Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPS cell-engineered heart tissue

Masahide Kawatou, Hidetoshi Masumoto, Hiroyuki Fukushima, Gaku Morinaga, Ryuzo Sakata, Takashi Ashihara and Jun K. Yamashita ()
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Masahide Kawatou: Center for iPS Cell Research and Application, Kyoto University
Hidetoshi Masumoto: Center for iPS Cell Research and Application, Kyoto University
Hiroyuki Fukushima: Center for iPS Cell Research and Application, Kyoto University
Gaku Morinaga: Center for iPS Cell Research and Application, Kyoto University
Ryuzo Sakata: Kyoto University Graduate School of Medicine
Takashi Ashihara: Shiga University of Medical Science
Jun K. Yamashita: Center for iPS Cell Research and Application, Kyoto University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Torsade de Pointes (TdP) is a lethal arrhythmia that is often drug-induced, thus there is an urgent need for development of models to test or predict the drug sensitivity of human cardiac tissue. Here, we present an in vitro TdP model using 3D cardiac tissue sheets (CTSs) that contain a mixture of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and non-myocytes. We simultaneously monitor the extracellular field potential (EFP) and the contractile movement of the CTSs. Upon treatment with IKr channel blockers, CTSs exhibit tachyarrhythmias with characteristics of TdP, including both a typical polymorphic EFP and meandering spiral wave re-entry. The TdP-like waveform is predominantly observed in CTSs with the cell mixture, indicating that cellular heterogeneity and the multi-layered 3D structure are both essential factors for reproducing TdP-like arrhythmias in vitro. This 3D model could provide the mechanistic detail underlying TdP generation and means for drug discovery and safety tests.

Date: 2017
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DOI: 10.1038/s41467-017-01125-y

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