Treatment of reentrant arrhythmias with drugs remains largely empiric. The long range goal of this research program is to investigate factors that are important in the initiation and termination of reentry in different types of reentry and mechanisms of antiarrhythmic action. This proposal focuses on interval- dependent changes conduction and action potential duration that cause unstable oscillations that can terminate reentry and the role of these oscillations for antiarrhythmic action of drugs.
The aims of this study are: 1) to examine the quantitative predictors of unstable oscillations based on the slopes of the conduction curve during the relative refractory period and the restitution curve that describes changes in action potential duration and to demonstrate that termination caused by cycle length oscillation occurs before the steady state wavelength exceeds the pathlength of the circuit; 2) to demonstrate how effects of different classes of antiarrhythmic drugs on use-dependent block of sodium channels and electrical restitution as well as effects on steady state properties influence the stability of reentry and whether they cause termination as a result of unstable oscillation; 3) to document the role of unstable oscillations of conduction and refractoriness and other factors in the termination of single beats or nonsustained runs of reentry and the stabilization of sustained reentry alter initiation by premature stimulation. These studies will be performed using an in vitro model of reentry around the tricuspid ring that allows detailed recording of activating sequence and transmembrane action potentials during reentry. This model involves reentry around a fixed barrier with incomplete recovery of excitability. A computer model of reentry will be used to evaluate determinants of stable or unstable oscillations of conduction and refractoriness. These studies should increase our understanding of the difference between reentrant circuits that support nonsustained tachycardias versus those that allow stabilization of sustained tachycardia and the mechanism by which some antiarrhythmic drugs terminate sustained reentry. This may lead to improved selection of antiarrhythmic therapy of patients with reentrant arrhythmias based on specific properties of the reentrant circuit deduced from responses to programmed stimulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038386-02
Application #
3354601
Study Section
Cardiovascular Study Section (CVA)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ingelmo, C; Frame, L H (2000) Mechanism for site-dependent differences in the shape of the resetting response curve in fixed barrier reentry. J Cardiovasc Electrophysiol 11:981-9
Fei, H; Yazmajian, D; Hanna, M S et al. (1997) Termination of reentry by lidocaine in the tricuspid ring in vitro. Role of cycle-length oscillation, fast use-dependent kinetics, and fixed block. Circ Res 80:242-52
Frame, L H; Rhee, E K; Bernstein, R C et al. (1996) Reversal of reentry and acceleration due to double-wave reentry: two mechanisms for failure to terminate tachycardias by rapid pacing. J Am Coll Cardiol 28:137-45
Fei, H; Frame, L H (1996) d-Sotalol terminates reentry by two mechanisms with different dependence on the duration of the excitable gap. J Pharmacol Exp Ther 277:174-85
Frame, L H (1996) Lessons from animal models of atrial arrhythmias. Cardiol Clin 14:471-81
Fei, H; Hanna, M S; Frame, L H (1996) Assessing the excitable gap in reentry by resetting. Implications for tachycardia termination by premature stimuli and antiarrhythmic drugs. Circulation 94:2268-77
Frame, L H; Rhee, E K; Fei, H et al. (1991) Proarrhythmic and antiarrhythmic effects of flecainide on nonsustained reentry around the canine atrial tricuspid ring in vitro. Pacing Clin Electrophysiol 14:1728-34
Frame, L H; Rhee, E K (1991) Spontaneous termination of reentry after one cycle or short nonsustained runs. Role of oscillations and excess dispersion of refractoriness. Circ Res 68:493-502
Stamato, N J; Frame, L H; Rosenthal, M E et al. (1989) Procainamide-induced slowing of ventricular tachycardia with insights from analysis of resetting response patterns. Am J Cardiol 63:1455-61