Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator

Abstract

Finding the silent skipped beat: Predicting arrhythmia-causing drugs using a high-throughput hybrid heart simulator.

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

“…This result is quite different from a previous report in humans by Johannesen et al (Johannesen et al, 2014), describing that verapamil hardly altered the corrected QT interval by Fridericia's formula at a peak plasma concentration of 130 ± 76 ng/mL (0.270 μmol/L). The IC 50 values of verapamil for Na + , L-type Ca 2+ and hERG K + channels have been reported to be 4.272, 0.333 and 0.201 μmol/L (Okada et al, 2015), respectively. Moreover, a selective L-type Ca 2+ channel blocker nifedipine and a specific hERG K + channel blocker E-4031 have been demonstrated to shorten and prolong the field potential duration, respectively in hiPSCCMs sheets (Harris et al, 2013).…”

In Silico Assessment of Antiarrhythmic Effects of Drug Ranolazine on Electrical Activity in Human Ventricular Myocardium

“…APD, ∆APD). We obtained ∆APD values ((∆APD = APD with ionic current inhibition ( Table 1,2 and 3) -APD placebo (under control conditions)) from simulation models using experimental values from [9,10].…”

“…We used drug concentrations and inhibitory actions of dofetilide and d,l-sotalol on ion channels in vitro from previously published data [10] as presented in Tables 2 and 3. Inhibitory actions (i.e.…”

The opportunities and challenges for biophysical modelling of beneficial and adverse drug actions on the heart

“…Voltage clamp experiments, performed as part of multiple ion channel screening, using cell lines, generate IC50 data that can be readily incorporated into computational models of varying levels of complexity. These models provide a unique method to link drug interactions at the molecular target level to predict altered function at increasingly integrated levels of function, from ionic currents to action potentials 31,32 , conduction (reentry) [33][34][35] and global heart rhythm itself (the ECG) [36][37][38][39] . This provides a quantitative link between pre-clinical protein kinetics assays and organ clinical indices.…”