Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

Kerstin N. Timm; Charith Perera; Vicky Ball; John A. Henry; Jack J. Miller; Matthew Kerr; James A. West; Eshita Sharma; John Broxholme; Angela Logan; Dragana Savic; Michael S. Dodd; Julian L. Griffin; Michael Murphy; Lisa C Heather; Damian J Tyler

doi:10.1038/s42003-020-01440-z

Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

Kerstin N. Timm, Charith Perera, Vicky Ball, John A. Henry, Jack J. Miller, Matthew Kerr, James A. West, Eshita Sharma, John Broxholme, Angela Logan, Dragana Savic, Michael S. Dodd, Julian L. Griffin, Michael Murphy, Lisa C Heather, Damian J Tyler

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Abstract

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity.

Original language	English
Article number	692
Number of pages	10
Journal	Communications Biology
Volume	3
DOIs	https://doi.org/10.1038/s42003-020-01440-z
Publication status	Published - 19 Nov 2020
Externally published	Yes

Bibliographical note

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Funding

This work was supported by a British Heart Foundation Immediate Postdoctoral Basic Science Research Fellowship to K.N.T. (FS/16/7/31843) and a British Heart Foundation Senior Fellowship to D.J.T. (FS/14/17/30634). K.N.T. would also like to acknowledge the Oxford BHF Centre of Research Excellence (grant code RE/18/3/34214). J.J.M. would like to acknowledge the support of a Novo Nordisk Postdoctoral Fellowship run in partnership with the University of Oxford.

Funders	Funder number
British Heart Foundation	FS/14/17/30634, FS/16/7/31843, RE/18/3/34214
Novo Nordisk UK Research Foundation	Postdoctoral Fellowship

Keywords

Heart failure
Metabolomics
Preclinical research
Predictive markers
Translational research

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Medicine
General Biochemistry,Genetics and Molecular Biology
Medicine (miscellaneous)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s42003-020-01440-zLicence: CC BY

PublishedFinal published version, 2.48 MBLicence: CC BY

Cite this

Timm, K. N., Perera, C., Ball, V., Henry, J. A., Miller, J. J., Kerr, M., West, J. A., Sharma, E., Broxholme, J., Logan, A., Savic, D., Dodd, M. S., Griffin, J. L., Murphy, M., Heather, L. C., & Tyler, D. J. (2020). Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI. Communications Biology, 3, Article 692 . https://doi.org/10.1038/s42003-020-01440-z

Timm, KN, Perera, C, Ball, V, Henry, JA, Miller, JJ, Kerr, M, West, JA, Sharma, E, Broxholme, J, Logan, A, Savic, D, Dodd, MS, Griffin, JL, Murphy, M, Heather, LC & Tyler, DJ 2020, 'Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI', Communications Biology, vol. 3, 692 . https://doi.org/10.1038/s42003-020-01440-z

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abstract = "Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity.",

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AU - Miller, Jack J.

AU - Kerr, Matthew

AU - West, James A.

AU - Sharma, Eshita

AU - Broxholme, John

AU - Logan, Angela

AU - Savic, Dragana

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AU - Griffin, Julian L.

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Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Mike Dodd

Cite this

Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Profiles

Mike Dodd

Cite this