Neuromodulation to Treat Patients With Heart Failure With Preserved Ejection Fraction

NCT03327649 | Completed Results DMC FDA Device

• 1 other identifier: 8251
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

Heart failure with preserved ejection fraction (HFpEF) is a leading cause of mortality in the elderly. Outcomes of patients with HFpEF are poor and so far, no treatment has been shown to decrease morbidity or mortality. Recent animal and human studies suggest that a systemic proinflammatory state, produced by comorbidities, including aging, plays a central role in the development of HFpEF, supporting the notion that attenuating the proinflammatory state is an attractive therapeutic target for HFpEF. We have previously shown that low-level transcutaneous electrical stimulation of the vagus nerve (tVNS) suppresses inflammation in patients with atrial fibrillation. The overall objective of this proposal is to examine the effects of tVNS on diastolic dysfunction, exercise capacity and inflammation in patients with HFpEF. Our specific aims include: 1. To examine the effect of intermittent (1 hour daily for 3 months) tVNS on diastolic dysfunction and exercise capacity, relative to sham stimulation, in patients with HFpEF and 2. To examine the effect of intermittent (1 hour daily for 3 months) LLTS on inflammatory cytokines relative to sham stimulation, in patients with HFpEF. The proposed proof-of-concept studies will provide the basis for the design of further human studies using LLTS among populations with HFpEF. In light of the increasing number of elderly patients with HFpEF and the poor success of the currently available treatment options, an alternative and novel approach such as tVNS has the potential to impact clinical practice and improve health outcomes among a large number of patients. It is anticipated that these investigations will contribute to the broader understanding of the role of inflammation in the pathogenesis of HFpEF and how its inhibition can be used to provide therapeutic effects. Moreover, it is anticipated that a better understanding of how modulation of inflammation affects one of the hallmarks of HFpEF, diastolic dysfunction, will lead to the development of novel pharmacological and non-pharmacological approaches to treat this disease.

Conditions

Heart Failure With Normal Ejection Fraction

Keywords

heart failure with preserved ejection fraction; inflammation

Outcome Measures

Primary Outcomes (2)

• E/e' (Early Mitral Inflow Doppler Velocity to the Early Diastolic Mitral Annulus Velocity)

  E/e' was measured by echocardiography. E/e' correlates very well with left ventricular end diastolic pressure. Higher numbers indicate elevated left ventricular end diastolic pressure.

  3 months

• Global Longitudinal Strain

  Global longitudinal strain was measured by echocardiography. It is a measure of longitudinal shortening of the myocardium as a percentage (change in length as a proportion to baseline length), thus explaining the negative values. Reduced global longitudinal strain has been associated with adverse clinical outcomes irrespective of left ventricular ejection fraction.

  3 months

Secondary Outcomes (3)

• Exercise Capacity

  3 months

• Inflammatory Cytokines

  3 months

• Minnesota Living With Heart Failure Questionnaire

  3 months

Study Arms (2)

Sham control

SHAM COMPARATOR

Patients will receive 1 hour of sham transcutaneous low level vagal stimulation daily for 3 months

Device: low level transcutaneous vagus nerve stimulation

Active treatment

EXPERIMENTAL

Patients will receive 1 hour of active transcutaneous low level vagal stimulation daily for 3 months

Device: low level transcutaneous vagus nerve stimulation

Interventions

low level transcutaneous vagus nerve stimulation DEVICE

Stimulation of the auricular branch of the vagus nerve

Active treatment; Sham control

Eligibility Criteria

• Age: 21 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HFpEF, defined as signs and symptoms of heart failure, LV ejection fraction ≥50%, brain natriuretic peptide ≥35pg/mL and echocardiographic evidence of diastolic dysfunction (left atrial volume index ≥34mL/m2, mitral E-wave velocity/mitral annular velocity ratio \[E/e'\]≥13 and e'\<9cm/s) plus 2 of the following 4 comorbidities:
• age ≥ 65,
• diabetes,
• hypertension and
• obesity, defined as body mass index ≥30kg/m2

You may not qualify if:

• LV ejection fraction \<40%
• significant valvular disorder (i.e., prosthetic valve or hemodynamically significant valvular diseases)
• recent (\<6 months) stroke, myocardial infarction or hospitalization for heart failure
• severe heart failure (class III or IV)
• end stage kidney disease
• recurrent vasovagal syncope
• history of vagotomy
• pregnancy
• sick sinus syndrome and 2nd or 3rd degree AV block (without a pacemaker).

Sponsors & Collaborators

• University of Oklahoma: lead

Study Sites (1)

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Related Publications (2)

• Goggins E, Inoue H, Okusa MD. Neuroimmune Control of Inflammation in Acute Kidney Injury and Multiorgan Dysfunction. J Am Soc Nephrol. 2025 Dec 1;36(12):2473-2484. doi: 10.1681/ASN.0000000813. Epub 2025 Jul 7.

  PMID: 40622772 DERIVED

• Stavrakis S, Elkholey K, Morris L, Niewiadomska M, Asad ZUA, Humphrey MB. Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction: A Pilot Randomized Clinical Trial. J Am Heart Assoc. 2022 Feb;11(3):e023582. doi: 10.1161/JAHA.121.023582. Epub 2022 Jan 13.

  PMID: 35023349 DERIVED

MeSH Terms

Conditions

Inflammation

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Stavros Stavrakis
• Organization: University of Oklahoma Health Sciences Center

stavros-stavrakis@ouhsc.edu

14052714742

Study Officials

• Stavros Stavrakis, MD, PhD

  University of Oklahoma

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: randomized controlled trial

Study Record Dates

• First Submitted: October 27, 2017
• First Posted: October 31, 2017
• Study Start: December 12, 2017
• Primary Completion: March 30, 2021
• Study Completion: September 30, 2021
• Last Updated: January 23, 2026
• Results First Posted: September 22, 2022

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Time Frame: 12 months after study completion

Locations

US (1)