The Evolving Roles of Human iPSC-Derived Cardiomyocytes in Drug Safety and Discovery  Gary Gintant, Bernard Fermini, Norman Stockbridge, David Strauss  Cell Stem Cell  Volume 21, Issue 1, Pages 14-17 (July 2017) DOI: 10.1016/j.stem.2017.06.005 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Electrophysiologic Basis for Human Stem Cell-Derived Cardiomyocytes in CiPA (A) A balance of inward and outward currents defines cardiac repolarization on a cellular level. Two inwardly directed depolarizing currents (red) are opposed by multiple outwardly directed repolarizing currents (green) active at different times during the action potential plateau that predominate to ensure repolarization and return to the resting membrane potential. (B) Delayed repolarization resulting from reduced net outward current with increasing IKr block (traces a→d) may lead to interruptions of repolarization termed early afterdepolarizations (EADs). EAD activity and drug-induced repolarization heterogeneity across the ventricular wall are mechanistically linked to TdP. Action potentials in (A) and (B) represent in silico reconstructions from the O’Hara-Rudy model. Note expanded timescale in (A) versus (B). (C) Waterfall plot of field potential recordings obtained from an MEA instrument illustrating concentration-dependent delayed repolarization with the IKr blocking drug dofetilide. Vertical bars represent repolarization wave markings and T1-3 represent traces obtained during ongoing drug equilibration. Cell Stem Cell 2017 21, 14-17DOI: (10.1016/j.stem.2017.06.005) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 The Role of Human Stem Cell-Derived Cardiomyocytes in the CiPA Paradigm hiPSC-CMs (red box, right) as well as early phase 1 clinical trials are used to detect unanticipated electrophysiologic effects of drugs on ventricular repolarization compared to reconstructions of cellular electrical activity derived from a human ventricular in silico model that define TdP proarrhythmic risk based on well-described clinical experiences with 28 drugs. Cell Stem Cell 2017 21, 14-17DOI: (10.1016/j.stem.2017.06.005) Copyright © 2017 Elsevier Inc. Terms and Conditions