Influence of pore hERG mutation on dofetilide proarrhythmic risk

The aim of this work was to study the influence of pore KCNH2 mutation on the effects of dofetilide. Markovian models of G604S/WT mutation and dofetilide have been introduced in guinea pig ventricular cellular model. The effects of this pore mutation affecting this channel were analyzed. The G604S/WT mutation accelerates the inactivation and recovery from inactivation. Using this mutated cellular model we have studied the effects of dofetilide concentrations (I Kr blocker). The results showed that the reduction of G Kr is the main factor in the APD prolongation in the case of G604S/WT mutation. The shift of the inactivation curve and the recovery from inactivation to the left accelerates the transition between the open and inactivated states. The action of dofetilide prolongs the APD in the G604S/WT epicardial and endocardial cells and even provokes EADs development in endocardial cells. In addition, exposure of G604S/WT to this drug amplifies the amplitude of the EADs generated in midmyocardial cells by the mutation alone. In conclusion, the heterozygous G604S hERG mutation increases the proarrhythmic risk of dofetilide prolonging the APD and enhancing the dispersion of repolarization.