Biomarker-guided optimization of transcutaneous vagal stimulation for atrial fibrillation

Abstract Atrial fibrillation (AF) is the most common clinically significant arrhythmia and is associated with increased cardiovascular morbidity and mortality. Recent evidence suggests that the autonomic nervous system plays a central role in the pathogenesis of AF, especially in the early stages and several studies from our group and

others have shown that autonomic modulation with vagus nerve stimulation (VNS) can suppress AF in experimental models. We have exciting preliminary data from our recently completed randomized clinical trial showing that in ambulatory patients with paroxysmal AF, chronic, intermittent transcutaneous VNS (tVNS) over

6 months resulted in a significant decrease in AF burden compared to sham stimulation. However, the response to tVNS was variable among individual patients, highlighting the notion that while tVNS is an emerging, promising modality for AF, the dosing and/or patient selection have to be optimized. Therefore, there is an urgent need to

develop biomarkers that could 1) determine the optimal dosing regimen and 2) select the ideal candidates for tVNS therapy, and thus optimally guide AF management. Our proposed studies will test the overall hypothesis that the effects of tVNS on autonomic tone and atrial substrate can be used to guide and optimize therapy.

Importantly, we have recently shown that P-wave alternans (PWA), a subtle beat-to-beat variation in the morphology of the P-wave, diminished in the active, compared to the sham group over a 6-month period and the decrease correlated with AF burden reduction. Therefore, we hypothesize that PWA is a useful tool for guiding

tVNS therapy for AF. We have also recently shown that the decrease in AF burden correlated with serum levels of neuropeptide Y (NPY), a surrogate marker of sympathetic activity. Therefore, our proposed studies will test the hypothesis that assessment of subtle beat-to-beat variations in the P-wave morphology of the

electrocardiogram (ECG) and serum levels of NPY can be used to first, determine the optimal parameters and second, guide tVNS treatment. Our specific aims are: 1. To determine the effects of tVNS on autonomic tone, atrial substrate and neuromodulators in patients with paroxysmal AF. 2. To investigate the chronic effects of

optimal tVNS on AF burden in patients with paroxysmal AF over a 6-month period, compared with sham stimulation and 3. To identify physiological and biochemical markers of response to chronic tVNS. We anticipate that the results of these studies will first, provide insights into the effects of tVNS on autonomic tone, AF substrate

and neuromodulators, and second, permit optimization of tVNS using PWA, NPY and metabolomic biomarkers to reduce AF burden of afflicted patients. By introducing an optimized tVNS treatment protocol, results from our proposed studies have the potential to overturn the current scientific paradigm for treatment of AF, and

thus, lead to major improvements in health care delivery. Because of the increasing number of patients with AF and the poor success and potential side effects of the available treatment options, an alternative approach such as tVNS has the potential to impact clinical practice and improve outcomes for these patients.