Available via license: CC BY-NC-SA 4.0
Content may be subject to copyright.
Address for correspondence: Dr. Barış Akdemir, Mail Code 508, 420 Delaware St SE
Minneapolis, MN, 55455-USA
E-mail: akdem002@umn.edu
Accepted Date: 10.06.2016
©Copyright 2016 by Turkish Society of Cardiology - Available online at www.anatoljcardiol.com
DOI:10.14744/AnatolJCardiol.2016.7129
804 Review
Barış Akdemir, David G. Benditt
Cardiovascular Division, Cardiac Arrhythmia and Syncope Center, University of Minnesota Medical School; Minneapolis, Minnesota-
USA
Vagus nerve stimulation: An evolving adjunctive treatment
for cardiac disease
Introduction
The sympathetic and parasympathetic components of the au-
tonomic nervous system (ANS) regulate the physiological func-
tion of a wide range of organs, glands, and involuntary muscles;
conversely, the ANS may also contribute importantly to both the
development and treatment of disease process in these very
same organ systems. By way of example, in cardiovascular medi-
cine, autonomic neural inuences play a crucial role in determin-
ing the clinical features and severity of a wide range of condi-
tions including hypertension, ischemic arrhythmia, heart failure,
and reex syncope (1). Further, drugs with predominant impact
on autonomic function (e.g., beta- and alpha-adrenergic blockers,
most antiarrhythmic agents, and angiotensin receptor blockers)
are the foundation for treatment of many of these abnormalities.
Additionally, apart from drugs, recently there has been increased
interest in electrical ANS stimulation for treatment of certain of
these disease states. In this regard, the role of direct neural stimu-
lation for therapeutic application may be dated to initial attempts
to stimulate the carotid sinus for amelioration of severe angina
pectoris (1, 2). However, as more effective medical and surgical
techniques were introduced, the carotid sinus electrical stimula-
tion approach largely vanished. On the other hand, indirect elec-
trical stimulation of the heart, and inevitably its peripheral nerves,
has been the subject of a number of clinical trials targeting treat-
ment of certain reex syncopal disorders, particularly carotid
sinus syndrome and vasovagal syncope (1, 3). While these latter
clinical trials have met with variable success, they have spurred a
resurgence of research designed to identify the potential clinical
utility of modifying ANS activity by direct electrical stimulation.
Perhaps the ANS region that offers the greatest current inter-
est for direct electrical stimulation is that of the complex neural
networks residing on the posterior aspect of the heart (particu-
larly the atria) (1, 4). These neural complexes communicate with
the central nervous system via neural connections traveling
predominantly along the great vessels of the thorax. In a recent
review we summarized the body of research examining these
complex networks and their probable contributions to cardiac
arrhythmias, including potentially life-threatening channelopa-
thies (4). In terms of current therapeutics, stimulation of certain
aspects of these neural networks, particularly the regions adja-
cent to the pulmonary veins, plays a role in certain atrial bril-
lation ablation strategies. In essence, induction of bradycardia
by atrial stimulation in the vicinity of the neural network of inter-
The vagus nerve is a major component of the autonomic nervous system and plays a critical role in many body functions including for example,
speech, swallowing, heart rate and respiratory control, gastric secretion, and intestinal motility. Vagus nerve stimulation (VNS) refers to any
technique that stimulates the vagus nerve, with electrical stimulation being the most important. Implantable devices for VNS are approved
therapy for refractory epilepsy and for treatment-resistant depression. In the case of heart disease applications, implantable VNS has been
shown to be beneficial for treating heart failure in both preclinical and clinical studies. Adverse effects of implantable VNS therapy systems
are generally associated with the implantation procedure or continuous on-off stimulation. The most serious implantation-associated adverse
effect is infection. The effectiveness of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, heart failure, and other
conditions remains under investigation. VNS merits further study for its potentially favorable effects on cardiovascular disease, especially heart
failure. (Anatol J Cardiol 2016; 16: 804-10)
Keywords: atrial fibrillation, heart failure, vagus nerve stimulation, ventricular arrhythmia
ABSTRACT
est is used to conrm proximity for purposes of radio-frequency
modication of efferent ANS inputs to the heart, which most like-
ly also alter afferent signals to the mid-brain (5, 6). Although the
ganglionic ablation strategy for atrial brillation ablation remains
controversial, the concept of direct ANS stimulation to identify a
ganglionic target continues to be employed in many clinical elec-
trophysiological laboratories for difcult cases (6).
Apart from targeting ganglionic plexus (GP), there are vari-
ous elements of the ANS that may be amenable to functional
modication by direct electrical stimulation. In this context, the
vagus nerve (10th cranial nerve) has the virtue of being readily
accessible (vagus nerve stimulation, VNS). The vagus is princi-
pally a mixed parasympathetic nerve, containing both afferent
and efferent sensory bers. Vagal nerve activity plays a promi-
nent role in heart rate and respiratory control, gastric secretion,
and intestinal motility. In addition, vagus nerve connections mod-
ulate the function of higher brain centers, forming the basis for
its potential use in many clinical disorders (1, 3, 4). For instance,
the vagus nerve plays a key role in blood pressure (BP) control.
Further, in conjunction with sympathetic “withdrawal” in reex
vasodepressor syncope, increased parasympathetic activity
largely traveling in the vagus nerve can act to substantially re-
duce BP. This latter attribute was investigated in our laboratory
and we demonstrated that enhanced vagal activity triggered in-
directly by carotid sinus stimulation acted to reduce systemic
BP even in the setting of sympathetic blockade and absence of
cardiac slowing (7). This and other similar observations provide
a reasonable basis for assessing the potential for direct vagal
stimulation to contribute to BP control in difcult to treat pa-
tients, and by virtue of afterload reduction, to possibly play a role
in treatment of both low cardiac output states, and diminishing
arrhythmia susceptibility in systolic heart failure (8).
Apart from its potential value for cardiovascular disease,
electrical stimulation of the vagus (either directly or indirectly)
has proved useful in treatment of a number of other medical
conditions. In this regard, electrical VNS has US Food and Drug
Administration (FDA) approval for management of epilepsy and
depression. In addition, VNS is being studied for possible ben-
ets in headache, gastric motility disorders, and asthma (9). This
article focuses primarily on development of clinical VNS for car-
diac applications, including consideration of VNS device types
(invasive or noninvasive), and potential adverse effects.
Development of clinical VNS
VNS and epilepsy
In the late 19th century, VNS was rst used to treat epilepsy
by American neurologist James Corning, but the method was as-
sociated with excessive adverse effects (e.g., bradycardia, syn-
cope) and was abandoned (10). More recently the concept has
been resurrected and is used clinically.
VNS effectiveness in epilepsy was demonstrated with early
animal studies (11, 12). Subsequently, clinical studies of implant-
able VNS Therapy System® (Cyberonics, Inc., Houston, TX, USA,
Fig.1) in patients with refractory epilepsy, showed a seizure
reduction of ≥50% in 24.5% to 46.6% of patients (13). The VNS
Therapy System® was approved for the treatment of medically
refractory epilepsy in Europe in 1994 and in the USA and Canada
in 1997. As of August 2014, over 100,000 VNS devices had been
implanted in more than 75,000 patients worldwide (14).
The mechanism(s) of VNS benet for epilepsy prevention
remains largely unknown. However, in this regard, we have re-
cently reported that ictal asystole may be a model for improving
understanding of 1 set of cortical sites that may trigger both va-
gal bradycardia and vasodepression mimicking a reex faint. In
essence, focal epilepsy arising in the right or left insular cortex
has been associated with both a drop in BP and at times brady-
cardia, and thereby may reect 1 cortical region in which electri-
cal stimulation may modify susceptibility to epilepsy, as well as
benecially reduce BP when desired (15, 16).
VNS and depression
VNS has also found a role in the management of treatment-
resistant depression (TRD). Several observations led to consid-
eration of this application, including in particular improvement
of mood and cognition in epilepsy patients after initiation of VNS
therapy, and usage of several anticonvulsant medications as
mood stabilizers and antidepressants in bipolar disorder.
Brain regions that are critical to mood regulation (orbital cor-
tex, limbic system) are targets for VNS. Rush et al. (17) designed
a study to investigate effect of VNS on TRD. In short-term VNS
therapy for TRD, there was no statistical difference between
VNS therapy “on” versus VNS “off,” in terms of the 24-item
Hamilton Depression Rating Scale (HRSD24) response. However,
the study was extended to 1 year in 205 patients, and ndings
indicated that the HRSD24 score improved signicantly in VNS
therapy group (p<0.001) (18). Based on these observations, VNS
therapy was approved by FDA for TRD patients ≥18 years old (19).
VNS and heart disease
As noted earlier, neural stimulation for amelioration of car-
diovascular disease has been the subject of study for many
Akdemir et al.
Vagus nerve stimulationAnatol J Cardiol 2016; 16: 804-10
Figure 1. Implantable vagus nerve stimulation therapy system (Car-
diotTM, BioControl-Medical, Yehud, Israel; Pulse Model 102 Genera-
tor, Cyberonics, Inc., Houston, TX, USA,)
805
years. Early interest focused on carotid sinus stimulation for
intractable angina and later for treatment of hypertension (2).
These applications are summarized further below, but were
based on the already well-known propensity for carotid sinus
massage to decrease heart rate and BP. More recently, direct
VNS has begun to be of special interest as an adjuvant therapy
in heart failure patients.
Carotid sinus nerve stimulation (CsNS)
for angina pectoris and hypertension
Stimulation of baroreceptors in the carotid sinuses and aortic
arch results in reex systemic arterial and splanchnic bed dila-
tion, and reduction of both heart rate and myocardial contracti-
lity (20). The heart rate and contractility changes occur as a con-
sequence of reduction in the frequency of sympathetic efferent
impulses to sinus node and ventricular muscle, and an increase
in the frequency of vagal impulses (21).
In the mid-20th century CsNS gained interest as a potential
means for alleviating drug-refractory angina pectoris, by de-
creasing myocardial oxygen consumption (i.e., decreased heart
rate and contractility) at a time when it was not possible to im-
prove myocardial blood supply (1, 22). Braunwald et al. (23), in
a landmark report, showed that carotid nerve stimulation de-
creased angina episodes and increased exercise tolerance in 15
of 22 patients who had stable coronary artery disease. However,
CsNS never became a mainstream therapy for angina pectoris
due to advances in both pharmacological and coronary reperfu-
sion strategies.
CsNS has also been investigated for systemic hypertension
for more than 40 years. An implantable CsNS therapy system
(Barostim neo™ System, CVRx Inc., Minneapolis, MN, USA, Fig. 2)
has CE (Conformité Européene) mark in Europe for the treatment
of hypertension patients. This device is currently under clinical
evaluation in the USA and Canada for the treatment of high blood
pressure and heart failure (24).
VNS for heart failure
That autonomic disturbances contribute importantly to the
progression of heart failure is now widely recognized (1, 22). In
this context, autonomic imbalance characterized by vagal with-
drawal and increased sympathetic activity has been shown to
play a major role in the worsening of both heart failure and its
prognosis. Specically, while sympathetic pre-dominance may
be benecial in acute cardiac events to maintain cardiac output,
chronically excessive sympathetic activity is detrimental, con-
tributing to adverse cellular calcium loading, left ventricular (LV)
remodeling, myocyte apoptosis, brosis, and electrical instability.
Clinical evidence from the Autonomic Tone and Reexes
after Myocardial Infarction study (25) and the Cardiac Insuf-
ciency Bisoprolol Study II (26) indicates that diminished cardiac
vagal activity and increased heart rate predict a high mortality
rate in congestive heart failure. Therefore, modulation of the
ANS (neuromodulation) with the aim of restoring a more normal
autonomic balance is gaining increasing interest as a potential
therapy for patients with heart failure. In this regard, it is hypoth-
esized that electrical stimulation of the vagus nerve may help to
normalize parasympathetic activation of cardiac control reex-
es and inhibit sympathetic hyperactivation (1, 27).
In preclinical studies, VNS has demonstrated improved
cardiac electrical and mechanical function. For instance, Li et
al. (28) showed improvement in hemodynamics, LV remodeling
and reduced neurohormonal activation with VNS in a rat infarct
model with heart failure. Study results showed a reduction in
mortality rate at 140 days (50% in the sham model and 14% with
VNS stimulation) (28).
An initial clinical study for heart failure included patients
with New York Heart Association (NYHA) class II-III heart failure
and LV ejection fraction (LVEF) <35%. This report demonstrated
improvement of LV end-systolic volume (LVESV), NYHA classi-
cation, and quality of life (29). A subsequent report on patients
with reduced EF and NYHA classes II-IV showed improvement in
LVEF, cardiac volume, and 6-minute walk test at 6 months, which
was maintained at 1 year (30).
The Increase of Vagal Tone in Heart Failure (INOVATE-HF)
trial (CardiotTM VNS therapy system; BioControl Medical, Ye-
hud, Israel, Fig. 1) is similarly assessing VNS in heart failure and
has just recently achieved target of 650 patients. Findings are
expected in December 2016.
Neural Cardiac Therapy for Heart Failure (Precision™, Bos-
ton Scientic Corporation, St. Paul, MN, USA) was a random-
ized controlled trial of VNS in patients with EF <35%, increased
LV end-diastolic dimensions (>55 mm), and NYHA classes III-IV,
but excluding patients with cardiac resynchronization therapy
devices; or QRS>130 milliseconds (31). Patients were random-
ized in a 2:1 fashion to VNS on or off for 6 months. The primary
endpoint was improvement in LV systolic dimensions; secondary
endpoints were improvement in other echocardiographic param-
Akdemir et al.
Vagus nerve stimulation Anatol J Cardiol 2016; 16: 804-10
Figure 2. Carotid sinus nerve stimulation therapy system (Barostim
neo™ System, CVRx Inc., Minneapolis, MN, USA)
806
eters and circulating biomarkers. The study failed to reach pri-
mary or secondary endpoints; however, it did show improvement
in quality of life and NYHA classication (31).
The Autonomic Neural Regulation Therapy to Enhance Myo-
cardial Function in Heart Failure (Cyberonics, Houston, TX, USA)
study investigated VNS of right or left cervical vagus in 60 patients
(32). The main inclusion criteria were EF <40%, LV end-diastolic
dimensions 50–80 mm, and QRS<150 milliseconds. There was
improvement in LVEF by 4.5%, but LVESV did not decrease signi-
cantly. There was again an improvement in quality of life, exercise
capacity, and NYHA classication. There was no signicant dif-
ference between left or right cervical vagus stimulation (32).
VNS for cardiac arrhythmias
Atrial brillation
As discussed earlier, supra-threshold VNS (i.e., electrical
stimulation of the vagus nerve at a voltage level that slows the
sinus rate or prolongs atrioventricular conduction) has been stu-
died in other cardiac and non-cardiac diseases. Supra-thresh-
old VNS has been used to induce and maintain atrial brillation
(AF), and animal studies have shown that supra-threshold VNS
can be utilized to induce and maintain AF in experiments. How-
ever, recent experimental and clinical studies show that low-lev-
el cervical VNS (i.e., the voltages/currents do not slow the sinus
rate or prolong atrioventricular conduction) induces effects op-
posite to supra-threshold VNS and plays an anti-arrhythmic role
in AF management. Since 2009, several studies have reported
the anti-arrhythmic role of low-level cervical VNS in AF popu-
lation (33–36). For example, Li et al. (33) showed that cervical
low-level VNS induced a progressive increase in AF threshold at
all pulmonary vein and atrial appendage sites. Yu et al. (34) also
demonstrated that cervical low-level VNS inhibited AF inducibil-
ity, prevented shortening of effective refractory period (ERP) at
pulmonary vein and atrial sites and increase of ERP dispersion
induced by activation of atrial GP. Finally, a series of recent stud-
ies also showed that cervical low-level VNS can prevent and/
or reverse atrial electrophysiological remodeling and autonomic
remodeling (35, 36).
Cervical VNS is an invasive approach in which cervical sur-
gery is needed to position vagal stimulation electrode and has
adverse effects that are discussed in detail below. Recently, a
noninvasive approach for VNS (nVNS), transcutaneous electri-
cal stimulation of the auricular branch of the vagus nerve located
at the tragus, has been used in some studies (Fig. 3). In these
studies, it has been shown that low-level nVNS suppressed
AF, reversed acute atrial electrophysiological remodeling, de-
creased sympathetic nerve activity and increased heart rate
variability (37, 38).
Ventricular arrhythmias
As noted earlier, different levels of parasympathetic stimu-
lation exert different anti-arrhythmic effects. Thus, it has been
shown that parasympathetic hyperactivity induces and main-
tains AF, but at the same time, parasympathetic hyperactivity
is protective for ventricular arrhythmias. In animal studies, cer-
vical supra-threshold VNS suppressed the incidence of ven-
tricular arrhythmias, especially ventricular tachycardia and
ventricular brillation during acute myocardial ischemia and
ischemia reperfusion (39, 40). Multiple mechanisms have been
described to explain this anti-arrhythmic effect of VNS, such as
its bradycardiac effect, anti-adrenergic effects, prevention of
the loss of phosphorylated connexin 43 proteins, and inhibition
of the opening of the mitochondrial permeability transition pore.
The anti-arrhythmic role of atrial GP stimulation has also been
investigated in several studies. In the normal heart, activation of
atrial GP prolonged ventricular ERP, decreased the slope of vent-
ricular action potential restitution curves and delayed action
potential duration (41). In the ischemic heart, atrial GP activity
signicantly inhibited the incidence of ventricular arrhythmias
during not only acute myocardial ischemia (42), but also isch-
emia reperfusion (43). Atrial GP stimulation also increased heart
rate variability and prevented the loss of connexin 43 induced by
ischemia/reperfusion (43).
VNS device types and adverse effects
Implantable VNS appears to be safe and well tolerated.
The electrodes are attached to the left or right vagus nerve
connected to a stimulating device implanted under the ante-
rior chest wall (Fig. 1). Stimulation is turned on or off by a mag-
net. The VNS device may operate using a wide variety of stim-
ulation parameters (output current, signal frequency, pulse
width, signal on time, signal off time). Currently approved
stimulation parameters are 0.25–3.5 mA (0.25 mA steps), 20–30
Hz (<10 Hz is ineffective, >50 Hz might induce nerve damage),
0.25–0.5 milliseconds pulse, signal on for 30–60 seconds, and
signal off for 5 minutes. (44, 45) A rapid stimulation of signal
on for 7 seconds and off for 14-21 seconds is also available
(46). The optimal VNS stimulation settings, however, remain
unknown.
Figure 3. Non-implantable vagus nerve stimulation systems: (a)
NEMOS® (transcutaneous vagus nerve stimulation; Cerbomed, Erlan-
gen, Germany), (b) gammaCore (noninvasive vagus nerve stimulation;
ElectroCore, Basking Ridge, NJ, USA)
a b
Akdemir et al.
Vagus nerve stimulationAnatol J Cardiol 2016; 16: 804-10 807
Adverse events (AEs) with VNS are generally associated
with implantation or continuous on-off stimulation. As is the
case with any implanted device, infection is the most serious
implantation-associated complication. Bradycardia and asys-
tole have also been described during implantation, as has vocal
cord palsy, which has been noted to persist up to 6 months, and
occurrence depends on surgical skill and experience. Recently,
a retrospective study (47) was published that was designed to
investigate surgical and hardware-related complications of VNS
implantation. Complications related to surgery occurred in 8.6%
and hardware complications in 3.7%. Table 1 summarizes comp-
lication rates related to surgery and hardware. Complication
rates in the rst 10 years of implantation experience were com-
pared with last 15 years implantation experience; similar surgi-
cal complication rates were found in both groups (8.9%, 9.2%)
but hardware-related complication rates were less in the last 15
years experience (7.3%, 2.3%).
The most frequent stimulation-associated AEs include voice
alteration, paresthesia, cough, headache, dyspnea, pharyngi-
tis, and pain. Table 2 summarizes stimulation-associated AEs in
clinical trials of the VNS Therapy System. The frequency of these
AEs declines with continued treatment (48). Treatment will likely
require a decrease in stimulation strength or intermittent or per-
manent device deactivation (9).
Alternative nVNS delivery systems such as that stimulating
the tragus of the ear avoid surgery-related complications and may
limit AEs related to the continuous on-off stimulation cycle of im-
plantable devices since nVNS devices can be adjusted to balance
efcacy and tolerability (49, 50). Efcacy could not be compared
between implantable VNS system and nVNS system at the time of
this review. Randomized prospective studies are needed to com-
pare efcacy of nVNS with implantable VNS therapy system.
Summary
Neuromodulation offers a potentially important new ap-
proach to enhance treatment of a range of cardiovascular disea-
ses. VNS is currently the neuromodulation method that has so far
received most clinical interest. Specically, by modifying sympa-
thetic/parasympathetic balance to the heart and other cardio-
vascular structures, VNS may offer an adjunct to conventional
treatment strategies for a number of inadequately controlled
cardiovascular conditions. At present, heart failure provides
the most important potential application, but additional study is
needed to ascertain whether VNS will provide substantial incre-
mental benet. However, other possible VNS opportunities may
include ameliorating inappropriate sinus tachycardia, preventing
AF and reducing propensity for sudden death in certain high-risk
populations.
Potential conflicts of interest: Dr. Benditt was an investigator for
the INOVATE-HF trial, but otherwise has no commercial or nancial con-
icts to declare. Dr. Benditt is supported in part by a grant from the Earl
E. Bakken family in support of heart-brain research.
Peer-review: Externally peer-reviewed.
Authorship contributions: Concept – D.B.; Design – D.B.; Supervi-
sion – D.B.; Literature search – B.A.; Writing – B.A.; Critical review – D.B.
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From Prof. Dr. Arif Aksit's collection
