SHIMIZU Tatsuya
   Department   Graduate School of Medical Science, Graduate School of Medical Science
   Position   Professor
Article types Original article
Language English
Peer review Peer reviewed
Title Induction of cardiac alternans in human iPS-derived cardiomyocytes through β-adrenergic receptor stimulation.
Journal Formal name：Physiological reports
Abbreviation：Physiol Rep
ISSN code：2051817X/2051817X
Domestic / ForeginForegin
Volume, Issue, Page 12(24),pp.e70152
Author and coauthor HINATA Yuto†, SASAKI Daisuke, MATSUURA Katsuhisa*, SHIMIZU Tatsuya*
Authorship Last author,Corresponding author
Publication date 2024/12
Summary Cardiac alternans (C-ALT) is a phenomenon of alternating strong and weak contractions in the heart and is considered a risk factor for the development of heart failure and arrhythmias. However, no model has been reported that can induce C-ALT in vitro using human cells, and the developmental mechanism of C-ALT has not been studied using human cells. In this study, we successfully induced C-ALT in vitro using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). By stimulating β-adrenergic receptor with isoproterenol on hiPSC-CMs cultured in atmospheric condition (with ~0.04% CO2), contractility and calcium transient were observed to alternately increase and decrease with each beat. In contrast, C-ALT was not induced in hiPSC-CMs cultured at 5% CO2 concentration. Since previous studies have linked C-ALT to problems with calcium regulation in the sarcoplasmic reticulum (SR), we exposed hiPSC-CMs to compounds that alter SR Ca2+ loading and analyzed their contractile responses. The results showed that exposure to verapamil, thapsigargin, and ryanodine either suppressed or eliminated C-ALT. In contrast, omecamtiv mecarbil and blebbistatin, which alter contractility without SR Ca2+ loading, did not induce or suppress C-ALT. These results suggest that C-ALT in hiPSC-CMs induced by isoproterenol may be due to abnormal regulation of the ryanodine receptor's opening and closing caused by excessive Ca2+ load in the SR from β-adrenergic receptor stimulation.
DOI 10.14814/phy2.70152
PMID 39715724