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Action of iron chelator on intramyocardial hemorrhage and cardiac remodeling following acute myocardial infarction

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Abstract

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia–reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI.

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Abbreviations

AMI:

Acute myocardial infarction

MVO:

Microvascular obstruction

IMH:

Intramyocardial hemorrhage

STEMI:

ST-segment elevation myocardial infarction

LAD:

Left anterior descending

MRI:

Magnetic resonance imaging

LGE:

Late gadolinium enhancement

SSFP:

Steady-state free precession

IR-GRE:

Inversion recovery gradient echo sequence

LV:

Left ventricle

EF:

Ejection fraction

EDV:

End-diastolic volume

ANOVA:

Analysis of variance

I/R:

Ischemia–reperfusion injury

MT:

Masson’s trichrome

PB:

Prussian blue

SD:

Standard deviation

DFP:

Deferiprone

DFO:

Desferoxamine

PPCI:

Primary percutaneous coronary intervention

EDTA:

Ethylenediaminetetraacetic acid

HF:

Heart failure

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Acknowledgements

We would like to thank ApoPharma Inc. for supplying us with deferiprone (Ferriprox®) for use in this study.

Funding

The study was funded by the Ontario Research Fund—Research Excellence (ORF-RE7-21). We also acknowledge support from the Sunnybrook Research Institute Summer Student Program. The pharmacokinetic analysis of deferiprone was funded by ApoPharma Inc.

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Authors and Affiliations

  1. Department of Physics and Physiology, University of Toronto, Toronto, ON, Canada

    Bita Behrouzi

  2. Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada

    Jill J. Weyers, Xiuling Qi, Jennifer Barry, Graham A. Wright & Nilesh R. Ghugre

  3. Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA

    John C. Wood

  4. Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Bradley H. Strauss, Graham A. Wright & Nilesh R. Ghugre

  5. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Graham A. Wright & Nilesh R. Ghugre

  6. ApoPharma Inc, Toronto, ON, Canada

    Vrajlal Rabadia, Dino Manca, John Connelly & Michael Spino

  7. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada

    Michael Spino

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  1. Bita Behrouzi
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  2. Jill J. Weyers
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  9. John C. Wood
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  12. Nilesh R. Ghugre
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Corresponding author

Correspondence to Nilesh R. Ghugre.

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Conflict of interest

A joint patent application between Sunnybrook Research Institute, Childrens Hospital Los Angeles and ApoPharma Inc. has been filed related to the methods of treatment with deferiprone in ischemia–reperfusion injury. NG, GW, JW, JC and MS have been listed as inventors on the patent application.

Ethics approval

Animal procedures were conducted in accordance with protocols approved by the Animal Care Committee of Sunnybrook Research Institute.

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Behrouzi, B., Weyers, J.J., Qi, X. et al. Action of iron chelator on intramyocardial hemorrhage and cardiac remodeling following acute myocardial infarction. Basic Res Cardiol 115, 24 (2020). https://doi.org/10.1007/s00395-020-0782-6

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  • DOI: https://doi.org/10.1007/s00395-020-0782-6

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