Neuromodulation to Treat Patients With Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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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.

Official Title
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Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure With Normal Ejection Fraction

Intervention / Treatment
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* Device: low level transcutaneous vagus nerve stimulation


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham control<br>Patients will receive 1 hour of sham transcutaneous low level vagal stimulation daily for 3 months | Device: low level transcutaneous vagus nerve stimulation<br>* Stimulation of the auricular branch of the vagus nerve<br>|
| Experimental: Active treatment<br>Patients will receive 1 hour of active transcutaneous low level vagal stimulation daily for 3 months | Device: low level transcutaneous vagus nerve stimulation<br>* Stimulation of the auricular branch of the vagus nerve<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise Capacity | 6 minute walk test | 3 months | 
| Inflammatory Cytokines | Serum inflammatory cytokines (tumor necrosis factor-alpha) | 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. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure with preserved ejection fraction, inflammation