Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating

  1. Rupamanjari Majumder
  2. Tim De Coster
  3. Nina Kudryashova
  4. Arie O Verkerk
  5. Ivan V Kazbanov
  6. Balázs Ördög
  7. Niels Harlaar
  8. Ronald Wilders
  9. Antoine A F de Vries
  10. Dirk L Ypey
  11. Alexander V Panfilov
  12. Daniel A Pijnappels  Is a corresponding author
  1. Leiden University Medical Center, Netherlands
  2. School of Informatics, The University of Edinburgh, United Kingdom
  3. Amsterdam UMC, Netherlands
  4. Ghent University, Belgium

Abstract

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 5.

Article and author information

Author details

  1. Rupamanjari Majumder

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3851-9225
  2. Tim De Coster

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4942-9866
  3. Nina Kudryashova

    Institute for Adaptive and Neural Computation, School of Informatics, The University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Arie O Verkerk

    Department of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2140-834X
  5. Ivan V Kazbanov

    Deaprtment of Physics and Astronomy, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Balázs Ördög

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Niels Harlaar

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Ronald Wilders

    Department of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1340-0869
  9. Antoine A F de Vries

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Dirk L Ypey

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Alexander V Panfilov

    Department of Physics and Astronomy, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  12. Daniel A Pijnappels

    Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    For correspondence
    D.A.Pijnappels@lumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6731-4125

Funding

European Research Council (ERC starting grant 716509)

  • Daniel A Pijnappels

Netherlands Organisation for Scientific Research (NWO Vidi grant 91714336)

  • Daniel A Pijnappels

Ammodo grant

  • Daniel A Pijnappels

Netherlands Organisation for Health Research and Development (project 114022503)

  • Antoine A F de Vries

Leiden Regenerative Medicine Platform Holding (LRMPH project 8212/41235)

  • Antoine A F de Vries

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Ethics

Human subjects: Conditional immortalization of human atrial myocytes was done with cells isolated from elective abortion material. Human tissue was obtained after individual permission using standard informed consent procedures. Experiments with these cells were performed in accordance with the national guidelines, approved by the Medical Ethical Committee of the Leiden University Medical Center (protocol P08.087), and conformed to the Declaration of Helsinki.

Version history

  1. Received: February 29, 2020
  2. Accepted: June 2, 2020
  3. Accepted Manuscript published: June 8, 2020 (version 1)
  4. Version of Record published: June 25, 2020 (version 2)

Copyright

© 2020, Majumder et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rupamanjari Majumder
  2. Tim De Coster
  3. Nina Kudryashova
  4. Arie O Verkerk
  5. Ivan V Kazbanov
  6. Balázs Ördög
  7. Niels Harlaar
  8. Ronald Wilders
  9. Antoine A F de Vries
  10. Dirk L Ypey
  11. Alexander V Panfilov
  12. Daniel A Pijnappels
(2020)
Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating
eLife 9:e55921.
https://doi.org/10.7554/eLife.55921

Share this article

https://doi.org/10.7554/eLife.55921

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