Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Abstract

Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated.Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics.Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (IKr) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of IKr similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs.Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.

Electrophysiological and calcium-handling development during long-term culture of human-induced pluripotent stem cell-derived cardiomyocytes

“…Direct comparisons should, therefore, be made with caution, ideally between groups studied under identical conditions. Nevertheless, similar to previous studies, our hiPSC-CM show a relatively immature phenotype characterized by less negative RMP, slower AP upstroke velocity and automaticity [ 8 , 18 , 26 ]. Lack of I K 1 is a hallmark of hiPSC-CM [ 23 , 50 ].…”

“…Bath solution contained (in mmol/L): CsCl 144, CaCl 2 2, MgCl 2 2, glucose 5, HEPES 10 (pH = 7.4 adjusted with CsOH). Pipette solution contained (in mmol/L) CsCl 20, EGTA 10, HEPES 10, CsF 110 (pH = 7.2 adjusted with CsOH) in accordance with a recently published protocol [ 26 ]. Cs + was used as a charge carrier due to its selectivity for the hERG channel [ 65 ].…”

“…Delayed rectifier (rapid component; I Kr ) tail currents were measured using a high-performance automated patch clamp system (SyncroPatch 384; Nanion Technologies GmbH) with a voltage-clamp protocol consisting of a holding potential of − 80 mV followed by a 2-s step to in accordance with a recently published protocol [26]. Cs + was used as a charge carrier due to its selectivity for the hERG channel [65].…”

Impacts of gene variants on drug effects-the foundation of genotype-guided pharmacologic therapy for long QT syndrome and short QT syndrome

“…Therefore, these drugs may be potential candidates for treating or preventing ventricular tachyarrhythmias in individuals with SQTS1 carrying the KCNH2 –N588K variant. 6 , 7 Other studies have shown that quinidine, disopyramide, 42 , 43 , 44 vernakalant, 45 but not sotalol, could prolong APD or suppress arrhythmia in hiPSC-CMs from an SQTS1-patient carrying KCNH2 –N588K. These findings suggest that KCNH2 –N588K may have different effects on drug responses, which could help explain why SQTS patients with KCNH2 –N588K have varying responses to hERG channel blockers.…”

“… 5 This variant has been shown to render the hERG channel resistant to some drugs. 4 , 6 , 7 Additionally, other gene variants have been reported to impact drug efficacy in patients with genetic arrhythmias. This review will summarise the reported data on drug effects from studies conducted in patients and experimental models of LQTS and SQTS with different gene variants, and will discuss the possible mechanisms through which gene variants affect drug efficacy (see Fig.…”