シミズ　タツヤ   SHIMIZU Tatsuya   清水　達也    所属   研究施設 研究施設    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Importance of beating rate control for the analysis of drug effects on contractility in human induced pluripotent stem cell-derived cardiomyocytes.
掲載誌名	正式名：Journal of pharmacological and toxicological methods 略　 称：J Pharmacol Toxicol Methods ISSNコード：1873488X/10568719
掲載区分	国外
巻・号・頁	118,pp.107228
著者・共著者	HINATA Yuto†, KAGAWA Yuki, KUBO Hirotsugu, KATO Eriko, BABA Atsushi, SASAKI Daisuke, MATSUURA Katsuhisa, SAWADA Kohei, SHIMIZU Tatsuya*
担当区分	最終著者,責任著者
発行年月	2022/11
概要	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.
DOI	10.1016/j.vascn.2022.107228
PMID	36273536