Computer modeling is used to study the effect of electrical coupling between a myocardial zone where early afterdepolarizations (EAD's) can develop and the normal neighboring tissue. The effects of such coupling on EAD development and on the likelihood of EAD propagation as an ectopic beat are studied. The influence on EAD formation is investigated by approximating two partially coupled myocardial zones modeled as two active elements coupled by a junctional resistance R. For R values lower than 800 omega cm2, the action potentials are transmitted to the coupled element, and for R values higher than 850 omega cm2 they are blocked. In both ranges of R, when the electrical coupling increases, the EAD's appear at more negative takeoff potentials with higher amplitudes and upstrokes. The EAD's are not elicited if the electrical coupling is too high. In a separate model of two one-dimensional cardiac fiber segments partially coupled by a resistance R, critical R values exist, between 42 and 54 omega cm2, that facilitate EAD propagation. These results demonstrate that in myocardial zones favorable to the formation of EAD, the electrical coupling dramatically affects initiation of EAD and its spread to the neighboring tissue.

The development of early afterdepolarizations (EADs) in Purkinje fibers and their propagation to ventricular muscle cells are studied by computer modeling. The Purkinje-ventricular system has been simulated by a two-dimensional model of a Purkinje fiber (PF) connected to a thin sheet of ventricular muscle tissue (VMT). EADs are induced in the PF by enhancing the fast second inward current, iCa,f, and blocking the delayed K+ current, iK, while the VMT is kept under physiological conditions. Different phenomena are observed depending on the EAD conditions applied. For 70% iK blockade and iCa,f enhancement greater than 60%, a single phase 3 EAD developed in the PF propagates to the VMT generating an ectopic beat. For 80% iK blockade and iCa,f enhancement in the range from 0% to 70%, multiple ectopic beats appear in the VMT. However, for iK blockades over 80%, action potentials in PF cells do not repolarize and the ectopic activity in the VMT disappears. In our simulations, the ionic mechanism underlying phase 3 EAD development is the reactivation of the fast sodium current in the PF. Our results demonstrate that there exists a critical range of EAD conditions that favor the development of EADs in the PF and their propagation to the VMT as ectopic activity. This phenomenon could underlie the genesis of some triggered arrhythmias.

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.

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Dofetilide selectively inhibits the rapid component of the delayed potassium current (I Kr IntroductionThe antiarrhythmic efficacy of drugs that induce prolongation of action potential duration (APD), through the blockade of the delayed rectifier current, I K , has been widely probed in reentrant arrhythmias. In different species, as guinea pig, I K consist on two components: a slowly activating component, I Ks , and a rapidly activating component, I Kr , sensitive to E -4031 or sotalol [1]. Dofetilide is an antiarrhythmic drug that specifically blocks the rapid component of the delayed rectifier potassium current I Kr [2][3][4]. In 1999, the U.S. Food and Drug Administration (FDA) approved dofetilide for the treatment of persistent atrial fibrillation and flutter. Dofetilide is classified as a pure class III antiarrhythmic agent because it produces only prolongation of action potential duration (APD), without any effect on the resting membrane potential, action potential amplitude or maximum rate of depolarization [4]. The effect of dofetilide on APD has been recorded in different myocardial tissues and species [5,6]. In all the myocardial tissues, blockade of I Kr by dofetilide induces a higher prolongation of APD, and hence, of the QT interval, as the concentration of dofetilide increases. Prolongation of APD is related with the increment of refractory period in cardiac tissue.While the efficacy of dofetilide as antiarrhythmic drug is related to the increment in refractoriness, the prolongation of QT may trigger the polymorphic ventricular tachycardia called torsade de pointes [7]. Different studies have found antiarrhythmic action of dofetilide in preventing and in terminating ventricular tachycardias [8] and in the prevention of atrioventriclar re-entrant tachycardia [9]. It has been also suggested that dofetilide may be useful in reducing the frequency of multiple episodes of monomorphic ventricular tachycardia and in increasing the efficacy of antitachycardia pacing in patients with implantable cardioverter-desfibrillator [10].Dofetilide is a potent blocker of I Kr . An IC 50 in the nanomolar range has been experimentally measured in guinea pig ventricular myocytes, namely 8. [3,13,16]. Once the block has been produced, the effect persists during a long period at rest, suggesting that the drug does not dissociate when the channel is closed; the drug seems to be trapped within the channel [3,16]. It has been recently suggested that dofetilide interacts with the channels in both the open and the inactivated states [17]. The interaction between dofetilide and receptor presents a very slow kinetics [11,13] and exhibits reverse use-dependence [2,16]. The increment in the dofetilide dose enhances the reverse-use dependence [2].The main objective of the present work is to develop a mathematical model of the I Kr block by dofetilide and to study the effect of different concentrations on the action potential characteristics.