Tragus Nerve Stimulation to Prevent AF

With the rising prevalence of atrial fibrillation (AF) and little on the horizon in terms of antiarrhythmic drug development, it is nice to see that there are nonpharmacological treatments other than catheter ablation under development. In the March issue of JACC, Stavrakis and colleagues published a paper on the effects of transcutaneous low-level tragus electrical stimulation (LLTS) on atrial electrophysiology and duration of pacing-induced AF.¹ 

It is known that the onset of AF is often associated with increases in both sympathetic and parasympathetic tone, and that autonomic innervation to the heart is rich in the posterior left atrium. Stimulation of the vagus nerve has been shown to have a paradoxical cardiac effect causing a decrease in vagal and adrenergic inputs to the left atrium. Implantation of a device that directly stimulates the vagus nerve can be accomplished, but is associated with some morbidity. However, stimulation of the tragus nerve at the ear can be performed noninvasively to stimulate the vagal nerve. Stavrakis and colleagues randomized 40 patients with paroxysmal AF undergoing catheter ablation to either one hour of LLTS or to a sham control. Baseline atrial effective refractory periods (ERPs), ease of AF inducibility with pacing, and the duration of induced AF were determined. Blood levels of inflammatory indicators were also measured. In the treatment group, they then stimulated the right ear using an energy output that was half the voltage that was shown to slow the sinus rate. This resulted in a stimulation output that was below the discomfort level in all patients. After one hour of either stimulation or no stimulation, atrial pacing and measurements were repeated. They found that LLTS shortened the duration of pacing-induced AF episodes and increased the cycle length of the AF consistent with an antiarrhythmic effect.

Although these findings with LLTS are promising, there are many reasons to be skeptical that low-level vagal nerve stimulation will ever be used to treat patients with AF. The first reason is that the effects of LLTS in this study were small. Although the increase in atrial ERPs was statistically significant [the ERP from the coronary sinus increased from 222.7 ± 41.0 ms to 230.8 ± 41.0 ms with LLTS versus from 253.3 ± 53.7 to 240.7 ± 50.6 in the control group (p=0.04)], these changes were not impressive. Note that the ERPs in the control baseline were much higher than in the treatment group at baseline. Therefore, there may actually be no effect and it may be that the differences are explained by regression to the mean. Even if the effect is real, the effect appears to be no more than that achieved with conventional antiarrhythmic drugs. A second reason to be skeptical is that the effects of LLTS were measured within 5 minutes after stopping stimulation. It is not clear why the atrial effects of LLTS would be persistent. However, there does appear to be an anti-inflammatory effect.

A third reason to be skeptical is related to the study design. Instead of simply comparing the effect of LLTS on the atrial ERPs, they compared the changes in each group from baseline to one hour later following induction of AF. This study design is reminiscent of prior human experiments performed by Daoud and others at the University of Michigan in the mid 1990s, during which the acute effects of pacing-induced AF on atrial refractoriness were determined.² In those studies, verapamil was shown to prevent the acute shortening of atrial refractory periods that occurs after pacing-induced AF. It is intriguing that LLTS appears to have effects that are similar to verapamil in this setting, suggesting a calcium-mediated effect of LLTS. However, pretreatment with verapamil was not found to prolong the time to recurrent AF after electrical cardioversion and never became standard medical therapy to prevent AF.³ 

It is interesting that low-level stimulation of the vagus nerve by noninvasively stimulating the tragus nerve at the right ear may have paradoxical effects on atrial electrophysiology that actually prolong the atrial ERP, slow the AF cycle length, and shorten AF episodes. However, the study by Stavrakis is far from conclusive. If indeed this intervention, LLTS, does have electrophysiological effects that promote sinus rhythm, it is not clear that it has the potential to have a clinically meaningful impact in the maintenance of sinus rhythm in patients with AF.

References

1. Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015;65:867-875.
2. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans. Circulation. 1997;96:1542-1550.
3. Van Noord T, Van Gelder IC, Tieleman RG, et al. VERDICT: the Verapamil versus Digoxin Cardioversion Trial: a randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2001;12(7):766-769.