NAD+ Deficiency Drives Metabolic Dysfunction-Associated Atrial Fibrillation

Atrial fibrillation (AF) is a cardiometabolic disease with obesity and diabetes as major risk factors. The cellular and molecular mechanisms by which obesity and metabolic stressors drive AF are poorly understood. Here we establish a new mouse model of spontaneous, obesity-induced AF. This two-hit model relies on genetic susceptibility coupled with an environmental factor of diet-induced obesity. Unbiased multi-omics analyses reveal cardiac conduction pathways, inflammation, and metabolic perturbations in AF. We demonstrate atrial NAD+ deficiency as a central pathological mediator in AF. Pharmacological replenishment of atrial NAD+ levels mitigates AF, protects against cardiac remodeling and fibrosis, reduces inflammation, and improves atrial metabolism. These results highlight the role of a metabolic pathway that could be therapeutically targeted for AF.