Model studies of cardiac arrhythmias: Reentry and arrhythmogenic activity of the single cell

Reentry is a major cause of arrhythmias following myocardial ischemia or infarction. Recent experiments demonstrated high degree of cellular uncoupling in cardiac tissue under ischemia conditions [1]. Our previous simulations [2,3] demonstrated that conduction disturbances which lead to reentry, such as slow conduction, décrémentai conduction and conduction block, can be caused by high degree of cellular uncoupling. Using a ring-shaped computer model of myocardial tissue we examined the effects of changes in cellular coupling and in membrane excitability on the initiation and maintenance of reentry [4]. The model represents a closed pathway of conduction in reentrant rhythm and is composed of 1500 cardiac cells of realistic dimensions. Cells are connected by a resistive network representing the gap junction. The electrical activity of the membrane is represented by the Beeler and Reuter model [5] with the Ebihara and Johnson [6] fast sodium current. By applying a properly timed premature stimulus, reentry could be induced. Whether reentry is sustained or nonsustained is determined by the degree of cellular uncoupling. As uncoupling is increased, velocity of propagation decreases and vulnerability to the induction of reentry increases. Mechanistically, the vulnerability is determined by the degree of functional inhomogeneity at the vulnerable window, which results mainly from inhomogeneity of the inactivation gate of the fast sodium channel. In contrast to the effect of cellular uncoupling, uniform reduction in membrane excitability resulted in slow propagation with decreased vulnerability due to reduced inhomogeneity in the state of the membrane at the vulnerable window. The reentrant action potential exhibits alternane, similar to those observed experimentally [7]. These alternane reflect alternations in the kinetics of slow ionic channels.