title: Modeling non-linear kinetics of hyperpolarized [1-(13)C] pyruvate in the crystalloid-perfused rat heart.
abstract: Hyperpolarized (13)C MR measurements have the potential to display non-linear kinetics. We have developed an approach to describe possible non-first-order kinetics of hyperpolarized [1-(13)C] pyruvate employing a system of differential equations that agrees with the principle of conservation of mass of the hyperpolarized signal. Simultaneous fitting to a second-order model for conversion of [1-(13)C] pyruvate to bicarbonate, lactate and alanine was well described in the isolated rat heart perfused with Krebs buffer containing glucose as sole energy substrate, or glucose supplemented with pyruvate. Second-order modeling yielded significantly improved fits of pyruvate-bicarbonate kinetics compared with the more traditionally used first-order model and suggested time-dependent decreases in pyruvate-bicarbonate flux. Second-order modeling gave time-dependent changes in forward and reverse reaction kinetics of pyruvate-lactate exchange and pyruvate-alanine exchange in both groups of hearts during the infusion of pyruvate; however, the fits were not significantly improved with respect to a traditional first-order model. The mechanism giving rise to second-order pyruvate dehydrogenase (PDH) kinetics was explored experimentally using surface fluorescence measurements of nicotinamide adenine dinucleotide reduced form (NADH) performed under the same conditions, demonstrating a significant increase of NADH during pyruvate infusion. This suggests a simultaneous depletion of available mitochondrial NAD(+) (the cofactor for PDH), consistent with the non-linear nature of the kinetics. NADH levels returned to baseline following cessation of the pyruvate infusion, suggesting this to be a transient effect.
authors.affiliation: Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Mariotti
authors.affiliation: CR-UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Orton
authors.affiliation: Department of Anatomy, Embryology and Physiology, AMC, UvA, Amsterdam, The Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Eerbeek
authors.affiliation: Laboratory Experimental Intensive Care Anesthesiology (LEICA), Department Anesthesiology, AMC, UvA, Amsterdam, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Ashruf
authors.affiliation: Laboratory Experimental Intensive Care Anesthesiology (LEICA), Department Anesthesiology, AMC, UvA, Amsterdam, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: Zuurbier
authors.affiliation: Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK.|The British Heart Foundation Centre of Research Excellence, The Rayne Institute, King's College London, St. Thomas' Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Southworth
authors.affiliation: Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK.|CR-UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, SM2 5NG, UK.|The British Heart Foundation Centre of Research Excellence, The Rayne Institute, King's College London, St. Thomas' Hospital, London, UK.
authors.forename: T R
authors.initials: TR
authors.lastname: Eykyn
mesh_terms: D000818:Animals; D002247:Carbon Isotopes; D000077324:Crystalloid Solutions; D005453:Fluorescence; D005947:Glucose; D006321:Heart / Q000502:physiology*; D007552:Isotonic Solutions / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009243:NAD / Q000378:metabolism; D017711:Nonlinear Dynamics; D010477:Perfusion; D019289:Pyruvic Acid / Q000378:metabolism*; D017208:Rats, Wistar
chemical_list: D002247:Carbon Isotopes; D000077324:Crystalloid Solutions; D007552:Isotonic Solutions; D009243:NAD; D019289:Pyruvic Acid; D005947:Glucose
keywords: Langendorff perfused heart; cardiac metabolism; dynamic nuclear polarization (DNP); hyperpolarized 13C