Dataset Information

Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.

ABSTRACT: Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of I_Kr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the I_Kr inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.

SUBMITTER: Zhang S

PROVIDER: S-EPMC9636227 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.

Zhang Shugang S Lu Weigang W Yang Fei F Li Zhen Z Wang Shuang S Jiang Mingjian M Wang Xiaofeng X Wei Zhiqiang Z

NPJ systems biology and applications 20221104 1

Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of I<sub>Kr</sub> was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Mar ...[more]

PMID: 36333337

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Project description:Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, I Ks. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased I Ks remain unclear. Possible pharmacological interventions of AF in the SQT2 condition also remain to be elucidated. Using computational modelling, we assessed the functional impact of SQT2 mutations on human sinoatrial node (SAN) pacemaking, atrial repolarisation and arrhythmogenesis, and efficacy of the anti-arrhythmic drug quinidine. Markov chain formulations of I Ks describing two KCNQ1 mutations - V141M and V307L - were developed from voltage-clamp experimental data and then incorporated into contemporary action potential (AP) models of human atrial and SAN cells, the former of which were integrated into idealised and anatomically detailed tissue models. Both mutations shortened atrial AP duration (APD) through distinct I Ks 'gain-of-function' mechanisms, whereas SAN pacemaking rate was slowed markedly only by the V141M mutation. Differences in APD restitution steepness influenced re-entry dynamics in tissue - the V141M mutation promoted stationary and stable spiral waves whereas the V307L mutation promoted non-stationary and unstable re-entrant waves. Both mutations shortened tissue excitation wavelength through reduced effective refractory period but not conduction velocity, which served to increase the lifespan of re-entrant excitation in a 3D anatomical human atria model, as well as the dominant frequency (DF), which was higher for the V141M mutation. Quinidine was effective at terminating arrhythmic excitation waves associated with the V307L but not V141M mutation, and reduced the DF in a dose-dependent manner under both mutation conditions. This study provides mechanistic insights into different AF/bradycardia phenotypes in SQT2 and the efficacy of quinidine pharmacotherapy.

Project description:The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd) human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT) and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D) transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP), and re-entry wavelength (WL) by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i) the QT interval, which was primarily due to IKr block, and (ii) the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This computational modeling study provides novel insights into the clinical efficacy of disopyramide and quinidine in the setting of SQT1; it also dissects ionic mechanisms underlying QT and ERP prolongation. Our findings show that both drugs demonstrate efficacy in reversing the SQT1 phenotype, and indicate that disopyramide warrants further investigation as an alternative to quinidine in the treatment of SQT1.

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Dataset Information

Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.

Publications

Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.

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