Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating
- Leiden University Medical Center, Netherlands
- School of Informatics, The University of Edinburgh, United Kingdom
- Amsterdam UMC, Netherlands
- 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
Rupamanjari Majumder
Daniel A Pijnappels
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
- 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
- Received: February 29, 2020
- Accepted: June 2, 2020
- Accepted Manuscript published: June 8, 2020 (version 1)
- 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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Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating
eLife 9:e55921.
https://doi.org/10.7554/eLife.55921
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