Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG

Journal article

Human embryonic stem cell-derived cardiomyocytes (hESC-CM) have been proposed as a new model for safety pharmacology. So far, a thorough description of their basic electrophysiology and extensive testing, and mechanistic explanations, of their overall pro-arrhythmic ability is lacking. Under standardized conditions, we have evaluated the sensitivity of hESC-CM to proarrhythmic provocations by blockade of hERG and other channels. Using voltage patch clamp, some ion current densities (pA/pF) in hESC-CM were comparable to adult CM: I Kr (-12.5±6.9), I Ks (0.65±0.12), I Na,peak (-72±21), I Na,late (-1.10±0.36), and I Ca,L (-4.3±0.6). I f density was larger (-10±1.1) and I K1 not existent or very small (-2.67±0.3). The low I K1 density was corroborated by low KCNJ2 mRNA levels. Effects of pro-arrhythmic compounds on action potential (AP) parameters and provocation of early afterdepolarizations (EADs) revealed that Chromanol293B (100μmol/l) and Bay K8644 (1μmol/l) both significantly prolonged APD 90. ATX-II (<1μmol/l ) and BaCl 2 (10μmol/l ) had no effect on APD. The only compound that triggered EADs was hERG blocker Cisapride. Computer simulations and AP clamp showed that the immature AP of hESC-CM prevents proper functioning of I Na-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. Lack of functional I K1 channels and shifted I Na channel activation cause a rather immature electrophysiological phenotype in hESC-CM, and thereby limits the potential of this model to respond accurately to pro-arrhythmic triggers other than hERG block. Maturation of the electrical phenotype is a prerequiste for future implementation of the model in arrhythmogenic safety testing. © 2012 Elsevier Ltd.

Authors: Jonsson, M; Vos, M; Mirams, G; Duker, G; Sartipy, P

• Journal: Journal of Molecular and Cellular Cardiology
• Volume: 52
• Issue: 5
• Pages: 998-1008
• Publication date: 2012-05-01
• DOI: 10.1016/j.yjmcc.2012.02.002
• EISSN: 1095-8584
• ISSN: 0022-2828
• Language: English
• Keywords: Stem cell-derived cardiomyocytes; Calcium channel; Potassium channel; Cardiac arrhythmias; Sodium channel; Safety pharmacology assay