Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling

Adeniran, Ismail; Harchi, Aziza El; Hancox, Jules C.; Zhang, Henggui

doi:10.1093/cvr/cvs082

Cited by 48 publications

(105 citation statements)

References 55 publications

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“…The fiber consisted of a 3.75-mm-long Endo region, a 5.25-mm-long Mid region and a 6-mm-long Epi region (APs for Endo cells, Mid cells and Epi cells under the basal condition are shown in Figure 1). The total length of the transmural cable was within the width range (~8–15 mm) of human ventricular wall (Drouin et al, 1995; Yan et al, 1998) and the proportions of each subdomain used in this study were consistent with those used in other studies (Zhang et al, 2008; Adeniran et al, 2012). The cellular uncoupling between the midmyocardium and epicardium was modeled with a 5-fold decrease in the diffusion coefficient at the epicardium-midmyocardium border, as previously suggested by Gima and Rudy (2002).…”

Section: Methodssupporting

confidence: 83%

Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

et al. 2017

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Acidosis has complex electrophysiological effects, which are associated with a high recurrence of ventricular arrhythmias. Through multi-scale cardiac computer modeling, this study investigated the mechanisms underlying the emergence of post-acidosis arrhythmia at the tissue level. In simulations, ten Tusscher-Panfilov ventricular model was modified to incorporate various data on acidosis-induced alterations of cellular electrophysiology and intercellular electrical coupling. The single cell models were incorporated into multicellular one-dimensional (1D) fiber and 2D sheet tissue models. Electrophysiological effects were quantified as changes of action potential profile, sink-source interactions of fiber tissue, and the vulnerability of tissue to the genesis of unidirectional conduction that led to initiation of re-entry. It was shown that acidosis-induced sarcoplasmic reticulum (SR) calcium load contributed to delayed afterdepolarizations (DADs) in single cells. These DADs may be synchronized to overcome the source-sink mismatch arising from intercellular electrotonic coupling, and produce a premature ventricular complex (PVC) at the tissue level. The PVC conduction can be unidirectionally blocked in the transmural ventricular wall with altered electrical heterogeneity, resulting in the genesis of re-entry. In conclusion, altered source-sink interactions and electrical heterogeneity due to acidosis-induced cellular electrophysiological alterations may increase susceptibility to post-acidosis ventricular arrhythmias.

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Section: Methodssupporting

confidence: 83%

Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

et al. 2017

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“…The lengths of each region were 3.75, 5.25 and 6 mm for ENDO, MIDDLE and EPI, respectively. These proportions and the total length are similar to those used in other studies [10, 36–38]. The diffusion coefficient, D was set at 0.0008 cm 2 /ms giving a conduction velocity (CV) of 52 cm/s through the fiber, which is relatively close to the experimental CV of ~50 cm/s [39, 40].…”

Section: Methodsmentioning

confidence: 81%

“…Experimentally obtained current–voltage ( I – V ) data [23] were used to modify the I K1 formulations for WT, WT-D172N and D172N conditions. This was achieved by simulating the experimental voltage-clamp protocol [23], with which the experimental data [23] were fitted to model equations by using the Broyden-Fletcher-Goldfarb-Shanno optimization algorithm following our previous study [10]. Relative current proportions for WT, WT-D172N and D172N conditions were scaled by using relative proportions of peak I Kir2.1 [23].…”

Section: Methodsmentioning

confidence: 99%

“…1 was modified to incorporate the D172N-induced changes in the channel kinetic properties, including (i) the marked augmentation of an outward Kir2.1 current through the D172N channel, and (ii) the rightward voltage shift of the peak repolarization current. The modified I K1 formulations for WT, WT-D172N and D172N conditions [10] are shown in Additional file 1.…”

Section: Methodsmentioning

confidence: 99%

“…The results from in vitro voltage clamp recordings have demonstrated an increased I K1 in the Kir2.1 channels during terminal repolarization of the action potentials (APs) [2]. Our previous computational studies [10] have shown that SQT3 abbreviated the AP duration (APD) and effective refractory period (ERP) and steepened APD restitution (APD-R) and ERP restitution (ERP-R) curves, which consequently shortened the QT interval and raised the T-wave amplitude. Whereas pro-arrhythmogenic effects of SQT3 in the human ventricles have been investigated [2, 10], less is known about the pharmacological agents that prevent incidence of arrhythmogenesis in SQT3 patients.…”

Section: Introductionmentioning

confidence: 99%

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Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study

2017

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BackgroundShort QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3.MethodsThe ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry.ResultsAmiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue’s temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue.ConclusionsAt the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12938-017-0369-0) contains supplementary material, which is available to authorized users.

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Effect of KCNQ1 G229D mutation on cardiac pumping efficacy and reentrant dynamics in ventricles: Computational study

Yuniarti

Setianto

Marcellinus

et al. 2018

Numer Methods Biomed Eng

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There is growing interest in genetic arrhythmia since mutations in gene which encodes the ion channel underlie numerous arrhythmias. Hasegawa et al reported that G229D mutation in KCNQ1 underlies atrial fibrillation due to significant shortening of action potential duration (APD) in atrial cells. Here, we predicted whether KCNQ1 G229D mutation affects ventricular fibrillation generation, although it shortens APD slightly compared with the atrial cell. We analyzed the effects of G229D mutation on electrical and mechanical ventricle behaviors (not considered in previous studies). We compared action potential shapes under wild-type and mutant conditions. Electrical wave propagations through ventricles were analyzed during sinus rhythm and reentrant conditions. I enhancement due to G229D mutation shortened the APD in the ventricular cells (6%, 0.3%, and 8% for endo, M, and epi-cells, respectively). The shortened APD contributed to 7% shortening of QT intervals, 29% shortening of wavelengths, 20% decrease in intraventricular pressure, and increase in end-systolic volume 17%, end-diastolic volume 7%, and end-diastolic pressure 11%, which further resulted in reduction in stroke volume as well as cardiac output (28%), ejection fraction 33% stroke work 44%, and ATP consumption 28%. In short, using computational model of the ventricle, we predicted that G229D mutation decreased cardiac pumping efficacy and increased the vulnerability of ventricular fibrillation.

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Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling

Abstract: Increased I(K1) due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.

Cited by 48 publications

References 55 publications

Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study

Effect of KCNQ1 G229D mutation on cardiac pumping efficacy and reentrant dynamics in ventricles: Computational study

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