In Silico Investigation of the CACNA1C N2091S Mutation in Timothy Syndrome

摘要

Experimental studies demonstrated that CACNA1C-N2091S led to a gain-of-function in the L-type calcium current (ICaL) linked to heritable Timothy Syndrome, but mechanisms by which the N2091S mutation promotes and perpetuates ventricular fibrillation remain unclear. This study sought to investigate the proarrhythmic effects of N2091S-induced ICaL. Using a dynamic ventricular myocyte model, we simulated ICaL, APs, Ca²⁺ transients ([Ca²⁺]i) and sarcoplasmic reticulum (SR) calcium profiles ([Ca²⁺]SR) in three cell types. Effects of the N2091S mutation on cell electrophysiology were quantified by changes in ICaL density, [Ca²⁺]i amplitude ([Ca²⁺]i(max)), SR calcium content ([Ca²⁺]SR(max)), action potential duration (APD) and AP shape. It was shown that the N2091S mutation increased ICaL(max), [Ca²⁺]i(max), [Ca²⁺]SR(max) and APD in three cell types. Compared with ENDO and EPI cells, MCELL cells with excessive prolongation of APD due to the N2091S mutation facilitated inducibility of early afterdepolarization (EAD)-mediated triggered activity. And the different EAD inducibility among the three cell types can amplify the electrical difference and thereby dispersion of repolarization, increasing susceptibility to ventricular arrhythmias. Thus, the N2091S mutation confers not only a trigger, but also a substrate for lethal ventricular arrhythmias.