Clinical trial NCT06398964: Effects of 2-week Ketosis on the Heart's Ketone Body Consumption, Utilization, and Energetic Efficiency in Patients With Chronic Heart Failure
Official title: Effects of 2-week Ketosis on Myocardial Ketone Body Consumption, Utilization, and External Efficiency in Patients With Chronic Heart Failure
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Heart Failure With Reduced Ejection Fraction
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
First posted: 2024-05-03
Enrollment: 12
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

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

Primary outcomes:
measure: Myocardial consumption of 3-OHB.
timeFrame: Participants meet for 2 examination days 4 weeks apart. This is a whole day involving 4 PET/CT scans each day.
Secondary outcomes:
measure: Myocardial oxygen consumption (MVO2)
timeFrame: Participants meet for 2 examination days 4 weeks apart. This is a whole day involving 4 PET/CT scans each day.
measure: Myocardial external efficacy
timeFrame: Participants meet for 2 examination days 4 weeks apart. This is a whole day involving 4 PET/CT scans each day.
measure: High resolution respirometry
timeFrame: 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.
measure: Single nucleus mRNA sequencing of skeletal muscle and cardiomyocytes.
timeFrame: 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.
measure: Proteomics of skeletal muscle and myocardial biopsies.
timeFrame: 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.
measure: Metabolomics of skeletal muscle and myocardial biopsies.
timeFrame: 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.
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
state: Region Midtjylland
Study officials:
affiliation: Aarhus University Hospital
name: Henrik Henrik, Professor
role: PRINCIPAL_INVESTIGATOR
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