AUTHOR=Carvalho A. B. , Coutinho Keyla Cristiny da Silva , Barbosa Raiana Andrade Quintanilha , Campos Dilza Balteiro Pereira de , Leitão Isabela de Carvalho , Pinto R. S. , Dos Santos D. Silva , Farjun Bruna , De Araújo Dayana da Silva , Mesquita Fernanda Cristina Paccola , Monnerat-Cahli G. , Medei E. H. , Kasai-Brunswick Tais Hanae , De Carvalho A. C. Campos TITLE=Action potential variability in human pluripotent stem cell-derived cardiomyocytes obtained from healthy donors JOURNAL=Frontiers in Physiology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.1077069 DOI=10.3389/fphys.2022.1077069 ISSN=1664-042X ABSTRACT=

Human pluripotent stem cells (PSC) have been used for disease modelling, after differentiation into the desired cell type. Electrophysiologic properties of cardiomyocytes derived from pluripotent stem cells are extensively used to model cardiac arrhythmias, in cardiomyopathies and channelopathies. This requires strict control of the multiple variables that can influence the electrical properties of these cells. In this article, we report the action potential variability of 780 cardiomyocytes derived from pluripotent stem cells obtained from six healthy donors. We analyze the overall distribution of action potential (AP) data, the distribution of action potential data per cell line, per differentiation protocol and batch. This analysis indicates that even using the same cell line and differentiation protocol, the differentiation batch still affects the results. This variability has important implications in modeling arrhythmias and imputing pathogenicity to variants encountered in patients with arrhythmic diseases. We conclude that even when using isogenic cell lines to ascertain pathogenicity to variants associated to arrythmias one should use cardiomyocytes derived from pluripotent stem cells using the same differentiation protocol and batch and pace the cells or use only cells that have very similar spontaneous beat rates. Otherwise, one may find phenotypic variability that is not attributable to pathogenic variants.