Effects of Ketones and Niacin in Heart Failure Patients (KETO-COX)

Ketones, 3-hydroxybutyrate (3-OHB), have shown to have beneficial hemodynamics effect in patients with hearth failure with reduced ejection fraction. The mechanisms behind these marked hemodynamic effects are currently unknown, but could involve prostaglandin-release. 3-OHB is the endogenous ligand for the G protein-coupled receptor hydroxy-carboxylic acid 2 (HCA2) receptor. This receptor has proven downstream effects on cAMP and systemic effects via release of prostaglandins.

In this present study we will investigate the cardiovascular effects of HCA2-receptor stimulation in heart failure patients.

Study Overview

• Status: Completed
• Conditions: Heart Failure, Systolic; Ketonemia
• Intervention / Treatment: Biological: Placebo NaCl; Biological: Niacin; Biological: Na-3-OHB

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 and 5% of all hospital admissions. The cornerstone in the medical treatment of chronic HF is a combination of ACE-inhibitors/ATII-receptor antagonists, beta-blockers and mineralocorticoid receptor antagonists. Despite major improvements in the management and care of patients with HF, the 1-year mortality in patients with HF is 13 % 4 and >50% of HF-patients are admitted within a 2.5 year period 5. 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 crucial for energy generation during fasting in the heart and brain during, exercise and severe illnesses. However, 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-OHB. It has been hypothesized that ketone bodies may act as a "superfuel" for the failing heart. In support of this, the glucose-lowering SGLT-2 inhibitor empagliflozin reduces the risk of hospitalizations and cardiovascular death in diabetic patients with HF and also increases circulating levels of 3-OHB.

By Positron Emission Tomography (PET) we have shown 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. The mechanisms behind these marked hemodynamic effects are currently unknown, but could involve prostaglandin-release. 3-OHB is the endogenous ligand for the G protein-coupled receptor hydroxy-carboxylic acid 2 (HCA2) receptor. This receptor has proven downstream effects on cAMP and systemic effects via release of prostaglandins.

3-OHB have affinity to the HCA2 receptor and possibly a downstream effect resulting in the release of prostaglandins. The prostaglandin synthesis is dependent of cyclooxygenase (COX) enzyme, which can be inhibited by aspirin (ASA).

Niacin, vitamin B3, has been used as a treatment for dyslipidemia. Niacin is also a ligand for HCA2 receptor and the downstream release of prostaglandin cause side effects such as cutaneous flushing.

In this study we will investigate the cardiovascular effects of HCA2-receptor stimulation in heart failure patients. This will be done by comparing infusion of 3-OHB (preceded with ASA) and niacin.

• Study Type: Interventional
• Enrollment (Actual): 12
• 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, Age ≥ 18 years old, LVEF ≤40%, New York Heart Association (NYHA) classification 2-3, Negative urine-HCG for women of childbearing potential, Ability to understand the written patient information and to give informed consent.

Exclusion Criteria:

• Symptomatic cardiac valve disease, Signs or history of major myocardial infarction (STEMI) within 1 month, Insulin treatment, Other disease or treatment making subject unsuitable for study participation as judged by the investigator.

Significant liver disease (defined by serum levels of alanine aminotransferase (ALAT) above 3 x upper limit of normal).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Niacin; 12 patients with Heart failure with reduced ejection fraction (HFrEF) investigated with echocardiography and right heart catheterization.	Biological: Placebo NaCl; Placebo; Biological: Niacin; B3 vitamin, Niacin
Experimental: Na-3-OHB; 12 patients with Heart failure with reduced ejection fraction (HFrEF) investigated with echocardiography and right heart catheterization. All patients will receive Aspirin before intervention and randomization.	Biological: Placebo NaCl; Placebo; Biological: Na-3-OHB; Na-3-OHB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac Output	L/min	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mixed venous saturation	SvO2	3 hours
Pulmonary wedge pressure	PWR	3 hours
Left ventricular ejection fraction	EF	3 hours
Circulating prostaglandin levels	prostaglandins	3 hours

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Nigopan Gopalasingam, MD, University of Aarhus; Principal Investigator: Henrik Wiggers, MD, PhD, DMSc, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2021
• Primary Completion (Actual): September 3, 2021
• Study Completion (Actual): September 3, 2021

Study Registration Dates

• First Submitted: January 8, 2021
• First Submitted That Met QC Criteria: January 8, 2021
• First Posted (Actual): January 11, 2021

Study Record Updates

• Last Update Posted (Actual): December 3, 2021
• Last Update Submitted That Met QC Criteria: December 2, 2021
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Acid-Base Imbalance; Acidosis; Heart Failure; Heart Failure, Systolic; Ketosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Niacin
• Other Study ID Numbers: 1010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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