Wave propagation enhances extracellular signal strength in small excitable tissues

Abstract

Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer new opportunities to study cardiac dynamics and drug responses. High-throughput platforms often rely on extracellular potential (EP) recordings, making signal strength critical for analysis. To examine how stimulation protocols shape EPs, we used a computational model of hiPSC-CMs cultured in a well geometry and compared extracellular recordings under uniform and localized stimulation. Uniform global stimulation activated all cells simultaneously, suppressed wave propagation, and produced only small extracellular signals despite robust transmembrane action potentials. Localized stimulation, by contrast, initiated traveling waves and generated strong, well-defined EPs. These findings show that the stimulation protocol directly determines EP strength in dish-based assays and have practical implications for the design and interpretation of high-throughput hiPSC-CM experiments and other in vitro electrophysiological measurements.