Synaptic Plasticity in the Epicardial Ganglionated Plexi (SNAP-GP)

Atrial fibrillation (AF) is the most common arrhythmia and the prevalence increase with age. Autonomic nervous system play a critical role in the initiation and maintenance of AF. The intrinsic cardiac autonomic nervous system includes ganglionated plexus (GP) modulate the level of parasympathetic activity to the heart. Experimental and clinical studies suggest that GP activation plays a significant role in clinical AF in both the initiation of and the maintenance of AF.

Synaptic plasticity is defined as the ability of synapses to change their strength of transmission. Plasticity of synaptic connections in the brain is a major focus of neuroscience research, as it is the primary mechanism underpinning learning and memory. Beyond the brain however, plasticity in peripheral neurons is less well understood, particularly in the GP neurons innervating the heart. The ability of these neurons to alter parasympathetic activity suggests that plasticity may indeed occur at the synapses formed on and by GP neurons. Such changes may not only fine-tune autonomic innervation of the heart, but could also be a source of maladaptive plasticity during atrial fibrillation.

Low level tragus stimulation (LLTS) has been shown to decrease AF burden among patients with paroxysmal AF. However, the exact mechanism remains unclear. The objective of this study is to examine changes in synaptic density of GP neurons in patients with paroxysmal AF and persistent AF compared to those without AF undergoing cardiac surgery. In addition, we aim to examine the effect of LLTS on the synaptic plasticity of the GP neurons. A group of patients undergoing open heart surgery will be randomized to active LLTS for 30 min (pulse width of 200 μs, amplitude of 20 mA and a pulse frequency of 20 Hz) or no stimulation. Biopsy from GP tissue will be taken immediately after stimulation and histological staining for choline acetyl transferase (ChAT), tyrosine hydroxylase (TH) and synaptophysin will be performed to examine synaptic plasticity.

Understanding the effect of LLTS on GP SP will help to determine whether changes in synaptic plasticity can increase or decrease autonomic tone of the heart, and its role in generating the aberrant electrical impulses in the GP around the pulmonary veins that can trigger and drive AF.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Device: Sham stimulation; Device: Parasym

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Stavros Stavrakis; Phone Number: 4052714742; Email: stavros-stavrakis@ouhsc.edu

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • OU Medical Center
      • Contact: Stavros Stavrakis, MD; Phone Number: 405-313-2197; Email: Stavros-Stavrakis@ouhsc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female patients older than 21 year old
2. Patient is going to have open heart surgery.

Exclusion Criteria:

1. Patients undergoing emergent open heart surgery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active stimulation; Patients undergoing cardiac surgery will be randomized to active low level tragus stimulation for 30 min (pulse width of 200 μs, amplitude of 20 mA and a pulse frequency of 20 Hz). Stimulation will be provided using the Parasym device.	Device: Parasym; Stimulation will be done under anesthesia for 30 minutes. Stimulation parameters include a pulse width of 200 μs, amplitude of 20 mA and a pulse frequency of 20 Hz. The Parasym devise (Parasym Health, London, UK) will be used for stimulation. The device will be connected to a clip electrode that will be attached to the external ear. In the active group, the ear clip electrode will be attached to tragus in the active stimulation group. This device has been deemed non-significant risk by the FDA. In the control group, no stimulation will be done.
Sham Comparator: Sham stimulation; Patients undergoing cardiac surgery will be randomized to sham stimulation for 30 min. The Parasym device will be placed on the patient's tragus, but no current will be delivered.	Device: Sham stimulation; Sham stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
choline acetyltransferase	Biopsy from ganglionated plexus (GP) tissue will be taken and histological staining for choline acetyl transferase (ChAT) will be performed	30 minutes
tyrosine hydroxylase	Biopsy from ganglionated plexus (GP) tissue will be taken and histological staining for tyrosine hydroxylase will be performed	30 minutes
synaptophysin	Biopsy from ganglionated plexus (GP) tissue will be taken and histological staining for synaptophysin will be performed	30 minutes

Collaborators and Investigators

• Sponsor: University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2021
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 27, 2021
• First Submitted That Met QC Criteria: September 2, 2021
• First Posted (Actual): September 5, 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: 11474

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes