Effects of the Antiarrhythmic Drug Dofetilide on Transmural Dispersion of Repolarization in Ventriculum. A Computer Modeling Study

Dofetilide is a class-Ill drug that inhibits the rapid component of the delayed potassium current (I_Kr). Experimental studies have shown that the different layers of ventricular muscle present differences in action potential duration (APD) and different responses to class III agents. It has been suggested that it contributes to APD heterogeneity in the ventricles. However, in vivo studies suggest that the strong cellular coupling reduces APD dispersion in intact heart. The aim of this paper is to study the effect of dofetilide on the action potentials (APs) in isolated ventricular cells and on APD dispersion in a strand of ventricular tissue. A mathematical model of dofetilide effects on I_Kr has been developed and incorporated into the Luo-Rudy dynamic model of ventricular AP. Our results show that dofetilide induces in midmyocardium cells a faster time-course inhibition of I_Kr than in endocardial or epicardial cells, and periods of instability with beat-to-beat APs variability. This behavior could favor temporal dispersion of repolarization between the different cells. The results also indicate that although dofetilide increases, the transmural gradient of APD in the ventricular wall, early after depolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions.