Low level non-invasive vagus nerve stimulation: A novel feasible therapeutic approach for atrial fibrillation

Abstract

1. Autonomic nervous system and arrhythmiasThe autonomic nervous system plays an important role in the mod-ulation of cardiac arrhythmogenesis, and autonomic nerve activity canact as a direct trigger of arrhythmias. In atrial fibrillation, sympatheticleft stellate ganglion (LSG) and atrial ganglionated plexus activations(GP) are the most common trigger [1].2. Anti-atrial fibrillation effects induced by low-level vagus nervestimulation (LL-VNS)Inpreviousstudies,wefoundthatlow-levelvagusnervestimulation(LL-VNS), at voltages substantially below that which slowed the sinusrate significantly increases the effective refractory period (ERP) in theatria as well as the pulmonary vein (PV) myocardium. Furthermore,AFinducibilityatthesesiteswassignificantlysuppressedandtheAFdu-rationwassubstantiallyshortenedaswell.Directneuralrecordingsalsoindicatethattheanti-arrhythmiceffectsofLL-VNSaremediatedbysup-pressingtheactivityofGP[2–5].Shenetal.alsodemonstratedthatcon-tinuous LL-VNS suppressed paroxysmal atrial tachyarrhythmias inambulatory, conscious dogs via the reduction of stellate ganglionnerve activity. Histologically, LL-VNS resulted in a significant reductionof sympathetic ganglion cells in the LSG [1].3. Beneficial effects of non-invasive LL-VNSOur recent study reported a noninvasive anti-arrhythmic ap-proach to deliver VNS by transcutaneous stimulation at the tragus,where the auricular branch of the vagus nerve is located. Non-invasive LL-VNS can reverse RAP-induced atrial remodeling and in-hibit AF inducibility, suggesting a potential non-invasive treatmentfor AF [6,7].Vagus nerve stimulation (VNS) is currently used to treat refractoryepilepsy and is being investigated as a potential therapy for a range ofconditions, includingventricularfibrillation,heart failure, tinnitus,obe-sity and Alzheimer's disease. However, the invasive nature (the VNSneurostimulator system has to be implanted by surgery and maycause some side effects, such as neck pain, coughing, swallowing diffi-culty, and voice alteration along with nausea and indigestion) and ex-pense limit the use of VNS in patient populations [8–11].Although, multiple experiment and clinical studies demonstratedthat ablation of targeted neural elements reduced the incidences of ar-rhythmias. Ablation approach has also multiple limitations. One limita-tionisthattheautonomicnervoussystemishighlyplastic.It ispossiblethat reinnervation can occur after the ablation procedures and negatetheeffectsofablation.Asecondlimitationisthattheatrialganglionatedplexusand stellateganglionare noteasily accessiblein humans. Athirdlimitation is that ablation of the ganglion causes irreversible changes oftheautonomicnervoussystem.Thelong-termeffectsofautonomicner-vous system denervation in patients with arrthymia are still unknown.Because of the above limitations, it is highly desirable to develop aneuromodulation method that can be easily terminated, without caus-ing permanent damage to the autonomic structures.We examined the effects of a noninvasive therapeutic modality tosubstitute for vagus nerve stimulation. We therefore propose a newneural interface approach to optimize cardiac autonomic tone. Thesedistinguishing features that underlie the potential clinical significanceof this therapeutic approach provide us a novel, noninvasive approachto treat arrhythmias. Notably, non-invasive LL-VNS exerted powerfulanti-arrhythmiceffectswhendeliveredtoeachanimalatasubstantiallylow voltage (80% below the threshold of slowing sinus rate). This ap-proach is potentially tolerable by ambulatory patients. A very recentclinical study alsoshowed that non-invasive LL-VNS in healthyhumansreduced sympathetic nerve activity [12]. Non-invasive LL-VNS cantherefore influence human physiology and provide a simple and inex-pensive alternative to invasive VNS.