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

Masahide Kawatou,Gaku Morinaga,Jun K Yamashita,Hiroyuki Fukushima,Takashi Ashihara,Ryuzo Sakata,Hidetoshi Masumoto

doi:10.1038/s41467-017-01125-y

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.

Highlights

Torsade de Pointes (TdP) is a lethal arrhythmia that is often drug-induced, there is an urgent need for development of models to test or predict the drug sensitivity of human cardiac tissue
Torsade de Pointes (TdP), a representative drug-induced lethal arrhythmia, is a polymorphic ventricular tachycardia (VT) that is characterized by a twisting wave appearance in electrocardiograms (ECGs) and leads to ventricular fibrillation and sudden death[6]
After 4 days of culture at 37 °C, we reduced the culture temperature to room temperature and collected the cells as self-pulsating cell sheets exclusively consisting of cardiomyocytes (94.7 ± 3.6% of total cells; flow cytometry)

Summary

Introduction

Torsade de Pointes (TdP) is a lethal arrhythmia that is often drug-induced, there is an urgent need for development of models to test or predict the drug sensitivity of human cardiac tissue. 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. The ICH S7B guidelines[7], which are currently used for the non-clinical pharmacological safety testing of human pharmaceuticals and include information concerning integrated risk assessments, set QT interval prolongation in ECGs as a major endpoint This prolongation reflects the delayed ventricular repolarization and is a cause of subsequent TdP. We generate an in vitro drug-induced TdP model that recapitulates the actual kinetics of TdP only with hiPSC-derived cell populations

Methods

Results

Conclusion