Hyperpolarized [1,4-13C2]Fumarate Enables Magnetic Resonance-Based Imaging of Myocardial Necrosis

Jack J. Miller; Angus Z. Lau; Per Mose Nielsen; Giles McMullen-Klein; Andrew J. Lewis; Nichlas Riise Jespersen; Vicky Ball; Ferdia A. Gallagher; Carolyn A. Carr; Christoffer Laustsen; Hans Erik Bøtker; Damian J. Tyler; Marie A. Schroeder

doi:10.1016/j.jcmg.2017.09.020

JACC: Cardiovascular Imaging

Volume 11, Issue 11, November 2018 DOI: 10.1016/j.jcmg.2017.09.020

Hyperpolarized [1,4-¹³C₂]Fumarate Enables Magnetic Resonance-Based Imaging of Myocardial Necrosis

Jack J. Miller, Angus Z. Lau, Per Mose Nielsen, Giles McMullen-Klein, Andrew J. Lewis, Nichlas Riise Jespersen, Vicky Ball, Ferdia A. Gallagher, Carolyn A. Carr, Christoffer Laustsen, Hans Erik Bøtker, Damian J. Tyler and Marie A. Schroeder

Author + information

vol. 11 no. 11 1594-1606

DOI:

https://doi.org/10.1016/j.jcmg.2017.09.020

Published By:

JACC: Cardiovascular Imaging

Print ISSN:

1936-878X

Online ISSN:

1876-7591

History:

Received January 15, 2017
Revision received September 19, 2017
Accepted September 21, 2017
Published online November 5, 2018.

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2018 The Authors

Author Information

Jack J. Miller, DPhil^a,^b,^c,^∗,
Angus Z. Lau, PhD^a,^c,^d,^∗,
Per Mose Nielsen, MSc^e,
Giles McMullen-Klein, BSc^a,
Andrew J. Lewis, MD, DPhil^c,
Nichlas Riise Jespersen, MD^e,
Vicky Ball, BSc^a,
Ferdia A. Gallagher, PhD^f,
Carolyn A. Carr, DPhil^a,
Christoffer Laustsen, PhD^e,
Hans Erik Bøtker, MD, PhD^e,
Damian J. Tyler, PhD^a,^c,^† and
Marie A. Schroeder, DPhil^e,^†^∗ (marie.a.schroeder{at}me.com)

^aDepartment of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
^bDepartment of Physics, University of Oxford, Oxford, United Kingdom
^cUniversity of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
^dPhysical Sciences, Sunnybrook Research Institute, Toronto, Canada
^eDepartment of Clinical Medicine, Aarhus University Hospital Skejby, Aarhus, Denmark
^fDepartment of Radiology, University of Cambridge, Cambridge, United Kingdom

↵∗Address for correspondence:
Dr. Marie A. Schroeder, Department of Clinical Medicine, The Faculty of Health Sciences, Aarhus University, Aarhus University Hospital, Skejby, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.

Graphical abstract

Abstract

Objectives The aim of this study was to determine if hyperpolarized [1,4–¹³C₂]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI).

Background MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4–¹³C₂]fumarate to [1,4–¹³C₂]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4–¹³C₂]malate imaging could measure necrosis after MI.

Methods Isolated perfused hearts were given hyperpolarized [1,4–¹³C₂]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4–¹³C₂]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI.

Results In isolated hearts, [1,4–¹³C₂]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4–¹³C₂]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R² = 0.904). In vivo, the quantity of [1,4–¹³C₂]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post-infarct. [1,4–¹³C₂]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4–¹³C₂]malate was not visible in control hearts.

Conclusions Malate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients.

Key Words

Footnotes

↵∗ Drs. Miller and Lau contributed equally to this work and are joint first authors.
↵† Drs. Tyler and Schroeder contributed equally to this work and are joint senior authors.
The authors acknowledge financial support from the British Heart Foundation (Fellowships FS/10/002/28078 & FS/14/17/30634, Programme Grant RG/11/9/28921), the OXFORD-BHF Centre for Research Excellence (grant RE/13/1/30181), and the Innovation Fund Denmark (grant 1308-00028B). They also acknowledge financial support from the National Institute for Health Research Oxford Biomedical Research Centre program, the EPSRC Doctoral Training Centre Grant & Doctoral Prize Fellowships (refs. EP/J013250/1 and EP/M508111/1), and Cancer Research UK.
Dr. Gallagher has received research funding from GE Healthcare and GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.