Neuromodulation of Inflammation and Endothelial Function

NCT ID: NCT05230732

Last Updated: 2025-04-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 158 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-09-01
• Study Completion Date: 2026-02-27

Brief Summary

Heart failure with reduced ejection fraction (HFrEF) is a major cause of mortality in United States. Aging is a major risk factor for adverse outcomes associated with HFrEF, with majority of the patient's over the age of 50, continuing to experience symptoms, reduced exercise capacity and poor quality of life. We have previously demonstrated that low level transcutaneous electrical stimulation of the vagus nerve at the tragus (LLTS) suppresses inflammation in patients with atrial fibrillation and diastolic dysfunction and improved endothelial dysfunction in patients with chronic heart failure. The overall objective of this proposal is to examine the effects of LLTS on heart failure symptoms, exercise capacity and quality of life in patients with HFrEF and simultaneously determine the impact of LLTS on the suppression of inflammation and improvement in endothelial function. Our specific aims include: 1. To examine the medium term effect of intermittent (1 hour daily for 3 months) LLTS on exercise capacity and quality of life, related to sham stimulation, in patients with HFrEF, 2. To determine the effects of medium-term LLTS on sympathovagal/autonomic balance (assessed by heart rate variability) and systemic inflammation in patients with HFrEF and 3. To determine the effects of medium-term LLTS on endothelial function in patients with HFrEF. The proposed proof-of-concept human studies will provide the basis for the design of further human studies using LLTS among larger populations with HFrEF. In light of the increasing number of elderly patients who continue to experience HFrEF symptoms, recognized is a key point of interest in this funding mechanism, and the suboptimal success of the currently available treatment options to ameliorate the problems mentioned above, an alternative novel approach such as LLTS has the potential to impact clinical practice and improve health outcomes among the large number of patients. It is anticipated that these investigations will contribute to a broader understanding of the role of autonomic imbalance, inflammation and endothelial dysfunction in the pathogenesis of HFrEF and how its inhibition can be used to provide therapeutic effects. Moreover, it is anticipated that a better understanding of how modulation of autonomic tone, inflammation and endothelial function affects one of the hallmarks of HFrEF will lead to the development of normal nonpharmacological and pharmacological approaches to treat this disease.

Detailed Description

Prospective randomized double-blind study of Lowlevel Tragus stimulation-LLTS vs. sham treatment.

We will require n=108 participants (54 in each group) to reach statistical significance and to account for potential drop-out (anticipated <5%, based on previous study in atrial fibrillation) from the study and 50 subjects below the age of 50 will be enrolled in the control group 2 for comparison purposes, for a total of 158 patients.

Aim 1:

Objective 1: measure the medium-term effects of LLTS on exercise capacity in subjects with HF - 6-minute walk distance (6MWD) will be performed at baseline and after 3 months of LLTS. Change in 6MWD from baseline to 3 months will be compared between experimental and sham groups. Duration of test: <10 minutes. A dedicated quite hallway exists in the translational geroscience laboratory which will enable performance of the test. Study will be performed by the research coordinator.

Objective 2: assess the effects of medium-term LLTS on quality of life in subjects with HF - quality of life will be determined using standard HF questionnaire (MLWHF score). This questionnaire will be administered at baseline and after 3 months. Duration of test: <15 minutes. Study will be administered by our research coordinator either on paper or tablet.

Aim2:

Objective 1: measure the effects of medium-term LLTS on sympathovagal balance in subjects with HF - Heart rate variability (HRV), a well-established, noninvasive measure of autonomic function, will be measured and analyzed via 10 min ECG using standard Labscribe and Kubios software. The amplitude and changes of the low (0.04-0.15Hz), high (0.15-0.4Hz) and the low frequency/high frequency ratio along with specific time domain variables (SDNN,SDANN,pNN50,rMSSD) will be determined to reflect autonomic imbalance.

Objective 2: assess the effects of medium-term LLTS stimulation on HF biomarkers, inflammation - using high sensitivity ELISA kits, NT-Pro BNP, sST2, Interleukins (6, 1), TNF-α, hsCRP will be assayed.

Aim 3:

Objective 1: assess the effects of medium-term LLTS on vascular endothelial function -Flow-mediated vasodilatation (FMD) will be used to assess %-change in brachial artery diameter upon the release of temporary 5-min blood flow occlusion to the extremity using ultrasonography (Phillips Affinity X70). This is a standard, validated technique to assess FMD. Average time to perform this study is ~20 minutes.

Conditions

Systolic Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Experimental

Active LLTS will be performed by use of a neuromodulation device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 12 weeks.

Group Type: EXPERIMENTAL

neuromodulation device

Intervention Type: DEVICE

Active LLTS will be performed by use of a neuromodulation device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 12 weeks

Control arm

Sham LLTS will be performed by use of a neuromodulation device with electrodes attached to the ear lobule. Stimulator will be applied continuously for 1 hour daily for 12 weeks.

Group Type: SHAM_COMPARATOR

SHAM

Intervention Type: DEVICE

Sham LLTS will be performed by use of a neuromodulation device with electrodes attached to the ear lobule. Stimulator will be applied continuously for 1 hour daily for 12 weeks

Interventions

neuromodulation device

Active LLTS will be performed by use of a neuromodulation device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 12 weeks

Intervention Type: DEVICE

SHAM

Sham LLTS will be performed by use of a neuromodulation device with electrodes attached to the ear lobule. Stimulator will be applied continuously for 1 hour daily for 12 weeks

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

Systolic heart failure with EF < or equal to 50%.

Exclusion Criteria

1. patients in overt congestive heart failure / recent acute myocardial infarction (< 4 weeks) or Unstable angina

2. Active malignancy

3. unilateral or bilateral vagotomy

4. pregnant patients

5. End stage liver disease

6. history of recurrent vasovagal syncope, Sick sinus syndrome with no pacemaker, 2nd or 3rd degree AV block.

7. Significant hypotension (Blood pressure < 90 mm Hg) secondary to autonomic dysfunction

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

University of Oklahoma

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tarun Dasari, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Oklahoma

Locations

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Tarun Dasari, MD,MPH

Role: CONTACT

tdasari@ouhsc.edu

4052714742

Cheryl Adams, RN

Role: CONTACT

cheryl-adams@ouhsc.edu

4052714742

Facility Contacts

Juvaria Anum

Role: primary

juvaria-anum@ouhsc.edu

4052713480

Brittany Karfonta

Role: backup

brittany-karfonta@ouhsc.edu

4052713480

Other Identifiers

5R21AG075639-02

Identifier Type: NIH

Identifier Source: secondary_id

View Link

14101

Identifier Type: -

Identifier Source: org_study_id