N2091S Mutation in L-type Calcium Channel Promotes Action Potential Alternans in M Cells of Human Ventricle: A Simulation Study

CACNA1C-N2091S mutation has increased risk for sudden cardiac death (SCD) and action potential (AP) alternans is closely related to ventricular arrhythmias and SCD. However, the contribution of N2091S mutation on AP alternans is unidentified. This study aimed to investigate the effect of N2091S mutation on AP alternans in ventricular myocytes. N2091S mutation apparently increased L-type calcium current (ICaL), which further prolonged the AP duration and increased the Ca
²
+ concentration. Subsequently, it has been proved that N2091S mutation caused a decrease in threshold of stimulation frequency for AP alternans and wider alternans vulnerable window in midmyocardial cells (M cells). Further study demonstrated that AP alternans was induced only when increasing maximal I
CaL
conductance (G
CaL
) exceeded a critical value (156.98% larger than that in WT). It produced the prolongation of AP plateau phase that led to the inhibition of inward I
NCX
and the increase of sarcoplasmic reticulum (SR) Ca
²
+ loading. Furthermore, the resulting incomplete recovery of I
CaL
promoted inward I
NCX
and decreased SR Ca
²
+ loading in the next pacing cycle, consequently facilitating the genesis of Ca
²
+ cycling and AP alternans. This study demonstrated that N2091S mutation made M cells more prone to arrhythmia and the increase of GCaL was the mainfactor for inducing alternans.