Repolarization reserve determines drug responses in human pluripotent stem cell derived cardiomyocytes

Abstract

Unexpected induction of arrhythmias in the heart is still one of the major risks of new drugs despite recent improvements in cardiac safety assays. Here we address this in a novel emerging assay system. Eleven reference compounds were administrated to spontaneously beating clusters of cardiomyocytes from human pluripotent stem cells (hPSC-CM) and the responses determined using multi-electrode arrays. Nine showed clear dose-dependence effects on field potential (FP) duration. Of these, the Ca(2+) channel blockers caused profound shortening of action potentials, whereas the classical hERG blockers, like dofetilide and d,l-sotalol, induced prolongation, as expected. Unexpectedly, two potent blockers of the slow component of the delayed rectifier potassium current (I(Ks)), HMR1556 and JNJ303, had only minor effects on the extracellular FP of wild-type hPSC-CM despite evidence of functional I(Ks) channels. These compounds were therefore re-evaluated under conditions that mimicked reduced "repolarization reserve," a parameter reflecting the capacity of cardiomyocytes to repolarize and a strong risk factor for the development of ventricular arrhythmias. Strikingly, in both pharmacological and genetic models of diminished repolarization reserve, HMR1556 and JNJ03 strongly increased the FP duration. These profound effects indicate that I(Ks) plays an important role in limiting action potential prolongation when repolarization reserve is attenuated. The findings have important clinical implications and indicate that enhanced sensitization to repolarization-prolonging compounds through pharmacotherapy or genetic predisposition should be taken into account when assessing drug safety.

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: Disease mechanisms and pharmacological rescue

“…The increased susceptibility to drug-induced arrhythmias of JLNS 1781A/A -and JLNS 478-2T/TCMs is likely a direct consequence of impaired I Ks and concomitant reduction of the repolarization reserve (49). One promising application of hiPSC-CMs is screening for proarrhythmic side effects of certain drugs (50,51).…”

Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes

“…A better approach is where a cell expressing many types of ion channels is used to more accurately assess all potential interactions. One group, using MEA, tested the effects of eleven reference compounds on electrical activity of iPSC-CMs [89]. Of these, 5 were hERG blockers, 2 were Ca 2+ channel blockers, 1 was a nonselective Ca 2+ channel/hERG blocker, 1 was a K ATP -channel blocker, and 2 were I Ks blockers.…”

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

“…Increasing attention is being paid to models for predicting drug-induced toxicity down to the single-patient level. Human iPSC-derived cardiomyocytes (iPSC-CMs) are proving useful in predicting a drug-induced prolonged action potential (also referred to as long QT), which places patients at high risk of life-threatening cardiac arrhythmias [177]. A recent study reported the use of iPSC-CMs in predicting doxorubicin-induced cardiotoxicity in cancer patients [178], suggesting the benefits of generating patient iPSCs and examining toxicity prior to initiating chemotherapy.…”