Response of human induced pluripotent stem cell-derived cardiomyocytes to several pharmacological agents when intrinsic syncytial pacing is overcome by acute external stimulation

We challenged human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) syncytia, mainly, CDI iCells with several classes of well-characterized pharmacological agents (including hERG blocker, Nav1.5 blocker, Cav1.2 blocker and opener, beta-adrenergic agonist, and I-f blocker) under pacing conditions, utilizing the Cardio-ECR instrument, a non-invasive platform featuring simultaneous and continuous measurement of synchronized beating rate and contractility (both signals were acquired simultaneously and well aligned). We found that: 1) with increasing acute stimulation rates (no pacing; 1, 1.5, and 2 Hz), beat interval was gradually shortened mainly in the relaxation phase of each beat cycle; 2) typical responses of iCells hiPSC-CMs to all tested pharmacological agents were either attenuated or even eliminated by pacing, in a concentration-and stimulation rate-dependent manner; and 3) when iCells were influenced by pharmacological agents and cannot follow pacing rates, they still beat regularly at exactly 1/2 or 1/3 of pacing rates. We concluded that when intrinsic syncytial pacing was overcome by faster, external stimulations, beat intervals of hiPSC-CMs were mainly shortened in the relaxation phase, instead of proportionally in each beat cycle, with increasing pacing rates. In addition, in response to pharmacological agents upon pacing, hiPSC-CMs exhibited distinct patterns of refractoriness, manifested by skipped beats in pacing-rate dependent manner, and attenuation (or even abolition) of the typical response evoked under spontaneous beating.