Pharmacologic treatment of reentrant arrhythmias remains largely empiric. Not all tachycardias respond the same way to a particular drug, and it is currently not possible to predict whether a drug gram is to relate the behavior of reentrant arrhythmias, including their initiation and termination and response to antiarrhythmic drugs, to specific characteristics of the reentrant circuit. This proposal continues to focus on the role of oscillations of cycle length and refractoriness on termination of reentry.
The Specific Aims are: 1) to describe the dynamics and mechanisms of cycle length oscillations and tachycardia terminations due to a) interval-dependent conduction and action potential duration, b) electrotonic interactions with bystander tissue, and c) switching between alternate paths; 2) to demonstrate how effects of different classes of antiarrhythmic drugs on use-dependent block of sodium channels and electrical restitution of action potential duration as well as a steady state effects on conduction and refractoriness affect patterns of oscillation and termination of reentry in circuits with specific properties; 3) to demonstrate the conditions for spontaneous initiation of reentry (without premature stimulation) and conversion of spontaneous nonsustained to sustained reentry. The studies will be performed using in vitro models of reentry around the canine atrial tricuspid ring and Purkinje fiber-ventricular muscle junction that allow correlation of activation sequence with transmembrane action potentials at critical sites in the circuit during reentry. The models involve reentry around a fixed path in which the duration of excitable gap and degree of recovery of excitability can be varied by adjusting an electronic delay. In some studies, intercellular coupling will be decreased using heptanol. Computer models of reentry will also be used to determine the relation between local dynamic electrical properties and patterns of oscillation and termination of reentry and of intermittent occurrence of reentrant premature beats. These studies should increase our understanding of the mechanisms of termination of reentrant tachycardias by drugs and the relationship between ectopic beats, nonsustained and sustained tachycardias. This investigation may lead to improved selection of antiarrhythmic drug therapy for patients with reentrant arrhythmias based on specific properties of the reentrant circuit that can be deduced from the spontaneous behavior of the tachycardia or responses to programmed stimulation.
