Periodic Reporting for period 4 - Bio-ICD (Biological auto-detection and termination of heart rhythm disturbances)
Periodo di rendicontazione: 2021-09-01 al 2023-02-28
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