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 (ICaL) 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 ICaL 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.
Highlights
Congenital long QT syndrome (LQTS) is characterized by an abnormally prolonged QT and high risk of ventricular arrhythmias in susceptible families (Goldenberg et al, 2008)
Our study confirmed that the effects of R858H-induced in the L-type calcium current (ICaL) are model independent. These results indicated that steep APD restitution (APDR) is not the mechanism of ventricular fibrillation (VF) caused by the R858H mutation
Our results suggest that R858H induced afterdepolarizations and transmural AP duration (APD) dispersion are responsible for the potential mechanisms underlying the formation of VF
Summary
Congenital long QT syndrome (LQTS) is characterized by an abnormally prolonged QT and high risk of ventricular arrhythmias in susceptible families (Goldenberg et al, 2008). The CACNA1C gene encodes CaV1.2 that is a subunit of L-type voltage-dependent calcium channel and gain-of-function mutations in CACNA1C have been suggested to be responsible for LQT8 manifestations, but the interplay between CACNA1C genotypes and malignant clinical phenotypes is likely complex (Giudicessi and Ackerman, 2013). A handful of other CACNA1C mutations were identified in patients exhibiting only modest QT prolongation (Gillis et al, 2012; Boczek et al, 2013, 2015a,b; Fukuyama et al, 2013, 2014; Hennessey et al, 2014; Wemhöner et al, 2015; Landstrom et al, 2016; Sutphin et al, 2016). Functional analysis of R858H mutant channels reveals a significant increase in the L-type calcium current (ICaL), relatively
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