ABSTRACT Inflammation and vascular leak are common findings across several pathologies associated with arrhythmias. These include atrial fibrillation (AF), which affects up to 3% of the US population. AF progressively worsens, and increases risk of stroke and cardiovascular disease. Thus, we urgently need novel, mechanistically-driven therapies for AF. Vascular leak in AF patients results from elevated serum levels of inflammatory cytokines such as vascular endothelial growth factor (VEGF). While the thrombogenic impact of vascular leak in AF is widely recognized, its role in arrhythmogenesis remains unclear. One possible link between vascular leak and arrhythmia may be myocardial edema. Recent work by the PI demonstrated that edema disrupts sodium channel (NaV1.5) –rich nanodomains within the intercalated disk (ID), slowing cardiac impulse propagation, and prompting arrhythmias. In preliminary studies, VEGF (at levels found in the serum of AF patients) elevated AF inducibility ex vivo and in vivo mouse experiments within 30 minutes. Therefore, we hypothesize that cytokine-induced vascular leak promotes cardiac edema, and contributes to atrial arrhythmias by disrupting NaV1.5-rich ID nanodomains. In this venture, we will employ cutting edge tools including super-resolution microscopy, 3D electron microscopy, and smart patch clamp to investigate the structural and functional impact of vascular leak on the structure and function of atrial IDs. Furthermore, we will utilize an innovative strategy peptide mimetics of adhesion domains will be used to selectively modulate the structure of different ID nanodomains. Aim 1 will use these peptides to investigate how different ID nanodomains contribute to atrial conduction, and probe fundamental mechanisms underlying these structure-function relationships. In new preliminary data, we demonstrate that VEGF- induced vascular leak induces swelling of ID nanodomains and translocation of NaV1.5 from these sites within 30 minutes. Aim 2 will investigate the acute structural and functional impacts of VEGF- induced vascular leak. Aim 3 will use ex vivo and in vivo models to test the efficacy of preserving the vascular barrier and/or ID nanodomains in preventing AF.