Biomarker-Guided Optimization of Transcutaneous Vagal Stimulation for Atrial (BiG tVNS-AF)

This proposal aims to determine the effects of tVNS on autonomic tone, atrial substrate and neuromodulators in patients with paroxysmal atrial fibrillation (AF), 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 identify physiological and biochemical markers of response to chronic tVNS.

Study Overview

• Status: Recruiting
• Conditions: Paroxysmal Atrial Fibrillation
• Intervention / Treatment: Device: Transcutaneous Electrical Nerve Stimulation Device

Detailed Description

This proposal aims to 1. To determine the effects of tVNS on autonomic tone, atrial substrate and neuromodulators in patients with paroxysmal atrial fibrillation (AF), 2. 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. For Aim 1, patients with paroxysmal AF will be randomized to a series of stimulation frequencies (5Hz, 10Hz, 20Hz) and intensities (50% below, and 1mA lower than, the discomfort threshold, respectively) in a cross-over design, to define optimal effects and 'dosing' of tVNS. Heart rate variability, a marker of autonomic tone and PWA, will be derived from 5-minute ECG. A subgroup of these patients, who present to the Electrophysiology laboratory for AF ablation, will be randomized to active or sham tVNS, using the optimal parameters determined above, for 5 minutes prior to any ablation, under baseline conditions, during isoproterenol or atropine infusion, and their combination. PWA will be estimated based on a 5-min ECG. The level of NPY will be measured from peripheral vein and coronary sinus samples. In this this Aim we will determine the optimal parameters for tVNS, and if the response to tVNS is dependent on the underlying autonomic tone. For Aim 2, Patients with paroxysmal AF not undergoing ablation, will be randomized to active tVNS (1 hour or 30 minutes, daily) or sham tVNS (1 hour daily) for 6 months, using the optimal tVNS parameters determined in Aim 1. AF burden will be monitored continuously using a smartwatch. In addition, all patients will receive a short trial of acute tVNS at baseline. This Aim will determine the minimum duration of tVNS needed to achieve a decrease in AF burden. Patients participating in the clinical trial described in Aim 2, will comprise the population of Aim 3. The hypothesis is that patients who respond acutely to tVNS at baseline, as assessed by PWA, are more likely to benefit from chronic tVNS therapy. Blood samples will be collected from patients participating in Aim 2, and their NPY levels and metabolomic profile will be correlated with AF burden. 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.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Natalia Wells-Serrano; Phone Number: 405-271-4742; Email: natalia-wellsserrano@ouhsc.edu

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Health Sciences Center
      • Contact: Stavros Stavrakis, MD; Phone Number: 405-271-9696; Email: Stavros-Stavrakis@ouhsc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Paroxysmal atrial fibrillation

Exclusion Criteria:

1. Sick sinus syndrome
2. 2nd and 3rd degree AV block (without pacemaker), bifascicular block or prolonged (PR>300ms) 1st degree AV block
3. History of vagotomy
4. Recurrent vasovagal syncope
5. Left ventricular ejection fraction < 40%
6. Significant valvular disorder (i.e., prosthetic valve or hemodynamic significant valvular diseases)
7. Recent stroke (< 3 months)
8. Myocardial infarction or hospitalization for heart failure (< 3 months)
9. Severe heart failure (NYHA Class IV)
10. End stage kidney disease on dialysis
11. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active TENS Stimulation	Device: Transcutaneous Electrical Nerve Stimulation Device; Low-level, electrical stimulation of the outer ear (LLTS), using a transcutaneous electrical nerve stimulation (TENS) device.
Sham Comparator: Inactive TENS Stimulation	Device: Transcutaneous Electrical Nerve Stimulation Device; Low-level, electrical stimulation of the outer ear (LLTS), using a transcutaneous electrical nerve stimulation (TENS) device.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of tVNS on Atrial fibrillation burden	AF burden, defined as the percent of time spent in AF over the total monitoring period, will be determined be based on continuous monitoring with an Apple watch	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of tVNS on neuropeptide Y	Neuropeptide Y levels will be determined using commercially available ELISA kits	6 months
Effects of tVNS on Autonomic Tone	We will use heart rate variability (HRV) to assess the effect of tVNS on autonomic tone. HRV will be derived from a 5-minute ECG.	6 months
Effects of tVNS on P wave alternans	A 12-lead, high resolution ECG will be performed to determine P wave alternance, using a software that analyzes subtle beta-to-beat variations in P wave amplitude. The percentage of beats showing P wave alternans divided by the total number of beats represents P wave alternans burden.	6 months

Collaborators and Investigators

• Sponsor: University of Oklahoma
• Investigators: Principal Investigator: Stavros Stavrakis, MD, University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2022
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): May 29, 2026

Study Registration Dates

• First Submitted: October 21, 2021
• First Submitted That Met QC Criteria: December 10, 2021
• First Posted (Actual): December 29, 2021

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: 13786

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No