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Cardiovascular Research 2001 50(2):301-313; doi:10.1016/S0008-6363(00)00293-5
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death

Colleen E. Clancy and Yoram Rudy*

Cardiac Bioelectricity Research and Training Center, Department of Physiology and Biophysics, Department of Biomedical Engineering, 509 Wickenden Building, Case Western Reserve University, Cleveland, OH 44106-7207, USA

* Corresponding author. Tel.: +1-216-368-4051; fax: +1-216-368-8672 yxr{at}po.cwru.edu

Background: A variety of mutations in HERG, the major subunit of the rapidly activating component of the cardiac delayed rectifier IKr, have been found to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to severe arrhythmogenic phenotypes leading to sudden cardiac death. Objective: We attempt to elucidate the mechanisms by which heterogeneous LQT2 genotypes can lead to prolongation of the action potential duration (APD) and consequently the QT interval on the ECG. Methods: We develop Markovian models of wild-type (WT) and mutant IKr channels and incorporate these models into a comprehensive model of the cardiac ventricular cell. Results: Using this virtual transgenic cell model, we describe the effects of HERG mutations on the cardiac ventricular action potential (AP) and provide insight into the mechanism by which each defect results in a net loss of repolarizing current and prolongation of APD. Conclusions: This study demonstrates which mutations can prolong APD sufficiently to generate early afterdepolarizations (EADs), which may trigger life-threatening arrhythmias. The severity of the phenotype is shown to depend on the specific kinetic changes and how they affect IKr during the time course of the action potential. Clarifying how defects in HERG can lead to impaired cellular electrophysiology can improve our understanding of the link between channel structure and cellular function.

KEYWORDS Arrhythmia (mechanisms); Computer modelling; K-channel; Long QT syndrome; Sudden death; Ventricular arrhythmias


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