Transcutaneous Vagus Nerve Stimulation in Heart Failure

Study Overview
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Brief Summary
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Several studies have shown that alterations in autonomic nervous system function are implicated in the onset and progression of numerous cardiovascular diseases. Direct stimulation of the vagus nerve by means of a sleeve placed around the vagus nerve represents one of the methodologies proposed in the field of neuromodulation. This study, which is proposed as a pilot study for further application of the method in subjects with cardiovascular disease aims to verify and consolidate evidence on cardiovascular autonomic effects in patients with heart failure. Vagal stimulation will be achieved noninvasively by applying an external stimulator to the auricular site.

Detailed Description
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The autonomic nervous system (ANS), through the interaction between the sympathetic and vagal systems, plays a key role in modulating the cardiovascular system. Multiple experimental data and clinical studies have shown that alterations in the activity of the ANS - characterized by a predominant sympathetic modulation associated with reduced vagal modulation - are implicated in the onset and progression of numerous cardiovascular diseases. For example, both an increase in sympathetic activity and a reduction in vagal activity are associated with an increased risk of death after myocardial infarction and heart failure, and a further reduction in vagal activity has been shown to precede the phases of hemodynamic instability (1 -2). Over the last few years, the modulation of the ANS through the implantation of devices has emerged as a new frontier for the treatment of heart failure (3). Although there is a wide interest in the scientific community for the potential represented by this therapeutic modality, nevertheless the different devices for neuromodulation therapy are implantable devices (whose application requires an invasive procedure) and therefore not free from risks and complications. Direct stimulation of the vagus nerve by means of a sleeve positioned around the vagus nerve in its right or left cervical portion and controlled by a pacemaker, represents one of the methods proposed in the field of neuromodulation (4). As for vagal stimulation, this can also be achieved non-invasively by applying an external stimulator in the ear (5). Transcutaneous nerve stimulation is a widely used procedure for the treatment of refractory epilepsy, while there is still limited experience evaluating its cardiovascular effects. Preliminary data in healthy volunteers have shown that: a) transcutaneous vagal stimulation, through the auricle, is able to activate the afferent vagal pathway up to the nucleus of the solitary tract (6), b) non-invasive stimulation of the vagus nerve is able to reduce sympathetic outflow (7). Recent clinical experience suggests its role also in the control of paroxysmal atrial fibrillation (8). Therefore, non-invasive vagus nerve stimulation could be a promising therapeutic option in the cardiovascular field. This study aims to evaluate the effects of long-term transcutaneous vagus nerve stimulation (tVNS) on autonomic parameters and other available physiological biomarkers that reflect long-term adjustment of autonomic neural regulation and to correlate the magnitude of the response to the baseline autonomic profile. A preliminary set of experiments will be conducted on healthy subjects to define the best tVNS protocol (in terms of frequency and site of stimulation) to induce acute changes in the autonomic profile.

Official Title
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EffecTs of tRanscutaneous vAgus Nerve Stimulation in Heart Failure Patients With Moderately rEduced or preseRved Left Ventricular Function

Conditions
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Heart Failure With Preserved Ejection Fraction, Heart Failure With Midrange Ejection Fraction

Intervention / Treatment
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* Device: Active tVNS
* Device: Sham tVNS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heart failure patients with moderately reduced or preserved ejection fraction Sinus rhythm New York Heart Association (NYHA) Class II-III Exclusion Criteria: Patients with implanted cardiac device (ICD, CRT), Patients with recent (< 3 months) cardiac surgery, Patients with recent (< 3 months) myocardial infarction, Patients with recent (< 3 months) revascularization Patients with an indication for cardiac surgery within the next 6 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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 study to evaluate the effects of 6-month tVNS (1 hour/day) in heart failure patients on autonomic biomarkers.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: active tVNS<br>Patients randomized to active treatment will be instructed to receive the stimulation at the tragus | Device: Active tVNS<br>* It is a non-invasive transcutaneous electrical stimulation of the auricular branch of the vagus nerve which innervates the skin of the human ear. These nerve fibers project directly to the solitary tract nucleus (NTS) in the brain stem (6).<br>|
| Placebo Comparator: sham tVNS<br>Patients randomized to active treatment will be instructed to receive the stimulation at the ear lobe | Device: Sham tVNS<br>* Sham stimulation is obtained by placing the stimulation electrode at the level of the earlobe. The stimulation is therefore administered and perceived in an area not innervated by vagal fibers.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate | beats/min | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baroreflex Sensitivity | ms/mmHg | 6 months |