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 I Kr and, therefore, action potential duration (APD). These mutations can affect various properties that determine I Kr 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 V 0.5, a negative shift of inactivation V 0.5, or by reducing maximal conductance. The largest reduction in APD is achieved by a positive shift of inactivation V 0.5. Altering the time constant of activation had relatively little effect. When two or more parameters were altered simultaneously, shifting inactivation V 0.5 had the dominant effect on APD, except for some extreme shifts of activation V 0.5 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 I Kr kinetic parameters that, in isolation, cause either shortening or prolongation of the AP. Therapeutics that alter I Kr conductance are potentially most beneficial.
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Benson, A.P., Al-Owais, M., Tong, W.C., Holden, A.V. (2009). HERG Effects on Ventricular Action Potential Duration and Tissue Vulnerability: A Computational Study. In: Ayache, N., Delingette, H., Sermesant, M. (eds) Functional Imaging and Modeling of the Heart. FIMH 2009. Lecture Notes in Computer Science, vol 5528. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-01932-6_19
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DOI: https://doi.org/10.1007/978-3-642-01932-6_19
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-01931-9
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