The Short QT Syndrome

Hancox, Jules C.; McPate, Mark J.; Harchi, Aziza El; Duncan, Rona S.; Dempsey, Chris E.; Witchel, Harry J.; Adeniran, Ismail; Zhang, Henggui

doi:10.1007/978-3-642-17575-6_23

Cited by 7 publications

(2 citation statements)

References 107 publications

(186 reference statements)

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“…Kv11.1 (hERG) is the molecular basis of I Kr in cardiomyocytes and plays an important role in cardiac repolarization [32,33]. The hERG K + channel current is the main current of action potential phase 3. hERG K + channel mutations can lead to hereditary arrhythmic syndrome characterized by prolongation or shorten QT interval and increased incidence of life-threatening arrhythmia [34][35][36]. Lee et al [22] found that vandetanib inhibited hERG current, I Na and I Ca-L .…”

Section: Discussionmentioning

confidence: 99%

[Retracted] Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib‐Induced QT Interval Prolongation

Zhang

Luo

et al. 2021

Oxidative Medicine and Cellular Longevity

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Inhibition of human ether-a-go-go-related gene (hERG) potassium channel is responsible for acquired long QT syndromes, which leads to life-threatening cardiac arrhythmia. A multikinase inhibitor, vandetanib, prolongs the progression-free survival time in advanced medullary thyroid cancer. However, vandetanib has been reported to induce significant QT interval prolongation, which limits its clinical application. Some studies have showed that ginsenoside Rg3 decelerated hERG K(+) channel tail current deactivation. Therefore, in this study, we aim to confirm whether ginsenoside Rg3 targeting hERG K(+) channel could be used to reverse the vandetanib-induced QT interval prolongation. Electrocardiogram (ECG) and monophasic action potential (MAP) were recorded using electrophysiology signal sampling and analysis system in Langendorff-perfused rabbit hearts. The current clamp mode of the patch-clamp technique was used to record transmembrane action potential. The whole-cell patch-clamp technique was used to record the hERG K+ current. In Langendorff-perfused hearts, vandetanib prolonged the QT interval in a concentration-dependent manner with an IC50 of 1.96 μmol/L. In human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), vandetanib significantly prolonged the action potential duration at 50%, 70%, and 90% repolarization (APD50, APD70, and APD90). In stable transfected human hERG gene HEK293 cells, vandetanib caused concentrate-dependent inhibition in the step and tail currents of hERG. As expected, ginsenoside Rg3 relieved vandetanib-induced QT interval prolongation in Langendorff-perfused heart and reversed vandetanib-induced APD prolongation in hiPSC-CMs. Furthermore, ginsenoside Rg3 alleviated vandetanib-induced hERG current inhibition and accelerated the process of the channel activation. Ginsenoside Rg3 may be a promising cardioprotective agent against vandetanib-induced QT interval prolongation through targeting hERG channel. These novel findings highlight the therapeutic potential of ginsenoside to prevent vandetanib-induced cardiac arrhythmia.

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Section: Discussionmentioning

confidence: 99%

[Retracted] Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib‐Induced QT Interval Prolongation

Zhang

Luo

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…It is characterized by an abnormally short QT interval on the ECG with a QT C interval of ~320 ms or less, tall and peaked T-waves, and increased T peak − T end width (Anttonen et al, 2009; Patel and Pavri, 2009; Couderc and Lopes, 2010; Cross et al, 2011; Gollob et al, 2011). Patients usually have structurally normal hearts and affected families tend to exhibit histories of syncope, abbreviated atrial and ventricular refractory periods, as well as increased susceptibility to atrial and ventricular arrhythmias and sudden death (Gaita et al, 2003; Schimpf et al, 2005; Giustetto et al, 2006; Hancox et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling

Adeniran¹,

Hancox²,

Zhang³

2013

Front. Physiol.

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Introduction: Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favorable to re-entry. Potential electromechanical consequences of the SQTS are less well-understood. The aim of this study was to utilize electromechanically coupled human ventricle models to explore electromechanical consequences of the SQTS.Methods and Results: The Rice et al. mechanical model was coupled to the ten Tusscher et al. ventricular cell model. Previously validated K+ channel formulations for SQT variants 1 and 3 were incorporated. Functional effects of the SQTS mutations on [Ca2+]i transients, sarcomere length shortening and contractile force at the single cell level were evaluated with and without the consideration of stretch-activated channel current (Isac). Without Isac, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca2+]i transients, sarcomere length shortening and contractile force. When Isac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca2+ transients, sarcomere shortening and contractile force. Single cell models were then incorporated into 3D human ventricular tissue models. The timing of maximum deformation was delayed in the SQTS setting compared to control.Conclusion: The incorporation of Isac appears to be an important consideration in modeling functional effects of SQT 1 and 3 mutations on cardiac electro-mechanical coupling. Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, our 3D simulations correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.

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Introduction to Ion Channels and the Cardiac Action Potential

Adeniran

2014

Modelling the Short QT Syndrome Gene Mutations

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The Short QT Syndrome

Cited by 7 publications

References 107 publications

[Retracted] Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib‐Induced QT Interval Prolongation

[Retracted] Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib‐Induced QT Interval Prolongation

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling

Introduction to Ion Channels and the Cardiac Action Potential

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