Project Summary/Abstract Postoperative atrial fibrillation (POAF) is the most common complication following open heart surgery, with an incidence of up to 50%. It is associated with significant morbidity, including stroke, heart failure, and hemodynamic compromise. For the treatment of POAF, there are two strategies, either rhythm control (restoring and maintaining sinus rhythm) or rate control (controlling ventricular rate). Medications used to maintain sinus rhythm are largely ineffective, and those used to control ventricular rates during POAF often cause hypotension. Therefore, to improve management of POAF, a non-pharmacologic treatment strategy could be implemented. The current non-pharmacologic treatment of POAF is direct current (DC) cardioversion, which is often needed to treat patients who are hemodynamically unstable. However, DC cardioversion is often ineffective, as the POAF usually returns quickly. Although a recent clinical trial showed that rhythm control and rate control are equivalent in terms of mortality, length of hospital stay, and complication rates, a longer duration of POAF is associated with worsened long-term survival and risk of AF recurrence. The lack of satisfactory treatment of POAF is due in large part to our insufficient understanding of its mechanism. In our canine sterile pericarditis model (an experimental counterpart to POAF), we demonstrated that activation and proliferation of epicardial inflammation occurring in the atria produces a loss of epicardial myocytes and an altered distribution of connexins 40 and 43. These changes are associated with non-uniform slowing of conduction, thus creating the vulnerable substrate for the spontaneous initiation and maintenance of POAF. Our epicardial mapping studies in this model demonstrated that POAF is caused by a reentrant circuit circulating around pulmonary veins. Our recent study in patients with POAF after open heart surgery showed that atrial electrograms during POAF recorded from selected left atrial (LA) sites demonstrated regular cycle lengths, consistent with a LA reentrant circuit similar to our canine model. Therefore, like other reentrant arrhythmias, the POAF rhythm has the potential to be pace terminated (rhythm control). When there is another mechanism maintaining POAF, a rate control approach using fat pad stimulation could be used to control the ventricular rate during POAF. The central hypothesis of our proposal is that when POAF is due to a reentrant mechanism, it can be terminated by a non-pharmacologic rhythm control strategy (overdrive pacing); when POAF is due to other mechanisms, it can be managed by a non-pharmacologic rate control approach (atrioventricular node fat pad stimulation). The hypothesis to be tested has three specific aims: Aim 1 is to develop non-pharmacologic approaches in our canine model. Aim 2 is to test the hypothesis that POAF is due to an anatomical reentrant circuit in patients after open heart surgery. Using entrainmen...