Effects of Experimental Hyperketonemia on Myocardial Metabolism
Condition: Healthy Volunteers
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Starvation and metabolic stress increase circulating ketone bodies, potentially providing the
      heart with an alternative oxidative fuel. Hyperketonemia reduces myocardial fatty acid
      consumption. It is unclear whether this is due to inhibited peripheral lipolysis or
      diminished uptake per se.

      Aim: To test whether infusion of 3-hydroxybutyrate (BHB) inhibits myocardial glucose and
      fatty acid uptake.

      Methods: Randomized, single blinded, cross-over interventional study in 8 healthy volunteers.
      Myocardial glucose and fatty acid metabolism studied by 11C-palmitate and 18F-FDG PET/CT.
      Experimental elevation of circulating ketone bodies by infusion of
      β-hydroxy-β-methylbutyrate.
    

Detailed description: 
      Background:

      Ketone bodies are produced by the liver in conditions of increased fatty acid oxidation,
      serving as important fuel sources during fasting and starvation. They are metabolized to
      acetyl-CoA which enters the tricarboxylic acid cycle, enabling ATP production independently
      of glycolysis and resulting in lower oxygen consumption per mole of produced ATP compared to
      glucose [ref]. Their primary physiological function appears to be as an alternative
      protein-sparing source of energy for extrahepatic tissues in times of reduced carbohydrate
      availability, preventing muscle wasting. The principal ketone bodies in humans are
      beta-hydroxybutyrate (BHB) and acetoacetate. Increased ketogenesis is a feature common to
      fasting, starvation and diabetes mellitus. Ketones have been shown to have a number of
      neuroprotective effects including anticonvulsant activity, improving cognitive function in
      Alzheimer's disease and decreasing the effects of acute brain injury and ischemic damage
      [ref], as well as antitumoral effect in gliomas. This has led to the suggestion that ketones
      could be used therapeutically for a number of diseases though currently the only recognized
      therapeutic use of ketones is in the form of ketogenic diets for the treatment of epilepsy.

      There are limited in vivo studies on the effect of ketones on the heart. It is known that
      fatty acids are the preferred myocardial fuel substrate and that this shifts to increased use
      of glucose, and to a lesser extent ketones, in times of acutely increased demand.
      Interestingly, acute ketone infusion in pigs appears to inhibit myocardial fatty acid
      oxidation. In vitro studies suggest ketones decrease myocardial glucose uptake and affect
      myocardial contractility, with either increased or decreased contractility when ketones are
      the only energy source. This has not been further investigated in vivo. It is therefore
      unclear to what extent ketones can contribute to myocardial metabolism in conditions of
      hyperketonemia, and how this affects contractility.

      The present project thus proposes to address the issues outlined above, by measuring human
      cerebral and cardiac uptake of energy substrates, together with functional parameters, using
      PET imaging and appropriate radiotracers, under experimental hyperketonemia.

      Hypotheses:

      1. An acute increase in blood ketone concentration without previous ketoadaptation will
      decrease cardiac palmitate and glucose uptake in healthy humans.

      Materials and methods

      Effect of acute ketone infusion on cardiac perfusion and 18F-FDG and 11C-palmitate uptake in
      healthy subjects:

      Study population: 10 healthy volunteers. All study subjects will be instructed to follow a
      standardised diet for 1 week before the study. On the study day, they will undergo a baseline
      dynamic cardiac PET scan with 15O-water followed by 11C-palmitate and 18F-FDG tracers,
      together with baseline blood samples, muscle biopsy and subcutaneous fat biopsy to assess
      peripheral metabolic status. An intravenous infusion of sodium betahydroxybutyrate will then
      be initiated at a concentration and rate sufficient to achieve 1-2 mM ketonemia after 30
      minutes (assessed by blood sample). A second dynamic PET scan identical to the first will
      then be performed under continuous ketone infusion at a constant rate. Finally, a second set
      of blood samples, muscle and subcutaneous fat biopsies will be taken after the scan before
      stopping the ketone infusion.

      Perspectives:

      The results of this research are expected to provide insights into how human heart metabolism
      respond to increased ketone bodies, and whether there are significant functional
      improvements. It should contribute to further understanding the possible therapeutic benefits
      of both exogenous ketone administration and of fasting in relation to cardiac function, with
      implications for the treatment of various diseases such as diabetes and heart failure.
      Knowledge of ketones' effects on the kinetics of various radionuclide tracers also has
      importance for the appropriate clinical use of diagnostic PET scans in patients with elevated
      blood ketone levels. In addition, the implementation and validation of a ketone PET tracer
      will allow further future non-invasive studies that directly measure ketone metabolism in
      various tissues and disease states.
    

Intervention name(s): Na-3-hydroxybutyrate; Saline
Intervention type(s): Other; Other
Intervention description(s): Infusion of Na-3-hydroxybutyrate (0.18 g/kg/hour) for 390 minutes; Infusion of 0.9 % saline
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: PET/CT; Heart failure; hydroxybutyrate