Intercellular Communication and Cardiac Arrhythmias

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DESCRIPTION (provided by applicant): Heart disease is often associated with the development of malignant ventricular arrhythmias and remains a major cause of mortality in the United States. Unfortunately, the underlying mechanisms responsible for initiation and maintenance of cardiac arrhythmias remains poorly understood. Fibrosis is associated with many forms of cardiovascular disease and is recognized as a major contributing cause of arrhythmias. Fibrosis is classically thought to indirectly contribute to cardiac electrophysiology by creating physical barriers to electrical conduction. However, numerous studies have suggested direct electrical coupling between myocytes and fibroblasts contributes to the electrophysiology of the normal and diseased heart. Although fibroblasts and myocytes express gap junction proteins, functional electrical coupling between these cell types is currently a subject of substantial debate. The long term objectives of this project are determine the contribution of fibroblast connexin expression to the electrophysiology of the normal and injured heart. This objective will be achieved using newly developed transgenic mice that lack connexin isoforms in fibroblasts and a novel cardiac injury model. Specific Aim 1 will determine the contribution of fibroblast connexin expression to the electrophysiological properties of the normal sinus node, atria and ventricles. The studies proposed will test the hypothesis that fibroblast connexin expression contributes to the electrophysiological properties of the sinus node, atria, and ventricles under normal physiological conditions. The experimental approach will include electrophysiological studies and detailed histological and morphological analysis of the sinus node, atria and ventricles of adult and senescent mice that lack connexin isoforms in fibroblasts. Specific Aim 2 will determine the contribution of fibroblast connexin expression to the conduction properties of injured cardiac tissue. Here, we will test the hypothesis that fibroblast connexin expression contributes to cardiac repair and the conduction properties of injured hearts. Detailed histology, high resolution optical mapping, microelectrode recordings, and arrhythmia analysis will be performed in mice that lack Cx43 and Cx45 in fibroblasts at selected time points after injury. Specific Aim 3 will determine the contribution of connexin expression in resident and bone marrow derived fibroblasts following cardiac injury. In this Specific Aim, we will test the hypothesis that connexin expression in resident and bone marrow derived fibroblasts contributes to the electrophysiological properties and arrhythmia dynamics of injured hearts. The contribution of connexin expression in resident and bone marrow derived fibroblasts will be determined using radiation chimeras. Hearts will be injured after bone marrow transplantation and studied at different time points. Detailed histology, high resolution optical mapping, microelectrode recordings, and arrhythmia analysis will be performed. The studies proposed in this application have wide ranging implications for the treatment of cardiac arrhythmias and will significantly contribute to our understanding of the basic principles that govern electrophysiology in healthy and injured hearts.