Name
Title | ||
|---|---|---|
HERG Effects on Ventricular Action Potential Duration and Tissue Vulnerability: A Computational Study |
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. |
Year | DOI | Venue |
|---|---|---|
2009 | 10.1007/978-3-642-01932-6_19 | FIMH |
Keywords | Field | DocType |
positive shift,activation v,computational study,tissue vulnerability,current i kr,ventricular action,inactivation v,apd alternans,extreme shift,negative shift,potential duration,dominant effect,combined effect,maximal conductance,herg effects,computational model,time constant,resting membrane potential,steady state,kinetics,computer model | Ventricular action potential,Myocyte,hERG,Membrane potential,Bifurcation analysis,Internal medicine,Long QT syndrome,Biophysics,Chemistry,Conductance,Time constant,Endocrinology | Conference |
Volume | ISSN | Citations |
5528 | 0302-9743 | 0 |
PageRank | References | Authors |
0.34 | 1 | 4 |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Alan P. Benson | 1 | 4 | 5.14 |
| Moza Al-Owais | 2 | 0 | 0.68 |
| Wing C. Tong | 3 | 0 | 0.34 |
| Arun V. Holden | 4 | 52 | 20.71 |