Effect of Transcutaneous Vagal Stimulation (TVS) on Endothelial Function in PAD (TVS-PAD)

Effect of Transcutaneous Vagal Stimulation (TVS) on Endothelial Function and Arterial Stiffness in Peripheral Artery Disease

Peripheral arterial disease (PAD) constitutes a major public health burden. The incidence of PAD increases with age and is associated with other comorbid cardiovascular disorders. Atherosclerosis which underlies PAD is associated with increased arterial stiffness and an enhanced inflammatory state as evidenced by increased levels of pro-inflammatory cytokines and markers. One the earliest signs of cardiovascular disease is endothelial dysfunction which is characterized by a decreased vasodilatory capacity of the vascular endothelium and this lesion predates the development of clinical atherosclerosis. Endothelial dysfunction has been shown to be widely prevalent in PAD. It is postulated that endothelial dysfunction is due to enhanced sympathetic drive, diminished parasympathetic drive, chronic inflammatory state all of which leads to reduced nitric oxide synthase activity in the vascular endothelium with subsequent loss of vasodilatory capacity. Studies have shown endothelial dysfunction to be reversible with pharmaco-therapeutic interventions, though these interventions are associated with their own adverse effects. Stimulation of Vagal nerve increases the parasympathetic activity while suppressing sympathetic drive, decreases inflammation and enhancing nitric oxide synthase activity. Recent experimental and clinical data suggest that low-level tragus nerve stimulation (by stimulating the auricular branch of the vagus nerve located at the tragus of the external ear) may produce the same desired neuromodulator effect compared to vagus nerve stimulation. It is however unknown if Transcutaneous Vagal Stimulation (TVS) would lead to improved endothelial function as measured by flow mediated dilatation (FMD) and laser speckle contrast imaging(LSCI), a non-invasive method of measuring endothelial function or decrease in arterial stiffness as measured by Pulse Wave Analysis (PWA), in patients with PAD. The objective of this study is to determine the impact of TVS on endothelial dysfunction as measured by FMD & LSCI and arterial stiffness. Study population will include patients with established diagnosis of PAD. After performing baseline FMD, LSCI and PWA patients will be randomized to TVS and sham stimulation with cross over. The patient randomized to TVS stimulation will obtain stimulation for 1 hour followed by measurement of FMD,LSCI and PWA. There will be a washout period of at least 24 hours with patient crossing over to the other arms thus serving as their self-control.

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction; Peripheral Artery Disease; Autonomic Imbalance
• Intervention / Treatment: Device: TVS; Device: Sham TVS

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73117
      • University of Oklahoma Health Sciences Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. peripheral arterial disease (PAD) - patients with an ankle-brachial index of <0.9
2. symptoms of intermittent claudication, rest pain, or minor tissue loss (Rutherford category I-V)

Exclusion Criteria:

1. patients with acute limb ischemia
2. Patients with overt congestive heart failure / recent acute myocardial infarction (< 3 months)
3. Premenopausal women and post-menopausal women on hormone supplements.
4. chronic inflammatory disease (systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease), or receiving therapy with steroids, cyclosporine, methotrexate or immunocompromised patients.
5. unilateral or bilateral vagotomy
6. Patients with bilateral upper extremity amputation
7. pregnant patients
8. prisoners
9. end-stage renal disease.
10. End-stage liver disease.
11. patients with BMI>34
12. Patients with upper extremity arterial disease
13. history of recurrent vasovagal syncope, Sick sinus syndrome, 2nd- or 3rd-degree atrioventricular block (AV) block, prolonged first degree AV block.
14. Refusal to sign a consent form.
15. Significant hypotension from autonomic dysfunction
16. Patients with pacemakers who have significant interaction with TVNS during testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Interventional Arm; Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour.	Device: TVS; Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour
SHAM_COMPARATOR: Control; Sham TVS will be performed by use of a Tragus stimulator device with electrodes attached to the ear lobule. Stimulator will be applied continuously for 1 hour.	Device: Sham TVS; Device will be applied but not to the Tragus of the ear but will be attached to the ear lobule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow mediated vasodilatation	Flow mediated vasodilatation will be tested. A change in the maximal diameter of the brachial artery(in mm) will be assessed immediately(within 10 minutes) after TVNS/sham stimulation.	Change from baseline to post stimulation(within 10 minutes of stimulation) with TVS/Sham stimulation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function in microcirculation	LSCI based calculation of perfusion unit before and after TVS/Sham stimulation	Change from baseline to post stimulation(within 20-30 minutes of stimulation) with TVS/Sham stimulation
Pulse wave analysis	Arterial elasticity. Augmentation pressure (AP) will be calculated which is expressed as a percentage of the aortic pulse pressure (PP) which is the difference of systolic and diastolic BP(mm Hg).	Change from baseline to post stimulation(within 15-20 minutes) with TVS/Sham stimulation.

Collaborators and Investigators

• Sponsor: University of Oklahoma

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 11, 2017
• Primary Completion (ACTUAL): May 30, 2020
• Study Completion (ACTUAL): May 30, 2020

Study Registration Dates

• First Submitted: October 12, 2017
• First Submitted That Met QC Criteria: February 19, 2018
• First Posted (ACTUAL): February 26, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 21, 2021
• Last Update Submitted That Met QC Criteria: December 20, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Vascular Diseases; Peripheral Arterial Disease
• Other Study ID Numbers: 8473

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
• product manufactured in and exported from the U.S.: No