7. Project Summary/Abstract The highest incidence of atrial fibrillation (AF) in patients referred for cardiac surgery is seen in patients with mitral valve (MV) disease. Approximately one third of patients referred for MV surgery have AF. Two to 2.5 million Americans suffer from MV disease and this prevalence is expected to double in the next 20 years. The worldwide burden of MV disease is even greater, and it is the most common underlying etiology of AF in the developing world. The most common underlying pathology is mitral regurgitation (MR).The purpose of this proposed project is to characterize the chronic structural, electrical, and mechanical remodeling of the atria in chronic MR in order to optimize and improve the surgical treatment of patients with both MR and AF. To realize this goal, our laboratory has created a novel model to look at left atrial volume overload that is physiologically similar to MR and has the advantage of being reversible, obviating the confounding effects of corrective surgery. A shunt is made between the left atrial appendage and the left ventricle (LV). We will also use two novel non-invasive technologies: electrocardiographic imaging and late gadolinium enhanced MRI to define the fibrotic substrates and the effect this has on atrial activation in patients with MR and AF. The specific aims are: Specific Aim 1. Define the electrical and mechanical substrates for AF in our chronic canine MR model by characterizing the detailed biatrial electrophysiology with the use of optical mapping, and correlating our mapping data with the underlying structural changes identified both by late gadolinium- enhanced MRI and histology. Specific Aim 2. Determine the degree and distribution of oxidative stress in the atria in our canine MR model. Define if the oxidative stress is originating in tissue, phagocytes or from both sources and then determine if the oxidative stress causes fibrosis by selectively inhibiting either one or both of these pathways. Specific Aim 3. Define the electrophysiological remodeling in patients with MR by using both electrocardiographic imaging (ECGI) and intraoperative mapping during normal sinus rhythm and AF. This electrical remodeling will be correlated with the underlying fibrosis determined by late gadolinium enhanced MRI. Successful completion of these aims will help define the underlying mechanisms for AF in MR. Specifically, it will help identify patients with MR who are at greatest risk of developing AF and will explain why some patients with severe MR develop AF and some do not develop AF.