Introduction: Optogenetic defibrillation offers a new approach for terminating cardiac arrhythmias based on timed activation of light-gated ion channels known as channelrhodopsins (ChR). So far, studies mainly used cation non-selective ChR, such as ChR2, or anion non-selective ChR, such as GtACR1. However, both terminate arrhythmias by membrane depolarisation, and thus, their activation may contribute to intracellular Ca and Na overload. In contrast, K-selective ChR (KChR) may be better alternatives, as their activation will keep cardiomyocytes (CM) close to their natural resting potential. Experiments indicate that WiChR, a predominantly K-selective ChR, presents a promising target for optical defibrillation.
Methods: Employing the O'Hara model of a human ventricular CM, we incorporated ChR2, GtACR1 or a KChR. For ChR2 and GtACR1, we used existing models and simulated illumination with 470 nm or 515 nm light at intensities of 5 mW/mm^2. For KChR we used a simple model including only a K-conductance (1.4 mS/cm^2) during light-activation. To assess CM behaviour without optogenetic manipulation, we paused the electrical pacing during the illumination period as a control scenario. Moreover, we are currently parameterising a computational model of WiChR to achieve a more realistic representation of KChR functionality.
Results: The simulations predict an increase in intracellular Ca and Na during activation of ChR2 and GtACR1. In the case of KChR, the results do not indicate significant differences in these ion concentrations compared to control (see Fig. 1).
Outlook: We will test our hypothesis that ChR ion selectivity determines the efficacy and safety of optogenetic defibrillation in 2D and 3D simulations.