HERG Effects on Ventricular Action Potential Duration and Tissue Vulnerability: A Computational Study

  • Alan P. Benson
  • Moza Al-Owais
  • Wing C. Tong
  • Arun V. Holden
Part of the Lecture Notes in Computer Science book series (LNCS, volume 5528)

Abstract

The mutations to hERG (the human Ether-a-go-go Related Gene) that cause long QT syndromes produce effects on the rapid delayed rectifier K +  current IKr and, therefore, action potential duration (APD). These mutations can affect various properties that determine IKr kinetics. We used computational models of human ventricular myocytes to identify which of these properties, when altered, cause profound changes to APD and transmural dispersion of repolarisation (TDR). Such increases in both APD and TDR is caused by a positive shift of activation V0.5, a negative shift of inactivation V0.5, or by reducing maximal conductance. The largest reduction in APD is achieved by a positive shift of inactivation V0.5. Altering the time constant of activation had relatively little effect. When two or more parameters were altered simultaneously, shifting inactivation V0.5 had the dominant effect on APD, except for some extreme shifts of activation V0.5 or moderate reductions of maximal conductance. HERG mutations observed clinically lie in the parameter range where maximal conductance has the dominant effect. Bifurcation analysis showed stable steady states (corresponding to physiological resting membrane potential) at all parameter values, and no APD alternans. We conclude that increased APD due to hERG mutations seen clinically are a combined effect of alterations to IKr kinetic parameters that, in isolation, cause either shortening or prolongation of the AP. Therapeutics that alter IKr conductance are potentially most beneficial.

Keywords

Cardiac computational model hERG long QT syndrome arrhythmia 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Alan P. Benson
    • 1
    • 2
  • Moza Al-Owais
    • 1
  • Wing C. Tong
    • 1
  • Arun V. Holden
    • 1
    • 2
  1. 1.Computational Biology LaboratoryInstitute of Membrane and Systems BiologyUK
  2. 2.Multidisciplinary Cardiovascular Research CentreUniversity of LeedsLeedsUK

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