Ketones in Heart Failure - Effects on Cardiac Efficiency

Phase 2

Completed

• Conditions: Ketonemia; Heart Failure, Systolic
• Interventions: Biological: Infusion of 3-OHB; Biological: Infusion of placebo

• Registration Number: NCT03073356
• Lead Sponsor: University of Aarhus

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.

Study Timeline

• Status Verified: 2017-01
• Study First Submitted: 2017-02-20
• Study First Submitted QC: 2017-03-02
• Study First Posted: 2017-03-08
• Study Start: 2017-03-17
• Primary Completion: 2017-11-16
• Study Completion: 2017-11-16
• Last Update Submitted: 2017-12-08
• Last Update Posted: 2017-12-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 44

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

Read More

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%

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Control - Healthy test subjects	Infusion of 3-OHB	Age matched subjects without symptoms of heart failure or ischemic heart disease N=10
HFrEF - Right heart catheterization	Infusion of placebo	Patients with heart failure (HFrEF) N=12
Control - Healthy test subjects	Infusion of placebo	Age matched subjects without symptoms of heart failure or ischemic heart disease N=10
HFrEF - Right heart catheterization study 2	Infusion of 3-OHB	Dose finding study (increasing dosage of 3-OHB)
HFrEF - Right heart catheterization study 2	Infusion of placebo	Dose finding study (increasing dosage of 3-OHB)
HFrEF - Heart failure patients investigated by PET	Infusion of 3-OHB	Patients with heart failure (HFrEF) N=12
HFrEF - Heart failure patients investigated by PET	Infusion of placebo	Patients with heart failure (HFrEF) N=12
HFrEF - Right heart catheterization	Infusion of 3-OHB	Patients with heart failure (HFrEF) N=12

Primary Outcome Measures

Name	Time	Method
Myocardial efficiency	1 day	Based on myocardial PET examinations
Cardiac output	1 day	Right sided heart catheterization

Secondary Outcome Measures

Name	Time	Method
Mixed venous saturation	1 day	Right sided heart catheterization
Myocardial oxygen consumption	1 day	Based on myocardial PET examinations
Myocardial perfusion	1 day	Based on myocardial PET examinations
Pulmonary and wedge pressure	1 day	Right sided heart catheterization

Trial Locations

Locations (1)

Dept. of cardiology, Aarhus university hospital Skejby; 🇩🇰 Aarhus, Region Midtjylland, Denmark