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J Pharmacol Toxicol Methods. 2018 May - Jun;91:18-26. doi: 10.1016/j.vascn.2017.12.004. Epub 2018 Jan 10.

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

Author information

1
Merck & Co., Inc., Safety & Exploratory Pharmacology Department, West Point, PA, USA. Electronic address: haoyu.zeng@merck.com.
2
Merck & Co., Inc., Safety & Exploratory Pharmacology Department, West Point, PA, USA.

Abstract

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, β-adrenergic agonist, and If 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 2Hz), 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.

PMID:
29330131
DOI:
10.1016/j.vascn.2017.12.004
[Indexed for MEDLINE]

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