Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

Abstract

-In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we examined their electrophysiological and electropharmacological properties by using the multi-electrode array system with a programmed electrical stimulation protocol. At pre-drug control, the conduction speed, effective refractory period and field potential duration were 0.14 ± 0.01 m/sec, 453 ± 10 msec and 361 ± 9 msec, respectively at a cycle length of 1,000 msec (n = 18). Shortening the pacing cycle length from 1,000 to 600 msec decreased the conduction speed and field potential duration, but prolonged the effective refractory period. Disopyramide, lidocaine and flecainide decreased the conduction speed but prolonged the effective refractory period and field potential duration, whereas the reverse was true for verapamil. Thus, conduction properties of the cell sheet may largely depend on the extent of Na + channel availability as is the case in the human ventricle. Importantly, there was no relationship between the conduction delay and 1 st spike amplitude reduction after the treatment of Na + channel blockers. These findings may provide crucial guide on future application of this new technology for early phase safety pharmacological screening of new chemical entities.

Circulating re-entrant waves promote maturation of hiPSC-derived cardiomyocytes in self-organized tissue ring

“…It is possible that the slower speed together with the shortened pacing interval and refractory period might have been caused by the higher beating frequency in the ReW groups relative to that in the zero ReW group ( Supplementary Fig. 5 and Supplementary Movie 3), which agrees with previous reports associated with excitable media [32][33][34][35][36] . Additionally, after the ReW was stopped, the speed of spontaneous beating in the two ReW group increased significantly (p = 0.01) to more than 10 cm s −1 (Fig.…”

Fibrosis Rescue Improves Cardiac Function in Dystrophin-Deficient Mice and Duchenne Patient–Specific Cardiomyocytes by Immunoproteasome Modulation

“…24 No significant difference was found in the percentage of cTnT2positive cells (92 AE 1 versus 81% AE 14% cTnT2 þ cells) ( Figure 4C). CMs-d-iPSCs had spontaneous beating with electrical activity similar to other reports in the literature 39,40 (Figure 4, DeG). Interestingly, through Poincare Plot the absence of unstable or abnormal beats as in arrhythmias was also determined ( Figure 4H).…”

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

“…2A demonstrates that the excitation wave was propagated in a concentric fashion at a steady speed. The baseline conduction speed of the excitation wave in the hiPS-CM sheet was 0.149 ± 0.038 m/sec (mean ± S.D., N = 25) in this study, which was close to the conduc-tion speed measured using a multi-electrode array system (Izumi-Nakaseko et al, 2017). The vehicle treatment had no effect on the parameters or the conduction speed up to 0.4% DMSO (Fig.…”

“…Human iPS-CMs express fundamental cardiac ion channels and can generate action potential (Honda et al, 2011;Ma et al, 2011), which makes them a useful nonclinical tool for assessing the proarrhythmic potential of drugs (Ando et al, 2017;Kitaguchi et al, 2017;Takasuna et al, 2017;Nozaki et al, 2016). Moreover, the hiPS-CMs can be formed into a two-dimensional sheet that is electrically coupled and contracts synchronously as a functional cluster, which are properties that allow us to evaluate cardiac contraction and conduction (Izumi-Nakaseko et al, 2017;Pointon et al, 2015). Hence the hiPS-CMs may enable us to evaluate diverse cardiac functional toxicities and are expected to be a novel nonclinical tool for cardiac safety assessment.…”