Modulation of Circulating Levels of the Ketone Body 3-hydroxybutyrate in Patients With Chronic Heart Failure: Cardiovascular Effects (KETO-KINETICS1)

The ketone body 3-hydroxybutyrate (3-OHB) is a naturally occurring energy substrate, and is associated with increased life span and improved health. We have previously shown that intravenous 3-OHB treatment increases myocardial blood flow > 70% in healthy humans and data from our group show that 3-OHB increases cardiac output by 40 % in patients with heart failure.

In this study the investigators aim to investigate:

1. If this effect is reproducible with a commercially available oral ketone supplements
2. The safety of commercially available ketone supplements in heart failure patients

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure; Ketosis; Ketonemia
• Intervention / Treatment: Dietary supplement: Ketone Monoester; Dietary supplement: Oral 3-hydroxybutyrate salts; Dietary supplement: Carbohydrate Placebo

Detailed Description

Heart Failure (HF) is a major public health issue because the disease affects 1-2% of the Western population and the lifetime risk of HF is 20%. HF is responsible for 1-2% of all healthcare expenditures. Despite major improvements in the management and care of patients with HF, the 1-year mortality in patients with HF is 13 % and >50% of HF-patients is admitted during a 2.5 year period. Furthermore patients with HF have markedly decreased physical capacity and quality of life. Thus, there is a need for new treatment modalities in this group of patients.

Ketone bodies are produced in the liver and are of vital importance in the human body for energy generation in the heart and brain during fasting, exercise and severe illness. Ketosis can be safely obtained using dietary supplements and can increase exercise capacity in athletes. The most important ketone bodies are 3-hydroxybutyrate (3-OHB) and acetoacetate. Recently, it was demonstrated that patients with severe HF have increased myocardial utilization of the ketone body 3-hydroxybutyrate.

We have shown, using positron emission tomography, that ketone body infusion reduces myocardial glucose uptake and increases myocardial blood flow in healthy subjects. Data from another study conducted by our group show a 40% increase in cardiac output during infusion of 3-OHB.

Presently there are no data on the clinical cardiovascular and metabolic effects of long-term oral ketone-supplementation in patients with chronic HF.

In this study the investigators will whether ketosis obtained by oral ketone supplements affects hemodynamics and contractile function.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic Heart Failure;
• NYHA class II-III
• Left Ventricular Ejection Fraction <40%

Exclusion Criteria:

• Diabetes or HbA1c > 48 mmol/mol
• Significant cardiac valve disease,
• Severe stable angina pectoris
• Severe comorbidity as judged by investigator,
• Inability to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single dose oral 3-hydroxybutyrate monoester; Cross-over study in 8 patients receiving single-dose oral 3-hydroxybutyrate monoester, 3-OHB salt and placebo.	Dietary supplement: Ketone Monoester; Commercially available ketone monoester in a dosage isocaloric to 3-OHB salts.
Experimental: Single dose oral 3-hydroxybutyrate Salt	Dietary supplement: Oral 3-hydroxybutyrate salts; Comercially available 3-hydroxybutyrate salts with 36 grams of 3-OHB salts three times daily.
Placebo Comparator: Single dose oral placebo; maltodextrin-based, isocaloric to ketone dosis.	Dietary supplement: Carbohydrate Placebo; Comercially available carbohydrate sports drink. The placebo dose is isocaloric to the 3-hydroxy butyrate dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac Output (L/min)	Right Heart Catherization	5 hours - Area under the curve

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricle Ejection Fraction (%)	Echocardiography	5 Hours - Area under the curve
Left Ventricular filling pressure (mmHg)	Right Heart Catherization	5 hours - Area under the curve

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Kristian H Christensen, MD, Aarhus Universitetshospital - Department of Cardiology

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2019
• Primary Completion (Anticipated): November 1, 2022
• Study Completion (Anticipated): November 1, 2022

Study Registration Dates

• First Submitted: May 20, 2019
• First Submitted That Met QC Criteria: June 19, 2020
• First Posted (Actual): June 23, 2020

Study Record Updates

• Last Update Posted (Actual): August 18, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Metabolism
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Acid-Base Imbalance; Acidosis; Heart Failure; Ketosis
• Other Study ID Numbers: KETO- CHF 1-10-72-362-18

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No