The broad and long-term objective of this research project is to develop mechanism-based therapies for paroxysmal atrial tachyarrhythmias including paroxysmal atrial fibrillation (PAF) and paroxysmal atrial tachycardia (PAT) in canine models. It is known that the autonomic nervous system (ANS) is important in controlling both heart rhythm and cardiac contractility. In the previous funding period, we successfully developed methods to record autonomic nerve activities in ambulatory dogs, and documented their importance in cardiac arrhythmogenesis in dogs with pacing-induced heart failure and intermittent rapid atrial pacing. We also for the first time developed methods to record intrinsic cardiac nerve activity (ICNA) to document its importance in triggering AF of ambulatory dogs. However, more studies need to be done before we can translate these new findings to patient care. We propose to pursue the following specific aims in the next funding period:
Aim 1 : Effects of GP ablation on AF. We will record bilateral stellate ganglion nerve activity (SGNA) and vagal nerve activity in dogs with and without cryoablation of superior left GP (SLGP) and ligament of Marshall (LOM) GPs in the heart. The results will be used to test the hypotheses that (1) GP ablation prevents spontaneous PAT and PAFs in ambulatory dogs and (2) The antiarrhythmic effects of GP ablation depends at least in part on successful reduction of coordinated firing between ECNA and ICNA.
Aim 2 : Effects of low-level vagus nerve stimulation (LL-VNS) on cardiac nerve activity and spontaneous atrial tachyarrhythmias. We will simultaneously measure left stellate ganglion nerve activity (SGNA) and superior left GP nerve activity (SLGPNA) while performing either LL-VNS or sham VNS in ambulatory dogs. The nerve recordings and histological findings will be used to test the hypothesis that (1) LL-VNS results in reduced SGNA, accompanied by structural neural remodeling in the left stellate ganglion and (2) LL-VNS can reduce the incidence of PAT and PAF in dogs with intermittent rapid atrial pacing.
Aim 3 : Effects of VNS on atrioventricular (AV) conduction during sustained AF. We will perform a study to test the hypothesis that left VNS can modulate AV node conduction through the activation of the inferior vena cava-inferior atrial GP (IVC- IAGP) during sustained AF, and that VNS can improve ventricular rate control by simultaneously reducing the SGNA and increasing IVC-IAGPNA.
Aim 4 : Differential extrinsic cardiac nerve activity (ECNA) and ICNA remodeling in heart failure. We will perform simultaneous SGNA, ligament of Marshall nerve activity (LOMNA) and left ventricular (LV) pressure recordings at baseline and during pacing-induced heart failure to test the hypotheses that (1) LOMNA directly control LV contractility at baseline, (2) Heart failure increases SGNA but reduces LOMNA, leading to ineffective neural control of LV contraction. (3) SGNA, not LOMNA, is responsible for atrial tachyarrhythmias in heart failure. All four aims have significant clinical relevance, and may lead to novel therapeutic approaches to controlling AF and heart failure.

Public Health Relevance

Atrial fibrillation is the most common arrhythmia in the United States and other developed countries. This research project is relevant to public health because it proposes to investigate the neural mechanisms of atrial fibrillation and to develop mechanism-based therapy of this important cardiac arrhythmia.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Doytchinova, Anisiia; Patel, Jheel; Zhou, Shengmei et al. (2015) Subcutaneous nerve activity and spontaneous ventricular arrhythmias in ambulatory dogs. Heart Rhythm 12:612-20
Robinson, Eric A; Rhee, Kyoung-Suk; Doytchinova, Anisiia et al. (2015) Estimating sympathetic tone by recording subcutaneous nerve activity in ambulatory dogs. J Cardiovasc Electrophysiol 26:70-8
Hoang, Allen; Shen, Changyu; Zheng, James et al. (2014) Utilization rates of implantable cardioverter-defibrillators for primary prevention of sudden cardiac death: a 2012 calculation for a midwestern health referral region. Heart Rhythm 11:849-55
Choi, Eue-Keun; Shen, Mark J; Lin, Shien-Fong et al. (2014) Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs. Europace 16:1083-91
Hellyer, Jessica; George Akingba, A; Rhee, Kyoung-Suk et al. (2014) Autonomic nerve activity and blood pressure in ambulatory dogs. Heart Rhythm 11:307-13
Yu, Chih-Chieh; Ai, Tomohiko; Weiss, James N et al. (2014) Apamin does not inhibit human cardiac Na+ current, L-type Ca2+ current or other major K+ currents. PLoS One 9:e96691
Chen, Peng-Sheng; Chen, Lan S; Fishbein, Michael C et al. (2014) Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 114:1500-15
Piccirillo, Gianfranco; Moscucci, Federica; D'Alessandro, Gaetana et al. (2014) Myocardial repolarization dispersion and autonomic nerve activity in a canine experimental acute myocardial infarction model. Heart Rhythm 11:110-8
Maruyama, Mitsunori; Ai, Tomohiko; Chua, Su-Kiat et al. (2014) Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles. Heart Rhythm 11:697-706
Seki, Atsuko; Green, Hunter R; Lee, Thomas D et al. (2014) Sympathetic nerve fibers in human cervical and thoracic vagus nerves. Heart Rhythm 11:1411-7

Showing the most recent 10 out of 132 publications