Biphasic effects on human atrial arrhythmogenicity of L-type calcium channel mutations associated with a Brugada/Short QT overlap syndrome - insights from a multiscale simulation study
Yirong Xiang, Jules C. Hancox, Henggui Zhang
TL;DR
This study uses computer models to explore how mutations in calcium channels can both increase and decrease the risk of heart rhythm disorders in the atria.
Contribution
The novel contribution is the discovery of biphasic arrhythmogenic effects of CACNA1C mutations in human atrial tissue through multiscale simulations.
Findings
Reduced L-type calcium channel activity shortened atrial repolarization and altered conduction velocity in a pacing-rate-dependent manner.
Large reductions in calcium channel activity increased arrhythmia risk, while moderate reductions had anti-arrhythmic effects.
Simulation models revealed bi-phasic effects in 1D, 2D, and 3D atrial tissues depending on the severity of channel dysfunction.
Abstract
Patients with abbreviated cardiac repolarization are at increased risk of cardiac arrhythmias including ventricular and atrial fibrillation (AF). In this computational simulation study, we investigated pro-arrhythmic effects of loss-of-function missense mutations in CACNA1C (A39V and G490R Cav1.2) identified in patients with a phenotype combining Brugada syndrome with shorter-than-normal QT intervals. Biophysically-detailed computational models of human atrial cells were modified to incorporate the functional impact of the CACNA1C encoded A39V and G490R mutations on the reduction of the maximal conductance (gCaL) of L-type calcium channels (LTCC). Varying levels of gCaL reduction were considered. Effects of deficient LTCC on atrial excitation and propagation were investigated by using cellular and multi-dimensional tissue models that included a one-dimensional atrial strand, a…
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Taxonomy
TopicsCardiac electrophysiology and arrhythmias · Cardiac Arrhythmias and Treatments · Ion channel regulation and function