RECEPTOR BASIS FOR MULTICENTRIC ORIGIN OF ATRIAL IMPULSE

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In contrast to the conventional description of predominant unifocal sinus node electrogenesis, it has been shown that atrial impulse origin begins multicentrically from several widely separated sites encompassing an area of 45 x 15 mm in the right atrium. Also, each separate pacemaker site is associated with a different upper rate limit resulting in dynamic switching between the atrial pacemakers (APMs) coincident with changes in cycle length or rate. The long-term thrust of this study is to understand the basic mechanisms underlying the atrial pacemaker complex and to extend these observations to man. The specific aims are to: 1) discriminate between actual multicentric impulse origin (MCO) and conduction of a singly formed impulse simulating MCO; 2) quantitate and define the mechanism of rate differences of the multiple APMs; 3) determine the mechanisms responsible for the coordination and control of the multiple and widely distributed APM components; 4) define the locations and functions of APMs in human subjects and compare this data with that obtained experimentally in dogs. These objectives necessitate a multidisciplined approach centered about the recording of atrial extracellular potentials (ECP) from up to 360 points in vivo and in vitro. HEART RATE AND P-WAVE MORPHOLOGY WILL BE NOTED AND ATRIAL ACTIVATION SEQUENCE AND POTENTIAL DISTRIBUTION MAPS WILL BE GENERATED DURING CONTROL CONDITIONS AND DURING CONDITIONS RESULTING FROM AUTONOMIC PERTURBATIONS (PHARMACOLOGIC INFUSIONS AND/OR NERVE STIMULATION). THE ISOLATED, PERFUSED RIGHT ATRIAL PREPARATION WILL BE NECESSARY TO DETERMINE THE DIRECT EFFECTS OF PHARMACOLOGIC INFUSIONS ON THE APM COMPLEX. DOSE-RESPONSE DATA WILL BE CORRELATED WITH APM LOCATION. THE INFUSION STUDIES AND RADIOLIGAND BINDING ANALYSES WILL BE DIRECTED AT THE ELUCIDATION OF ATRIAL CHRONOTROPIC RECEPTOR MECHANISMS. RESULTS OBTAINED FROM THE ECP WILL REQUIRE CORRELATIONS TO BE MADE WITH POTENTIALS AT THE INTRACELLULAR LEVEL. ACTIVATION SEQUENCE AND POTENTIAL DISTRIBUTION DATA WILL BE OBTAINED FROM THE HUMAN HEART AT THE TIME OF CARDIAC SURGERY; DATA WILL BE COLLECTED DURING SPONTANEOUS CHANGES IN CYCLE LENGTH AND INITIATING CONDITIONS AS WELL AS BEFORE AND AFTER CHRONOTROPICALLY ACTIVE CARDIAC DRUGS ARE ADMINISTERED. These studies should provide a new basis for understanding the control of atrial rate and rhythm, the mechanisms of certain complex normal and abnormal rhythms characterized by alternating long and short cycle sequences, insight into atrial bradyarrhythmias and certain ectopic tachyarrhythmias, and the basis for changes in the P wave of the surface ECG.