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

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,I-late (-1.10 +/- 0.36), and I-Ca,I-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 (100 mu mol/l) and Bay K8644 (1 mu mol/l) both significantly prolonged APD(90). ATX-II (<1 mu mol/l) and BaCl2 (10 mu mol/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. (C) 2012 Elsevier Ltd. All rights reserved.