Functional and Metabolic Effects of Ketone Bodies on Human Atrial Tissue in Patients With and Without Heart Failure

Overview

This proof of concept study aims to evaluate the effects of applying ketone bodies to human atrial tissue biopsies using an atrial strips model and high resolution respirometry.

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Basic Science
  • Masking: None (Open Label)
• Study Primary Completion Date: January 31, 2024

Detailed Description

Ketone bodies are high energy molecules which are naturally occurring in the body during fasting or stress. Recently, ketone bodies have been shown to improve cardiac function in patients with heart failure(1) through a mechanism, which has yet to be elaborated. We wish to evaluate the effects of ketone body administration on cardiac tissue subjected to ischemia reperfusion injury. We will evaluate contractile force of the and the mitochondrial performance. Cardiac atrial tissue will be obtained from patients undergoing coronary artery bypass grafting (CABG) or valve replacement surgery. Patients will be recruited after signing an informed consent and allocated in heart failure / non-heart failure groups based on a clinical evaluation.

Interventions

• Dietary Supplement: 3-hydroxybuturate
  • 3-hydroxybuturate will be administered directly as a modified Krebs Henseleit buffer in a super perfused atrial strips model

Arms, Groups and Cohorts

• Other: Heart failure
  • Ejection fraction < 45%
• Other: Non-heart failure
  • Ejection fraction > 45%

Clinical Trial Outcome Measures

Primary Measures

• Contractile force recovery
  • Time Frame: Outcome will be assessed within a year when the inclusion of patients is complete
  • Atrial strips model, contractile force (nm*mm^-1) during stabilization, ischemia and reperfusion

Secondary Measures

• Mitochondrial respiratory capacity
  • Time Frame: Outcome will be assessed within a year when the inclusion of patients is complete
  • High Resolution Respirometry, Complex I and Complex I+II respiration (pmol O2 · s-1·mg-1) assessed via a substrate and inhibitor (SUIT) protocol.
• Mitochondrial Reactive Oxygen Species production
  • Time Frame: Outcome will be assessed within a year when the inclusion of patients is complete
  • High Resolution FluoRespirometry, Complex I and Complex I+II linked ROS generation measured with AmplexUltra red and H2O2 interaction fluorescense

Participating in This Clinical Trial

Inclusion Criteria

• EF < / > 45%, hospitalized for elective CABG or heart valve surgery Exclusion Criteria:

• Myocardial infarction within 4 weeks, atrial fibrillation, medically treated thyroid disease, oral treatment with opioids.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 85 Years

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • University of Aarhus
• Collaborator
  • Aarhus University Hospital
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Hans Erik Bøtker, M.D., Prof., Study Director, Aarhus University Hospital
• Overall Contact(s)
  • Jacob Seefeldt, B.M, +45 41178633, jacob.seefeldt@clin.au.dk

References

Nielsen R, Moller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, Harms HJ, Frokiaer J, Eiskjaer H, Jespersen NR, Mellemkjaer S, Lassen TR, Pryds K, Botker HE, Wiggers H. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation. 2019 Apr 30;139(18):2129-2141. doi: 10.1161/CIRCULATIONAHA.118.036459.