Tomography

Vol. 3 No. 3 - Sep 2017

Tomography is a scientific journal for publication of articles in imaging research

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Imaging Regional Metabolic Changes in the Ischemic Rat Heart In Vivo Using Hyperpolarized [1- 13 C]Pyruvate Mette Hauge Lauritzen 1,2 , Peter Magnusson 1 , Christoffer Laustsen 1,3 , Sadia Asghar Butt 1 , Jan Henrik Ardenkjær-Larsen 1,5,6 , Lise Vejby Søgaard 1, *, Olaf B. Paulson 1,2,4 , and Per Åkeson 1 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark; 2 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 3 Department of Clinical Medicine, MR Research Centre, Aarhus University Hospital, Aarhus, Denmark; 4 Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 5 Department of Electrical Engineering, Technical University of Denmark, Kongens Lyngby, Denmark; and 6 GE Healthcare, Brøndby, Denmark * Deceased 2014. Corresponding Author: Olaf B. Paulson, MD Neurobiology Research Unit, N 6931, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; E-mail: olaf.paulson@nru.dk Key Words: magnetic resonance imaging, cardiac metabolism, ischemic heart disease, myocardial infarction, hyperpolarized 13 C pyruvate, rat model Abbreviations: Magnetic resonance imaging (MRI), gadolinium (Gd), electrocardiogram (ECG), left anterior descending (LAD), magnetic resonance (MR), repetition time (TR), echo time (TE) We evaluated the use of hyperpolarized 13 C magnetic resonance imaging (MRI) in an open-chest rat model of myocardial infarction to image regional changes in myocardial metabolism. In total, 10 rats were exam- ined before and after 30 minutes of occlusion of the left anterior descending coronary artery using hyperpo- larized [1- 13 C]pyruvate. Cardiac metabolic images of [1- 13 C]pyruvate and its metabolites [1- 13 C]lactate, [1- 13 C]alanine, and [ 13 C]bicarbonate were obtained before and after ischemia. Significant reduction in the [1- 13 C]alanine and [1- 13 C]lactate signals were observed in the ischemic region post ischemia. The severity of the ischemic insult was verified by increased blood levels of troponin I and by using late contrast-en- hanced MRI that showed enhanced signal in the ischemic region. This study shows that hyperpolarized MRI can be used to image regional metabolic changes in the in vivo rat heart in an open-chest model of isch- emia reperfusion. Hyperpolarized MRI enables new possibilities for evaluating changes in cardiac metabo- lism noninvasively and in real time, which potentially could be used for research to evaluate new treatments and metabolic interventions for myocardial ischemia and to apply knowledge to future application of the technique in humans. INTRODUCTION Changes in myocardial metabolism are known to be one of the earliest markers of ischemic heart disease (1). Rodent animal models offer unique opportunities to study these changes. How- ever, imaging the rat heart in vivo offers several challenges. In comparison to humans or pigs, the rat heart is much smaller (;20 mm in length) with a relatively thinner myocardium, and furthermore, it beats 5– 6 times faster (up to 450 bpm). Despite this, some of the most used and best characterized models of cardiac diseases are developed in rats. Hyperpolarized [1- 13 C]pyruvate magnetic resonance imag- ing (MRI), an emerging imaging technique, can assess and vi- sualize regional metabolic changes in intact beating heart in real time (2-7). The advantage of hyperpolarization is that the mag- netic resonance spectroscopy signal from 13 C-labeled metabo- lites can be increased .10,000-fold (8), making it possible to detect low concentrations of the metabolites in vivo and to create metabolic images of the signal. Moreover, hyperpolarized MRI enables monitoring of several steps in metabolic pathways, adding information of fluxes through specific enzymes in the cardiac myocytes cytosol and mitochondria. It can further easily be used in combination with conventional proton MRI to assess cardiac anatomy, function, perfusion, and viability with gado- linium (Gd)-based contrast agents. In this study, hyperpolarized [1- 13 C]pyruvate was used. Py- ruvate is the end product of glycolysis and a key substrate for energy production through tricarboxylic acid cycle. After intra- venous injection, hyperpolarized [1- 13 C]pyruvate is taken up by the myocytes and converted into [1- 13 C]lactate via the enzyme lactate dehydrogenase and [1- 13 C]alanine via alanine amino- transferase, both enzymes located in the cytosol. Furthermore, [1- 13 C]pyruvate is converted into acetyl coenzyme A via the pyruvate dehydrogenase enzyme complex in the mitochondrial membrane, and in the process, the 13 C-atom in the C-1 position of the pyruvate molecule is transferred to (13) CO 2 in equilib- rium with the large bicarbonate pool via the enzyme carbonic RESEARCH ARTICLE ABSTRACT © 2017 The Authors. Published by Grapho Publications, LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ISSN 2379-1381 http://dx.doi.org/10.18383/j.tom.2017.00008 TOMOGRAPHY.ORG | VOLUME 3 NUMBER 3 | SEPTEMBER 2017 123

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