Applicability of Human Induced Pluripotent Stem Cell-derived Myocardial Sheet to the Study of Arrhythmias:From the Viewpoint of <I>in silico</I> Arrhythmology

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  • ASHIHARA Takashi
    Department of Cardiovascular Medicine, Heart Rhythm Center, Shiga University of Medical Science
  • KUROKAWA Junko
    Department of Bio-informational Pharmacology, Tokyo Medical and Dental University, MRI
  • KANDA Yasunari
    Division of Pharmacology, National Institute of Health Sciences
  • HARAGUCHI Ryo
    National Cerebral and Cardiovascular Center
  • INADA Shin
    National Cerebral and Cardiovascular Center
  • NAKAZAWA Kazuo
    National Cerebral and Cardiovascular Center
  • HORIE Minoru
    Department of Cardiovascular Medicine, Heart Rhythm Center, Shiga University of Medical Science

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Other Title
  • ヒトiPS細胞由来心筋細胞シートの不整脈研究への応用可能性：<I>in silico</I>不整脈学の観点から
  • ヒトiPS細胞由来心筋細胞シートの不整脈研究への応用可能性 : in silico不整脈学の観点から
  • ヒト iPS サイボウ ユライ シンキン サイボウ シート ノ フセイミャク ケンキュウ エ ノ オウヨウ カノウセイ : in silico フセイミャクガク ノ カンテン カラ

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Abstract

Background: Recently, myocardial sheets consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) have been used to clarify the mechanisms of inherited arrhythmias and to evaluate the efficacy of antiarrhythmic drugs. However, whether the electrophysiological properties of the hiPSC-CM are the same as those of the original human cardiomyocytes (hCM) remains unclear. Indeed, hiPSC-CM has automaticity, longer action potential duration (APD), smaller action potential amplitude (APA), and positively shifted diastolic potential (DP). Methods: To clarify this issue, we constructed in silico models of hCM and hiPSC-CM sheets based on the experimental data, and performed simulations of spiral wave (SW) reentry. Then we analyzed the SW behaviors in the in silico myocardial sheets, and also evaluated the effects of IKr blockade. Results: ( 1 )The in silico model of hiPSC-CM had spontaneous activations 0.5-1 Hz, longer APD, smaller APA, and DP positively shifted by∼15 mV. ( 2 )Conduction velocity (CV) in the hiPSC-CM sheet was∼5 cm/s, which was only∼1/10 of the CV in the hCM sheet. ( 3 )Mean cycle length (mCL) of excitations during SW reentry in the hiPSC-CM sheet was∼0.9 Hz, whereas that in the hCM sheet was∼5 Hz and identical to that of human VF. ( 4 )Both CV and mCL during SW reentry in the model of hiPSC-CM sheet were highly consistent with previous experimental data. ( 5 )The mCL of SW reentry in hCM sheet was markedly prolonged by IKr blockade, whereas that in hiPSC-CM sheet was shortened. Conclusion: The SW behavior and the antiarrhythmic drug efficacy in the in silico models of hCM and hiPSC-CM sheets are different. Our findings suggest that such in silico analytical approach might fill the gap between hCM and hiPSC-CM when we apply the hiPSC-CM sheet to clinical practice.

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