Heart Failure With Normal Ejection Fraction
Conditions
Keywords
heart failure with preserved ejection fraction, inflammation
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.
Interventions
Stimulation of the auricular branch of the vagus nerve
Sponsors
University of Oklahoma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double blind
Intervention model description
randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
21 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| E/e' (Early Mitral Inflow Doppler Velocity to the Early Diastolic Mitral Annulus Velocity) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exercise Capacity | 3 months | 6 minute walk test |
| Inflammatory Cytokines | 3 months | Serum inflammatory cytokines (tumor necrosis factor-alpha) |
| Minnesota Living With Heart Failure Questionnaire | 3 months | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStavros Stavrakis, MD, PhD
University of Oklahoma
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sham Control Patients will receive 1 hour of sham transcutaneous low level vagal stimulation daily for 3 months
low level transcutaneous vagus nerve stimulation: Stimulation of the auricular branch of the vagus nerve | 24 |
| Active Treatment Patients will receive 1 hour of active transcutaneous low level vagal stimulation daily for 3 months
low level transcutaneous vagus nerve stimulation: Stimulation of the auricular branch of the vagus nerve | 24 |
| Total | 48 |
Baseline characteristics
| Characteristic | Active Treatment | Total | Sham Control |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 33 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 15 Participants | 8 Participants |
| Age, Continuous | 69.8 years STANDARD_DEVIATION 8.8 | 70.1 years STANDARD_DEVIATION 8.9 | 70.3 years STANDARD_DEVIATION 9.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 39 Participants | 20 Participants |
| Region of Enrollment United States | 24 participants | 48 participants | 24 participants |
| Sex: Female, Male Female | 16 Participants | 32 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 3 / 24 | 4 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
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.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | E/e' (Early Mitral Inflow Doppler Velocity to the Early Diastolic Mitral Annulus Velocity) | 10.4 ratio | Standard Deviation 1.5 |
| Active Treatment | E/e' (Early Mitral Inflow Doppler Velocity to the Early Diastolic Mitral Annulus Velocity) | 9.9 ratio | Standard Deviation 1.5 |
Primary
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.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | Global Longitudinal Strain | -16.1 percentage of myocardial shortening | Standard Deviation 2.5 |
| Active Treatment | Global Longitudinal Strain | -18.6 percentage of myocardial shortening | Standard Deviation 2.5 |
Secondary
Exercise Capacity
6 minute walk test
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | Exercise Capacity | 326.9 meters | Standard Deviation 140.4 |
| Active Treatment | Exercise Capacity | 352.7 meters | Standard Deviation 158.8 |
Secondary
Inflammatory Cytokines
Serum inflammatory cytokines (tumor necrosis factor-alpha)
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | Inflammatory Cytokines | 11.3 pg/mL | Standard Deviation 2.5 |
| Active Treatment | Inflammatory Cytokines | 8.7 pg/mL | Standard Deviation 2.2 |
Secondary
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.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | Minnesota Living With Heart Failure Questionnaire | 36.6 units on a scale | Standard Deviation 14.8 |
| Active Treatment | Minnesota Living With Heart Failure Questionnaire | 23.8 units on a scale | Standard Deviation 14.8 |