PROJECT SUMMARY Atrial fibrillation (AF), a leading cause of stroke, is an increasingly prevalent arrhythmia in the United States due to an aging population with predisposing conditions (e.g. heart failure, obesity, diabetes, high blood pressure, etc.). Although, there have been great technological advances in the treatment of AF, the current therapies still remain insufficient due to a limited understanding of the mechanisms that drive and maintain AF. Clinical studies currently lack reliable functional and structural mapping approaches necessary to resolve the detailed course of fast electrical activity during AF as a result of the highly complex patient-specific 3D structure of the human atria. Consequently, there remains a significant debate around the mechanism driving AF, the cause of these drivers, and how best to locate and treat these patient-specific drivers in patients with cardiac diseases. Therefore our study aims to develop a novel, paradigm-shifting framework that clearly identifies the exact electro-anatomical AF substrates, or AF driver “fingerprints”, for optimal AF treatment in humans. Our preliminary data led us to hypothesize that a limited number of patient-specific sustained reentry circuits through fibrotically-insulated muscular bundles within the 3D atrial wall are responsible for the maintenance of AF. We will test this hypothesis, directly in explanted human atria, by integrating high resolution simultaneous endo-epicardial and panoramic optical mapping, clinical multi-electrode mapping, 3D structural gadolinium-enhanced MRI, and 3D heart-specific computational models to define the spatiotemporal and structural fingerprints of AF drivers in the human atria. Accurately defining the specific atrial functional-structural fingerprints of AF drivers will allow us to test the novel Substrate Modulating Ablation of Reentrant Tracks (SMART), a minimally damaging, personalized treatment of AF. This translational research is a critical step toward the development of new patient-specific therapies whereby AF drivers can be accurately defined, targeted, and successfully treated to cure the most common arrhythmia in the United States.