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.
Highlights
Short QT syndrome (SQTS), described initially by Gussak et al, in 2000 (Gussak et al, 2000), is a rare, inheritable heart disease associated with abbreviated corrected QT interval (QTc) and sudden cardiac death (SCD)
We demonstrated that quinidine, ajmaline, amiodarone, ivabradine, and mexiletine but not amiodarone, flecainide and ranolazine prolonged APD and reduced epinephrine induced arrhythmic events in hiPSC-CMs from the SQT1-patient (SQT1-hiPSC-CMs) (Zhao et al, 2019).To check whether these drugs affect hERG channel currents (IKr) differentially in hiPSC-CMs from healthy donor and the SQTS1patient, drug effects on IKr were analyzed in both the healthy and diseased cells
We investigated the effects of quinidine, ajmaline, amiodarone, ivabradine, flecainide, mexiletine and ranolazine on gating kinetics of hERG channels in hiPSC-CMs from a SQT1patient with N588k mutation
Summary
Short QT syndrome (SQTS), described initially by Gussak et al, in 2000 (Gussak et al, 2000), is a rare, inheritable heart disease associated with abbreviated corrected QT interval (QTc) and sudden cardiac death (SCD). A small number of drugs including disopyramide, nifekalant, quinidine, flecainide, sotalol, ibutilide and propafenone have been tested by in vivo studies on SQTS1 (Abriel and Rougier, 2013), among which only quinidine has shown profit effect in the treatment (Mizobuchi et al, 2008; Giustetto et al, 2011; Mazzanti et al, 2017; El-Battrawy et al, 2018; El-Battrawy et al, 2019). In human-induced stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS type 1, besides quinidine, disopyramide, ajmaline, ivabradine and mexiletine but not sotalol, amiodarone, flecainide and ranolazine showed profitable (APD-prolonging and antiarrhythmic) effects (Shinnawi et al, 2019; Zhao et al, 2019; Lan et al, 2020)
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