Periodic Reporting for period 4 - Bio-ICD (Biological auto-detection and termination of heart rhythm disturbances)
Reporting period: 2021-09-01 to 2023-02-28
Heart rhythm disorders (i.e. cardiac arrhythmias) remain a large and growing cause of mortality and morbidity, including stroke and heart failure. One example of the commonality of arrhythmia, is atrial fibrillation, which is expected to affect more than 20% of the population above 65. However, treatment of arrhythmias is generally still suboptimal, while our knowledge of the underlying mechanisms remains incomplete. Hence, these heart rhythm disturbances represent one of the biggest challenges in modern medicine as it current socioeconomic impact is enormous without the perspective of any breakthrough improvement. Current methods to study and treat arrhythmia are based on chemistry (i.e. drug therapy) and electronics (i.e. ablation and device therapy), which come with inherent limitations such as poor specificity, irreversible changes, hospital-restricted use, and severe pain. All these limitation could be overcome by allowing the heart itself to detect and termination arrhythmia to restore normal rhythm. That is why this projects will break loose from current paradigms and methods, by investigating whether and how the heart itself can be enabled to detect and terminate heart rhythm disorders, which is here referred to as biological auto-detection and termination. In order to explore this novel concept of fully biological defibrillation, my team will investigate how forced expression of engineered proteins could i) allow cardiac tissue to become a detector of arrhythmias through rapid sensing of acute changes in electrophysiology upon their initiation. And how after detection, ii) this cardiac tissue (now as effector), could terminate the arrhythmia by generating a painless electroshock through activation of these proteins. To this purpose, we will (1) first explore the requirements for such detection & termination by studying arrhythmia initiation and termination in rat models of atrial & ventricular arrhythmias using optical probes and light-gated ion channels. These insights will (2) guide computer-based screening of virtual proteins to identify those properties allowing effective arrhythmia detection & termination. These data will be used for (3) rational engineering of proteins with the desired properties, followed by their (4) forced expression in cardiac cells, slices and whole hearts to assess anti-arrhythmic potential & safety.
My ERC StG project included 4 major objectives, which are listed below with corresponding research and technological achievements.
1. To study the changes in electrophysiology upon arrhythmia initiation in rat (i) atrial and (ii) ventricular cell, slice and whole heart models using optical probes, followed by termination of these arrhythmias using light-gated ion channels and LED illumination. Different types of light-gated ion channels were expressed to investigate the effects of their activation by light to study the termination of arrhythmias. These studies provided important quantitative insight into the requirement of biological detection and termination of arrhythmias.
2. To design and test different virtual ion channels in corresponding computer models of atrial and ventricular arrhythmias. Different models of a Bio-ICD channels were created and implemented in these models. These efforts resulted in the identification of effective Bio-ICD channels in terms of arrhythmia detection and termination, of which the functional effects on arrhythmias were tested in vitro by means of dynamic patch clamp.
3. To engineer protein-based ion channels with the desired properties. The most promising Bio-ICD channel designs were selected for protein engineering experiments. By trail-and-error these properties were modified and refined to realize the Bio-ICD gating as predicted by computer modeling. The expression of these modified channels in monolayers of neonatal rat cardiomyocytes appeared to result in early termination of the arrhythmias as compared to controls.
4. To study the anti-arrhythmic potential, and underlying mechanisms, of selected promising Bio-ICD ion channels in isolated hearts after forced cardiac expression in adult rats subjected to pro-arrhythmic interventions. For these studies, channels were expressed in the adult rat heart using adeno-associated viral vectors. During follow-up, induction and perpetuation of cardiac arrhythmias was investigated suggesting that is was more difficult to induce sustained arrhythmias as compared to controls.
References:
eLife, 2018. 10.7554/eLife.41076
Eur Heart J, 2018. 10.1093/eurheartj/ehy689
Sci Trans Med, 2019. 10.1126/scitranslmed.aau6447
Eur Heart J, 2020. 10.1093/eurheartj/ehaa609
eLife, 2020. 10.7554/elife.55921
Cardiovasc Res, 2022. 10.1093/cvr/cvab294
1. To study the changes in electrophysiology upon arrhythmia initiation in rat (i) atrial and (ii) ventricular cell, slice and whole heart models using optical probes, followed by termination of these arrhythmias using light-gated ion channels and LED illumination. Different types of light-gated ion channels were expressed to investigate the effects of their activation by light to study the termination of arrhythmias. These studies provided important quantitative insight into the requirement of biological detection and termination of arrhythmias.
2. To design and test different virtual ion channels in corresponding computer models of atrial and ventricular arrhythmias. Different models of a Bio-ICD channels were created and implemented in these models. These efforts resulted in the identification of effective Bio-ICD channels in terms of arrhythmia detection and termination, of which the functional effects on arrhythmias were tested in vitro by means of dynamic patch clamp.
3. To engineer protein-based ion channels with the desired properties. The most promising Bio-ICD channel designs were selected for protein engineering experiments. By trail-and-error these properties were modified and refined to realize the Bio-ICD gating as predicted by computer modeling. The expression of these modified channels in monolayers of neonatal rat cardiomyocytes appeared to result in early termination of the arrhythmias as compared to controls.
4. To study the anti-arrhythmic potential, and underlying mechanisms, of selected promising Bio-ICD ion channels in isolated hearts after forced cardiac expression in adult rats subjected to pro-arrhythmic interventions. For these studies, channels were expressed in the adult rat heart using adeno-associated viral vectors. During follow-up, induction and perpetuation of cardiac arrhythmias was investigated suggesting that is was more difficult to induce sustained arrhythmias as compared to controls.
References:
eLife, 2018. 10.7554/eLife.41076
Eur Heart J, 2018. 10.1093/eurheartj/ehy689
Sci Trans Med, 2019. 10.1126/scitranslmed.aau6447
Eur Heart J, 2020. 10.1093/eurheartj/ehaa609
eLife, 2020. 10.7554/elife.55921
Cardiovasc Res, 2022. 10.1093/cvr/cvab294
Chemistry and electronics are currently the two mainstays of cardiac arrhythmia treatment. The outcome of this project indicated that biology may provide unique and much desired means to study and treat these disorders in a different manner, thereby creating the possibility of acute, yet shockfree termination of cardiac arrhythmias. Concrete examples include the progress as displayed in one of the publications where it was showed that a particular type of arrhythmia, those maintained by so-called spiral waves, can be fully controlled by local activation of light-gated ion channels, allowing its termination on a biological, trauma-free basis. Another example of progress beyond the current state of art is the introduction of the concept of fully biological defibrillation by means of so-called Bio-ICD channels allowing the heart itself to detect and terminate arrhythmias. Collectively, these new insights could lay the basis for the development of radically new approaches for arrhythmia management in which a diseased organ begets its own remedy through genetic engineering allowing effective and trauma-free treatment from within.