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

Jieyun Bai,Kuanquan Wang,Henggui Zhang,Yongfeng Yuan,Qince Li

doi:10.1038/srep31262

Abstract

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.

Highlights

Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT)
The increases of action potential duration (APD) and effective refractory period (ERP) were inhomogeneous for the three different cell types, indicating an augmented transmural heterogeneity of APD across the ventricle wall in the G1911R mutation condition, leading to an increased dispersion of repolarisation
It has been reported that the G1911R mutation caused a gain-of-function of CaV1.2, mechanisms by which the CACNA1C G1911R mutation facilitate and perpetuate organ-scale VT remain unclear

Summary

Introduction

Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT). 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. Mutations caused a gain-of-function of CaV1.2 L-type calcium channel, leading to an increased calcium influx, resulting in a dramatic AP prolongation[19,23,26] and afterdepolarization-triggered activity[10,17,24,25] They steepened the action potential duration restitution (APDR) curve, disrupted rate-dependent cardiac excitation dynamics and promoted the development of alternans[24]. We hypothesized that the increased ICaL in the G1911R mutation augmented repolarization dispersion through the transmural ventricular wall with intrinsic repolarization heterogeneity, leading to an increased tissue’s vulnerability to generate unidirectional conduction block of excitation waves, facilitating the genesis of VT In this process, the midmyocardial (MCELL) region severed as an excitable obstacle for stabilizing and sustaining VT. Idealized two-dimensional (2D) and realistic three-dimensional (3D) models with a MCELL island were built to simulate the initiation and maintenance of re-entry and examine effects of G1911R mutation on the genesis of VT

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Conclusion