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Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study.

ABSTRACT: The KCNQ1 S140G mutation, which is involved in I_Ks current, affects atrial fibrillation. However, little is known about its effect on the mechanical behavior of the heart. Therefore, we assessed the influence of the KCNQ1 S140G mutation on ventricular electrophysiological stability and mechanical pumping performance using a multi-scale model of cardiac electromechanics. An image-based electromechanical model was used to assess the effect on electrical propagation and arrhythmogenesis of the KCNQ1 S140G mutation. In addition, it was used to compare the mechanical response under the wild-type (WT) and S140G mutation conditions. The intracellular calcium transient obtained from the electrophysiological model was applied as an input parameter to a mechanical model to implement excitation-contraction coupling. The I_Ks current equation was modified to account for expression of the KCNQ1 S140G mutation, and it included a scaling factor (?) for mutant expressivity. The WT and S140G mutation conditions were compared at the single-cell and three-dimensional (3D) tissue levels. The action potential duration (APD) was reduced by 60% by the augmented I_Ks current under the S140G mutation condition, which resulted in shorter QT interval. This reduced the 3D sinus rhythm wavelength by 60% and the sustained re-entry by 56%. However, pumping efficiency of mutant ventricles was superior in sinus rhythm condition. In addition, the shortened wavelength in cardiac tissue allowed a re-entrant circuit to form and increased the probability of sustaining ventricular tachycardia and ventricular fibrillation. In contrast, under the WT condition, a normal wavelength (20.8 cm) was unlikely to initiate and sustain re-entry in the cardiac tissue. Subsequently, the S140G mutant ventricles developed a higher dominant frequency distribution range (2.0-5.3 Hz) than the WT condition (2.8-3.7 Hz). In addition, stroke volume of mutant ventricles was reduced by 65% in sustained re-entry compared to the WT condition. In conclusion, signs of the S140G mutation might be difficult to identify in sinus rhythm even though the mutant ventricles show shortened QT interval. This suggests that the KCNQ1 S140G mutation increases the risk of death by sudden cardiac arrest. In addition, the KCNQ1 S140G mutation can induce ventricular arrhythmia and lessen ventricular contractility under re-entrant conditions.

SUBMITTER: Jeong DU

PROVIDER: S-EPMC6080549 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study.

Jeong Da Un DU Lim Ki Moo KM

Frontiers in physiology 20180731

The KCNQ1 S140G mutation, which is involved in I<sub>Ks</sub> current, affects atrial fibrillation. However, little is known about its effect on the mechanical behavior of the heart. Therefore, we assessed the influence of the KCNQ1 S140G mutation on ventricular electrophysiological stability and mechanical pumping performance using a multi-scale model of cardiac electromechanics. An image-based electromechanical model was used to assess the effect on electrical propagation and arrhythmogenesis ...[more]

PMID: 30108508

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Project description:There are representative electrical parameters for understanding the mechanism of reentrant waves in studies on tachyarrhythmia, namely the action potential duration (APD), dominant frequency, phase singularity, and filament. However, there are no studies that have directly identified the correlation between these electrophysiological parameters and cardiac contractility. Therefore, we have identified individual and integrative correlations between these electrical phenomena and contractility during tachyarrhythmia by deriving regression equations and also investigated the electrophysiological parameters affecting cardiac contractility during tachyarrhythmia. We simulated ventricular tachyarrhythmia with 48 types of electrical patterns by applying four reentry generation methods and changing the electrical conductivity of the potassium channel, which has the greatest effect on ventricular tissue. The mechanical responses reflecting electrical complexity were obtained through deterministic simulations of excitation-contraction coupling. We used the stroke volume and amplitude of myocardial tension (ampTens) as the variables representing contractility. We derived stochastic models through single- and multivariable regression analyses to identify the electrical parameters affecting contractility during tachyarrhythmia. In single-variable regression analysis, the APD, dominant frequency, and filament, excluding phase singularity, have statistically significant correlations with the stroke volume and ampTens. Among them, the APD has the maximum influence on these two mechanical parameters (standard beta coefficient: 0.859 for stroke volume, 0.930 for ampTens). The stochastic model using all four electrical parameters fails to accurately predict contractility owing to the multicollinearity between the APD and dominant frequency. We have rederived the multi-variable stochastic model using three electrical parameters without the APD. The filament has the greatest effect on the stroke volume stochastically (standard beta coefficient: 0.853 and 0.752). The dominant frequency has the greatest effect on ampTens statistically (standard beta coefficient: -0.813). We conclude that among the electrical parameters, the APD has the highest individual influence on mechanical contraction, and the filament has the highest integrative influence in both statistical terms.

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 ? 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:BackgroundHeart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression.ObjectiveIn this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation.MethodsTwo different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias.ResultsSimulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+/Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure.ConclusionAn extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.

Dataset Information

Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study.

Publications

Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study.

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