't meet this specific heart function criterion.

Inclusion Criteria

My heart's pumping ability is below 40%.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ketone esters or placebo daily for 12 weeks

12 weeks

Baseline and post-intervention MRI scans

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketone Ester
• Placebo

Trial Overview The study tests the effects of ketone esters on the heart compared to a placebo. Participants will be randomly assigned to receive either the ketone ester or placebo, and their heart health will be monitored using cardiac MRI before and after a 12-week period.

Participant Groups

Group I: Ketone ester supplement Experimental Treatment 1 Intervention

Ketone ester given daily for 12 weeks and scanned before and after intervention with MRI.

Group II: Placebo Placebo Group 1 Intervention

Placebo given that mimics taste, weight, and size of the interventional supplement mirroring the same time points as the ketone ester supplement group. Mirrored imaging with MRI as well.

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Findings from Research

Chronic supplementation of ketone bodies, specifically using a ketone ester, significantly improved heart function in mice with established heart failure, preventing further decline in cardiac performance over two weeks.

The treatment not only elevated blood levels of β-hydroxybutyrate without causing ketoacidosis but also reduced heart muscle hypertrophy and fibrosis, suggesting that ketone therapy could be a promising approach for managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart. Takahara, S., Soni, S., Phaterpekar, K., et al.[2022]

Chronic oral supplementation with ketone esters (KE) significantly improved heart function in rodent models of heart failure, with the KE-1 diet preventing left ventricular dysfunction and the KE-2 diet enhancing recovery post-myocardial infarction (MI).

The KE-2 diet not only improved heart function but also normalized myocardial ATP levels and altered gene expression related to ketone metabolism, suggesting that ketone bodies can serve as an effective alternative fuel for the failing heart.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. Yurista, SR., Matsuura, TR., Silljé, HHW., et al.[2021]

The study demonstrated that the ketone body acetoacetate can be used as a radiotracer to assess heart failure in a rat model induced by doxorubicin, showing increased blood levels and mitochondrial uptake in the heart, indicating its potential as an alternate nutrient for cardiac function.

Kinetic analysis using [(11)C]-acetoacetate revealed decreased uptake rates in heart failure rats, correlating with a significant reduction in left ventricular ejection fraction, suggesting that this radiotracer can effectively evaluate cardiac function without the need for stress testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure. Croteau, E., Tremblay, S., Gascon, S., et al.[2016]

In heart failure, the heart struggles to produce enough energy due to decreased mitochondrial metabolism, but ketone bodies can serve as an alternative energy source, potentially improving heart function.

While ketogenic diets alone have shown limited benefits for heart function, intravenous ketone infusions and ketone ester cocktails may enhance cardiac performance, suggesting that boosting ketone oxidation could be a promising treatment strategy for heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone metabolism in the failing heart. Lopaschuk, GD., Karwi, QG., Ho, KL., et al.[2021]

Ketone metabolic modulation shows promise as a novel treatment for heart failure (HF), particularly in patients with reduced ejection fraction, as it may enhance myocardial energy use during the disease's progression.

Current evidence suggests that exogenous ketone therapy could provide beneficial effects in both animal models and humans with HF, indicating a potential new therapeutic approach alongside traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. Selvaraj, S., Kelly, DP., Margulies, KB.[2021]

In a 28-day study involving 59 healthy adults, the novel exogenous ketone diester bis-hexanoyl-(R)-1,3-butanediol (BH-BD) was found to be well-tolerated and safe, with no significant differences in tolerability scores compared to a placebo.

BH-BD effectively increased blood ketone levels one hour after consumption, indicating its potential for promoting nutritional ketosis without adverse effects on vital signs or laboratory measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Chen, O., Blonquist, TM., Mah, E., et al.[2021]

A study involving 24 healthy adults showed that consuming a ketone monoester three times a day for 28 days safely elevated blood ketone levels without affecting body weight, blood glucose, cholesterol, or kidney function.

The only reported side effect was mild nausea in a small number of instances, indicating that the ketone monoester is well-tolerated for sustained use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Soto-Mota, A., Vansant, H., Evans, RD., et al.[2020]

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

A ketone ester supplement can induce acute nutritional ketosis, which changes how the body uses energy during exercise, particularly in elite cyclists.

This shift in energy utilization leads to reduced lactate production and improved performance in time-trial events, suggesting potential benefits for athletes during prolonged or intense exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fueling Performance: Ketones Enter the Mix. Egan, B., D'Agostino, DP.[2018]

In a study involving 12 participants previously hospitalized for COVID-19, a single oral dose of ketone ester did not improve left ventricular ejection fraction (LVEF), indicating no significant impact on overall heart function.

However, the ketone ester did lead to a significant increase in global longitudinal strain (GLS), suggesting potential benefits in myocardial function, even though it did not affect cardiac output or blood oxygen saturation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral ketone esters acutely improve myocardial contractility in post-hospitalized COVID-19 patients: A randomized placebo-controlled double-blind crossover study. Wodschow, HZ., Davidovski, FS., Christensen, J., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

[(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure. [2016]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Ketone metabolism in the failing heart. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Fueling Performance: Ketones Enter the Mix. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Oral ketone esters acutely improve myocardial contractility in post-hospitalized COVID-19 patients: A randomized placebo-controlled double-blind crossover study. [2023]