On the Relation between HERG Channel Block in Cell Line and Action Potential Prolongation in Human iPSC Cardiomyocytes

Blockade of rapid delayed rectifier current (IKr) can lead to cardiac arrhythmia, which is a major concern in drug discovery and development. Drug safety tests involve the voltage clamp measurements on HEK cells expressing hERG potassium channels (Kv11.1) and high affinity hERG channel inhibition is widely accepted predictor of Torsade de Point arrhythmias (TdP). There is, however, evidence that multiple ion channel block prevent EADs and TdP arrhythmias. To address this question we estimated the IC50 values of the established hERG channel inhibitor dofetilide and 13 derivatives using a planar patch clamp system and HEK cells expressing hERG (Kv11.1) channels. Additionally we examined action potential prolongation in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) in response to dofetilide and its derivatives. The arrhythmogenic potency was assessed by estimating the concentration required to prolong the action potential (AP) to 150% of control duration. In 11 out of 14 cases hERG inhibition was accompanied by a prolongation of AP the concentration of drugs inducing 150% increase of the AP duration correlated well with IC50 of hERG channels block (r = 0.94, p 200 µM). We conclude that the simultaneous block of depolarizing L-type calcium currents or cardiac sodium current offsets the effect of hERG block. Experimental data are supported by simulations of drug-induced changes in hiPSC-CMs action potentials. Our data support the new cardiac safety paradigm (CiPA) that discrimination between safe and unsafe drugs should address hERG inhibition and additionally their action on inward currents.