Theoretical analysis of low-power optogenetic suppression of action potentials in human ventricular cardiomyocytes expressed with potassium-selective channelrhodopsins.

Effective suppression of cardiac tachyarrhythmias and shortening of action potential duration (APD) remain major challenges in cardiac optogenetics due to the non-selectivity of ion-conducting channelrhodopsins (ChRs). We present a comprehensive theoretical analysis of optogenetic suppression of electrical activity and temporally precise shortening of APD in human ventricular cardiomyocytes (HVCMs) expressed with WiChR and HcKCR1 potassium (K⁺)-selective ChRs that exhibit reversal potentials close to the diastolic membrane potential of the targeted cardiac cells. Our simulations show that K⁺-selective ChRs provide more efficient hyperpolarizing control compared to cation-selective variants. Our computational simulations show that WiChR exhibits action-potential suppression at very low irradiance (4 × 10⁻² mW/mm²), while HcKCR1 could not achieve full suppression at 10 mW/mm². This makes WiChR a much stronger and more effective option for optical inhibition in human ventricular cardiomyocytes. At irradiance of 1 × 101 mW/mm², our simulations show that WiChR hyperpolarizes the membrane to -83.14 mV, closely approaching the K⁺ equilibrium potential, whereas HcKCR1 reached − 82.39 mV. The results are important for the treatment of cardiac arrhythmias and long QT syndrome. This work provides mechanistic insight into low-power optogenetic control of cardiac electrophysiology and offers quantitative predictions to guide future in vitro and in vivo investigations aimed at developing safer and more precise alternatives to electrical pacing and defibrillation technologies.