Pore hERG mutation A561V increases dofetilide proarrhythmic risk. A simulation study

Abstract

The aim of this work was to study the influence of pore KCNH2 mutation on the effects of dofetilide. Markovian models of A561V/WT mutation and dofetilide have been introduced in guinea pig ventricular cellular model. The effects of this pore mutation affecting this channel were analyzed. Using this mutated cellular model we have studied the effects of dofetilide concentrations (IhERG blocker). The results showed that the reduction of the rapid component of delayed rectifier potassium current conductance is the main factor in the prolongation of duration of action potential in the case of A561V/WT mutation. The action of dofetilide prolongs the duration of action potential in the A561V/WT epicardial and endocardial cells. In addition, exposure of A561V/WT to this drug amplifies the amplitude of the early after depolarizations generated in midmyocardial cells by the mutation alone. In conclusion, the heterozygous A561V/WT pore hERG mutation increases the proarrhythmic risk of dofetilide prolonging the duration of action potential and enhancing the dispersion of repolarization.