Transcutaneous Vagus Nerve Stimulation in Heart Failure

NCT ID: NCT05789147

Last Updated: 2025-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-15
• Study Completion Date: 2024-12-31

Brief Summary

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

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.

Conditions

Heart Failure With Preserved Ejection Fraction; Heart Failure With Midrange Ejection Fraction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

active tVNS

Patients randomized to active treatment will be instructed to receive the stimulation at the tragus

Group Type: ACTIVE_COMPARATOR

Active tVNS

Intervention Type: DEVICE

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).

sham tVNS

Patients randomized to active treatment will be instructed to receive the stimulation at the ear lobe

Group Type: PLACEBO_COMPARATOR

Sham tVNS

Intervention Type: DEVICE

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.

Interventions

Active tVNS

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).

Intervention Type: DEVICE

Sham tVNS

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.

Intervention Type: DEVICE

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Istituti Clinici Scientifici Maugeri SpA

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Istituti Clinici Scientifici Maugeri IRCCS

Pavia, PV, Italy

Countries

Italy

References

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Reference Type: BACKGROUND

PMID: 9482439 (View on PubMed)

Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, Pozzoli M, Opasich C, Tavazzi L. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation. 1997 Nov 18;96(10):3450-8. doi: 10.1161/01.cir.96.10.3450.

Reference Type: BACKGROUND

PMID: 9396441 (View on PubMed)

Schwartz PJ, La Rovere MT, De Ferrari GM, Mann DL. Autonomic modulation for the management of patients with chronic heart failure. Circ Heart Fail. 2015 May;8(3):619-28. doi: 10.1161/CIRCHEARTFAILURE.114.001964. No abstract available.

Reference Type: BACKGROUND

PMID: 25991804 (View on PubMed)

Klein HU, Ferrari GM. Vagus nerve stimulation: A new approach to reduce heart failure. Cardiol J. 2010;17(6):638-44.

Reference Type: BACKGROUND

PMID: 21154273 (View on PubMed)

Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II. Headache. 2016 Feb;56(2):259-66. doi: 10.1111/head.12650. Epub 2015 Sep 18.

Reference Type: BACKGROUND

PMID: 26381725 (View on PubMed)

Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015 May-Jun;8(3):624-36. doi: 10.1016/j.brs.2014.11.018. Epub 2014 Dec 6.

Reference Type: BACKGROUND

PMID: 25573069 (View on PubMed)

Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16.

Reference Type: BACKGROUND

PMID: 25164906 (View on PubMed)

Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, Lockwood D, Lazzara R, Po SS. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015 Mar 10;65(9):867-75. doi: 10.1016/j.jacc.2014.12.026.

Reference Type: BACKGROUND

PMID: 25744003 (View on PubMed)

Maestri R, Pinna GD. POLYAN: a computer program for polyparametric analysis of cardio-respiratory variability signals. Comput Methods Programs Biomed. 1998 Apr;56(1):37-48. doi: 10.1016/s0169-2607(98)00004-2.

Reference Type: BACKGROUND

PMID: 9617526 (View on PubMed)

Pinna GD, Maestri R, Torunski A, Danilowicz-Szymanowicz L, Szwoch M, La Rovere MT, Raczak G. Heart rate variability measures: a fresh look at reliability. Clin Sci (Lond). 2007 Aug;113(3):131-40. doi: 10.1042/CS20070055.

Reference Type: BACKGROUND

PMID: 17381425 (View on PubMed)

Pinna GD, Maestri R, Raczak G, La Rovere MT. Measuring baroreflex sensitivity from the gain function between arterial pressure and heart period. Clin Sci (Lond). 2002 Jul;103(1):81-8. doi: 10.1042/cs1030081.

Reference Type: BACKGROUND

PMID: 12095408 (View on PubMed)

Maestri R, Pinna GD, Robbi E, Cogliati C, Bartoli A, Gambino G, Rengo G, Montano N, La Rovere MT. Impact of optimized transcutaneous auricular vagus nerve stimulation on cardiac autonomic profile in healthy subjects and heart failure patients. Physiol Meas. 2024 Jul 17;45(7). doi: 10.1088/1361-6579/ad5ef6.

Reference Type: RESULT

PMID: 39016202 (View on PubMed)

Other Identifiers

RF-2016-02364803

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

CE 2182

Identifier Type: -

Identifier Source: org_study_id