title: Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study.
abstract: BACKGROUND
  High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and-most recently-treatment with sodium-glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow.
  
  
  RESULTS
  Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na-3-hydroxybutyrate (KETONE) or (2) during 390 minutes infusion of saline (SALINE), together with a concomitant low-dose hyperinsulinemic-euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by15O-H2O positron emission tomography/computed tomography, myocardial fatty acid metabolism by11C-palmitate positron emission tomography/computed tomography and MGU by18F-fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na-3-hydroxybutyrate infusion increased circulating Na-3-hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia (MGU [nmol/g per minute]: 304±97 [SALINE] versus 156±62 [KETONE],P<0.01), whereas no effects were observed on palmitate uptake oxidation or esterification. Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%.
  
  
  CONCLUSIONS
  Ketone bodies displace MGU and increase myocardial blood flow in healthy humans; these novel observations suggest that ketone bodies are important cardiac fuels and vasodilators, which may have therapeutic potentials.
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark lars.christian.gormsen@clin.au.dk.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Gormsen
authors.affiliation: Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Svart
authors.affiliation: Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henrik Holm
authors.initials: HH
authors.lastname: Thomsen
authors.affiliation: Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Esben
authors.initials: E
authors.lastname: Søndergaard
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mikkel H
authors.initials: MH
authors.lastname: Vendelbo
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Nana
authors.initials: N
authors.lastname: Christensen
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars Poulsen
authors.initials: LP
authors.lastname: Tolbod
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hendrik Johannes
authors.initials: HJ
authors.lastname: Harms
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Roni
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Wiggers
authors.affiliation: Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
authors.affiliation: Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000368:Aged; D002250:Carbon Radioisotopes; D003326:Coronary Circulation / Q000187:drug effects*; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D064368:Healthy Volunteers; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007657:Ketone Bodies / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D010104:Oxygen Radioisotopes; D010168:Palmitates; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D014867:Water
chemical_list: D002250:Carbon Radioisotopes; C000615233:Carbon-11; D007657:Ketone Bodies; D010104:Oxygen Radioisotopes; C000615263:Oxygen-15; D010168:Palmitates; D019275:Radiopharmaceuticals; D014867:Water; D019788:Fluorodeoxyglucose F18; D005947:Glucose; D020155:3-Hydroxybutyric Acid
keywords: 11C‐palmitate; 18F‐fluorodeoxyglucose; cardiac metabolism; hyperketonemia; myocardial glucose uptake; myocardial perfusion; nuclear medicine; positron emission tomography/computed tomography