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Intravenous Followed by X-ray Fused with MRI-Guided Transendocardial Mesenchymal Stem Cell Injection Improves Contractility Reserve in a Swine Model of Myocardial Infarction

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Abstract

The aim of this study is to determine the effects of early intravenous (IV) infusion later followed by transendocardial (TE) injection of allogeneic mesenchymal stem cells (MSCs) following myocardial infarction (MI). Twenty-four swine underwent balloon occlusion reperfusion MI and were randomized into 4 groups: IV MSC (or placebo) infusion (post-MI day 2) and TE MSC (or placebo) injection targeting the infarct border with 2D X-ray fluoroscopy fused to 3D magnetic resonance (XFM) co-registration (post-MI day 14). Continuous ECG recording, MRI, and invasive pressure-volume analyses were performed. IV MSC plus TE MSC treated group was superior to other groups for contractility reserve (p = 0.02) and freedom from VT (p = 0.03) but had more lymphocytic foci localized to the peri-infarct region (p = 0.002). No differences were observed in post-MI remodeling parameters. IV followed by XFM targeted TE MSC therapy improves contractility reserve and suppresses VT but does not affect post-MI remodeling and may cause an immune response.

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Abbreviations

MI:

Myocardial infarction

MSC:

Mesenchymal stem cell

XFM:

X-ray fused to MRI

IV:

Intravenous

TE:

Transendocardial

LAD:

Left anterior descending

MRI:

Magnetic resonance imaging

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Acknowledgments

The authors would like to thank Craig Schneider and Medtronic, Minneapolis, MN for providing Reveal XT implanted loop recorders and assisting with device interrogation. Many thanks also to Peter Altman and Biocardia Inc. (San Carlos, CA) for making Helix catheters/Morph catheters available to us for pre-clinical studies.

Funding

This work was supported by the NIH/NHLBI Production Assistant for Cellular Therapies (PACT) contract number HHSN268201000010C. Statistical consultation support was provided by National Institutes of Health grant UL1TR000427 to the University of Wisconsin Institute of Clinical Translational Research from the National Center for Advancing Translational Sciences (NCATS).

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Eric G. Schmuck, Jill M. Koch, Timothy A. Hacker, Nicholas Hendren, Cathlyn Leitzke, John M. Centanni & Amish N. Raval

  2. Division of Cardiovascular Medicine, Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, H4/568 Clinical Sciences Center, 600 Highland Ave, Madison, WI, 53792-3248, USA

    Charles R. Hatt, Michael T. Tomkowiak & Amish N. Raval

  3. Division of Radiology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Karl K. Vigen

  4. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Ying-qi Zhao & Zhanhai Li

  5. Waisman Biomanufacturing Facility, Madison, WI, USA

    Derek J. Hei

  6. Research Animal Resources Center, University of Wisconsin, Madison, WI, USA

    Denise Schwahn

  7. Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Jaehyup Kim & Peiman Hematti

Authors
  1. Eric G. Schmuck
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  2. Jill M. Koch
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  16. Amish N. Raval
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Corresponding author

Correspondence to Amish N. Raval.

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Conflict of Interest

The authors declare that they have no competing interests.

Human Studies/Informed Consent

No human studies were carried out by the authors for this article.

Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

Additional information

Associate Editor Angela Taylor oversaw the review of this article

Clinical Relevance Statement

There is evidence to suggest that single dose administration of bone marrow-derived mesenchymal stem cells for the treatment of myocardial infarction offers short-term benefit. In clinical practice, serial dosing may be required; however, this has not been tested in pre-clinical models. Our data suggest that a biologically plausible and clinically practical delivery approach of intravenous followed by transendocardial catheter delivery of bone marrow-derived mesenchymal stem cells improves contractile reserve and suppresses ventricular arrhythmias.

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Schmuck, E.G., Koch, J.M., Hacker, T.A. et al. Intravenous Followed by X-ray Fused with MRI-Guided Transendocardial Mesenchymal Stem Cell Injection Improves Contractility Reserve in a Swine Model of Myocardial Infarction. J. of Cardiovasc. Trans. Res. 8, 438–448 (2015). https://doi.org/10.1007/s12265-015-9654-0

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