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NEUROMODULATION OF THE FAILING HEART: LOST IN
TRANSLATION?
Mirnela Byku, M.D., PhD and Douglas L. Mann, M.D.
Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine,
Washington University School of Medicine, St Louis, MO 63110
SUMMARY
Sympathovagal imbalance contributes to progressive worsening of HF (HF) and is associated with
untoward clinical outcomes. Based on compelling pre-clinical studies which supported the role of
autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord
stimulation (SCS), vagus nerve stimulation (VNS) and baroreceptor activation therapy (BAT) in
patients with HF with a reduced ejection fraction (HFrEF). While the phase II studies with BAT
remain encouraging, the larger clinical studies with SCS and VNS have yielded disappointing
results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation
in the failing heart, as well provide a critical review of the recent clinical trials that have sought to
modulate autonomic tone in HF patients. This review will conclude with an analysis of some of
the difficulties in translating device-based modulation of the autonomic nervous from pre-clinical
models into successful clinical trials, as well as provide suggestions for how to move the field of
neuromodulation forward
OVERVIEW OF THE CARDIAC AUTONOMIC NERVOUS SYSTEM
Details of the complex regulation of the autonomic nervous system (ANS) have been
provided in several recent reviews, and will be discussed here only briefly in order to
provide the proper context for the discussion of the clinical studies of device-based
modulation of the autonomic nervous system (“neuromodulation”) in heart failure (HF) (1,
2). The ANS consists of the parasympathetic nervous system (PNS) and the sympathetic
nervous system (SNS). Physiologically, these two systems are diametrically opposed, yet
work together synergistically in a reciprocal manner, in order to provide the cardiovascular
system with the ability to respond quickly to both internal and external stimuli (3). Both the
SNS and the ANS are reflex circuits comprised of “motor” (efferent) fibers that convey
information from the central nervous system to the heart (Figure 1), and “sensory” (afferent)
sympathetic and parasympathetic fibers that convey information from the heart to the central
nervous system. The heart also receives afferent parasympathetic input from a series of
Corresponding Author: Douglas L. Mann, M.D., Cardiovascular Division, 660 South Euclid Ave. Campus PO Box 8066, St Louis,
MO 63110-1093, Phone: (314) 362 - 8908, Fax: (314) 454 – 5550, dmann@dom.wustl.edu.
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JACC Basic Transl Sci
. Author manuscript; available in PMC 2016 August 22.
Published in final edited form as:
JACC Basic Transl Sci
. 2016 April ; 1(3): 95–106. doi:10.1016/j.jacbts.2016.03.004.
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mechanosensitive nerve endings in large arteries and the carotid sinuses, collectively
referred to as baroreceptors, because they are sensitive to changes in blood pressure and
blood volume. The baroreceptors from the carotid arteries have axons in the
glossopharyngeal nerve, and those from the aorta have axons that travel in the vagus nerve.
The baroreflex is a major homeostatic mechanism for maintaining blood pressure, and is
responsible for controlling the afterload of the heart. Baroreceptors are activated by the
opening of mechanosensitive ion channels within the sensory terminals, which in turn
activate vagal afferent fibers that terminate in the nucleus tractus solitarius in the medulla
oblongata. Increased baroreflex activity (e.g. in hypertension) results in a reflex increase in
parasympathetic activity that triggers a reflex inhibition of sympathetic tone, thus restoring
autonomic balance. Conversely, decreased baroreflex activity (e.g. in hypotension) results in
withdraw of parasympathetic tone that results in a reflex increase in sympathetic tone.
SYMPATHOVAGAL IMBALANCE IN HEART FAILURE
The clinical syndrome of HF with a reduced ejection fraction (HFrEF) is associated with
sustained activation of the sympathetic nervous system that is accompanied by a withdrawal
of parasympathetic tone (2) (4) (5). Although these disturbances in autonomic control were
initially attributed to loss of the inhibitory input from arterial or cardiopulmonary
baroreceptor reflexes, there is increasing evidence that excitatory reflexes may also
participate in the autonomic imbalance that occurs in HF (2). Under normal conditions
inhibitory inputs from ‘high pressure’ carotid sinus and aortic arch baroreceptors and the
‘low pressure’ cardiopulmonary mechanoreceptors are the principal inhibitors of
sympathetic outflow, whereas discharge from the non-baroreflex peripheral chemoreceptors
and muscle ‘metaboreceptors’ are the major excitatory inputs to sympathetic outflow. The
parasympathetic limb of the baroreceptor heart rate reflex is also responsive to arterial
baroreceptor afferent inhibitory input. At rest, healthy individuals display low sympathetic
discharge and high rate variability. In HF patients the peripheral baroreflex responses
become suppressed (“blunted”) as HF worsens (6). Blunting of the peripheral arterial and
cardiopulomary baroreceptors results in a derepression of the sympathetic outflow from the
central nervous systems and a net increase in efferent sympathetic nerve activity that is
accompanied by decreased efferent parasympathetic tone. Consequently, patients with HF
have a loss of heart rate variability, and increased peripheral vascular resistance (2).
Dysregulation of the autonomic nervous system in HF has received considerable attention
over the past 3 decades, because of the well-recognized association between increased
sympathetic activity and “neurohormonal” activation. Although increased sympathetic
stimulation provides short-term support for the cardiovascular system, the sustained
activation of the SNS is maladaptive in the long-term because it is directly toxic to the heart
and circulation and also leads to activation of the renin-angiotensin system, which can also
be deleterious to the heart and circulation (reviewed in (7)). However, the role of the PNS in
the pathophysiology of HF is less well understood. In isolated organ preparations, human in
vitro data, and in animal models, local muscarinic receptor stimulation results in inhibition
of norepinephrine (NE) release from sympathetic nerve terminals (8) (9). In vivo, it has been
shown that cardiac NE spillover was greater in patients with HF than those with normal LV
function, and that infusion with acetylcholine attenuates the amount of NE release in these
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patients. This effect was not seen in the presence of atropine, suggesting that it is mediated
via muscarinic receptor activation (10) (11). The ATRAMI (Autonomic Tone and Reflexes
After Myocardial Infarction) trial was the first large multicenter clinical study to examine
impairment in vagal activity as a prognostic marker following myocardial infarction.
ATRAMI enrolled 1284 post myocardial infarction patients and followed them over a 2 year
period, and showed that patients with depressed baroreflex sensitivity (a marker of decreased
vagal activity) had decreased survival (5). The depressed baroreflex sensitivity was also
shown to be associated with a worse NYHA class and higher mortality in HF patients. The
prognostic value of the depressed baroreflex sensitivity among patients with HFrEF was also
observed in the presence of beta-blocker therapy (12, 13). The above observations have led
to the development of various device-based therapies that are designed to restore the
sympathovagal imbalance in patients with heart failure, as well be discussed below.
THERAPEUTIC MODULATION OF THE AUTONOMIC NERVOUS SYSTEM IN
HEART FAILURE
It bears emphasis that many of the current therapies for HFrEF patients reverse the
sympathovagal imbalance that develops in HF, including pharmacologic therapy with beta-
blockers and angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor
blockers, exercise training, and cardiac resynchronization therapy (reviewed in (14)).
Despite the tremendous progress in treating patients with heart failure, the great majority of
patients with HF will eventually develop worsening HF (15). Thus, there continues to be an
unmet need for new therapies for treating patients with heart failure. To this end, there has
been growing interest in directly modulating the autonomic nervous system as a means of
counteracting the sympathovagal imbalance that develops in heart failure. In the following
review, we will focus on the pre-clinic and clinical studies that have employed spinal cord
stimulation (SNS), vagus nerve stimulation (VNS) and baroreceptor activation therapy
(BAT) in heart failure, with the goal of deconstructing these studies in order to better
understand why it has been so difficult to translate the encouraging pre-clinical studies into
successful phase II/III clinical trials. The important therapeutic areas of renal nerve
denervation and left cardiac sympathetic denervation have been the subject of several recent
reviews and will not be discussed herein (1).
Vagus nerve stimulation (VNS)
VNS has been used in humans, and is FDA approved for the treatment of epilepsy (1997)
and refractory depression (2005). The device that is used for the treatment of epilepsy and
depression is composed of a pulse generator, a bipolar lead that is implanted in the mid
cervical portion of the left vagus nerve, and delivers a biphasic current that continuously
cycles between on and off periods to stimulate afferent vagus nerve fibers. Importantly, 2 of
3 VNS devices used in patients with HFrEF were developed for use in patients with epilepsy
and/or depression
Pre-clinical studies of VNS—The salutary role VNS in the heart was first shown by a
series of experimental studies by Scwartz and colleagues, who demonstrated that VNS
prevented ventricular fibrillation induced by acute myocardial ischemia in the setting of a
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healed myocardial infarction (16). In animal models of HF VNS resulted in increased
survival (17), improved ventricular function (17, 18), as well as decreased inflammation
(18). Indeed, the anti-inflammatory effects of VNS following ischemia and reperfusion
injury are accompanied by a reduction in the number of macrophages and apoptotic cells,
that is paralleled by decreased levels of circulating pro-inflammatory cytokines (19), which
has been referred to as the “cholinergic anti-inflammatory reflex”(20).
Clinical studies of VNS (see Table 1)—In the clinical setting VNS is performed by
placing an electrode cuff around the right or left cervical vagus (21, 22), thereby stimulating
both the efferent and afferent vagus nerve fibers. It should be recognized that stimulation of
afferent vagus nerve fibers experimentally can have profound effects on the activity of the
contralateral efferent parasympathetic tone (increased activity) and efferent sympathetic tone
(inhibition of activity). However, it is unclear at the time of this writing whether it is
preferable to stimulate afferent of efferent vagus nerve fibers.
Four clinical studies of VS in humans have been completed and published thus far (Table 1).
The first VNS study in humans was the CardioFit pilot, which enrolled 32 patients with a
history of chronic NYHA class II–IV HF and a LVEF < 35% (22). The patients were already
receiving optimal medical treatment (OMT) with beta-blockers, ACE inhibitors/ARBs and
loop diuretics. Additionally, 19 of the 32 patients had an ICD. The CardioFit system is a
“closed loop” device system with an intracardiac RV sensing lead and a bipolar cuff placed
around the right cervical vagus nerve (Figure 2A). The stimulation intensity of VNS, which
was limited by patient symptoms of hoarseness and/or referred jaw pain, was uptitrated to
4.1±1.2 mA. A clear demonstration of efferent vagus nerve stimulation in the CardioFit pilot
trial was demonstrated by the change in resting heart rate during the trial, which decreased
significantly during from 82±13 bpm to 76±13 bpm during the study. At 6 months ~ 60% of
patients improved by at least one NYHA class (Figure 3) and the Minnesota Living with
Heart Failure Questionnaire quality of life score improved signifcantly, as did the distance
on the 6-min walk test. An analysis (blinded) of the 2-D echocardiograms showed that there
was a significant reduction in LV end-systolic volume, and a significant increase in LVEF
(from 22±7% to 29±8%), whereas there was a non-significant decrease in LV end-diastolic
volume. A pre-specified follow-up of a group of patients at 1 (n= 23) and 2 years (n = 19)
showed that many of the beneficial effects of VNS were maintained.
The Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in
Patients With Chronic Heart Failure (ANTHEM-HF) study (23) enrolled 60 patients with
NYHA class II and III HF, LVEF <40% and QRS <150 ms. Patients were randomized to
either left or right cervical VNS using a proprietary “open loop” VNS system (Figure 2B)
that did not incorporate a RV sensing lead. The stimulation amplitude of VNS was uptitrated
over a 10 week period, with an average stimulation amplitude of 2.0 ± 0.6 mA. The primary
efficacy end-point was the change in LV end-systolic volume. The LVEF increased by 4.5 %
(p<0.05) in the pooled analysis of right and left VNS, whereas there was a non-significant
change in LV end-systolic volume compared to baseline values. Overall, 77% of patients
improved by at least one NYHA class at 6 months, with a significant improvement in the
Minnesota Living with Heart Failure score. Although there was a trend towards greater
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improvement with right sided VS, these differences were not significant statistically (Figure
4).
The Neural Cardiac Therapy for Heart Failure (NECTAR-HF) study enrolled 96 patients
with NYHA class II and III HF, LVEF <35%, a QRS <130 ms and LV end-diastolic diameter
>55 mm (24). All of the patients enrolled received a device implant, and were then
randomized to 2:1 to active treatment or sham treatment for the first 6 months, followed by
active treatment for all patients from 6–12 months. The device used in NECTAR-HF was
also an open loop system (Figure 2B), similar to the one used in ANTHEM-HF, that
employed a helical bipolar electrode. The stimulation amplitude of VNS was uptitrated and
attained an average stimulation amplitude of 1.42 ± 0.8 mA, which was less than that which
was achieved in the CardioFit pilot trial or the ANTHEM-HF trial. The primary efficacy
end-point, which was the change in LV end-systolic diameter at 6 month follow-up, was not
significantly different (p = 0.60) in the treatment and the control group. Secondary end
points, including LV end-diastolic dimension, LV end-systolic volume, LVEF, peak V02, and
N-terminal pro- brain natriuretic peptide were not different between groups. However, there
were statistically significant improvements in quality of life scores for the Minnesota Living
with Heart Failure Questionnaire, and the New York Heart Association class in the group
receiving treatment. Interestingly, an assessment of blinding, which was performed at 6
months revealed that 70% of the patients assigned to active treatment correctly guessed their
randomization group, which was likely secondary to side effects of VNS with this device.
The increase of Vagal Tone in Heart Failure (INOVATE-HF) was a pivotal phase III multi-
center randomized clinical trial designed to assess the effects of VNS using the CardioFit™
closed loop system (Figure 2B) in patients with symptomatic HF despite optimal medical
therapy (25, 26). A total of 707 enrolled patients with NYHA Class III symptoms,
LVEF<40% and LV end diastolic size 50–80mm, were randomized 3:2 to either active
treatment with device implantation, or no implantation. One month after implantation,
patients in the treatment arm underwent multiple scheduled visits over 4-weeks, during
which time the stimulation output was gradually increased with a goal of achieving current
of 3.5 to 5.5 mA. Importantly, the stimulation protocol for INOVATE-HF differed slightly
from the protocol that was used in the CardioFit pilot, in that the on time for stimulation was
5.1±0.8 sec in INOVATE-HF and was 7.1±4.8 sec in the pilot trial. The primary end point of
this study was a composite of all-cause mortality or unplanned HF hospitalizations. There
were 2 co-primary safety endpoints: freedom from procedure and system-related
complication events at 90 days and number or patients with all-cause death or complications
at 12 months. On December 15, 2015, INOVATE-HF was stopped by the Steering
Committee on the recommendation of the independent Data and Safety Monitoring Board,
after the second planned interim analysis showed that the trial was unlikely to show a
statistically significant benefit in the treatment arm. Patients were followed for up to 4.3
years with a mean follow-up 16 months. The primary efficacy outcome occurred in 30.3% in
the VNS group compared with 25.8% in the control group (hazard ratio, 1.14; 95%
confidence interval [CI], 0.86 to 1.53; p = 0.37) (Figure 5). Quality of life, New York Heart
Association Class and 6 minute walking distance were favorably affected by VNS (p < 0.05
for all); however, the LV end-systolic volume index was not different between groups (p =
0.36). The effects of treatment on six pre-specified subgroups for the primary efficacy
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composite outcome showed that the only significant treatment by subgroup interaction was
for gender with worse outcomes with VNS among females (p=0.03); however, a multivariate
analysis of the primary efficacy endpoint showed that gender was not an independent
predictor of outcome. No statistically significant differences in heart rates were observed
between control and VNS therapy arms. Of note, the mean stimulation current in INOVATE-
HF was 3.9± 1.0 mA at the 6-month follow-up visit, with 73% of patients achieving the goal
of ≥ 3.5 mA.
Spinal Cord Stimulation (SCS)
Spinal cord stimulation (SCS) has been used for over 40 years to treat chronic intractable
pain. The concept for spinal cord stimulation (SCS) originated following the revolutionary
gate theory for the origin of pain, which raised the possibility of suppressing pain by
“closing the gate” by activation of large diameter afferent fibers (27) The benefits of SCS
have been reported in patients with refractory angina both due to end stage CAD and cardiac
syndrome X (28). Interestingly, SCS fared similarly to surgical and laser endomyocardial
revascularization in severe refractory angina, without an increase in ischemic events,
suggesting that the improvement in this condition was more complex than the suppression of
the nociceptive influx associated with myocardial ischemia. SCS applied at the C7–C8 or
T1–T6 levels (Figure 2C) theoretically exerts its effects through activation of ANS, with a
resultant overall increase in parasympathetic tone.
Pre-Clinical Studies of SCS—In an animal model of MI, preemptive SCS resulted in
marked infarct size reduction, which was attenuated by alpha and beta -receptor blockade,
suggesting an SNS inhibition by SCS (29). SCS also reduced the occurrence of VT/VF from
59 to 23% in a canine model in which ventricular arrhythmias were elicited by transient
myocardial ischemia (30). In a subsequent study (31) 28 dogs with HF induced by anterior
MI and rapid pacing were assigned for five weeks to: no therapy, carvedilol or SCS
(delivered at T4/T5 region for 2 hours, 3 times a day). LVEF that had declined to 18% after
the induction of heart failure, recovered to 28%, 34% and 47%, respectively, in the control,
carvedilol and SCS groups. Subsequent studies using the same animal model showed that
SCS was superior to carvedilol + ramipril. Zipes and coworkers raised the interesting
possibility that SCS at the T1–T2 level enhanced parasympathetic activity based on the
observation that SCS resulted in a significant increase in sinus cycle length and the AH
interval, which could be abolished by bilateral vagal transection (32). Other pre-clinical
studies have shown that SCS results in reduced burden of VT/VF and greater improvements
in EF in myocardial infarction animal models compared to controls, possibly via SNS
inhibition and/or PNS stimulation (30) (33) (34).
Clinical Studies of SCS (see Table 2)—Based on pre-clinical models, several clinical
studies with spinal cord stimulation have been conducted in patients with heart failure. The
Spinal Cord Stimulation for Heart Failure (SCS HEART) study (35) evaluated the safety and
efficacy of an implanted a SCS device in 17 patients with NYHA III or ambulatory NYHA
IV HF. The primary efficacy endpoint was based on a composite score of changes in NYHA
class, peak maximum O2 consumption, left ventricular end systolic-volume and LVEF.
Analysis at 6 months showed that 73% of patients had improvement in ≥4/6 efficacy
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parameters and that there were no reported deaths or device-device interactions. At 18
months follow-up, two patients died, two were hospitalized for HF and there were no
device-device interactions. Four patients with VT/VF before receiving the SCS therapy
continued with VT/VF requiring ICD intervention.
The largest randomized clinical trial of SCS in heart failure, the Determining the Feasibility
of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure (DEFEAT-HF)
randomized controlled study has been completed recently (36). DEFEAT-HF enrolled 81
patients with NYHA Class III HF and a mean LVEF of 29 ± 5%, with 66 successfully
randomized and implanted with the SCS device system. All of the patients were implanted
with a SCS device that consisted of a single 8 electrode lead in the epidural space. The
electrode was connected to an SCS stimulator, which was placed subcutaneously in the
lateral abdominal wall. Stimulation electrodes were placed to encompass the T2 to T4 level.
Patients were randomized 3:2 to SCS or optimal medical therapy (control) for 6 months;
after 6 months the control patients were crossed over to the active therapy arm and 12-month
data were collected in both randomization arms. The stimulation in the treatment group was
programmed on for 12 h a day, on the basis of individual sleep/wake cycles, at a stimulation
frequency of 50 Hz, 200 ms pulse duration, and output set at 90% maximum tolerated
voltage determined while sitting. The primary study end point was a reduction in the LV
end-systolic volume index after six months of SCS therapy in the treatment arm vs. the
control arm. Secondary outcomes included change in peak O2 consumption and change in
N-terminal pro-BNP at six months. The results of the DEFEAT-HF trial show that, compared
to guideline directed medical therapy alone, thoracic (T2 to T4) SCS in patients with NYHA
functional class III HFrEF, did not lead to changes in LV structural remodeling (LV end-
systolic volume index) at 6 months (Figure 6). Moreover, thoracic SCS did not lead to
significant improvements in peak VO2 nor circulating levels of NT-proBNP at 6 months.
There were no differences between the groups in freedom from death or hospitalization for
HF at 6 months, change on Minnesota Living with Heart Failure Score, change in NYHA
class or change in 6-minute walk distance. SCS appeared to be safe and well tolerated in
patients with NYHA functional class III HF, consistent with the observation in patients
without HF.
Baroreflex Activation Therapy (BAT)
Baroreceptor activation therapy (BAT) was initially developed for the treatment of resistant
hypertension. Electrical stimulation of the baroreceptor fibers located in the carotid sinus
(Figure 2D), leads to centrally mediated reduction of sympathetic outflow and increased
parasympathetic tone, resulting in reduced systemic vascular resistance (37). Baroreceptor
activation therapy using a proprietary first-generation implantable carotid sinus stimulator
(The Rheos Baroreflex Hypertension Therapy System [CVRx, Minneapolis, Minn., USA])
was studied in patients with severe hypertension refractory to medical therapy. Implantation
of the device involves exposure of the carotid sinuses and positioning of the electrodes on
the carotid surface. The leads are than tunnelled subcutaneously and connected to the
stimulation device placed on the chest. Data from the Device Based Therapy in
Hypertension (DEBUT) trial with BAT showed substantial reductions in patients with
refractory hypertension (38). A second generation Barostim
neo
™ system, consists of a
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single lead that requires less dissection of the carotid artery for implantation, and has a
battery life of 3 years.
Pre-Clinical Studies of BAT—Several preclinical studies in large animal HF models
have shown that monotherapy with BAT improves global LV systolic and diastolic function
and partially reverses LV remodeling both globally and at cellular and molecular levels.
When evaluated in dogs using a coronary artery microembolization model, BAT resulted in a
significant decrease in LV end-diastolic pressure and circulating plasma norepinephrine.
BAT also normalized the expression of cardiac beta1-adrenergic receptors, beta-adrenergic
receptor kinase, and reduced interstitial fibrosis and cardiac myocyte hypertrophy (39). In a
pacing-induced tachycardia model of heart failure, BAT was shown to improve survival,
although arterial pressure, resting heart rate, and left ventricular pressure were not different
over time in BR-activated versus control dogs (40).
Clinical Studies of BAT (see Table 3)—The first clinical experience with BAT in HF
was a single-center, open-label evaluation in patients (n = 11) with NYHA class III HF and
an LVEF
<
40% (41), wherein patients were treated with BAT for 6 months. This study
showed that there was a significant and sustained 30% reduction in SNS activity, as
measured by microneurography of the peroneal nerve, that was accompanied by an overall
improvement in in NYHA functional class, quality of life score, and 6-minute hall walk
(6MHW) distance. Cardiac structure and function, assessed by 3-dimensional
echocardiography, also improved. The rate of HF hospitalization was also substantially
decreased compared with the 12 months before implantation of the BAT system. More
recently, the Barostim
neo
™ system was evaluated in 146 patients with NYHA Class III HF
and a LVEF ≤ 35%, who were randomized to guideline directed medical therapy + BAT
(n=76) or to guideline directed medical therapy alone (n=70). BAT is up-titrated over a
series of follow-up visits, with a focus on achieving therapeutic stimulation without side
effects, such as excessive reductions in heart rate or blood pressure. When compared to
control subjects, patients assigned to BAT had an improvement in the 6-minute walk test, in
a quality of life scores, in NYHA Class ranking and in NT-pro-BNP values at 6 months.
There was a trend towards a decrease in HF hospitalizations in BAT treated patients;
however, there was no significant difference in LVEF or other echocardiographic parameters
between the BAT and the control group. Importantly, there was no difference between the
BAT and the control group with respect to major adverse and neurological and
cardiovascular events (42). In a subsequent analysis of the same patients, the most
pronounced effect of BAT was observed in patients not treated with cardiac
resynchronization patients, possibly because there is less sympathovagal imbalance in this
subgroup of HF patients (43). Based on the positive results of these earlier trials a large
pivotal trial is planned: Barostim Therapy for Heart Failure (BeAT-HF [NCT02627196]).
The trial will randomize 480 patients with NYHA class III HF (LVEF ≤ 35%) in a 1:1
fashion to receive optimal medical therapy or optimal medical therapy plus BAT. The
primary outcome measures for BeAT-HF will be the rate of cardiovascular mortality and HF
mortality at study completion (efficacy endpoint) and major adverse neurological and
cardiovascular events at 6 months (safety endpoint).
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NEUROMODULATION OF THE FAILING HEART: LOST IN TRANSLATION?
The recent disappointing results of the DEFEAT-HF and INOVATE-HF trials raise the
important question of whether device-based modulation of the autonomic system is a viable
therapeutic strategy for patients with HF. The precise reason(s) why the pre-clinical and
early clinical studies that supported the concept of neuromodulation have failed to translate
into clinically meaningful endpoints in randomized clinical trials is not known; however, it
may relate, at least in part, to the well-recognized problems associated with replicating the
results of open-label trials that lack a proper randomized control group, or to the
phenomenon of “regression to the mean” that plagues the reproducibility of small clinical
trials. These statements notwithstanding, there are several issues that are unique to device-
based strategies designed to modulate the autonomic nervous system that warrant further
discussion .
Dose Matters
One of the consistent lessons learned from pharmacologic trials in HF trials is that choosing
the proper dose is critical (44). While choosing the proper dose in HF trials remains as much
an art as a science, choosing the proper stimulation parameters for devices to achieve
clinically meaningful modulation of the autonomic nervous system is even more
challenging, in large measure because of the lack of clear method for establishing the correct
excitation parameters and/or duty cycles. For example, choosing the proper “dose” for VNS
is critical, insofar as the vagus nerve is comprised of bundles of small unmyelinated (C-
fibers) and larger myelinated (A-fibers and B-fibers) nerves, whose activation properties are
distinctly different. Because large diameter fibers reach activation threshold at lower
stimulation intensities than smaller diameter fibers do, VNS results in the recruitment A-
fibers at lower stimulation thresholds, and recruitment of B-fibers at higher thresholds and
then ends with recruitment of C-fibers at higher stimulation thresholds (45). When
uptitrating the stimulus strength of the VNS devices in the setting of clinical trials, the
amplitude of the stimulus current is often limited by patient symptoms (e.g. cough,
dysphonia) and/or untoward hemodynamic effects (e.g. bradycardia, hypotension). Thus, the
populations of afferent and efferent vagus nerve fibers that are activated by VNS will vary
depending on the stimulus strength employed, and may therefore differ from patient to
patient even though these patients are receiving the “same” treatment. Germane to this
discussion, it is important to recognize that the stimulation amplitudes used for VNS in
NECTAR-HF (1.2mA), ANTHEM (2.0 mA), the CardioFit pilot trial (4.2 mA) and
INOVATE-HF (3.9 mA) were all quite different. What is unclear from these studies is that
with the exception of the CardioFit pilot trial, in which VNS resulted in a decrease in heart
rate and increased heart rate variability, it is unclear whether the various VNS stimulation
protocols used in clinical trials were sufficient 1) to stimulate the vagus nerve and/or 2)
inhibit the SNS. Beyond stimulus strength, choosing the proper duty cycle is largely empiric,
and is again selected to minimize the side effects of VNS. Importantly, the duty cycle for
VNS for the pivotal INOVATE-HF trial, wherein there was no change in heart rate, was
different from the duty cycle used for the CardioFit pilot trial, wherein therein there was a
decrease in heart rate. Whether this change in the duty cycle was clinically important, and or
explains the disparate outcomes in these 2 trials is not known.
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Choosing the proper site of stimulation, strength of stimulation and duty cycle for SCS is
also challenging from the standpoint of designing clinical trials. Pertinent to this discussion,
previous work in dogs has shown that SCS delivered at the T4 level demonstrates a greater
antiarrhythmic effect (33), whereas that at the T1 level is associated with a heightened
parasympathetic tone (32). In the SCS HEART study (35) continuous SCS was performed at
the mid-line and left of the midline at T1 and T3 levels, whereas intermittent SCS was
conducted at midline of T2 for T4 levels in the DEFEAT-HF trial (36). The stimulators in the
SCS Heart study were programmed to deliver continuous therapy 24 hours/day at 50 Hz
whereas SCS in the DEFEAT-HF trial was for 12 hours/day at 50 Hz and was based on
individual sleep/wake cycles. Whether the differences in clinical outcomes in these two trials
is attributable to the site of stimulation, strength of stimulation and duty cycle is unknown.
Moreover, similar to the problem with VNS discussed above, it is unclear whether the
various protocols that were used in the SCS HEART study and DEFEAT-HF trial were
sufficient to restore the proper sympathovagal balance in patients with heart failure. Viewed
together, the observations with regard to the difficulties with VNS and SCS suggest that
there is a critical need to be able to perform “dose” response studies that will allow
investigators to have a better understanding of the types of stimulation protocols that will be
most efficacious.
Afferent vs. Efferent Stimulation
As noted above, VNS is accomplished by placing an electrode cuff around the right or left
cervical vagus, resulting in stimulation of both efferent and afferent fibers of the vagus
nerve. The device and stimulation protocols used in the NECTAR-HF and ANTHEM trials
were designed to stimulate afferent vagus nerve fibers, whereas the device and stimulation
protocol uses in the CardioFit pilot trial and INOVATE-HF trial were designed, in theory, to
stimulate efferent vagus nerve fibers. From a conceptual standpoint it may be more
advantageous to stimulate afferent vagus nerve fibers, insofar as stimulation of the afferent
vagus nerve fibers has been shown experimentally to decrease sympathetic efferent nerve
fiber activity to the heart (46), which is believed to be beneficial based on a wealth of
experimental and clinical observations. Moreover, that majority of the preganglionic vagal
fibers terminate in small ganglia located on the posterior surfaces of the atrium, whereas far
fewer ganglia reside in ventricular tissue, raising the question of whether direct stimulation
of efferent vagus nerve fibers is beneficial. However, it bears emphasis that is it currently
unknown whether stimulating afferent vagus nerves, efferent vagus nerves or a combination
of afferent and efferent vagus nerves is more beneficial in the setting of heart failure. Similar
types of difficult questions can be raised about SCS, where electrode placement can lead to
inhibition of SNS trafficking to the heart and/or in increased parasympathetic tone in the
heart. Thus, there are a number of important questions about how to target device-based
autonomic modulatory strategies.
The need to identify reliable “physiologic biomarkers” of autonomic tone
The results of the DEFEAT-HF and INOVATE-HF trials raise a number of important
questions about how one might design future device-based clinical trials of autonomic
modulation in heart failure. Based on the foregoing discussion there is a need to identify
physiological measurements that will allow investigators in future trials to determine: 1) the
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proper site of stimulation, 2) the proper strength of stimulation, and 3) the proper duty cycle
for device-based therapies. Although there are no direct physiological measurement that
reflect the restoration of normal sympathovagal tone in heart failure, there are a number
“physiological biomarkers” that reflect excessive SNS activation in heart failure.
Conceptually, normalization of markers of excessive SNS activation could be used as a
surrogate for the restoration of “normal” autonomic tone, assuming that one could ascertain
how much normalization was required. The measurements of excessive SNS activation that
have been studied in HF include plasma or urinary norepinephrine (NE) levels, assessment
of local tissue NE spillover, muscle sympathetic nerve activity (MSNA), uptake of the
iodine 123I-metaiodobenzylguanidine (123I-MIBG) in the heart, baroreflex sensitivity, and
heart rate variability (2). Currently, MSNA and 123I-MIBG imaging are considered to be the
most accurate direct measurements of SNS activity in HF patients. As noted above the early
studies with BAT showed that there was a sustained decrease in MSNA following BAT,
suggesting that MSNA might be used to assess the normalization of autonomic tone in future
studies.
CONCLUSIONS
HF progresses, at least in part, because of increased activity of the sympathetic nervous
system that is accompanied by concomitant withdrawal of parasympathetic activity. Despite
the use of guideline directed medical therapy, most patients will ultimately develop
worsening HF that is accompanied by increased morbidity and mortality. In the foregoing
review, we have discussed the rationale for neuromodulation of the failing heart, as well as
summarized the recent clinical experience with VNS, BAT, and SCS. Although the pre-
clinical studies and early clinical studies with VNS and SCS appeared promising, the larger
clinical trials have been neutral with respect to the primary clinical end points. The pivotal
trial with BAT should start enrolling patients shortly, but will not report results for several
years. Thus, for the short-term we will be left to question whether neuromodulation is a
viable therapeutic strategy for treating patients with heart failure.
While the tendency for investigators and investors is to walk away from therapeutic areas
that do not yield immediate positive results, particularly with regard to cardiac devices that
are invasive and hence entail some procedural risk, it is instructive to recall that cardiac
resynchronization therapy, which is now a class I indication in HF patients, took over 2
decades to evolve from a concept in animal models to wide-spread clinical application.
Although the initial results of the early large clinical trials with device-based autonomic
modulation of the failing heart have been disappointing, given how little we currently
understand about how to modulate the autonomic nervous system in heart failure, these
initial results are perhaps not at all surprising. This statement notwithstanding, the progress
in this field over the past 5 years has been astounding, and it clear that we have now entered
an exciting new therapeutic era that may one day allow clinicians to use both devices and
drugs to restore the proper sympathovagal balance in heart failure.
LIST OF ABBREVIATIONS
ACE Angiotensin converting enzyme inhibitor
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ANS Autonomic Nervous System
ARB Angiotensin receptor blocker
BAT Baroreceptor Activation Therapy
HF Heart Failure
HFrEF Heart Failure with a reduced ejection fraction
LVEF Left Ventricular Ejection Fraction
MSNA Muscle sympathetic nervous activity
MI Myocardial Infarction
NE Norepinephrine
NYHA New York Heart Association Class
OMT Optimal Medical Therapy
PNS ParasympatheticNervous System
SCS Spinal Cord Stimulation
SNS Sympathetic Nervous System
VNS Vagus Nerve Stimulation
References
1. 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; 8:619–28. [PubMed: 25991804]
2. Floras JS. Sympathetic nervous system activation in human heart failure: clinical implications of an
updated model. J Am Coll Cardiol. 2009; 54:375–85. [PubMed: 19628111]
3. Armour JA. Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp
Physiol. 2004; 287:R262–R271. [PubMed: 15271675]
4. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic
mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious
dogs with and without a myocardial infarction. Circulation. 1988; 78:969–79. [PubMed: 3168199]
5. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-
rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI
(Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998; 351:478–
84. [PubMed: 9482439]
6. Marin-Neto JA, Pintya AO, Gallo JL, Maciel BC. Abnormal baroreflex control of heart rate in
decompensated congestive heart failure and reversal after compensation. Am J Cardiol. 1991;
67:604–10. [PubMed: 2000793]
7. Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and
beyond. Circulation. 2005; 111:2837–49. [PubMed: 15927992]
8. Vanhoutte PM, Levy MN. Prejunctional cholinergic modulation of adrenergic neurotransmission in
the cardiovascular system. Am J Physiol. 1980; 238:H275–H281. [PubMed: 6245589]
9. Matko J, Matyus L, Szollosi J, et al. Analysis of cell surface molecular distributions and cellular
signaling by flow cytometry. J Fluoresc. 1994; 4:303–14. [PubMed: 24233604]
Byku and Mann Page 12
JACC Basic Transl Sci
. Author manuscript; available in PMC 2016 August 22.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
10. Azevedo ER, Parker JD. Parasympathetic control of cardiac sympathetic activity: normal
ventricular function versus congestive heart failure. Circulation. 1999; 100:274–9. [PubMed:
10411852]
11. Newton GE, Parker AB, Landzberg JS, Colucci WS, Parker JD. Muscarinic receptor modulation of
basal and beta-adrenergic stimulated function of the failing human left ventricle. J Clin Invest.
1996; 98:2756–63. [PubMed: 8981921]
12. La Rovere MT, Pinna GD, Maestri R, et al. Prognostic implications of baroreflex sensitivity in
heart failure patients in the beta-blocking era. J Am Coll Cardiol. 2009; 53:193–9. [PubMed:
19130988]
13. De Ferrari GM, Schwartz PJ. Vagus nerve stimulation: from pre-clinical to clinical application:
challenges and future directions. Heart Fail Rev. 2011; 16:195–203. [PubMed: 21165697]
14. Lopshire JC, Zipes DP. Device therapy to modulate the autonomic nervous system to treat heart
failure. Curr Cardiol Rep. 2012; 14:593–600. [PubMed: 22833301]
15. Merlo M, Stolfo D, Anzini M, et al. Persistent recovery of normal left ventricular function and
dimension in idiopathic dilated cardiomyopathy during long-term follow-up: does real healing
exist? J Am Heart Assoc. 2015; 4:e001504. [PubMed: 25587018]
16. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal
stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction.
Circ Res. 1991; 68:1471–81. [PubMed: 2019002]
17. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly
improves long-term survival after chronic heart failure in rats. Circulation. 2004; 109:120–4.
[PubMed: 14662714]
18. Zhang Y, Popovic ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic
control and attenuates systemic inflammation and heart failure progression in a canine high-rate
pacing model. Circ Heart Fail. 2009; 2:692–9. [PubMed: 19919995]
19. Calvillo L, Vanoli E, Andreoli E, et al. Vagal stimulation, through its nicotinic action, limits infarct
size and the inflammatory response to myocardial ischemia and reperfusion. J Cardiovasc
Pharmacol. 2011; 58:500–7. [PubMed: 21765369]
20. Tracey KJ. The inflammatory reflex. Nature. 2002; 420:853–9. [PubMed: 12490958]
21. Schwartz PJ, De Ferrari GM, Sanzo A, et al. Long term vagal stimulation in patients with advanced
heart failure: first experience in man. Eur J Heart Fail. 2008; 10:884–91. [PubMed: 18760668]
22. De Ferrari GM, Crijns HJ, Borggrefe M, et al. Chronic vagus nerve stimulation: a new and
promising therapeutic approach for chronic heart failure. Eur Heart J. 2011; 32:847–55. [PubMed:
21030409]
23. Premchand RK, Sharma K, Mittal S, et al. Autonomic Regulation Therapy via Left or Right
Cervical Vagus Nerve Stimulation in Patients with Chronic Heart Failure: Results of the
ANTHEM-HF Trial. J Card Fail. 2014; 20:808–16. [PubMed: 25187002]
24. Zannad F, De Ferrari GM, Tuinenburg AE, et al. Chronic vagal stimulation for the treatment of low
ejection fraction heart failure: results of the neural cardiac therapy for heart failure (NECTAR-HF)
randomized controlled trial. Eur Heart J. 2014
25. Hauptman PJ, Schwartz PJ, Gold MR, et al. Rationale and study design of the INcrease Of Vagal
TonE in Heart Failure study: INOVATE-HF. Am Heart J. 2012; 163:954–62. [PubMed: 22709747]
26. Gold MR, van Veldhuisen DJ, Hauptman PJ, et al. Vagus Nerve Stimulation for the Treatment of
Chronic Systolic Heart Failure: Primary Results From the INcrease Of Vagal TonE in Heart Failure
(INOVATE-HF)Trial (abstr). J Am Coll Cardiol. 2016
27. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965; 150:971–9. [PubMed:
5320816]
28. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation
on vascular diseases: a review of experimental studies. Auton Neurosci. 2008; 138:9–23.
[PubMed: 18083639]
29. Southerland EM, Milhorn DM, Foreman RD, et al. Preemptive, but not reactive, spinal cord
stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic
neurons. Am J Physiol Heart Circ Physiol. 2007; 292:H311–H317. [PubMed: 16920800]
Byku and Mann Page 13
JACC Basic Transl Sci
. Author manuscript; available in PMC 2016 August 22.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
30. Issa ZF, Zhou X, Ujhelyi MR, et al. Thoracic spinal cord stimulation reduces the risk of ischemic
ventricular arrhythmias in a postinfarction heart failure canine model. Circulation. 2005;
111:3217–20. [PubMed: 15956128]
31. Rosas-Ballina M, Olofsson PS, Ochani M, et al. Acetylcholine-synthesizing T cells relay neural
signals in a vagus nerve circuit. Science. 2011; 334:98–101. [PubMed: 21921156]
32. Olgin JE, Takahashi T, Wilson E, Vereckei A, Steinberg H, Zipes DP. Effects of thoracic spinal
cord stimulation on cardiac autonomic regulation of the sinus and atrioventricular nodes. J
Cardiovasc Electrophysiol. 2002; 13:475–81. [PubMed: 12030530]
33. Lopshire JC, Zhou X, Dusa C, et al. Spinal cord stimulation improves ventricular function and
reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation. 2009;
120:286–94. [PubMed: 19597055]
34. Liu Y, Yue WS, Liao SY, et al. Thoracic spinal cord stimulation improves cardiac contractile
function and myocardial oxygen consumption in a porcine model of ischemic heart failure. J
Cardiovasc Electrophysiol. 2012; 23:534–40. [PubMed: 22151312]
35. Tse HF, Turner S, Sanders P, et al. Thoracic Spinal Cord Stimulation for Heart Failure as a
Restorative Treatment (SCS HEART study): first-in-man experience. Heart Rhythm. 2015;
12:588–95. [PubMed: 25500165]
36. Zipes DP, Neuzil P, Theres H, et al. Determining the Feasibility of Spinal Cord Neuromodulation
for the Treatment of Chronic Systolic Heart Failure: The DEFEAT-HF Study. JACC Heart Fail. 16
A D; 4:129–36. [PubMed: 26682789]
37. Grassi G, Seravalle G, Quarti-Trevano F, et al. Sympathetic and baroreflex cardiovascular control
in hypertension-related left ventricular dysfunction. Hypertension. 2009; 53:205–9. [PubMed:
19124679]
38. Krum H, Sobotka P, Mahfoud F, Bohm M, Esler M, Schlaich M. Device-based antihypertensive
therapy: therapeutic modulation of the autonomic nervous system. Circulation. 2011; 123:209–15.
[PubMed: 21242507]
39. Sabbah HN, Gupta RC, Imai M, et al. Chronic electrical stimulation of the carotid sinus baroreflex
improves left ventricular function and promotes reversal of ventricular remodeling in dogs with
advanced heart failure. Circ Heart Fail. 2011; 4:65–70. [PubMed: 21097604]
40. Zucker IH, Hackley JF, Cornish KG, et al. Chronic baroreceptor activation enhances survival in
dogs with pacing-induced heart failure. Hypertension. 2007; 50:904–10. [PubMed: 17846349]
41. Gronda E, Seravalle G, Brambilla G, et al. Chronic baroreflex activation effects on sympathetic
nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept
study. Eur J Heart Fail. 2014; 16:977–83. [PubMed: 25067799]
42. Abraham WT, Zile MR, Weaver FA, et al. Baroreflex Activation Therapy for the Treatment of
Heart Failure With a Reduced Ejection Fraction. JACC Heart Fail. 2015; 3:487–96. [PubMed:
25982108]
43. Zile MR, Abraham WT, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart
failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac
resynchronization therapy. Eur J Heart Fail. 2015; 17:1066–74. [PubMed: 26011593]
44. Mann DL, Deswal A. Angiotensin-receptor blockade in acute myocardial infarction--a matter of
dose. N Engl J Med. 2003; 349:1963–5. [PubMed: 14610159]
45. Castoro MA, Yoo PB, Hincapie JG, et al. Excitation properties of the right cervical vagus nerve in
adult dogs. Exp Neurol. 2011; 227:62–8. [PubMed: 20851118]
46. Schwartz PJ, Pagani M, Lombardi F, Malliani A, Brown AM. A cardiocardiac sympathovagal
reflex in the cat. Circ Res. 1973; 32:215–20. [PubMed: 4685965]
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Figure 1.
The autonomic nervous system. Diagram of preganglionic and postganglionic sympathetic
and parasympathetic fibers (Reproduced with permission from Klauber RE, Cardiovascular
Pharmacology Concepts: Autonomic Ganglia http://cvpharmacology.com/
autonomic_ganglia)
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Figure 2.
Schematic demonstrating the location and stimulation sites for device-based
neuromodulation modality. (A) Vagus nerve stimulator placed in right subpectoral region
with standard transvenous pacing/sensing lead placed in RV (closed loop) and vagus nerve
stimulating lead (dotted white lines) tunneled to cervical vagus region. (B) Vagus nerve
stimulator placed in right subpectoral region with vagus nerve stimulating lead (dotted white
lines) tunneled to cervical vagus region (open loop). (C) SCS generator implant in abdomen
or paraspinous region with stimulation lead (black line) placed in dorsal epidural space at
thoracic level 4. (D) Baroreflex stimulation generator placed in right subpectoral region with
bilateral stimulation leads tunneled to the carotid baroreceptor region. (Modifed and adapted
from Lopshire JC, Zipes DP. Device therapy to modulate the autonomic nervous system to
treat heart failure.
Curr Cardiol Rep
2012; 14:593–600).
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Figure 3.
Results of the CardioFit System Pilot Trial. (A) Change in NYHA classification at 3 and 6
months after VNS. (B) Change in LV end-systolic volume index at 3 and 6 months.
(Reproduced with permission from De Ferrari GM, Crijns HJ, Borggrefe M, et al. Chronic
vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure.
Eur Heart J 2011; 32:847–55).
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Figure 4.
Primary clinical end point of the ANTHEM-HF trial. Mean and 95% confidence intervals of
echocardiographic changes after 6 months of autonomic regulation therapy (overall, left-side
treatment, and right-side treatment). (Key: LVEF, left ventricular ejection fraction; LVESV,
left ventricular end-systolic volume; LVESD, left ventricular end-systolic diameter.
(Reproduced with permission from Premchand RK, Sharma K, Mittal S, Monteiro R et al.
Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in
Patients with Chronic Heart Failure: Results of the ANTHEM-HF Trial.
J Card Failure 2014
;
20:808–16).
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Figure 5.
Primary efficacy end point of the INOVATE-HF trial. There was no significant difference in
the primary composite outcome of death from any cause or a worsening HF event in the
VNS treatment arm when compared with the control group (hazard ratio, 1.14; 95%
confidence interval 0.86 -1.53; p = 0.37) (Reproduced with permission from Gold MR, van
Veldhuisen DJ, Hauptman PJ, et al. Vagus Nerve Stimulation for the Treatment of Chronic
Systolic Heart Failure: Primary Results From the INcrease Of Vagal TonE in Heart Failure
(INOVATE-HF) Trial (abstr). J Am Coll Cardiol 2016).
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Figure 6.
Primary efficacy end point of the DEFEAT-HF trial. There was no significant difference in
the change in LVESV index over 6 months between the SCS and control group (p = 0.30).
The bottom line of the box equals the 25th percentile, the top line equals the 75th percentile,
the line within the box equals the median, and the asterisk equals the mean. Reproduced
with permission from Zipes DP, Neuzil P, Theres H, et al. Determining the Feasibility of
Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure: The
DEFEAT-HF Study. JACC Heart Fail 16; 4:129–36)
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Table 1
Vagal Nerve Stimulation
Study Acronym Study Design Patient Characteristics N Outcomes Results
CardioFit™ (NCT00461019) Non-randomized Open label NYHA II–III
EF < 35% 32 1°: Occurrence of all system and/or procedure
related adverse events (6mo)
2°: NYHA class, 6MWD, LVESV, MLHFQ QoL
scores
No sig adverse events
Sig improvement in NYHA class, 6MWD,
LVESV and QoL scores
NECTAR-HF (NCT01385176) Randomized Double blind NYHA II–III
EF ≤ 35%
LVESD >5.5cm
QRS<130ms
96 1°: LVESD (6mo)
2°: NYHA class, VO2 max, SF-36 and MLHFQ
QoL scores, pro-BNP
No sig change in LVESD
Sig improvement in NYHA class and QoL
scores
ANTHEM-HF (NCT01823887) Randomized Open label NYHA II–III
EF ≤ 40%
QRS<150ms
60 1°:Change in EF and LVESV (6mo)
2°:NYHA class, 6MWD, MLHFQ QoL scores,
LVESD, HRV, BNP
Sig increase in EF (4.5%); no change in
LVESV
Sig improvement in NYHA class and QoL
score
INOVATE-HF (NCT01303718) Randomized Open label NYHA III
EF ≤ 40%
LVESD 5–8cm
730 1°: Composite all - cause mortality/HF
hospitalizations (end of study); freedom from
procedure/system related complications (90days);
all-cause death or complications (12mo)
2°:LVESV index, 6MWD, KCCQ QoL scores,
hospitalization free days
No significant difference in all - cause
mortality and HF hospitalizations;
significant improvement in 6MWD, KCCQ
QoL; no safety issues identified
NYHA- New York Heart Association Class; EF-Ejection Fraction; 6MWD-6 Minute Walk Distance; LVESV-Left Ventricular End Systolic Volume; LVESD-Left Ventricular End Systolic Diameter; VO2
Max-Maximum Volume Of Oxygen Consumed; MLHFQ-Minnesota Living With Heart Failure Questionnaire; SF-36-Short Form 36 Questionnaire; Qol-Quality Of Life; BNP-Brain Natriuretic Peptide;
HRV-Heart Rate Variability; KCCQ-Kansas City Cardiomyopathy Questionnaire
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Table 2
Spinal cord stimulation
Study Acronym Study Design Patient Characteristics N Outcomes Results
SCS HEART (NCT01362725) Non-randomized Open label NYHA III–IV
EF 20–35% 17 1°: Safety and efficacy (composite of change in NYHA
class, VO2max, LVESV, EF) (6mo)
2°: long term safety (24mo)
Sig improvement in >4/6 efficacy
parameters, without significant adverse
events
No sig long term complications
DEFEAT-HF (NCT01112579) Randomized Single blind NYHA III
EF ≤ 35%
LVESD 5.5–8cm
QRS<120ms
66 1°: LVESV index (6mo)
2°: VO2 max, pro-BNP No sig change in LVESV index
No sig change in VO2 max or pro-BNP
level
Methodist SCS (NCT01124136) Randomized Double blind NYHA III–IV
EF ≤ 30% 9 1°:safety (composite of worsening HF, hospilatizations,
arrhythmia, device-device interaction) and efficacy
(change in EF, VO2 max, BNP, QoL scores) (2years)
No adverse events and no interference
with ICD
No significant change in EF or BNP
TAME-HF (NCT01820130) Non-randomized Open label NYHA III
EF ≤ 40%
LVESD 5–8cm
0 1°: change in LVEDV, NYHA class and 6MWD (6mo)
2°: safety, QoL scores, VO2max, LV systolic and
diastolic fnc
Withdrawn
NYHA- New York Heart Association Class; EF-Ejection Fraction; VO2 Max-Maximum Volume Of Oxygen Consumed; LVESV-Left Ventricular End Systolic Volume; LVESD-Left Ventricular End
Systolic Diameter; BNP-Brain Natriuretic Peptide; Qol-Quality Of Life; LVEDV- Left Ventricular End Diastolic Volume; 6MWD-6 Minute Walk Distance
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Table 3
Baroreflex Activation Therapy
Study Acronym Study Design Patient Characteristics N Outcomes Results
Rheos® DHF (NCT00718939) Randomized Double blind EF > 45%
Elevated BNP or pro-BNP 6 1°: LVMI; safety (occurrence of all adverse
events) (6mo)
2°: Change in blood pressure, BNP or pro-BNP,
QoL scores
Pending
Barostim Neo HF (NCT01471860)
AND
Barostim HOPE4HF (NCT01720160)
Randomized Open label NYHA III
EF ≤ 35% 146 1°: Safety (system and procedure related adverse
event); Efficacy (change in NYHA class, QoL
scores, 6MWD) (6mo)
No significant adverse events;
Significant improvement in 6MWD,
NYHA class, QoL scores, pro-BNP
level
BeAT-HF (NCT02627196) Randomized Open Label NYHA III
EF ≤ 35% 800 1°: Cardiovascular mortality and HF morbidity (5
yrs); MANCE (6mo) Pending (estimated 2021)
EF-Ejection Fraction; BNP-Brain Natriuretic Peptide; LVMI- Left Ventricle Mass Index; Qol-Quality Of Life; NYHA- New York Heart Association Class; 6MWD-6 Minute Walk Distance; MANCE-
Major Adverse Neurological And Cardiovascular Events
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