Effects of Low-Intensity Autonomic Nerve Stimulation on Atrial Electrophysiology

Background and Objectives: The cardiac autonomic nervous system is an emerging target for therapeutic control of atrial fibrillation (AF). We evaluated the effects of low-intensity autonomic nerve stimulation (LI-ANS) on atrial electrophysiology, AF vulnerability, and neural remodeling. Subjects and Methods: Fourteen dogs were subjected to 3 hours rapid atrial pacing (RAP, 5 Hz) and concomitant high frequency LI-ANS (20 Hz, at voltages 40% below the threshold) as follows: no autonomic stimulation (control, n=3); or right cervical vagus nerve (RVN, n=6), anterior right ganglionated plexi (ARGP, n=3), and superior left ganglionated plexi (SLGP, n=2) stimulation. Programmed and burst atrial pacing were performed at baseline and at the end of each hour to determine atrial effective refractory period (ERP), window of vulnerability (WOV), and inducibility of sustained AF. Results: Atrial ERP was significantly shortened by 3 hours RAP (in control group,${\Delta}ERP=-47.9{\pm}8.9%$, p=0.032), and RAP-induced ERP shortening was attenuated by LI-ANS (in LI-ANS group, ${\Delta}ERP=-15.4{\pm}5.9%$, p=0.019; vs. control, p=0.035). Neither WOV for AF nor AF inducibility changed significantly during 3 hours RAP with simultaneous LI-ANS. There was no significant difference between the control and LI-ANS group in nerve density and sprouting evaluated by anti-tyrosine hydroxylase and anti-growth associated protein-43 staining. Among the various sites for LI-ANS, the ARGP-stimulation group showed marginally lower ${\Delta}WOV$ (p=0.077) and lower nerve sprouting (p=0.065) compared to the RVN-stimulation group. Conclusion: Low-intensity autonomic nerve stimulation significantly attenuated the shortening of atrial ERP caused by RAP. ARGP may be a better target for LI-ANS than RVN for the purpose of suppressing atrial remodeling in AF.