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; Henggui Zhang

doi:10.3389/fphys.2017.00771

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

Front Physiol. 2017 Oct 4:8:771. doi: 10.3389/fphys.2017.00771. eCollection 2017.

Authors

Jieyun Bai¹, Kuanquan Wang¹, Yashu Liu¹, Yacong Li¹, Cuiping Liang¹, Gongning Luo¹, Suyu Dong¹, Yongfeng Yuan¹, Henggui Zhang^{1

2

3}

Affiliations

¹ School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China.
² Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.
³ Space Institute of Southern China, Shenzhen, China.

Abstract

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_CaL ) augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations 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_CaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model), but rather to a novel blocking mechanism.

Keywords: CACNA1C mutations; L-type calcium channel; Long QT syndrome; Timothy syndrome; computational cardiac modeling; dispersion of repolarization; ventricular fibrillation.