Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue

Saucerman, Jeffrey J., Healy, Sarah N., Belik, Mary E., Puglisi, Jose L. and McCulloch, Andrew D. (2004) Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue. Circulation Research, 95 12: 1216-1224. doi:10.1161/01.RES.0000150055.06226.4e


Author Saucerman, Jeffrey J.
Healy, Sarah N.
Belik, Mary E.
Puglisi, Jose L.
McCulloch, Andrew D.
Title Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue
Journal name Circulation Research   Check publisher's open access policy
ISSN 0009-7330
1524-4571
Publication date 2004-12
Sub-type Article (original research)
DOI 10.1161/01.RES.0000150055.06226.4e
Volume 95
Issue 12
Start page 1216
End page 1224
Total pages 9
Place of publication Baltimore, MD, USA
Publisher Lippincott, Williams & Wilkins for the American Heart Association
Language eng
Subject 1103 Clinical Sciences
Abstract The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the IKs channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of [beta]-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with [beta]-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between [beta]-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
Keyword [beta]-adrenergic signaling
arrhythmia
long-QT syndrome
computational model
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 79 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 86 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 12 Apr 2010, 15:07:31 EST by Laura McTaggart on behalf of Faculty Of Health Sciences