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

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.

In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation

“…was developed to simulate electrical waves under the AF-induced SND condition in the presence of drugs. In the 1D cable model, the mathematical model of the human atrial myocyte developed in our previous study [47][48][49][50][51][52] was used, and AF was simulated by introducing electrical remodelling based on experimental data [53][54][55][56][57][58][59][60][61][62] (listed in the Supplementary Table 8). The membrane potential is described by:…”

In Silico Investigation of the CACNA1C N2091S Mutation in Timothy Syndrome

“…Computational modeling has shed valuable light on the ionic mechanisms underlying complex ventricular contractions. Gain-of-function muations, which include G406R [8], G402S&G406R [9] and R858H [10], were associated with APD prolongation, intracellular calcium handling abnormalities and triggered activity. In additon, alterations in calcium signaling (CaMKII) due to increased [Ca 2+ ]i arising from these mutation also partly contritubed to triggered activity [11].…”

Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

“…There is considerable evidence supporting the pathogenicity of this R858H variant, given the following: its identification in the two LQT8 pedigrees, one Japanese and one New Zealand, and at least one further Japanese symptomatic singleton patient, and with co‐segregation with phenotypic symptomatic status in the New Zealand family; from observations of in vitro biophysical assays in which the variant had been expressed in Chinese hamster ovary cells (Fukuyama, Ohno, et al, ); from computer simulations of the dynamics of human ventricular cells (Bai et al, ; Fukuyama, Ohno, et al, ); and from the population analyses conducted by ourselves as outlined above.…”