Clinical trial NCT03073356: Ketones in Heart Failure - Effects on Cardiac Efficiency
Official title: Effects of Ketones on Cardiac Function and Oxygen Consumption in Heart Failure Patients With Reduced Ejection Fraction and Healthy Test Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure, Systolic
Ketonemia
Keywords: Myocardial metabolism
Positron emission tomography
Echocardiography
Right sided heart catheterization
Lead sponsor: University of Aarhus
Sponsor class: OTHER
First posted: 2017-03-08
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized dobbel-blinded crossover
Primary purpose: TREATMENT

Brief summary: Ketones may have beneficial effects on myocardial metabolism and hemodynamics. In the present study, healthy test subjects and patients with heart failure with reduced ejections fraction will be investigated in a randomized cross-over design with ketone infusions and placebo. Myocardial efficiency and hemodynamics will be evaluated.

Detailed description: The prevalence of patients with heart failure and reduced ejection fraction (HFrEF) is 1-2%, and the lifetime risk of heart failure at age 55 years is approximately 30%. Despite advances in treatment, hospitalization rate and mortality remains high. It is well known that myocardial metabolism changes during development of HFrEF, and may contribute to contractile dysfunction. However, the myocardium can be considered an omnivore regarding substrate utilization, conferring an important adaptive property. Hence, it metabolizes either glucose, lipids, lactate, amino acids or ketones (3-hydroxybutyrate) depending on substrate availability, hormonal status and cardiac demands. These substrates differ with regard to myocardial energy efficiency (MEE) (cardiac work related to oxygen consumption). Since high MEE is associated with a better prognosis in HFrEF, manipulating substrate uptake could be a new treatment modality in heart failure patients.

Recently, it was shown that the human myocardium increases 3-hydroxybutyrate (3-OHB) metabolism during development of HFrEF. These changes may be beneficial as 3-OHB could increase myocardial efficiency and lower oxidative stress by scavenging free radicals. However, until now this has not been investigated in clinical trials, and the effect of 3-OHB on cardiac function, oxygen consumption and perfusion remains undetermined in HFrEF patients.

In the present study the investigators will evaluate whether elevated circulating 3-OHB affect myocardial oxygen consumption, MEE and perfusion in healthy subjects and patients with HFrEF, and whether 3-OHB affect hemodynamics and contractile function.

10 healthy test subjects and 20 HFrEF patients will be subjected to placebo and 3-OHB infusion in a randomized cross-over design. Acetate-PET, echocardiography and right sided heart catheterization will be applied.

Eligibility criteria: Inclusion Criteria:

* For participants with heart failure:
* Symptoms of Heart failure NYHA 2-3
* LVEF\<40%

For all participants:

* Negative HCG for women in the pregnant age

Exclusion Criteria:

* Significant cardiac valve disease
* Signs or history of major myocardial infarction (STEMI) within 3 months
* Other disease or treatment making subject unsuitable for study participation
* Treatment for diabetes or HbA1c level \>7%

Primary outcomes:
measure: Myocardial efficiency
timeFrame: 1 day
measure: Cardiac output
timeFrame: 1 day
Secondary outcomes:
measure: Myocardial perfusion
timeFrame: 1 day
measure: Myocardial oxygen consumption
timeFrame: 1 day
measure: Pulmonary and wedge pressure
timeFrame: 1 day
measure: Mixed venous saturation
timeFrame: 1 day
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Dept. of cardiology, Aarhus university hospital Skejby
state: Region Midtjylland
Study officials:
affiliation: Dept. of Cardiology
name: Roni R Nielsen, MD PHD
role: PRINCIPAL_INVESTIGATOR
References: