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

Abstract

Dofetilide is a class-III 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 afterdepolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions.

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

“…We updated our previous dofetilide model [21] to additionally include the experimentally observed 70-fold preferential binding to the inactivated state relative to the open state [22] and to mimic the clinically observed 16 % prolongation of the QT interval produced by the therapeutic dose 8.22 nM [23] (summarized in Figure 1D). Figures 1 A–C show the kinetics of the simulated (lines) I Kr block by 50 nM dofetilide (A and B) and the washout of 3 μM (C) (solid lines) together with experimental results (symbols) for comparison: [24] (A), [25] (B) and [26](C).…”

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

“…We updated our previous dofetilide model [21] to additionally include the experimentally observed 70-fold preferential binding to the inactivated state relative to the open state [22] and to mimic the clinically observed 16% prolongation of the QT interval produced by the therapeutic dose 8.22 nM [23] (summarized in Fig. 1D).…”

Kinetics of Drug Interaction with the Kv11.1 Potassium Channel

“…The importance of considering kinetics in understanding the proarrhythmic properties of drugs is a widely accepted concept, and many groups have used kinetic descriptions of binding in their in silico analyses (Brennan et al, 2009;Zhou et al, 2009;Saiz et al, 2011;Di Veroli et al, 2013b). However, none of these studies has directly measured the kinetics of block and unblock but, rather, inferred kinetics from more complex pulsing protocols.…”

“…In the pursuit of an in silico approach to assessing the proarrhythmic propensity of QT-prolonging drugs, this type of detailed kinetic constraint is critical in working toward a unified model. There are multiple model structures that have been proposed for drug interaction with K v 11.1 (Zhou et al, 2009;Saiz et al, 2011;Di Veroli et al, 2013b) that, at least in part, likely stem from the variety of relatively complex protocols used to obtain the data that constrains them. We would argue that our back-to-basics approach of directly measuring the block and unblock without complex pulsing protocols allows development of models at the fundamental level, which can be further refined in the future with more complex experimental datasets that, for example, include activation and deactivation as well as inactivation.…”