Optotermination of spiral wave reentry by a membrane-targeted phototransducer

Optostimulation is rapidly emerging as a promising approach to control cardiac bioelectricity, combining minimal invasiveness with unparalleled spatiotemporal precision and reversibility. Building on previous findings demonstrating that Ziapin2, a membrane-targeted molecular photoswitch, can modulate cardiomyocyte electrophysiology upon visible light stimulation, we evaluated its potential to precisely terminate reentry-based arrhythmias. Reentrant activity was induced in aligned laminar cardiac microtissues from human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), using an S1S2 electrical pacing protocol in wild-type tissues and rapid pacing combined with catecholamine exposure in gene-edited microtissues harboring the CPVT-associated S404R variant in the RYR2 gene. Photostimulation disrupted spiral wave dynamics in Ziapin2-loaded tissues, whereas it had no effect on vehicle-treated controls. These results provide proof of principle for Ziapin2-mediated optotermination of arrhythmias and highlight its potential as a precise, non-genetic, and minimally invasive strategy for arrhythmia modulation.