Role of CaMKII and PKA in Early Afterdepolarization of Human Ventricular Myocardium Cell: A Computational Model Study.

Ling Dai,Yinglan Gong,Dingchang Zheng,Yunliang Zang,Ling Xia

doi:10.1155/2016/4576313

Abstract

Early afterdepolarization (EAD) plays an important role in arrhythmogenesis. Many experimental studies have reported that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and β-adrenergic signaling pathway are two important regulators. In this study, we developed a modified computational model of human ventricular myocyte to investigate the combined role of CaMKII and β-adrenergic signaling pathway on the occurrence of EADs. Our simulation results showed that (1) CaMKII overexpression facilitates EADs through the prolongation of late sodium current's (I NaL) deactivation progress; (2) the combined effect of CaMKII overexpression and activation of β-adrenergic signaling pathway further increases the risk of EADs, where EADs could occur at shorter cycle length (2000 ms versus 4000 ms) and lower rapid delayed rectifier K+ current (I Kr) blockage (77% versus 85%). In summary, this study computationally demonstrated the combined role of CaMKII and β-adrenergic signaling pathway on the occurrence of EADs, which could be useful for searching for therapy strategies to treat EADs related arrhythmogenesis.

Highlights

Afterdepolarizations (EADs) are triggered before the completion of repolarization [1] and associated with polymorphic ventricular tachyarrhythmia for long QT syndrome patients [2]
The results indicate that the delayed deactivation of INaL, rather than its amplitude variation, contributes to the formation of Early afterdepolarization (EAD)
This study developed a modified computational model of human ventricular myocardium cell based on the ORd human model with the integration of regulation mechanism by calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) [20], with which their effects on EADs have been investigated

Summary

Introduction

Afterdepolarizations (EADs) are triggered before the completion of repolarization [1] and associated with polymorphic ventricular tachyarrhythmia for long QT syndrome patients [2]. Prolongation of action potential duration (APD) and recovery of L-type Ca2+ current have been reported as two important factors for the occurrence of EADs [3]. Any factors that could change the intensity or time sequence of these currents may lead to the occurrence of EADs [4,5,6,7,8]. It has been reported that CaMKII phosphorylates ICaL, leading to increased amplitude and APD prolongation and facilitating the occurrence of EADs [10, 11]. It would be useful to understand and quantify these regulatory roles. It is very difficult for the laboratory experiments to achieve this

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Results

Conclusion