Project Summary/Abstract Atrial fibrillation (AF) is the most common sustained arrhythmia with approximately one quarter of all adults developing AF by the age of 80. AF can be symptomatic with people experiencing palpitations, racing heart, syncope, congestive heart failure, and cardioembolic stroke. Epidemiologically, aging is associated with AF and increasing obesity confers a stepwise higher lifetime risk of AF. Atrial myopathy and AF are thus expected to become more rampant with the obesity and type 2 diabetes epidemics and the aging population. The molecular mechanism(s) by which obesity leads to atrial fibrillation is poorly understood. We have developed a new mouse model of spontaneous atrial fibrillation triggered by obesity. We found that nicotinamide adenine dinucleotide (NAD+) and the Atf6 ER stress pathway are perturbed in obesity-induced atrial fibrillation. Importantly, correcting NAD+ levels in the heart ameliorates atrial fibrillation. In this proposal, we seek to follow up on these studies and assess the mechanisms by which NAD+ pathways protect against atrial fibrillation. We will pursue the following specific aims: 1. Dissect the role of the NAD+ pathway in obesity- induced AF. 2. Assess the role of the Atf6 ER stress pathway in obesity-induced AF. The overall goal of these studies is to gain greater insight into the molecular pathogenesis of metabolic diseases and AF that may ultimately lead to new treatments to prevent or ameliorate AF.

Public Health Relevance Atrial fibrillation is an insidious disease with metabolic risk factors such as obesity, diabetes, and aging that can range from asymptomatic to causing congestive heart failure and stroke. Despite our long-term recognition of these risk factors, it is currently not known how the disease can be prevented in people with obesity and diabetes. In this proposal, we aim to assess the mechanisms by which these metabolic risk factors contribute to atrial fibrillation.