Impact of Antiarrhythmic Drugs on the Outcome of Short QT Syndrome

El‐Battrawy, Ibrahim; Besler, Johanna; Li, Xin; Liu, Huan; Zhao, Zhihan; Liebe, Volker; Schimpf, Rainer; Lang, Siegfried; Wolpert, Christian; Zhou, Xiaobo; Akın, İbrahim; Borggrefe, Martin

doi:10.3389/fphar.2019.00771

Cited by 24 publications

(18 citation statements)

References 26 publications

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“…The therapeutic approaches for SQTS are challenging for physicians because of the low prevalence and rare cases. Until now, 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, 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).…”

Section: Introductionmentioning

confidence: 99%

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

Huang

Liao

et al. 2021

Front. Pharmacol.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Huang

Liao

et al. 2021

Front. Pharmacol.

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“…Risk stratification and valid pharmacological therapies have not yet been established due to the low number of patients with SQTS [ 2 ]. Quinidine, which blocks several potassium channels including I to and I Kr , was reported to prolong the QT interval and reduce the incidence of life-threatening arrhythmias in patients with SQTS [ 85 , 86 ]. Other antiarrhythmic drugs, such as sotalol, amiodarone, disopyramide, and β-blockers, failed to show beneficial effects on SQTS [ 86 ].…”

Section: Lqts and Sqtsmentioning

confidence: 99%

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Nakajima

Tamura

Kurabayashi

et al. 2021

IJMS

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Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

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“…Until now, there has been very limited research to test drug effects in SQTS patients. A few anti-arrhythmic drugs such as disopyramide, quinidine, sotalol, ibutilide have been tested in SQT1 patients, but only quinidine has been shown to be effective in the treatment [5].…”

Section: Introductionmentioning

confidence: 99%

Computer Modelling the Effects of Chloroquine on KCNJ2 D172N and E299V Mutations-linked Short QT Syndrome

Luo

Wang

et al. 2020

2020 Computing in Cardiology Conference (CinC)

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Short QT syndrome (SQTS) is an inherited cardiac disease characterized by ventricular tachyarrhythmias leading to sudden cardiac death (SCD). SQT3 has been linked to the D172N or E299V gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K + current (IK1). Until now, the only effective therapy is implantation of a defibrillator whereas clinical drug therapy is little known about it. Previous studies reported that anti-malarial drug chloroquine was an effective inhibitor of the mutant Kir2.1 channels. The effectiveness of chloroquine has demonstrated in SQT3 associated with D172N mutation, there is a reason to believe that it may be useful in the other mutations in SQT3, such as E299V mutation. Therefore, we aim to predict and compare the potential effects of drug chloroquine on SQT3 D172N and E299V mutations. In this study, the ten Tusscher model of ventricular cell was coupled with the SQT3 mutant IK1 patch clamp data. Our simulation data showed that chloroquine prolonged the ventricular cell action potential duration (APD) and QT interval under SQT3 condition, and demonstrated that chloroquine produced a therapeutic effect on different mutant SQT3. This study provides new evidence that chloroquine may be a potential generic drug for the treatment of SQTS.

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Impact of Antiarrhythmic Drugs on the Outcome of Short QT Syndrome

Cited by 24 publications

References 26 publications

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

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

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Computer Modelling the Effects of Chloroquine on KCNJ2 D172N and E299V Mutations-linked Short QT Syndrome

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