Role of Stretch in Focal Atrial Fibrilation

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DESCRIPTION (provided by applicant): The candidate wishes to pursue an academic and research career in cardiac electrophysiology, with a primary focus on the pathophysiology of atrial arrhythmias in animal models. He has dedicated one of the last two years of his fellowship (in clinical cardiac electrophysiology) to the animal lab, and has already done considerable work in understanding the electrophysiology of the pulmonary veins and their role in the genesis of atrial fibrillation (AF). A better understanding of the underlying mechanisms of AF is crucial to the development of effective preventive and therapeutic strategies for this arrhythmia. Recent observations suggest that in a large number of patients, AF may be originating from focal "triggers" in the pulmonary veins. The electrophysiologic properties of these focal sources are poorly defined, however. With the aid of high-resolution optical mapping, the candidate has recently described heterogeneous conduction and repolarization within the pulmonary veins, and has demonstrated micro re-entry in this region. This project aims to further characterize the electrophysiologic properties of canine pulmonary veins, in response to acute or chronic atrial stretch. It is expected that this mentored award will allow the candidate to develop the analytical as well as the technical and methodological skills he requires to develop into an independent physician-scientist. The candidate's mentors have a long track record of pathbreaking investigation in basic and clinical arrhythmia research; in addition, the animal research facilities at the Krannert Institute are amongst the finest in the world. Specific Aim 1 will attempt to study the effects of acute balloon stretch/dilatation on the electrophysiology of normal, canine pulmonary veins. Both high-density endocardial catheter mapping (in the intact dog) and high-resolution optical mapping (in a Langendorff preparation) will be utilized to study the pulmonary veins. In Specific Aim 2, we will examine electrophysiologic characteristics of the pulmonary vein in the setting of chronic atrial dilatation. A canine model of chronic mitral regurgitation will be used for this purpose. Optical mapping will be performed in a Landendorff preparation to determine the electrophysiology in the intact vein. Histologic and gap junction studies will be also performed as part of this aim. In addition, we will study the electrophysiology of isolated pulmonary vein cardiomyocytes.