The proposed research addresses the questions: How do drugs terminate reentry? Why do they fail to terminate reentry? And how can one predict antiarrhythmic efficacy. The long range goal of this research program is to foster development of a more effective approach to selection of drugs based on the premise that specific properties of the reentrant circuit determine whether a drug will be antiarrhythmic. The primary focus is on dynamic behavior of reentry and the role of oscillations of cycle length and refractoriness in the termination of reentry. The six specific aims are: 1) To describe the mechanisms and dynamics of cycle length oscillation due to (a) interval-dependent conduction and action potential duration, (b) electronic interaction with bystander tissue, (c) path switching; 2) To study the role of pathway geometry, including proximity of lateral boundaries, on termination of reentry by antiarrhythmic drugs; 3) To investigate mechanisms of antiarrhythmic drug action due to fixed block, dynamic effects on the conduction and ADP restitution curve and effects on bystander tissue; 4) To demonstrate autonomic modulation of drug termination due to fixed block or cycle length oscillations; 5) to find dynamic patterns that identify important properties of the reentrant circuit and mechanisms of termination of reentry; and 6) To determine the structural basis for susceptibility to fixed block and dissociation of bystander tissue. The studies will be performed using two simple experimental models of reentry with different circuit properties: the canine atrial tricuspid ring in vitro and reentry around a cryolesion in the rabbit ventricular epicardium after cryoalblation of the endocardium in Langendorff perfused hearts. Histological studies will be performed to analyze the structural basis for critical sites if variable conduction and block and for bystander tissue that activates late or intermittently in the atrial tricuspid ring.
