Effects of 2-week Ketosis on the Heart's Ketone Body Consumption, Utilization, and Energetic Efficiency in Patients With Chronic Heart Failure

NCT06398964 | Completed

• 1 other identifier: KETO-CHF-PET
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Heart Failure (HF) is a significant health concern, affecting around 1-2% of people in Western countries. The risk of developing HF during a lifetime is about 20%. Despite advancements in HF care, the one-year mortality rate for HF patients remains high. HF patients also experience reduced physical capacity and quality of life. The heart relies heavily on a process called oxidative metabolism for energy, and this process requires a continuous supply of energy sources like fatty acids, glucose, and ketone bodies. In HF, there's a shift in how the heart uses these energy sources, which affects its efficiency. Ketone bodies such as 3-OHB, are molecules that can provide the heart with a more efficient energy source compared to traditional ones like fatty acids or glucose. They are produced in the liver and are important for supplying energy during fasting, exercise, and illness. Recent research suggests that 3-OHB might have benefits for HF patients beyond just providing energy. It seems to reduce inflammation and oxidative stress in the heart. Some studies in healthy individuals have shown that infusing 3-OHB increases blood flow to the heart. In HF patients, the investigators aim to explore the cardiac effects of a two-week supplement of 3-OHB. The aim is to investigate if this supplement can increase the heart's consumption and utilization of 3-OHB. The study involves 12 patients with HF and reduced ejection fraction (HFrEF). The patients will receive a ketone ester supplement four times a day for two weeks, and then they'll take an isocaloric placebo supplement for another two weeks. The investigators will use positron emission tomography (PET) to study the cardiac oxygen consumption and 3-OHB uptake. This is done by injection of tracers (11-C-3-OHB and 11-C-acetate). The study will also look at myocardial external efficiency (MEE) and myocardial blood flow (MBF). For a subset of participants, the investigators will also take myocardial biopsies and perform more detailed analyses, e.g. respirometry and electron microscopy or single nucleus mRNA sequencing, proteomics and metabolimcs, to understand the impact of the supplement on the heart's cellular structures and functions, transcriptome, proteome and metabolome. Ultimately, this study aims to determine whether supplementing HF patients with 3-OHB can improve the heart's energy usage and potentially provide other beneficial effects. This research might pave the way for new treatments that enhance the heart's function and quality of life for HF patients.

Conditions

Heart Failure With Reduced Ejection Fraction

Outcome Measures

Primary Outcomes (1)

• Myocardial consumption of 3-OHB.

  Uptake of the ketone radiotracer measured in µmol/min/g tissue in the myocardium will be calculated using kinetic modeling techniques using aQuant Research software.

  Participants meet for 2 examination days 4 weeks apart. This is a whole day involving 4 PET/CT scans each day.

Secondary Outcomes (6)

• Myocardial oxygen consumption (MVO2)

  Participants meet for 2 examination days 4 weeks apart. This is a whole day involving 4 PET/CT scans each day.

• Myocardial external efficacy

  Participants meet for 2 examination days 4 weeks apart. This is a whole day involving 4 PET/CT scans each day.

• High resolution respirometry

  Participants meet for 2 examination days 4 weeks apart. For a subset of participants, 1 myocardial biopsy and 2 skeletal muscle biopsies will be taken at each examination day.

• Single nucleus mRNA sequencing of skeletal muscle and cardiomyocytes.

  Participants meet for 2 examination days 4 weeks apart. For a subset of participants, 1 myocardial biopsy and 2 skeletal muscle biopsies will be taken at each examination day.

• Proteomics of skeletal muscle and myocardial biopsies.

  Participants meet for 2 examination days 4 weeks apart. For a subset of participants, 1 myocardial biopsy and 2 skeletal muscle biopsies will be taken at each examination day.

Study Arms (2)

3-hydroxybutyrate

ACTIVE COMPARATOR

Dietary Supplement: 3-hydroxybutyrat

Isocaloric placebo drink

PLACEBO COMPARATOR

Dietary Supplement: Isocaloric placebo drink

Interventions

3-hydroxybutyrat DIETARY_SUPPLEMENT

The intervention is administered as a drink.

3-hydroxybutyrate

Isocaloric placebo drink DIETARY_SUPPLEMENT

The intervention is administered as a drink.

Isocaloric placebo drink

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diabetes or HbA1c \> 48 mmol/L
• significant cardiac valve disease
• severe stable angina pectoris
• severe comorbidity as judged by the investigator
• inability to give informed consent
• Age \<55 years
• Other disease or treatment making subject unsuitable for study participation as judged by the investigator

You may not qualify if:

• Chronic heart failure
• NYHA class II-III
• left ventricular ejection fraction (LVEF) \<40%
• Negative urine-HCG for women with childbearing potential

Sponsors & Collaborators

• Aarhus University Hospital: lead

Study Sites (1)

Aarhus University Hospital

Aarhus, Central Jutland, 8200, Denmark

Location

Related Publications (10)

• Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017 Apr;3(1):7-11. doi: 10.15420/cfr.2016:25:2.

  PMID: 28785469 BACKGROUND

• McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available.

  PMID: 34447992 BACKGROUND

• Kolwicz SC Jr, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res. 2013 Aug 16;113(5):603-16. doi: 10.1161/CIRCRESAHA.113.302095.

  PMID: 23948585 BACKGROUND

• Selvaraj S, Kelly DP, Margulies KB. Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. Circulation. 2020 Jun 2;141(22):1800-1812. doi: 10.1161/CIRCULATIONAHA.119.045033. Epub 2020 Jun 1.

  PMID: 32479196 BACKGROUND

• Gormsen LC, Svart M, Thomsen HH, Sondergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Botker HE, Moller N. Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study. J Am Heart Assoc. 2017 Feb 27;6(3):e005066. doi: 10.1161/JAHA.116.005066.

  PMID: 28242634 BACKGROUND

• Yurista SR, Nguyen CT, Rosenzweig A, de Boer RA, Westenbrink BD. Ketone bodies for the failing heart: fuels that can fix the engine? Trends Endocrinol Metab. 2021 Oct;32(10):814-826. doi: 10.1016/j.tem.2021.07.006. Epub 2021 Aug 26.

  PMID: 34456121 BACKGROUND

• Nielsen R, Moller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, Harms HJ, Frokiaer J, Eiskjaer H, Jespersen NR, Mellemkjaer S, Lassen TR, Pryds K, Botker HE, Wiggers H. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation. 2019 Apr 30;139(18):2129-2141. doi: 10.1161/CIRCULATIONAHA.118.036459.

  PMID: 30884964 BACKGROUND

• Monzo L, Sedlacek K, Hromanikova K, Tomanova L, Borlaug BA, Jabor A, Kautzner J, Melenovsky V. Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester. Metabolism. 2021 Feb;115:154452. doi: 10.1016/j.metabol.2020.154452. Epub 2020 Nov 26.

  PMID: 33248064 BACKGROUND

• Ho KL, Zhang L, Wagg C, Al Batran R, Gopal K, Levasseur J, Leone T, Dyck JRB, Ussher JR, Muoio DM, Kelly DP, Lopaschuk GD. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency. Cardiovasc Res. 2019 Sep 1;115(11):1606-1616. doi: 10.1093/cvr/cvz045.

  PMID: 30778524 BACKGROUND

• Thai PN, Miller CV, King MT, Schaefer S, Veech RL, Chiamvimonvat N, Bers DM, Dedkova EN. Ketone Ester D-beta-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice. J Am Heart Assoc. 2021 Oct 5;10(19):e020729. doi: 10.1161/JAHA.120.020729. Epub 2021 Sep 29.

  PMID: 34583524 BACKGROUND

Study Officials

• Henrik Henrik, Professor

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 23, 2023
• First Posted: May 3, 2024
• Study Start: November 21, 2023
• Primary Completion: April 8, 2025
• Study Completion: April 8, 2025
• Last Updated: September 4, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)