TY - JOUR
AU1 - Pijnappels, Daniël A
AB - Replacing metal, algorithms and shocks by ion channels as a Biologically Integrated Cardiac Defibrillator (BioICD) is discussed by Daniël A. Pijnappels, PhD Cardiac arrhythmias and electrical defibrillation Contractions of the heart are triggered by electrical waves that are generated and propagated by well-coupled cardiomyocytes expressing various ion channels. Disturbances in these electrophysiological processes can lead to cardiac arrhythmias, ranging from an atrial flutter to ventricular fibrillation (VF). While long-lasting global efforts have resulted in a significant improvement in the treatment of arrhythmias, these disorders remain a large and growing problem worldwide, with high annual mortality and morbidity rates, and enormous health-care costs. This is partly due to suboptimal efficacy, specificity, tolerability, safety, and/or cost effectiveness of the current treatment options.1 However, for acute termination of arrhythmias, one approach has proven to be very effective: the delivery of electric shocks to arrhythmic cardiac tissue.2,3 Its effectiveness is emphasized by the wide-spread use of software-driven electronic devices to control cardiac rhythm by applying these traumatizing electric shocks to cardiac tissue in an attempt to terminate atrial or ventricular arrhythmias (electrical cardioversion/defibrillation). Once such a device is implanted, as with the implantable cardioverter-defibrillator (ICD) for ventricular arrhythmias,4 continuous monitoring of the heart rhythm is ensured, thereby enabling rapid detection of arrhythmias for automatic delivery of an electric shock to restore sinus rhythm (SR). Due to their non-biological nature, these devices have a number of inherent shortcomings not least, limited battery life, and technical malfunction, but most importantly for the patient, the severe pain, anxiety, and depression resulting from the electroshocks, especially when delivered inappropriately.5 Studies have indicated that around 20% of patients with an ICD suffer from a post-traumatic stress disorder and up to 40% show anxiety and depressive symptoms. In addition, these devices are expensive, while health-care costs are already huge and still rising. Nevertheless, as there are no reasonable alternatives that are equally effective, electroshock therapy for cardiac arrhythmias is still undeniably important, thereby further underlining the major remaining challenges in current cardiac arrhythmia management. An intriguing common feature between ICDs and ion channels The ICD device is the product of electronic engineering and contains metal, software, and wires to establish a system in which both a detector (i.e. sensor of electrical activity) and effector (i.e. electroshock generator) are incorporated. Nature also makes use of such detector–effector systems where they control different physiological processes. Such systems are the product of cells, genes, and proteins and involve a regulated variable, set point, and signalling between detector and effector. Given their highly conservative nature, these biological systems are considered to be effective means to rapidly respond to sudden changes that, if sustained, may cause harm. Blood flow and immune regulation are examples of such systems. In contrast, the heart appears to be devoid of a robust biological detector–effector system for counteracting sustained hazardous arrhythmias. Those that are not sustained typically terminate spontaneously.6 The heart does however, have many different ion channels, which generate various electrical currents by opening and closing. This so-called gating is mainly voltage-dependent, meaning that certain ion channels in the cardiomyocyte membrane only open and close upon sensing a certain voltage.7 An ion channel can therefore be considered as a functional detector–effector unit. This notion creates a rationale to engineer an ion channel protein and integrate it into the plasma membranes of cardiomyocytes to serve the same function as an ICD device, namely rapid detection and termination of arrhythmias. To this end, the properties of ion channels (i.e. their gating mechanisms) should be modified in such a way that the channels only open in response to arrhythmia initiation, by detection of acute changes in electrophysiology. Next, these channels should stay open long enough to generate an electrical current shock, rendering the tissue temporarily unexcitable or refractory, thereby terminating the arrhythmia and resetting the tissue to its resting state, as an ICD shock. This shock, however, would be generated by electromotive forces in our own heart cells and would therefore be unnoticed by the patient. Given its biological nature, such a new type of defibrillation would be completely free of any hardware and software. In addition, because the cardiac tissue itself produces the electrical current for arrhythmia termination, no tissue damage will occur as with high-voltage shocks from electrodes, which can only last for a few milliseconds because of their harmful nature. Taken together, upon forced expression of these ion channels, the heart itself would become able to detect and terminate an arrhythmia and thereby serve as a biologically integrated cardiac defibrillator (BioICD). Recently, we have explored and provided the first proof-of-concept for such self-restoration of cardiac rhythm by anti-arrhythmic ion channel gating. The heart as an implantable cardioverter-defibrillator: self-restoration of cardiac rhythm by anti-arrhythmic ion channel gating In a recent publication in eLife, our group showed that integration of ion channels with newly designed gating properties (i.e. BioICD channels) into cardiomyocytes did indeed allow the tissue to detect an arrhythmia and to generate an ionic current for its termination, all based on ion channel gating. In order to obtain these studies, we first had to design the BioICD channels, the full description of which can be found in our article.8 Essentially, this concerns an ion channel that is able to sense the frequency of electrical activity through gating mechanisms that are controlled by the cell’s membrane potential. Such gating results in temporal summation of activation at high frequencies, leading to a higher number of ion channel subunits in their open state (see Figure 1A). Once these BioICD channels were expressed in a 2D in silico model of a human cardiomyocyte monolayer, re-entrant tachyarrhythmias were no longer sustained, but terminated within seconds upon their initiation, by subsequent activation of the BioICD channels. These results were confirmed for polymorphic ventricular tachyarrhythmias and fibrillation induced in similar models, as well as for those arising from a fibrotic substrate. Figure 1. Open in new tabDownload slide (A) Summarizing figure showing a cultured human atrial cardiomyocyte subjected to dynamic clamp to study and confirm the anti-arrhythmic effects of the biologically integrated cardiac defibrillator (BioICD) current. Optical stimulation of these cells (eYFP positive because of optogenetic modification14) allowed a controlled increase in activation frequency to mimic fibrillation (dots indicate pacing frequency). Lower right panel shows accumulation of current that is injected in the cell, resulting in prolonged depolarization and restoration of rhythm via programmed feedback. (B). BioICD channel expression in the virtual human heart enabled self-restoration of sinus rhythm within seconds upon induction of atrial or ventricular fibrillation, while in control hearts fibrillation persisted. This figure is the product of and redistributed under, the Creative Commons Attribution 4.0 International Public License. Figure 1. Open in new tabDownload slide (A) Summarizing figure showing a cultured human atrial cardiomyocyte subjected to dynamic clamp to study and confirm the anti-arrhythmic effects of the biologically integrated cardiac defibrillator (BioICD) current. Optical stimulation of these cells (eYFP positive because of optogenetic modification14) allowed a controlled increase in activation frequency to mimic fibrillation (dots indicate pacing frequency). Lower right panel shows accumulation of current that is injected in the cell, resulting in prolonged depolarization and restoration of rhythm via programmed feedback. (B). BioICD channel expression in the virtual human heart enabled self-restoration of sinus rhythm within seconds upon induction of atrial or ventricular fibrillation, while in control hearts fibrillation persisted. This figure is the product of and redistributed under, the Creative Commons Attribution 4.0 International Public License. In all cases, initiation of the arrhythmia caused a sudden increase in activation frequency, which caused the BioICD channels to open and generate an electrical current causing depolarization throughout the tissue, leading to the termination of arrhythmic electrical activity and thereby allowing SR to be restored. Encouraged by the results, we next explored the expression of BioICD in the virtual human heart. Here, it was shown that for both atrial and ventricular arrhythmias, including fibrillation, activation of these BioICD channels resulted in swift arrhythmia termination to allow rapid and stable restoration of SR (Figure 1B). No drugs, catheter, or electrode were needed for termination. Instead, the incorporation of just one new type of ion channel allowed the heart itself to detect and terminate a broad range of arrhythmias and all within seconds upon their initiation. In a final set of experiments, we aimed to study the effects of BioICD channel gating in living cardiomyocytes. For this purpose, a particular electrophysiological technique was applied, called dynamic clamp. This technique allows the injection of the BioICD current in living cardiomyocytes in relation to the real-time measured membrane potential of the cells, in this case, human atrial cardiomyocytes.9 Upon increasing the activation frequency of these cardiomyocytes to fibrillation levels (e.g. 8 Hz), the resulting BioICD current did indeed build up to cause prolonged membrane depolarization, thereby interrupting the abnormally high activation frequency, as observed in the human heart models (Figure 1A). Importantly, as with the other studies, no significant deviations in membrane potential were found at SR level (e.g. 1 Hz), nor at physiological increases in activation frequency (e.g. 2 Hz). Perspective Further exploration of this concept of self-restoration of cardiac rhythm by anti-arrhythmic ion channel gating requires additional in-depth modelling studies to further improve our understanding of BioICD channels, aimed at identifying the most robust and broadly applicable BioICD channel with the highest translational potential. Next, the actual construction of BioICD channels and their expression in cardiac tissue are necessarily next steps. For the construction, essential knowledge about ion channel structure–function relationships is available for guidance.10 Also, the molecular tools required for the targeted manipulation of these relationships are readily present for exploration.11 For the expression of the BioICD channels, we can rely on the vast experience and robust methods from the field of cardiac gene therapy.12 Nevertheless, this exploration will be challenging with various hurdles to overcome, but is worth the effort given the combination of the unique perspective for arrhythmia management and the urgent need for more effective, yet pain-free treatment options for cardiac arrhythmias. This perspective involves continuous, acute, and automatic termination of arrhythmias to restore SR in a shockless and hard/software-free manner. This would not only offer a fully biological and pain/damage-free alternative to current ICD therapy, but also an ambulatory treatment option for atrial fibrillation (AF) patients. Currently, this group of patients is left without such option, since device therapy for AF is not well tolerated because of the electric shocks required for AF termination while the patient is fully conscious.13 Taken together, our study indicates how the creation of new biology (here BioICD channels to establish a biological detector–effector system for cardiac rhythm control) could be used for therapeutic purposes, which may not only offer distinct new benefits for cardiac arrhythmia management, but also for the management of other disturbed cardiovascular processes. Funding The work on self-restoration of cardiac rhythm (biological defibrillation) is supported by personal funding from the European Research Council (starting grant 716509) to D.A.P. Conflict of interest: none declared. References References are available as supplementary material at European Heart Journal online. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
TI - The heart as its own defibrillator
JF - European Heart Journal
DO - 10.1093/eurheartj/ehaa609
DA - 2020-08-07
UR - https://www.deepdyve.com/lp/oxford-university-press/the-heart-as-its-own-defibrillator-jXYdFNUi6b
SP - 2829
EP - 2832
VL - 41
IS - 30
DP - DeepDyve
ER -