Ketones in Heart Failure - Effects on Cardiac Efficiency

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Ketones on Cardiac Function and Oxygen Consumption in Heart Failure Patients With Reduced Ejection Fraction and Healthy Test Subjects

Conditions
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Heart Failure, Systolic, Ketonemia

Intervention / Treatment
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* Biological: Infusion of 3-OHB
* Biological: Infusion of placebo


Participation Criteria
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Eligibility Criteria
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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%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized dobbel-blinded crossover
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control - Healthy test subjects<br>Age matched subjects without symptoms of heart failure or ischemic heart disease N=10 | Biological: Infusion of 3-OHB<br>* Increase in 3-OHB levels<br>* Other names: Na-3-OHB;Biological: Infusion of placebo<br>* NaCl<br>* Other names: NaCl;|
| Experimental: HFrEF - Heart failure patients investigated by PET<br>Patients with heart failure (HFrEF) N=12 | Biological: Infusion of 3-OHB<br>* Increase in 3-OHB levels<br>* Other names: Na-3-OHB;Biological: Infusion of placebo<br>* NaCl<br>* Other names: NaCl;|
| Experimental: HFrEF - Right heart catheterization<br>Patients with heart failure (HFrEF) N=12 | Biological: Infusion of 3-OHB<br>* Increase in 3-OHB levels<br>* Other names: Na-3-OHB;Biological: Infusion of placebo<br>* NaCl<br>* Other names: NaCl;|
| Experimental: HFrEF - Right heart catheterization study 2<br>Dose finding study (increasing dosage of 3-OHB) | Biological: Infusion of 3-OHB<br>* Increase in 3-OHB levels<br>* Other names: Na-3-OHB;Biological: Infusion of placebo<br>* NaCl<br>* Other names: NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial efficiency | Based on myocardial PET examinations | 1 day | 
| Cardiac output | Right sided heart catheterization | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial perfusion | Based on myocardial PET examinations | 1 day | 
| Myocardial oxygen consumption | Based on myocardial PET examinations | 1 day | 
| Pulmonary and wedge pressure | Right sided heart catheterization | 1 day | 
| Mixed venous saturation | Right sided heart catheterization | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial metabolism, Positron emission tomography, Echocardiography, Right sided heart catheterization