Deactivation of Per-Arnt-Sim domain mutation increases the proarrhythmic risk of dofetilide

The aim of this work was to study the influence of PAS hERG R56Q mutation on the effects of dofetilide. The R56Q/WT mutation acts to increase the rate of deactivation. Markovian models of R56Q/WT mutation and dofetilide have been introduced in mammalian (modified Faber-Rudy) ventricular cellular model. Using this mutated ventricular cellular model we have studied the effects of dofetilide concentrations (I_Kr blocker). The results showed that increased rates of deactivation produce a rightward shift in the voltage dependence of activation and rectification. Deactivation occurs earlier, resulting in less repolarizing current late in the action potential where I_Kr usually plays a major role in repolarization and determining APD. Morever, the action of dofetilide increases the APD in the R56QIWT epicardial and endocardial cells, enhancing the diference in APD between both cell types. In addition, dofetilide amplifies the amplitude of the EADs that the R56QIWT mutation provokes in midmyocardial cells. In conclusion, the heterozygous R56Q hERG mutation increases the proarrhythmic risk of dofetilide prolonging the APD and enhancing the dispersion of repolarization.