CARDIAC IMPULSE INITIATION AND REPOLARIZATION

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The general hypothesis for this Project is that sympathetic innervation contributes importantly to the changes in ion channels that occur developmentally and to the evolution of specific receptor-effector pathways. We hypothesize as well that in the setting of incomplete sympathetic innervation abnormalities of specific ion channels and signal transduction pathways set the stage for lethal arrhythmias. This hypothesis derives from our earlier work on both beta-and alpha-adrenergic signaling and developmental changes in electrophysiology in the normal canine, rat and rabbit heart. We now focus on two canine models of disordered innervation: (a) surgical interruption of the sympathetic nerves to the heart in the first 24 hours of life, and (b) familial failure of innervation to a portion of the anteroseptal left ventricle in Germ Shepherd Dogs. Important, surgical right stellectomy and thoracic sympathectomy is characterized by asystolic sudden death in the first weeks of life; whereas the familial failure of innervation results in ventricular tachycardia and sudden death at 4-5 months of life. We perform intact animal, isolated tissue and single myocyte experiments to study the electrophysiology (focussing on repolarization and impulse initiation), ionic currents (focussing initially on I/ks and I/kr), signal transduction (focussing on beta-receptors, G proteins and adenylate cyclase) and molecular physiology (focusing initially on mRNA for canine ERG and on KvLQT1 and minK), with a view towards working vertically from the ECG of the intact animal through the molecular mechanisms responsible for arrhythmic events. Moreover, in cooperation with all other Projects on the Program, we shall achieve an understanding of the relationship between nerve-myocyte interaction, evolution of signaling processes and evolution of electrophysiologic control mechanisms. The significance of the proposed research is that it not only utilizes multiple approaches in an attempt to understand the control of rhythm and arrhythmias in the proposed models, but the models, themselves, incorporate features important clinically, in that they are relevant to pause-dependent tachycardias, those triggered by delayed after depolarizations, and to catecholamine-or exercise-dependent tachycardias that tend to afflict otherwise healthy young individuals.