Clin Res Cardiol 108, Suppl 1, April 2019

Intrinsic action potential triangulation predicts risk for early afterdepolarisations in engineered heart tissue from hiPSC-cardiomyocytes exposed to IKr blocker

T. Krause1, A. Hansen1, C. Meyer2, T. Eschenhagen1, T. Christ1, M. Lemoine2

1Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg; 2Klinik für Kardiologie mit Schwerpunkt Elektrophysiologie, Universitäres Herzzentrum Hamburg GmbH, Hamburg;

Background: Compound-induced repolarisation abnormalities are an important issue in drug development since they may lead to life-threatening ventricular arrhythmias and sudden cardiac death. In vitro induction of early afterdepolarisations (EAD) indicates a high risk by a compound to induce arrhythmias in vivo. Action potential (AP) measurements in 3D engineered heart tissue (EHT) produced from human induced pluripotent stem cell-induced cardiomyocytes (hiPSC-CM) are expected to increase sensitivity and selectivity when compounds are tested for their risk to impair repolarisation in humans. However, recently we found EAD in ~50% of EHT exposed to the IKr blocker E-4031. Therefore we aimed to identify whether intrinsic action potential properties of EHT may influence the risk to develop EAD upon IKr block. Methods: APs were measured with sharp microelectrodes (37 °C, 1 Hz) in EHT produced from three different hiPSC-cell lines (two in-house: C25 and ERC018 and one commercially available: iCell2). IKr current was blocked by 1 µmol/L E-4031. Action potential triangulation (APT) was defined as APD90-APD40. Results: E-4031 increased APD90 in EHT from 258±18 ms to 511±23 ms (+111±10%; n=36, p<0.001). 17 out of 36 EHT (47%) developed EAD at 1 µmol/L E-4031. There was no difference in the relative risk to develop EAD within the three cell lines used (number of EHT with EAD: C25 (7/13), ERC018 (4/11) and iCell2 (6/12), n.s. Chi2-test). Basal APD90 did not differ between EHT that developed EAD upon IKr block (278±32 ms; n=17) and those that did not (241±18 ms, n=19). The same holds true for APD90 in the presence of E-4031 (542±35 ms, n=17 vs. 483±29 ms, n=19, n.s.). In contrast, APT was larger in EHT that developed EAD than in EHT without EAD not only when IKr was blocked (354±23 ms, n=17 vs 269±24 ms, n=19, p=0.0165, unpaired t-test), but even under drug-free control conditions (147±18 ms, n=17 vs. 100±7 ms n=19, p=0.017). Conclusions: In EHT from hiPSC-CM intrinsic AP parameters have an impact on the risk to develop EAD upon IKr block. Large APT favours EAD development, while APD90 does not. Intrinsic APT should be considered before using hiPSC-CM to detect compound-induced repolarisation abnormalities like EAD.

https://www.abstractserver.com/dgk2019/jt/abstracts//P544.htm