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Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes

View ORCID ProfileKenta Nakamura, Lauren E. Neidig, View ORCID ProfileXiulan Yang, Gerhard J. Weber, View ORCID ProfileDanny El-Nachef, Hiroshi Tsuchida, Sarah Dupras, Faith A. Kalucki, Anu Jayabalu, Akiko Futakuchi-Tsuchida, Daisy S. Nakamura, View ORCID ProfileSilvia Marchianò, View ORCID ProfileAlessandro Bertero, Melissa R. Robinson, Kevin Cain, Dale Whittington, View ORCID ProfileHans Reinecke, View ORCID ProfileLil Pabon, View ORCID ProfileBjörn C. Knollmann, Steven Kattman, R. Scott Thies, W. Robb MacLellan, View ORCID ProfileCharles E. Murry
doi: https://doi.org/10.1101/2021.02.15.431108
Kenta Nakamura
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
3Division of Cardiology, Department of Medicine, University of Washington, Seattle
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  • ORCID record for Kenta Nakamura
Lauren E. Neidig
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
4Department of Comparative Medicine, University of Washington, Seattle
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Xiulan Yang
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
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Gerhard J. Weber
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
3Division of Cardiology, Department of Medicine, University of Washington, Seattle
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Danny El-Nachef
6Sana Biotechnology, Seattle, Washington
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Hiroshi Tsuchida
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Sarah Dupras
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Faith A. Kalucki
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Anu Jayabalu
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Akiko Futakuchi-Tsuchida
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Daisy S. Nakamura
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
3Division of Cardiology, Department of Medicine, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Silvia Marchianò
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
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Alessandro Bertero
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
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Melissa R. Robinson
3Division of Cardiology, Department of Medicine, University of Washington, Seattle
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Kevin Cain
7Department of Biostatics, University of Washington, Seattle
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Dale Whittington
8Department of Medicinal Chemistry, University of Washington, Seattle
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Hans Reinecke
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
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Lil Pabon
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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Björn C. Knollmann
9Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
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Steven Kattman
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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R. Scott Thies
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
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W. Robb MacLellan
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
3Division of Cardiology, Department of Medicine, University of Washington, Seattle
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Charles E. Murry
1Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle
2Center for Cardiovascular Biology, University of Washington, Seattle
3Division of Cardiology, Department of Medicine, University of Washington, Seattle
5Department of Laboratory Medicine & Pathology, University of Washington, Seattle
6Sana Biotechnology, Seattle, Washington
10Department of Bioengineering, University of Washington, Seattle
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  • For correspondence: murry@uw.edu
  • Abstract
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Abstract

Background Engraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation.

Objectives We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden.

Methods hPSC-CM were transplanted into the infarcted porcine heart by surgical or percutaneous delivery to induce EA. Following a screen of antiarrhythmic agents, a prospective study was conducted to determine the effectiveness of amiodarone plus ivabradine in preventing cardiac death and suppressing EA.

Results EA was observed in all subjects, and amiodarone-ivabradine treatment was well-tolerated. None of the treated subjects experienced the primary endpoint of cardiac death, unstable EA or heart failure compared to 5/8 (62.5%) in the control cohort (hazard ratio 0.00; 95% confidence interval, 0–0.297; p = 0.002). Overall survival including two deaths in the treated cohort from immunosuppression-related infection showed borderline improvement with treatment (hazard ratio 0.21; 95% confidence interval, 0.03–1.01; p = 0.05). Without treatment, peak heart rate averaged 305 ± 29 beats per min (bpm), whereas in treated subjects peak daily heart rate was significantly restricted to 185±9 bpm (p = 0.006). Similarly, treatment reduced peak daily EA burden from 96.8 ± 2.9% to 76.5 ± 7.9% (p = 0.003). Antiarrhythmic treatment was safely discontinued after approximately one-month of treatment without recrudescence of arrhythmia.

Conclusions The risk of engraftment arrhythmia following hPSC-CM transplantation can be reduced significantly by combined amiodarone and ivabradine drug therapy.

Condensed Abstract Engraftment arrhythmia (EA) is a transient but serious complication of cardiac remuscularization therapy. Using a porcine model of cardiac remuscularization and EA, ivabradine and amiodarone were independently effective in suppressing tachycardia and arrhythmia, respectively. Baseline amiodarone combined with adjunctive ivabradine successfully prevented cardiac death, unstable EA and heart failure (hazard ratio 0.00; 95% confidence interval, 0–0.297; p = 0.002) and significantly suppressed peak daily heart rate and arrhythmia burden (p=0.006 and 0.003, respectively). Antiarrhythmic treatment was successfully discontinued after one-month without recrudescence of arrhythmia. We conclude that EA can be suppressed by combined amiodarone and ivabradine drug therapy.

Competing Interest Statement

KN, MRR, BCK and WRM are advisors to Sana Biotechnology. DE, HT, SD, FAK, AJ, AF, DSN, SK, RST and CEM are employees of Sana Biotechnology. CEM is a scientific founder and equity holder of Sana Biotechnology.

Footnotes

  • Disclosures: KN, MRR, BCK and WRM are advisors to Sana Biotechnology. DE, HT, SD, FAK, AJ, AF, DSN, SK, RST and CEM are employees of Sana Biotechnology. CEM is a scientific founder and equity holder of Sana Biotechnology.

  • Abbreviations

    CI
    Confidence interval
    EA
    Engraftment arrhythmia
    ECG
    Electrocardiogram
    hESC-CM
    Human embryonic stem cell-derived cardiomyocyte
    hPSC-CM
    Human pluripotent stem cell-derived cardiomyocyte
    MI
    Myocardial infarction
    NHP
    Non-human primate
    PF
    Purkinje fiber
    VF
    Ventricular fibrillation
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes
    Kenta Nakamura, Lauren E. Neidig, Xiulan Yang, Gerhard J. Weber, Danny El-Nachef, Hiroshi Tsuchida, Sarah Dupras, Faith A. Kalucki, Anu Jayabalu, Akiko Futakuchi-Tsuchida, Daisy S. Nakamura, Silvia Marchianò, Alessandro Bertero, Melissa R. Robinson, Kevin Cain, Dale Whittington, Hans Reinecke, Lil Pabon, Björn C. Knollmann, Steven Kattman, R. Scott Thies, W. Robb MacLellan, Charles E. Murry
    bioRxiv 2021.02.15.431108; doi: https://doi.org/10.1101/2021.02.15.431108
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    Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes
    Kenta Nakamura, Lauren E. Neidig, Xiulan Yang, Gerhard J. Weber, Danny El-Nachef, Hiroshi Tsuchida, Sarah Dupras, Faith A. Kalucki, Anu Jayabalu, Akiko Futakuchi-Tsuchida, Daisy S. Nakamura, Silvia Marchianò, Alessandro Bertero, Melissa R. Robinson, Kevin Cain, Dale Whittington, Hans Reinecke, Lil Pabon, Björn C. Knollmann, Steven Kattman, R. Scott Thies, W. Robb MacLellan, Charles E. Murry
    bioRxiv 2021.02.15.431108; doi: https://doi.org/10.1101/2021.02.15.431108

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