Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models

Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT). Although the CACNA1C mutations were well identified in patients with cardiac arrhythmias, mechanisms by which cardiac arrhythmias are generated in such genetic mutation conditions remain unclear. In this study, we identified a novel mechanism of VT resulted from enhanced repolarization dispersion which is a key factor for arrhythmias in the CACNA1C G1911R mutation using multi-scale computational models of the human ventricle. The increased calcium influx in the mutation prolonged action potential duration (APD), produced steepened action potential duration restitution (APDR) curves as well as augmented membrane potential differences among different cell types during repolarization, increasing transmural dispersion of repolarization (DOR) and the spatial and temporal heterogeneity of cardiac electrical activities. Consequentially, the vulnerability to unidirectional conduction block in response to a premature stimulus increased at tissue level in the G1911R mutation. The increased functional repolarization dispersion anchored reentrant excitation waves in tissue and organ models, facilitating the initiation and maintenance of VT due to less meandering rotor tip. Thus, the increased repolarization dispersion caused by the G1911R mutation is a primary factor that may primarily contribute to the genesis of cardiac arrhythmias in Timothy Syndrome.