Clayton Wiggins

Background: Atrial fibrillation (AF) is the most common pathological arrhythmia in the United States, with its prevalence expected to grow to 12.1 million people by 2030. Despite the pressing need to address this disease, current therapies fall short for preventing disease progression for many patients¹. There is growing interest in the role that the autonomic nervous system (ANS) plays in the pathophysiology of AF and how it can be used for novel, effective, and non-invasive therapies.

Research Objectives: In this literature review, we reviewed the role of the ANS in AF and emerging neuromodulation therapies for AF.

Methods: Initial literature review consisted of PubMed searches such as “atrial fibrillation,” “(atrial fibrillation) AND (pathophysiology),” and “(atrial fibrillation) AND (autonomic).” Information gained from these searches prompted targeted searches such as “(atrial fibrillation) AND (sympathetic nervous system),” “(atrial fibrillation) AND (vagal stimulation),” and “(atrial fibrillation) AND (exercise).”

Results: Both adrenergic (sympathetic) and vagal (parasympathetic) hyperinnervation contribute to the development of AF due to changes in Ca²⁺ channels and membrane potential². Furthermore, autonomic dysfunction promotes substrate changes in atrial tissue causing the progression from early, trigger-based AF to permanent, substrate-based AF¹. Interestingly, lower levels of vagal activity reduce AF occurrence while higher levels promote it^3,4. Literature search of adrenergic neuromodulation, such as stellate ganglion blockade, did not yield many results for treating AF specifically. Vagal neuromodulation yielded better results, with therapies such as low-level vagus nerve stimulation and low-level tragus stimulation reducing arrhythmogenicity and reducing inflammatory cytokines associated with AF progression^3,5-8. Clinical trials of exercise as a neuromodulation therapy showed benefit in reducing AF burden that was separate from its benefit on risk factors such as BMI and BP^9,10. Research suggests this is due to its benefits on autonomic regulation, and this is supported by moderate exercise levels and mind-body exercises such as yoga conferring the most benefit^11,12.

Conclusion: Emerging research shows promising results for neuromodulation therapies as an addition to standard of care for AF. Less invasive therapies such as low-level tragus stimulation and moderate exercise can reduce AF burden while slowing disease progression. Exercise should thus be considered by clinicians as a therapy for AF separate from its risk factor mitigation. These promising studies show an impetus for clinical trials that can add these therapies to standard of care and reduce the need for medication and procedures in modern AF treatment.

Works Cited:

1. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2024 Jan 2;149(1):e167]. Circulation. 2024;149(1):e1-e156. doi:10.1161/CIR.0000000000001193
2. Rebecchi M, Fanisio F, Rizzi F, et al. The Autonomic Coumel Triangle: A New Way to Define the Fascinating Relationship between Atrial Fibrillation and the Autonomic Nervous System. Life (Basel). 2023;13(5):1139. Published 2023 May 8. doi:10.3390/life13051139
3. Zhang SJ, Huang CX, Zhao QY, et al. The Role of α7nAChR-Mediated Cholinergic Anti-Inflammatory Pathway in Vagal Nerve Regulated Atrial Fibrillation. Int Heart J. 2021;62(3):607-615. doi:10.1536/ihj.18-510
4. Tavares L, Rodríguez-Mañero M, Kreidieh B, et al. Cardiac Afferent Denervation Abolishes Ganglionated Plexi and Sympathetic Responses to Apnea: Implications for Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2019;12(6):e006942. doi:10.1161/CIRCEP.118.006942
5. Chen M, Zhu T, Wu Z, et al. LL-VNS attenuates SK2 expression and incidence of arrhythmias following acute myocardial infarction in rats. Front Cardiovasc Med. 2023;9:1034888. Published 2023 Jan 11. doi:10.3389/fcvm.2022.1034888
6. Stavrakis S, Humphrey MB, Scherlag B, et al. Low-Level Vagus Nerve Stimulation Suppresses Post-Operative Atrial Fibrillation and Inflammation: A Randomized Study. JACC Clin Electrophysiol. 2017;3(9):929-938. doi:10.1016/j.jacep.2017.02.019
7. Jiang Y, Po SS, Amil F, Dasari TW. Non-invasive Low-level Tragus Stimulation in Cardiovascular Diseases. Arrhythm Electrophysiol Rev. 2020;9(1):40-46. doi:10.15420/aer.2020.01
8. Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015;65(9):867-875. doi:10.1016/j.jacc.2014.12.026
9. Pathak RK, Elliott A, Middeldorp ME, et al. Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation: The CARDIO-FIT Study. J Am Coll Cardiol. 2015;66(9):985-996. doi:10.1016/j.jacc.2015.06.488
10. Elliott AD, Verdicchio CV, Mahajan R, et al. An Exercise and Physical Activity Program in Patients With Atrial Fibrillation: The ACTIVE-AF Randomized Controlled Trial. JACC Clin Electrophysiol. 2023;9(4):455-465. doi:10.1016/j.jacep.2022.12.002
11. Chung MK, Eckhardt LL, Chen LY, et al. Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association. Circulation. 2020;141(16):e750-e772. doi:10.1161/CIR.0000000000000748
12. Lakkireddy D, Atkins D, Pillarisetti J, et al. Effect of yoga on arrhythmia burden, anxiety, depression, and quality of life in paroxysmal atrial fibrillation: the YOGA My Heart Study. J Am Coll Cardiol. 2013;61(11):1177-1182. doi:10.1016/j.jacc.2012.11.060