Heart Failure With Normal Ejection FractionNCT03327649
Neuromodulation to Treat Patients With Heart Failure With Preserved Ejection Fraction
A study testing low level transcutaneous vagus nerve stimulation in people with Heart Failure With Normal Ejection Fraction, run by University of Oklahoma at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 90 years
- Conditions the study is for
- Heart Failure With Normal Ejection Fraction
- What is being tested?
- low level transcutaneous vagus nerve stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 52 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Dec 2017to 30 Sep 2021
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- history of vagotomy
- pregnancy
- sick sinus syndrome and 2nd or 3rd degree AV block (without a pacemaker).
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
About this study
Official title: Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction
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.
- Being tested
- low level transcutaneous vagus nerve stimulation
- Keywords
- heart failure with preserved ejection fraction, inflammation
- Medical subject headings
- Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
low level transcutaneous vagus nerve stimulationDevice
Stimulation of the auricular branch of the vagus nerve
| Study group | Role | What they receive |
|---|---|---|
| Sham control | Sham comparator | Patients will receive 1 hour of sham transcutaneous low level vagal stimulation daily for 3 months Receives: 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 Receives: Device: low level transcutaneous vagus nerve stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 3 months
Secondary outcomes (3)
Exercise Capacity
6 minute walk test
Measured: 3 months
Inflammatory Cytokines
Serum inflammatory cytokines (tumor necrosis factor-alpha)
Measured: 3 months
Minnesota Living With Heart Failure Questionnaire
The Minnesota Living with Heart Failure Questionnaire is a well validated measure of quality of life in patients with heart failure. It can have a score 0 to 105, with higher scores reflecting worse quality of life.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2017
- Study start12 Dec 2017
- Primary completion30 Mar 2021
- Study completion30 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Heart Failure With Normal Ejection FractionStudies of the same condition, open and under way.
- More trials run by University of OklahomaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- randomized controlled trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oklahoma
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Stavros Stavrakis, MD, PhD, Principal investigator, University of Oklahoma
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03327649
- Sponsor's protocol ID
- 8251
- Status last verified
- Jan 2026
- First submitted
- 27 Oct 2017
- Last updated
- 23 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- Yes: A biologic repository will be maintained and consideration of its use for future research (linked only to de-identified data) will be integrated into the initial informed consent process for this study. Data needed for independent verification of research results will be made publicly available within 12 months of the end of the funding period (and any no-cost extension).
Publications
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.
PubMed 40622772Stavrakis 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.
PubMed 35023349
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction
- ClinicalTrials.gov ID
- NCT03327649
- Acronym / sponsor ID
- 8251
- Keywords
- heart failure with preserved ejection fraction, inflammation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- University of OklahomaUniversity, hospital or other
- Study start
- 12 Dec 2017 (actual)
- Primary completion
- 30 Mar 2021 (actual)
- Study completion
- 30 Sep 2021 (actual)
- First posted
- 31 Oct 2017 (actual)
- Results
- Posted 22 Sep 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| Sham control | Sham comparator | Device: low level transcutaneous vagus nerve stimulationPatients will receive 1 hour of sham transcutaneous low level vagal stimulation daily for 3 months |
| Active treatment | Experimental | Device: low level transcutaneous vagus nerve stimulationPatients will receive 1 hour of active transcutaneous low level vagal stimulation daily for 3 months |
Who may qualify
- Ages
- 21 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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:
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| low level transcutaneous vagus nerve stimulationStimulation of the auricular branch of the vagus nerve | Device | Active treatment, Sham control |
Primary outcome
E/e' (Early Mitral Inflow Doppler Velocity to the Early Diastolic Mitral Annulus Velocity)
Time frame: 3 months
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.
Global Longitudinal Strain
Time frame: 3 months
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 secondary outcomes
Exercise Capacity
Time frame: 3 months
Inflammatory Cytokines
Time frame: 3 months
Minnesota Living With Heart Failure Questionnaire
Time frame: 3 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40622772Goggins 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.
- Derived from this study: PubMed 35023349Stavrakis 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.
- Individual participant dataSharing planned: Yes. A biologic repository will be maintained and consideration of its use for future research (linked only to de-identified data) will be integrated into the initial informed consent process for this study. Data needed for independent verification of research results will be made publicly available within 12 months of the end of the funding period (and any no-cost extension).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stavros Stavrakis, MD, PhD principal investigator
University of Oklahoma
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing low level transcutaneous vagus nerve stimulation in people with Heart Failure With Normal Ejection Fraction, run by University of Oklahoma at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Sep 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
E/e' (Early Mitral Inflow Doppler Velocity to the Early Diastolic Mitral Annulus Velocity) (time frame: 3 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03327649, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jan 2026.