Project Summary/Abstract Atrial fibrillation (AF) is the most common tachyarrhythmia, with the number of Americans diagnosed estimated at more than six million. It is associated with an increased risk of stroke, heart failure, and all-cause mortality. In patients with paroxysmal AF, which most often is initiated by triggers from the pulmonary veins (PVs), pulmonary vein isolation (PVI) has been relatively effective in treating AF. However, in patients with persistent and long-standing persistent (LSP) AF, ablation treatment of AF, which includes PVI, has been only modestly effective because of the lack of patient-specific “mechanistic” targets to ablate. As a result, the ablation procedure is largely an empiric “one size fits all” approach. To emphasize that fact, recent clinical trials in patients with persistent and LSP AF involving endocardial catheter ablation or surgical ablation showed that there was no significant difference in the rate of freedom from AF between patients who underwent PVI alone and those who underwent PVI plus additional empiric ablation lesion sets. Furthermore, ablation lesions beyond the PVI significantly increased the need for implantation of a permanent pacemaker. All this supports the need for 1) identifying the mechanism(s) that maintain AF by activation pattern; 2) understanding the effects of each ablation lesion set on atrial activation patterns responsible for maintaining AF so that we can determine what changes in activation patterns created by the ablation lesion are critical for terminating AF and preventing its recurrence. Thereby, ablation therapy of persistent and LSP AF could change from a largely empiric approach to a patient-specific targeted approach. Our recent studies using simultaneous, biatrial, high density (510 - 512 electrodes), epicardial contact mapping in patients with persistent and LSP AF undergoing open heart surgery found that wave fronts emanating from focal sources and breakthrough sites maintained AF. Also, our preliminary studies in patients with persistent and LSP AF showed that AF was still present immediately after surgical ablation, and was associated with continued activation patterns described above. The central hypothesis of this proposal is that persistent AF after surgical ablation is due to the continuation of baseline focal sources maintaining AF, and that interrupting their activation will terminate AF. The hypothesis to be tested has three specific aims: Aim 1 is to identify focal sources in patients with persistent and LSP AF. Aim 2 is to test the hypothesis that a continuation of wave fronts emanating from focal sources after surgical ablation (PVI ± additional linear ablation lines) maintains AF. We will investigate the effects of each ablation lesion set on the activation behavior of baseline focal sources and breakthrough sites. Aim 3 is to test the hypothesis that targeted ablation of focal sources will reliably terminate AF. We will develop an efficient ablation ...