Development of Atrial Impulse Initiation and Conduction

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DESCRIPTION (provided by applicant): Atrial rhythm disorders are the most common type of sustained arrhythmias and contribute significantly to cardiac related morbidity and mortality. The electrophysiological substrates for many cardiac rhythm disturbances are set in place early in heart development. Although a number of genes and signaling pathways involved in specification and differentiation of the early embryonic heart, major gaps in our understanding of the functional implications of such findings remain. In particular, we know little about the electrophysiologic properties of the major atrial structures during development and how their alteration contributes to an arrhythmogenic substrate. This proposal focuses on the developmental aspects of impulse initiation and the genesis of atrial conduction. The central hypothesis we will test is that impulse initiation in the sinus node and coordinated conduction through the atria to the AV node results from the developmental modulation of ion channels and connexin expression. We will test this hypothesis by pursuing the following 3 specific aims: SPECIFIC AIM 1. Determine the electrophysiological features that accompany the formation of a mature sinoatrial node with emphasis on the role played by the inward rectifier current (IK1). SPECIFIC AIM 2. Determine the role of developmental changes of connexin expression in impulse initiation and propagation in the mouse sinus node and atria. SPECIFIC AIM 3. Determine the relative contributions of cellular excitability and intercellular coupling in impulse initiation and atrial conduction. Our overall goal is to generate information that will directly impact our understanding of the basic electrophysiological events underlying mammalian heart development and their role in the formation of atrial arrhythmias. Our findings are expected to have a major impact on human health, because they will allow us to form new strategies to prevent major frequently occurring cardiac arrhythmias.