Importance of beating rate control for the analysis of drug effects on contractility in human induced pluripotent stem cell-derived cardiomyocytes.

Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical cardiotoxicity predictive model. Most studies on this were conducted under spontaneous beating conditions and involved video-based analyses. Cardiac contractility is known to be influenced by beating rates; accordingly, beating rate control is recommended to accurately analyze the effects of drugs on cardiac contractility. Therefore, we investigated the relationship between contraction parameters and beating rates of cardiac cell sheet tissues by directly measuring the contraction force and compared the effects of ion channel drugs (mexiletine, ranolazine, and dofetilide) on contraction parameters under spontaneous beating conditions with those under pacing (1 Hz) conditions. To characterize the contraction/relaxation kinetics, we introduced a novel analysis tool, called a "C-V loop," a plot of contraction force versus force-changing rate ("velocity"). When we increased the beating rate, the contraction force, force-changing rate, and relaxation time markedly decreased. The occurrence frequencies of beating arrest and irregular beats at high concentration ranges of mexiletine and ranolazine were more suppressed in paced samples than in spontaneously beating ones. We also found that relaxation time increased by treatment with dofetilide and contraction amplitude decreased in a concentration-dependent manner by mexiletine treatment only in the samples under pacing. These drug responses were consistent with the previous reports using human samples. These results indicated that beating rate control is necessary to stably evaluate the effects of drugs on contractility and that tests under 1-Hz pacing are more relevant to clinical settings.
Competing Interests: Declaration of Competing Interest Yuto Hinata, Yuki Kagawa, and Hirotsugu Kubo are employees of Nihon Kohden Corporation. The University of Tokyo received research funding from Nihon Kohden Corporation. Tatsuya Shimizu is a stakeholder in CellSeed Inc. Tokyo Women's Medical University receives research funding from CellSeed Inc. and Nihon Kohden Corporation. Katsuhisa Matsuura and Tatsuya Shimizu are inventors of bioreactor systems.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)