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Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling

Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling AimsOne form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K+ current (IK1). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias.Methods and resultsThe ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to IK1 based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N ‘mutant’ IK1 led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 ‘mutant’ IK1 also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.ConclusionIncreased IK1 due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiovascular Research Oxford University Press

Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling

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References (67)

Publisher
Oxford University Press
Copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. For permissions please email: journals.permissions@oup.com
Subject
ORIGINAL ARTICLES
ISSN
0008-6363
eISSN
1755-3245
DOI
10.1093/cvr/cvs082
pmid
22308236
Publisher site
See Article on Publisher Site

Abstract

AimsOne form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K+ current (IK1). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias.Methods and resultsThe ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to IK1 based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N ‘mutant’ IK1 led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 ‘mutant’ IK1 also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.ConclusionIncreased IK1 due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.

Journal

Cardiovascular Research – Oxford University Press

Published: Apr 1, 2012

Keywords: Arrhythmia Inward rectifier Short QT syndrome Ventricular fibrillation

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