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

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengying Huang ◽  
Zhenxing Liao ◽  
Xin Li ◽  
Zhen Yang ◽  
Xuehui Fan ◽  
...  
Keyword(s):  
Time Constant ◽  
Healthy Donor ◽  
Channel Gating ◽  
Drug Effects ◽  
Herg Channel ◽  
Syndrome Type ◽  
Short Qt Syndrome ◽  
Window Current ◽  
Qt Syndrome

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.

scholarly journals Arrhythmogenesis in the Short-QT Syndrome Associated With Combined HERG Channel Gating Defects

2006 ◽  
Vol 70 (4) ◽  
pp. 502-508 ◽  
Author(s):  
Hideki Itoh ◽  
Minoru Horie ◽  
Makoto Ito ◽  
Keiji Imoto
Keyword(s):  
Channel Gating ◽  
Herg Channel ◽  
Short Qt Syndrome ◽  
Qt Syndrome

Functional Hyperactivity in Long QT Syndrome Type 1 Pluripotent Stem Cell-Derived Sympathetic Neurons

2021 ◽  
Author(s):  
Annika Winbo ◽  
Suganeya Ramanan ◽  
Emily Eugster ◽  
Annika Rydberg ◽  
Stefan Jovinge ◽  
...  
Keyword(s):  
Pluripotent Stem Cell ◽  
Sympathetic Neurons ◽  
Compound Heterozygous ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Long Qt ◽  
Action Potential Frequency ◽  
Qt Syndrome ◽  
Potential Frequency

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two LQT1 patients with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterisation of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay and whole-cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared to healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted noradrenaline. hiPSC-SNs at 60±2.2 days in vitro had healthy resting membrane potentials (-60±1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased noradrenaline release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarisation, compared to age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared to heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.

scholarly journals 57PA-6 inhibits gain-of-function KIR2.1 channels associated with short QT syndrome type 3 and congenital atrial fibrillation

EP Europace ◽  
2017 ◽  
Vol 19 (suppl_3) ◽  
pp. iii2-iii2
Author(s):  
MAG Van Der Heyden ◽  
M. Veldhuis ◽  
J. Zandvoort ◽  
MJC Houtman ◽  
K. Duran ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Syndrome Type ◽  
Short Qt Syndrome ◽  
Gain Of Function ◽  
Qt Syndrome ◽  
Type 3
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