Neuromodulation of Inflammation and Endothelial Function

Neuromodulation of Inflammation and Endothelial Function to Treat Elderly Patients With Systolic Heart Failure

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.

Study Overview

• Status: Recruiting
• Conditions: Systolic Heart Failure
• Intervention / Treatment: Device: neuromodulation device; Device: SHAM

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.

• Study Type: Interventional
• Enrollment (Estimated): 158
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tarun Dasari, MD,MPH; Phone Number: 4052714742; Email: tdasari@ouhsc.edu
• Study Contact Backup: Name: Cheryl Adams, RN; Phone Number: 4052714742; Email: cheryl-adams@ouhsc.edu

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73117
      • Recruiting
      • University of Oklahoma Health Sciences Center
      • Contact: Juvaria Anum; Phone Number: 405-271-3480; Email: juvaria-anum@ouhsc.edu
      • Contact: Brittany Karfonta; Phone Number: 4052713480; Email: brittany-karfonta@ouhsc.edu
      • Principal Investigator: Tarun Dasari, MD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Device: 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
Sham Comparator: 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.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6MWD	6 minute walk distance	Change in 6MWD after 12 weeks compared to baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QoL	Quality of life will be assessed using the Minnesota living with heart failure questionnaire	Change in QoL after 12 weeks compared to baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
FMD	Flow mediated vasodilatation will be assessed using vascular ultrasound measuring brachial artery diameter change with standard 5 minute BP cuff occlusion test.	Change in FMD after 12 weeks compared to baseline
HRV	heart rate variability	Change in HRV after 12 weeks compared to baseline
Inflammation	Inflammatory cytokines will assayed at baseline and after 4 weeks of stimulation. Cytokines assayed : Il1B,IL-6,IL-17,TNF-a,TGF-b,CRP etc- expressed in pg/ml units).	Change in inflammatory markers after 12 weeks compared to baseline

Collaborators and Investigators

• Sponsor: University of Oklahoma
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Tarun Dasari, MD, MPH, University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: January 10, 2022
• First Submitted That Met QC Criteria: February 4, 2022
• First Posted (Actual): February 9, 2022

Study Record Updates

• Last Update Posted (Estimated): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 29, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Murmurs; Heart Failure; Inflammation; Systolic Murmurs; Heart Failure, Systolic
• Other Study ID Numbers: 14101; 5R21AG075639-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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