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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-11-19

AUTHORS

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 P. Murphy, Lisa C. Heather, Damian J. Tyler

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. More... »

PAGES

692

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s42003-020-01440-z

DOI

http://dx.doi.org/10.1038/s42003-020-01440-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1132740319

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33214680


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22 schema:description 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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29 schema:keywords additional mitochondrial dysfunction
30 agents
31 biomarkers
32 cancer patients
33 carbohydrate metabolism
34 cardiac functional decline
35 cardiotoxic side effects
36 cardiotoxicity
37 changes
38 chemotherapeutic agents
39 clinical imaging techniques
40 clinical trials
41 congestive heart failure
42 decline
43 detection
44 doxorubicin
45 dysfunction
46 early detection
47 early signs
48 effect
49 factors
50 failure
51 flux
52 functional decline
53 heart failure
54 hitherto
55 imaging
56 imaging techniques
57 key factors
58 loss
59 magnetic resonance imaging
60 metabolic flux
61 metabolic signatures
62 metabolism
63 mitochondrial carbohydrate metabolism
64 mitochondrial dysfunction
65 mitochondrial loss
66 patients
67 potential
68 rats
69 resonance imaging
70 serious cardiotoxic side effects
71 side effects
72 signatures
73 signs
74 stress
75 technique
76 trials
77 vivo
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