Channelrhodopsin Ion Selectivity Determines Mechanisms and Efficacy of Optogenetic Defibrillation in Human Atria and Ventricles

Optogenetic defibrillation uses light-gated ion channels to terminate cardiac arrhythmias through targeted illumination. Previous studies assessed the feasibility of using either cation (e.g. ChR2) or anion (e.g. GtACR1) non-selective channels, both of which depolarise resting cardiomyocytes upon photoactivation. In contrast, recently identified light-gated K ⁺ -channels (e.g. WiChR) suppress cardiomyocyte activity while maintaining the membrane potential near its resting state. Here, we use biophysically detailed simulations to compare the defibrillation potential of ChR2, GtACR1, and WiChR. Single-cell simulations show that activation of ChR2 and GtACR1 markedly increase diastolic intracellular Ca ²⁺ concentration (by 42.6% and 52.6%, respectively), whereas WiChR induces only minimal changes (4.0% increase), suggesting a lower pro-arrhythmogenic risk. WiChR activation, however, slightly increases intracellular Na ⁺ levels (by 15.1% compared to 0.1% and 3.4% for ChR2 and GtACR), consistent with the residual Na ⁺ permeability of all currently available K ⁺ -selective channelrhodopsins. Simulations of human ventricles and atria demonstrate that GtACR1 most effectively terminates re-entrant arrhythmias at low light intensities, while WiChR achieves comparable efficacy at light levels ≥5 mW/mm ² . Complementary tissue-scale simulations reveal that defibrillation is either based on depolarisation within the excitable gap, followed by fast Na ⁺ channel inactivation (depolarising variants ChR2 and GtACR1), or based on a reduction in membrane resistance supporting arrhythmia termination at sufficiently high light levels (large-conductance ion channels GtACR1 and WiChR). Overall, our findings identify channelrhodopsin ion selectivity as a key determinant of both arrhythmia termination success and mechanisms underlying defibrillation.