Introduction
Cardiac arrhythmias are the major cause of sudden death. Optogenetic defibrillation is a promising research area with the potential to terminate both atrial and ventricular arrhythmias based on timed activation of genetically introduced light-gated ion channels, so-called channelrhodopsins (ChR). So far, optogenetic defibrillation studies in animal models mainly used cation non-selective CChR, such as channelrhodopsin-2 (ChR2) and the red-shifted ChR ReachR.[1] However, CChR terminate arrhythmia by membrane depolarisation, and intrinsically conduct both Ca2+ and Na+. We thus hypothesise that using CChR for cardiac defibrillation may contribute to intracellular overload of Ca2+ and Na+. In contrast, K+-selective ChR (KChR) may be potent alternatives, as their activation will keep the cells close to their natural resting potential, and may not induce changes in the intracellular concentrations of Ca2+ and Na+. Experiments indicate that WiChR, a predominantly K+-selective ChR isolated from Wobblia lunata, presents a promising target for optical defibrillation.[2] In order to test these hypotheses, we performed numerical simulations.
Methods
We used the O’Hara model of a human ventricular cardiomyocyte (CM)[3] and embedded either ChR2[4] or a KChR. For KChR, we used a simple Ohmic current without nonlinear effects through selectivity and competition. After bringing the model to steady state, we electrically paced CM for 5 s (1 Hz). We then simulated illumination, i.e., activation of either ChR2 (470 nm, 5 mW/mm2) or KChR (conductance change from 0 to 1.4 mS/cm2) for 10 s. As a control scenario, to assess CM behaviour without optogenetic manipulation, we stopped the electrical pacing during the illumination period.
Results and Conclusion
During illumination, ChR2-expressing CM have a depolarised resting potential, compared to control, while KChR-expressing CM show membrane hyperpolarisation (see Figure 1A and B, respectively). As hypothesised, the simulations indicate an increase in intracellular Ca2+ and Na+ during activation of ChR2, while in the case of KChR, they did not predict significant differences in these ion concentrations, compared to control.
Future work will focus on the explicit modelling of WiChR as well as the assessment of arrhythmia risk due to elevated Ca2+ and Na+ in tissue simulations. We also assess the hypothesis in on-going wet lab experiments. We aim to develop KChR as optogenetic tools for arrhythmia termination in whole hearts and animal models.
Figure 1. A) Membrane voltage Vm, intracellular Ca2+ concentration [Ca]i and Na+ concentration [Na]i for ChR2-expressing ventricular CM. B) The same for KChR-expressing CM. Red solid lines correspond to results with ChR activation, black dotted lines denote the control case. Markers represent pacing events with ChR (red triangles) and control (black dots). Blue shaded area highlights the ChR-activation period.
References
[1] Bruegmann T et al. J Clin Investig (2017) [DOI: 10.1172/JCI88950]
[2] Vierock J et al. Sci Adv (2022) [DOI: 10.1126/sciadv.add7729]
[3] O’Hara T et al. PLOS Comput Biol (2011) [DOI: 10.1371/journal.pcbi.1002061]
[4] Williams J et al. PLOS Comput Biol (2013) [DOI: 10.1371/journal.pcbi.1003220]
Acknowledgements
The authors are part of the SFB 1425, Heterocellular Nature of Cardiac Lesions: Identities, Interactions, Implications
