ANTIFIBRILLATORY MECHANISMS OF INTRAPERICARDIAL AGENTS

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (the applicant's description verbatim): Intrapericardial drug administration has the intrinsic advantage of delivering high concentrations of compounds to intracardiac nerves, coronary vessels and myocardium while minimizing adverse side effects of systemic drug administration. Contact with these critical structures has the potential for novel antiarrhythmic actions. These include containment of profibrillatory effects of adrenergic nerves, coronary dilation without systemic hypotension, direct actions on the superficial sinus node without depressing contractility, and direct stabilization of electrical properties of the atria and ventricles. Available data indicate that intrapericardially administered agents have significant potential for suppressing arrhythmias, but the precise mechanisms involved have not been adequately defined. Another important limitation to development of intrapericardial antiarrhythmic therapy has been lack of access. We will employ our new technique which permits rapid (3-5 min), safe transvenous access to the normal pericardial space (Circulation 1998:98:2331). Specific Aims: 1. To test systematically the coronary hemodynamic and cardiac electrophysiologic effects of intrapericardial delivery of agents which act on critical epicardial sites including intracardiac nerves, coronary vessels, and epicardially dense transient outward current (Ito) channels in normal canines. 2. To determine the mechanisms whereby intrapericardially administered agents reduce cardiac vulnerability to arrhythmias during acute coronary artery occlusion and reperfusion. 3. To characterize the efficacy of intrapericardial agents in protecting against the profibrillatory effects of sympathetic nerve stimulation superimposed on acute myocardial ischemia and reperfusion. Cardiac vulnerability will be quantified by measuring epicardial and transmural dispersion of repolarization, by tracking T-wave alternans magnitude, a beat-to-beat variation in morphology of that waveform, and by monitoring spontaneous arrhythmias. Using the proposed methodologies and epicardial site-directed intrapericardial agents, important insights should emerge regarding antifibrillatory mechanisms of intrapericardial compounds. Ultimately, the proposed studies could lead to improved therapeutic approaches for suppression of life-threatening arrhythmias.