Developing In Silico Descriptions Of Herg Channel Gating

The human ether a-go-go related gene (hERG) encodes the pore forming subunit of the cardiac delayed rectifier potassium channel. Mutations in hERG that disrupt gating can cause Long QT syndrome type 2, a disorder of cardiac repolarisation characterised by prolongation of the QT interval and risk of sudden cardiac death due to ventricular arrhythmias. There is therefore considerable interest in developing accurate mathematical descriptions of hERG gating in order to simulate the effect of hERG mutants on cardiac action potentials at both the cellular and tissue levels.In the first part of this study we have used a 5 state Markov model (1) minimised to in vitro electrophysiological data to describe hERG ionic currents associated with two clinically relevant mutants: G584S and G572S. These Markov descriptions were incorporated into models of the human ventricular action potential (2) and used to simulate the effects of these mutants on action potential waveforms and responses to premature stimuli. The results of our simulations for each mutant correlated well with the reported clinical phenotypes and were able to show how compensatory currents can contribute to phenotypic variability between families carrying the same hERG mutation.In the second part of this study we compare the abilities of several Markov schemes to reproduce hERG currents. In doing so we evaluate their suitability for our goal of incorporating mathematical descriptions of hERG into whole heart simulations as a way of assessing how altered hERG function predisposes to the development of arrhythmias triggered by premature beats.Our results demonstrate how in silico techniques lend an additional level of insight into understanding and characterising clinical mutations.1) Lu et al., J. Physiol. (2001), 537, 843-851.2) ten Tusscher KH, Panfilov AV., Am. J. Physiol. (2006) 291, H1088-100.