Effects of Ketones and Niacin in Heart Failure Patients

Heart Failure, Systolic Clinical Trial

— KETO-COX  

Official title:

Effects of Ketones and Niacin in Heart Failure Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04703361
• Other study ID #: 1010
• Status: Completed
• Phase: Phase 2
• Start date: February 15, 2021
• Est. completion date: September 3, 2021

Study information

• Verified date: October 2020
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: September 3, 2021
• Est. primary completion date: September 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Systolic
• Ketonemia
• Ketosis

Intervention

Biological:
• Placebo NaCl
Placebo
• Niacin
B3 vitamin, Niacin
• Na-3-OHB
Na-3-OHB

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus

Sponsors (1)

Lead Sponsor	Collaborator
University of Aarhus

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cardiac Output	L/min	3 hours
Secondary	Mixed venous saturation	SvO2	3 hours
Secondary	Pulmonary wedge pressure	PWR	3 hours
Secondary	Left ventricular ejection fraction	EF	3 hours
Secondary	Circulating prostaglandin levels	prostaglandins	3 hours