Project Summary Two and a half million people suffer from atrial fibrillation (AF) in the United States, costing $26 billion annually. It is currently unknown whether age-induced inflammation from atherosclerosis induces atrial remodeling and fibrosis resulting in AF, although both age and atherosclerosis are major risk factors for developing AF. Age-specific therapies for AF are currently lacking and pose significant risks in the elderly, including increased risk of bleeding and falls. The long-term goals of this research are to determine the mechanisms of how aging, atherosclerosis, and inflammation interact to enhance AF and to develop novel therapies targeting these inflammatory mechanisms. The focus of this proposal is to test the hypothesis that macrophages in the atrial myocardium or epicardial adipose tissue mediate inflammation with atherosclerosis and aging which dysregulates ion channels and leads to AF. To test this hypothesis, we will use a murine model of atherosclerosis, the low-density lipoprotein receptor knockout (Ldlr-/-) mouse, and we will pursue 2 specific aims. First, we will determine if AF inducbility is dependent on inflammation and metabolic derangement from atherosclerosis. In order to complete this aim, we will maintain young wild-type (WT) mice on a chow diet or switch them to a high fat diet (HFD) for 3 months, and we will treat young Ldlr-/- mice similarly. We will determine whether vascular inflammation in the Ldlr-/- mice fed a HFD on top of metabolic derangement in WT mice fed a HFD is required for AF. We will also assess atrial remodeling, inflammation, macrophage accumulation and phenotype, and ion channel dysfunction. Our second aim will be to determine the role of atrial macrophages on AF inducibility during atherosclerosis and aging. Based on our preliminary data, we hypothesize that macrophages are critical for AF. Thus, we will enumerate and phenotype macrophages in the atrial myocardium in young and aged Ldlr-/- and WT mice fed a chow diet or switched to a HFD for 3 months. We will also acutely deplete macrophages via pharmacologic approaches to determine if their absence reduces AF. Again, we will assess atrial remodeling, ion channel properties, and macrophage accumulation and phenotype. The proposed research will provide novel insights into the complex interplay between aging, atherosclerosis, and AF and will generate new cellular and molecular pathways to be developed into therapies to reduce the burden of AF in older people.