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.

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 two-dimensional idealized atrial sheet and three-dimensional human atria with realistic anatomical structure and detailed electrophysiology. Our results showed that reduced LTCC activity from the CACNA1C A39V and G490R mutations accelerated atrial repolarization, leading to shortened action potential duration and effective refractory period, as well as the loss of their rate-dependence. At the tissue level, decreased gCaL shortened the wavelength of atrial excitation waves, slowed down atrial conduction velocity (CV) at low pacing rates but increased it at high pacing rates. It also showed bi-phasic arrhythmogenic effects in One-dimensional (1D), Two-dimensional (2D) and Three-dimensional (3D) tissue simulations. A large reduction in ICaL increased tissue susceptibility to initiation and maintenance of atrial re-entrant excitation waves, while a moderate reduction showed anti-arrhythmic effects due to an increased meandering area of re-entrant excitation waves that led to early self-termination of the reentry. In conclusion, this study provides new mechanistic insights into understanding of biphasic effects of loss-of-function LTCC mutations on atrial pro-arrhythmias.