Abstract—Intermittent vagal nerve stimulation (VNS) has emerged as a potential therapy to treat cardiovascular diseases by delivering electrical stimulation to the vagus nerves. The purpose of this study was to investigate the electrophysiological changes in the atrium resulting from long-term intermittent VNS therapy in the chronic myocardial infarction (MI) rat model. MI was induced via left anterior descending coronary artery (LAD) ligation in male Sprague-Dawley rats, randomized into two groups: MI (implanted with non- functional VNS stimulators) and MI-VNS (implanted with functional VNS stimulators and received chronic intermittent VNS treatment) groups. Further, a sham group was used as control in which MI was not performed and received non- functional VNS stimulators. At 12 weeks, optical mapping of right atrium (RA) of sinus rhythm was performed. Our results demonstrated that chronic MI changed the electrical properties of the atrium action potentials and resulted in reduced action potential duration at 50% (APD 50 ) and 80% (APD 80 ) repolarization. Chronic right cervical VNS restored the APD back to healthy heart APD values. Additionally, APD heterogeneity index increased as a result of the chronic MI. Chronic VNS was not found to alter this increase. By calculating PR intervals from weekly ECG recordings of anaesthetized rats, we demonstrated that chronic MI and intermittent VNS did not affect the AV conduction time from the atria to the ventricles. From our study, we conclude the MI decreased the APD and increased APD spatial dispersion. VNS increased the APD back to healthy normal values but did change the APD spatial dispersion and the electrical conduction in the RA. I. INTRODUCTION Myocardial infarction (MI) is the most common cause of heart failure (HF) [1], [2]. Current therapies designed to treat MI patients include conventional pharmacological and mechanical device-based interventions. While these approaches have improved the prognosis of patients with MI, the mortality rate still remains high [3]. *These authors have contributed equally to the study. Research was supported in part by Cyberonics Inc. and the following funding sources: NSF PHY09574683, NSF CMMI-1233951 (E.G.T), NSF CAREER PHY-125541 (E.G.T), UMN IEM Exploratory Grant, and UMN Grant-in-Aid. X. Xie, S. W. Lee, C. Johnson, J. Ippolito, B.H. KenKnight, and E. G. Tolkacheva are with the Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455 USA Corresponding Author: E.G. Tolkacheva (Phone: 612-626-2719, Fax: 612- 626-6583, Email: talkacal@umn.edu) Vagal nerve stimulation (VNS) is an adjunctive procedure involving the stimulation of the vagus nerve with electrical impulses. Clinically, VNS is already currently being used to treat intractable epilepsy and treatment- resistant depression [4], [5]. Recently, modulation of nerve activity through cardiac VNS has emerged as a potential therapy for cardiovascular diseases [6]. It has been shown that chronic VNS can inhibit sudden cardiac death [7] and markedly suppress arrhythmias [8] in MI animal models. Peripheral cardiac nerve stimulation can also modify atrial and ventricular contractile functions [9], [10]. It has been reported that chronic VNS may improve left ventricular function and the quality of life in chronic HF patients with severe systolic dysfunction [6]. It is well known that parasympathetic vagal nerves extensively innervate the atria. The vagus nerve (parasympathetic) system communicates with the heart through the intracardiac ganglia, which are divided into the sinoatrial (SA) and atrioventricular (AV) nodes [11]. It is thought that VNS might have a significant effect on atrial electrophysiological properties due to dense vagal innervations. However, the effects of chronic VNS on the atrium remain unclear. Additionally, there are controversial findings on whether VNS is linked to atrial fibrillation (AF). Specifically, VNS has been shown to shorten the duration of action potential (APD) in atrial myocytes and reduce the atrial absolute refractory period, facilitating the induction of AF by a single atrial ectopic beat and the presence of multiple reentrant circuits coexisting in the atrial myocardium [12], [13]. Furthermore, animal studies involving vagal denervation have suggested that VNS may be proarrhythmic [14], [15]. Nonetheless, there are also studies that have shown that VNS can inhibit spontaneous activities of isolated cardiac myocytes from rabbit pulmonary veins [16] and canine superior vena cava [17]. In addition, it has been shown that the use of phenylephrine to enhance the vagal tone suppresses focal AF originating in the pulmonary veins in patients [13], [18]. Low-level VNS has also been implemented in ambulatory dogs to reduce atrial tachy-arrhythmias [19]. Therefore, further investigations are required to determine the exact role of VNS on the electrophysiological properties of atria. The objective of this study was to use high resolution optical mapping techniques to evaluate the changes in atrial electrophysiology due to chronic intermittent VNS in a chronic MI rat model. We aimed to identify whether these changes might potentially promote or inhibit the creation of substrates for atrial arrhythmias. To our knowledge, this is the first study to characterize the electrophysiological Intermittent Vagal Nerve Stimulation Alters the Electrophysiological Properties of Atrium in the Myocardial Infarction Rat Model *Xueyi Xie, *Steven W. Lee, Christopher Johnson, Joseph Ippolito, Bruce H. KenKnight, Elena G. Tolkacheva