First-in-human study backs neuromodulation to treat paroxysmal atrial fibrillation

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A first-in-human study shows low level transcutaneous electrical vagus nerve stimulation, a completely non-invasive approach, suppresses paroxysmal atrial fibrillation.

The study, recently published in the Journal of the American College of Cardiology, has shown that transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation and decreases inflammatory cytokines in patients with paroxysmal atrial fibrillation.

Stavros Stavrakis Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, USA, and colleagues set out to examine the antiarrhythmic and anti-inflammatory effects of LLTS in humans and demonstrated that the duration and inducibility of atrial fibrillation, as well as inflammatory cytokines, were supressed LLTS of the auricular branch of the vagus nerve at the tragus. The senior author, Sunny S Po, professor of Medicine, director, Clinical Electrophysiology and associate director, Heart Rhythm Institute told Cardiac Rhythm News: “By shortening the atrial fibrillation duration and supressing the inflammatory process, this therapy may prevent atrial fibrillation from progressing to more advanced stages.”


While the current therapy to maintain sinus rhythm in patients with atrial fibrillation that cannot be controlled by medication is either surgical or catheter ablation, there is a growing interest in examining if neuromodulation, a nonpharmacological and nonablative therapy, can be used to manage drug-refractory atrial fibrillation because despite being more efficacious than antiarrhythmic drugs, the long-term outcome of ablation for paroxysmal atrial fibrillation is disappointing with the event-free survival being less than 50% at five years, the authors note.


Previously published animal studies have demonstrated that LLTS suppresses atrial fibrillation in canines.

The investigators randomised 40 patients with paroxysmal atrial fibrillation who presented for ablation to either one hour of LLTS (n=20) or sham control (n=20).


By attaching a flat metal clip onto the tragus, they produced LLTS (20Hz) in the right ear using a Grass S88 stimulator (Natus Neurology). The authors emphasise that this voltage is substantially (50%) lower than the voltage slowing the sinus rate. They then induced atrial fibrillation under general anaesthesia, by burst atrial pacing at baseline and after one hour of LLTS or sham treatment.


Stavrakis and colleagues collected blood samples from the coronary sinus and the femoral vein at those time points and then analysed them for inflammatory cytokines, including tumour necrosis factor alpha and C-reactive protein, using a multiplex immunoassay.


The team found no differences in baseline clinical and echocardiographic characteristics between the two groups, although a trend towards increased prevalence of diabetes in the control group might have had clinical significance. The results of the study showed that pacing-induced atrial fibrillation duration decreased significantly by 6.3±1.9 minutes compared with baseline in the LLTS group, but not in the control patients (p=0.002 for comparison between groups).

Atrial fibrillation cycle length increased significantly from baseline by 28.8±6.5ms in the LLTS group, but not in control subjects (p=0.0002 for comparison between groups). Systemic levels (from the femoral vein) tumour necrosis factor-alpha and C-reactive protein levels decreased significantly only in the LLTS group. These decreases were not seen from the samples taken from the coronary sinus.


In the study, patients were followed at one month, three months and approximately every three months after. During follow-up, five patients in each group experienced recurrence of atrial fibrillation or atrial tachycardia.


“Our results support the emerging paradigm of neuromodulation to treat atrial fibrillation,” the authors write.


In an accompanying editorial in the same journal, Suraj Kapa and David J Callans, Section of Cardiac Electrophysiology, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA, write: “These patients were studied under general anaesthesia, so one must wonder whether the “type” of atrial fibrillation reflected by inducibility under general anaesthesia necessarily reflects what is seen clinically; inducibility or lack thereof at the end of traditional ablation does not correlate with risk of clinical recurrence.[…] Furthermore, it will be critical to determine the level of stimulation required to achieve the desired suppressive effect.”


Kapa and Callans also highlight the importance of this study, which they note, is aimed to understand the fundamental nature of atrial fibrillation and its pathophysiology. They comment: “Many have argued that electrophysiology, once mostly intellectual pursuit firmly grounded in our understanding of physiology has lost its way. By rediscovering our past to help innovate our future, we may be able to again harness the elegance of the neural-cardiac interface to better manage our patients more safely, effectively and thoughtfully.”

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