Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation - HHM

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Wednesday, 4 October 2017

Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation

Jieyun Bai , Kuanquan Wang , Yashu Liu , Yacong Li , Cuiping Liang , Gongning Luo , Suyu Dong , Yongfeng Yuan and Henggui Zhang




Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF.

The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics. R858H “mutant” L-type calcium current ( I ) augmented sarcoplasmic reticulum calcium content, leading to the development of after depolarizations at the single cell level and focal activities at the tissue level.

It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H “mutant” tissue more vulnerable to the induction of reentry compared with other conditions.

 In conclusion, altered I due to the CACNA1C R858H mutation increases arrhythmia risk due to after depolarizations and increased tissue vulnerability to unidirectional conduction block.

However, the observed reentry is not due to after depolarizations (not present in our model), but rather to a novel blocking mechanism.


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