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JACC: HEART FAILURE
VOL. 3, NO. 10, 2015
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STATE-OF-THE-ART PAPER
Novel Interventional Therapies to
Modulate the Autonomic Tone in
Heart Failure
Neal A. Chatterjee, MD,* Jagmeet P. Singh, MD, DPHIL*y
JACC: HEART FAILURE CME
This article has been selected as the month’s JACC: Heart Failure CME
(ANS) in the pathophysiology of heart failure; 2) the current state of
activity, available online at http://www.acc.org/jacc-journals-cme by
knowledge related to ANS modulation for the treatment of heart fail-
selecting the CME tab on the top navigation bar.
ure; and 3) the implications of these data related to clinical practice
and future research.
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CME Editor Disclosure: Deputy Managing Editor Mona Fiuzat, PharmD,
The American College of Cardiology Foundation (ACCF) is accredited by
FACC, has received research support from ResMed, Gilead, Critical
the Accreditation Council for Continuing Medical Education (ACCME) to
Diagnostics, Otsuka, and Roche Diagnostics. Tariq Ahmad, MD, MPH, has
provide continuing medical education for physicians.
received a travel scholarship from Thoratec. Robert Mentz, MD, has
received a travel scholarship from Thoratec; research grants from
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Gilead; research support from ResMed, Otsuka, Bristol-Myers Squibb,
AstraZeneca, Novartis, and GlaxoSmithKline; and travel related to
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Novartis, and GlaxoSmithKline. Adam DeVore, MD, has received research
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CME Objective for This Article: After reading this article, the reader
Issue date: October 2015
should be able to discuss: 1) the role of the autonomic nervous system
Expiration date: September 30, 2016
From the *Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts; and the yCardiac Arrhythmia Service, Department of Medicine, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts. Dr. Singh has received research grants from Boston Scientific, St. Jude Medical, Medtronic,
and Sorin Group; and has been a consultant for Boston Scientific, St. Jude Medical, Medtronic, Sorin Group, CardioInsight, and Respicardia. Dr. Chatterjee has reported that he has no relationships relevant to the contents of this paper to
disclose.
Manuscript received March 18, 2015; revised manuscript received April 17, 2015, accepted May 1, 2015.
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
Novel Interventional Therapies to Modulate the
Autonomic Tone in Heart Failure
ABSTRACT
Heart failure (HF) represents a significant and expanding public health burden associated with increasing prevalence and
exponential growth in related health care costs. Contemporary advances in both pharmacological and nonpharmacological therapies have often been restricted in application and benefit. Given the critical role of the autonomic nervous
system (ANS) in maintaining cardiovascular homeostasis in the failing heart, there has been increasing interest in the role
of ANS modulation as a therapeutic modality in HF. In this review, we highlight the anatomy of the ANS and its role in the
pathophysiology of HF, as well as metrics of its assessment. Given the limitations associated with pharmacological ANS
modulation, including lack of specificity and medication intolerance, we focus in this review on contemporary nonpharmacological ANS modulation therapies. For each therapy—vagal nerve stimulation, carotid baroreceptor stimulation,
spinal cord stimulation, and renal denervation—we review the rationale for modulation, pre-clinical and clinical assessments, as well as procedural considerations and limitations. We conclude by commenting on novel technologies and
strategies for ANS modulation on the horizon. (J Am Coll Cardiol HF 2015;3:786–802) © 2015 by the American College
of Cardiology Foundation.
H
eart failure (HF) represents a significant
ANATOMY, REFLEXES, AND REGULATION OF
and expanding public health burden aff-
THE ANS
ecting nearly 25 million patients globally
(1,2). In the United States alone, the prevalence of
In its most reductive form, the ANS primarily com-
HF is nearly 6 million and is estimated to double
prises 2 systems: the sympathetic and parasym-
by the year 2030 (2). Although contemporary strate-
pathetic. The sympathetic nervous system (SNS)
gies in the management of HF have improved sur-
serves a predominant cardioacceleratory function,
vival after diagnosis, overall mortality remains high
and its activation is associated with augmentation of
because nearly one-half of patients die within 5
heart rate (HR), increased ventricular contraction, and
years (3). The expanding prevalence of HF, coupled
enhanced atrioventricular conductivity. In counter-
with improved survival after diagnosis, has framed
balance, the parasympathetic nervous system (PNS)
an exponential growth in HF-related costs, estimated
serves a predominant cardioinhibitory function as-
to range between $30 and $60 billion, and are ex-
sociated with attenuation of HR and ventricular
pected to more than double in the next 20 years
contraction, reduced arterial stiffness, and increased
(2,4).
venous capacitance. The dynamic interaction of these
In the face of rising HF morbidity, mortality,
2 limbs of the ANS, modulated by physiological inputs
and costs, there have been important contempo-
and reflexes, ultimately regulates the hemodynamic
rary advances in both pharmacological (5) and
and electrical functions of the heart and vascular
nonpharmacological therapies (6), although their
system (Central Illustration).
application and benefit are often restricted to a
Understanding the anatomy of the ANS is critical to
subset of patients (7). In this context, given the
defining the scope of its therapeutic targeting and
long-recognized
autonomic
modulation (Figure 1A). The SNS output is located in
nervous system (ANS) function and HF, there is
the spinal column (first thoracic to fourth lumbar
increasing interest in ANS modulation as a thera-
segments), extending rostrally and caudally to the
peutic modality. In this review, we highlight the
adjacent paravertebral ganglia forming the sympa-
anatomy of the ANS and its role in the pathophys-
thetic trunk. SNS signals are carried via pre-ganglionic
iology of HF, as well as metrics of its assessment.
neurons to post-ganglionic ganglia, which are either
We then review contemporary nonpharmacological
located directly on viscera (adrenal cortex, smooth
ANS modulation therapies in HF before commenting
muscle cells of blood vessels) or, in the case
on
of myocardial input, organized into 2 major ganglia
novel
horizon.
relationship
technologies
and
between
strategies
on
the
(superior cervical and stellate) (9). For myocardial SNS
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Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
ABBREVIATIONS
input, post-ganglionic fibers coalesce into
sinus, aortic arch) and centrally (brainstem). There are
AND ACRONYMS
cardiac nerves (superior, middle, inferior)
additional low-threshold polymodal receptors (sensi-
whose sympathetic fibers extend to the heart
tive to both mechanical and chemical stimuli) present
and travel subepicardially. For peripheral
in the walls of all cardiac chambers that stimulate SNS
SNS inputs, stimulation of post-ganglionic
output in the setting of reduced receptor activity (10).
ganglia leads to secretion of epinephrine
The ANS is further modulated through bidirectional
from the adrenal cortex or local release of
feedback
epinephrine and norepinephrine (NE) near
system (RAAS). For example, reduced renal perfu-
peripheral vessels. Secretion of these sym-
sion (reflective of reduced cardiac output) is associ-
pathetic transmitters bind adrenergic re-
ated with release of renin and downstream synthesis
NO = nitric oxide
ceptors in the myocardium (predominantly b-
of angiotensin II (ATII), which functions centrally to
NYHA = New York Heart
receptors
lusitropic,
increase SNS activity (14,15) while also inhibiting
inotropic, and dromotropic effects) and pe-
baroreflex-mediated suppression of SNS tone (16,17).
riphery ( a -receptors with vasoconstrictive
Inversely, increased SNS output leads to increased
effects) to exert their end-organ influence
renin secretion (14).
ANS = autonomic nervous
system
CBS = carotid body stimulation
HF = heart failure
HRR = heart rate recovery
HRV = heart rate variability
NE = norepinephrine
Association
PET = positron emission
tomography
PNS = parasympathetic
with
chronotropic,
the
renin-angiotensin-aldosterone
AUTONOMIC FUNCTION AND HF. The ANS plays a
(10).
nervous system
from
By contrast, PNS visceral innervation is
critical compensatory role in maintaining cardiovas-
aldosterone system
reflected by regional nerve inputs (oculomo-
cular homeostasis in the failing heart. Reduction in
SNS = sympathetic nervous
tor, facial, glossopharyngeal, vagal, sacral).
cardiac output leads to stimulation of multiple car-
system
Myocardial PNS innervation is via the vagus
diovascular reflexes (low-flow stimulation of arterial
VNS = vagal nerve stimulation
nerve with pre-ganglionic origins in the
baroreceptors,
VTA = ventricular
central nervous system (medulla, nucleus
tion of venous baroreceptors, and reduced activity
RAAS = renin-angiotensin-
increased
blood
volume
stimula-
ambiguus). The vagus nerve and its branches
of intramyocardial receptors) and activation of
synapse on myocardial ganglionated plexuses located
neurohormonal axes (reduced renal perfusion and
within the epicardial fat pads of the atria and ven-
RAAS stimulation) culminating in stimulation of the
tricles, with additional concentration of inputs
SNS. Increased SNS activity is well described in pa-
involving the vena cava, coronary sinus, and ostia of
tients with systolic HF (18) and has recently been
the pulmonary veins. The concentration of PNS
implicated in the pathogenesis of HF with preserved
innervation is generally greater in the atria compared
ejection fraction (19,20). Increased sympathetic in-
with the ventricles, where PNS fibers extend sub-
puts maintain cardiac output initially via positive
endocardially
(11).
inotropic and chronotropic effects. Over time, how-
Peripherally, PNS inputs on blood vessels can lead to
ever, chronic activation of the SNS and withdrawal of
vasorelaxation (via nitric oxide [NO] pathways) or
PNS input lead to progressive myocardial dysfunc-
vasoconstriction (via activation of smooth muscle)
tion, neurohormonal activation, and increased sus-
(12).
ceptibility to malignant arrhythmias. Indeed, more
tachyarrhythmia
into
the
ventricular
muscle
The extracardiac inputs of both the SNS and PNS
than 3 decades ago, Cohn et al. (21) demonstrated that
further interact with a complex network of intrinsic
plasma NE levels were independently predictive of
cardiac neurons (approximately 43,000 in the adult
mortality in patients with systolic HF. Chronic acti-
heart) known as the epicardial neural plexus (9)
vation of SNS inputs leads to reduced cardiac
(Figure 1B). Through organization into ganglionated
neuronal density and responsiveness (22), dysfunc-
subplexuses on the surface of atria and ventricles
tion of SNS reflexes including augmentation of
(with proximity to both the sinoatrial and atrioven-
excitatory arterial baro- and chemoreceptor inputs
tricular nodes) (8), the epicardial neural plexus adds
(23), as well as subcellular myocardial dysfunction
an additional layer of cardio-cardiac regulation of
(increased apoptosis, abnormal calcium handling,
autonomic function (13).
increased interstitial fibrosis) (23–25). In addition to
The homeostatic functions of the ANS are modu-
abnormalities of the SNS, withdrawal and attenuation
lated by autonomic reflexes as well as integration with
of PNS input has also been implicated in the patho-
neurohormonal axes. Stress-sensitive baroreceptors
genesis of HF (12). PNS alterations include reduced
(mechanoreceptors) are present in both high-pressure
vagal ganglionic activity as well as loss of PNS re-
arterial (carotid sinus, aortic arch) and low-pressure
ceptor density and neurotransmitter activity (12,26).
venous systems (atria/pulmonary arterial interface,
Sympathovagal imbalance in HF, including loss of
systemic veins), whereas chemoreceptors responsive
PNS inhibition of SNS reflex arcs (27–29), has been
to changes in arterial oxygen and carbon dioxide
associated with increased resting HR and worse clin-
concentration are present both peripherally (carotid
ical outcomes in HF (30). Reduced PNS activity may
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
further contribute to HF pathogenesis through dys-
including resting HR, frequency and time domain
regulation of NO signaling (12,31,32) as well as loss of
analysis of HR variability (HRV), provocative ma-
PNS inhibition of inflammatory cytokine release
neuvers assessing baroreflex sensitivity, and mea-
(33,34) and RAAS activation (35).
sures of heart recovery following exercise (55–59).
Electrophysiologically,
HF
with
Resting HR has been viewed simplistically as a mea-
neuronal and ionic channel remodeling (36,37) as well
sure of the net effect of SNS and PNS input to the
as abnormal SNS and PNS discharges (38). SNS-
sinus node, although this obviously has its limita-
mediated effects on the electrical refractory period,
tions as a static assessment (59). Beat-to-beat vari-
spatial heterogeneity of electrical remodeling, ionic
ability in HR (HRV) has long been recognized to be
channel remodeling, and aberrancy of intracellular
under the control of ANS inputs (60) and is assessed
calcium handling may underlie the increased risk of
using either time-domain (variation in R-R intervals)
ventricular tachyarrhythmias and sudden cardiac
or frequency domain (spectral analysis assessing
death in patients with HF (39,40). PNS influences
distribution of R-R intervals) methods (59). Fre-
in HF are more complex as vagal stimulation has been
quency domain measures of HRV (e.g., the ratio of
shown to reduce ventricular ectopy and ventricular
low- and high-frequency variance, which are under
tachyarrhythmias (41), whereas increased atrial PNS
SNS and PNS control, respectively) may reflect sym-
tone has been associated with atrial fibrillation (37).
pathovagal balance (61), although the relationship
MEASURING
FUNCTION. Objective
between discrete measures of HRV and limbs of the
assessment and quantification of ANS activity is
ANS is not always linear and is further subject to in-
AUTONOMIC
is
associated
essential to defining ANS pathology as well as target-
fluence from non-ANS inputs (respiration, thermo-
ing and assessing the efficacy of ANS interven-
regulation) (58,60). Provocation (including exercise)
tions. Conceptually, ANS activity can be measured
has also been utilized to assess ANS function
directly or indirectly and reflect general or regional
including, for example, post-exercise HR recovery,
assessment (Table 1). Historically, SNS activity was
which is thought to reflect parasympathetic reac-
measured via plasma NE levels utilizing radioimmu-
tivation and SNS withdrawal (59). Each of these
noassay of regional venous or arterial blood (21,42,43).
electrical variables—resting HR, time and frequency
Unfortunately, plasma NE levels are at best a crude
domain measures of HRV, and HR recovery—has
assessment of SNS function subject to the heteroge-
demonstrated prognostic utility in patients with and
neity of synthesis, reuptake and clearance of NE in
without
different tissue beds (44,45). More direct quantifica-
particular practical interest, intracardiac devices
tion of SNS activity includes microneurography, which
have the capacity to measure multiple noninvasive
measures post-ganglionic SNS neuronal firing within
electrical surrogates of ANS function (e.g., resting
cutaneous or muscular vasculature (46,47), although
HR, HRV) (63). Device-based measures of ANS
this is resource intensive and subject to measurement
surrogates have been shown to predict HF hos-
variability (48).
pitalization and mortality (64,65) and may offer
There has also been significant efforts to utilize
cardiovascular
disease
(30,55,59,62).
Of
future opportunities to dynamically regulate stimu-
neuronal imaging of ANS activity. Positron emission
lation
tomography coupled with radiolabeled analogs of
parameters.
and
pacing
rates
in
response
to
these
NE (49–51) can assess myocardial NE concentration as
well as adrenergic receptor density, although the
NONPHARMACOLOGICAL
prognostic implications of these measures in pa-
IN HF. Given the implicate role of the ANS in the
MODULATION
OF
ANS
tients with HF have been inconsistent (52). One
pathogenesis of HF, there has been expanding interest
particular neuronal imaging surrogate that has gained
in the role of ANS modulation as HF therapy. The
increasing traction has been use of the NE analogue
salutary effects of established pharmacotherapies for
Semi-
HF, including b-blockade and RAAS inhibitors, are
quantitative measures of MIBG imaging such as
thought, in part, to be related to modulation of ANS
reduced heart-to-mediastinal (H/M) ratio or reduced
tone and related reductions in arrhythmia and favor-
washout rate of radiotracer have been predictive of
able ventricular remodeling (10). Indeed, the mortality
arrhythmia and adverse cardiovascular events, even
benefit associated with b-blockade in HF is closely
after accounting for standard predictors as demon-
related to the degree of HR reduction (30), and thera-
strated in the ADMIRE-HF (AdreView Myocardial Im-
pies targeted at elevated resting HR in HF have been
aging for Risk Evaluation in Heart Failure) trial (54).
associated with improved clinical outcome as shown
123
I-metaiodobenzylguanidine
(MIBG)
(53).
Most practical in the noninvasive assessment of
with use of ivabradine in the SHIFT (Systolic Heart
ANS activity are electrocardiographic surrogates
Failure Treatment with the I f Inhibitor Ivabradine)
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Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
Autonomics in Heart Failure
C EN T RA L IL LUSTR AT I ON
OCTOBER 2015:786–802
Autonomic Dysfunction and Heart Failure Pathogenesis
(Lower left) Schematic demonstrating the synergistic relationships between autonomic imbalance, neurohormonal activation, and the pathogenesis of heart failure.
(Lower right) Schematic highlighting the interactions between the central nervous system, heart, and kidneys. Anatomic sites of autonomic modulation are highlighted.
ATII ¼ angiotensin II; AV ¼ atrioventricular; HR ¼ heart rate; LV ¼ left ventricular; NO ¼ nitric oxide; PNS ¼ parasympathetic nervous system; RAAS ¼ renin-angiotensinaldosterone system; SA ¼ sinoatrial; SNS ¼ sympathetic nervous system.
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
trial (66). There are important limitations, however, of
both afferent and efferent fibers organized into 1 of 3
pharmacological strategies to modulate ANS tone,
types (A–C), each with distinct stimulation thresh-
including lack of specificity in modulating discrete
olds, conductive properties, and organ targets. The
limbs of the ANS and frequent side effects associated
efficacy of VNS turns on the ability of the device to
with medication intolerance. For example, although
selectively stimulate and inhibit appropriate vagal
the centrally acting agent moxonidine was shown
nerve fibers. Strategies for selective targeting in-
to significantly reduce plasma NE in select patients
clude electrode design as well as modulation of
with HF (67), it was associated with increased mor-
stimulation intensities and waveforms. For example,
tality in randomized controlled assessment (68),
the CardioFit VNS system (BioControl Medical,
highlighting the potential dangers associated with
Yehudi, Israel) utilizes a multicontact electrode
nonspecific sympatholysis in HF (69). These limita-
designed to preferentially activate vagal efferent
tions
fibers in the right cervical vagus nerve. The stimula-
have
spurred
the
development
of
non-
pharmacological approaches of ANS modulation,
tion lead was designed to recruit myocardial-specific
including vagal nerve stimulation (VNS), spinal cord
efferent vagal B-fibers with minimal recruitment of
stimulation (SCS), baroreceptor stimulation, and
vagal A-fibers that could lead to unwanted central
renal denervation.
side effects (78). The system additionally incorporates a right ventricular lead to provide backup
VAGAL NERVE STIMULATION
pacing in the event of VNS-mediated bradycardia.
Following implantation of the vagal cuff, the stimu-
Myocardial input of the PNS is organized via
lation lead is subsequently tunneled to an infracla-
the vagus nerve—the left and right vagus nerves
vicular pocket (Figure 2B). The efficacy of myocardial
responsible for regulation of cardiac contractility and
vagal nerve targeting is confirmed by up-titration of
sinoatrial function (9,70). More than 4 decades ago,
the amplitude of stimulation (target usually w5.5 mA)
Braunwald et al. (71) demonstrated dysfunction of the
associated with a reduction in HR of 5 to 10 beats and
PNS in HF. Subsequent elegant animal models of HF
without side effects (neck pain, coughing, swallowing
suggested that VNS was associated with normaliza-
difficulty, nausea) (79,80). Of note, alternative pro-
tion of abnormal ANS surrogates (HRV, baroreflex
cedural approaches to VNS that have shown early
sensitivity, plasma NE) and improved survival (72,73).
promise include endovascular stimulation at the
Importantly, the salutary influence of vagal nerve
coronary sinus ostium and/or superior vena cava (81).
modulation in HF almost certainly extends beyond
The first human study of VNS employed the afore-
influence on autonomic measures (resting HR, HRV)
mentioned CardioFit system in 8 patients with HF,
and includes its impact on ventricular NO signaling,
demonstrating safety as well as significant improve-
inflammatory cytokine activation, and neurohor-
ments in HF symptoms and LV end-systolic volumes
monal activation (12). For example, NO is known to
(82). De Ferrari et al. (79) subsequently led an open-
modulate parasympathetic influences on ventricular
label multicenter trial of the CardioFit device in 32
contractility (74), and VNS-associated improvement
patients with symptomatic HF and reduced LV ejec-
in left ventricular (LV) systolic function is closely
tion (left ventricular ejection fraction [LVEF] <35%)
correlated with normalization of NO expression (75).
showing significant improvements in functional sta-
Similarly, vagal nerve stimulation has been shown to
tus and favorable LV remodeling (improved LVEF,
reduce expression of multiple inflammatory cyto-
reduced LV systolic volumes). These initial favorable
kines (e.g., tumor necrosis factor [TNF]- a , interleukin
studies led to 3 randomized controlled assessments of
[IL]-6, IL-1), which have been implicated in the
VNS, including NECTAR-HF (Neural Cardiac Therapy
pathogenesis of HF, including aberrant b -adrenergic
for Heart Failure), ANTHEM-HF (Autonomic Neural
signaling, increased myocyte apoptosis, increased
Regulation Therapy of Enhance Myocardial Function
myocardial fibrosis, and ultimately, adverse LV
in Heart Failure), and INOVATE-HF (Increase of Vagal
remodeling (76,77).
Tone in Congestive Heart Failure) (83–85) trials
Implantation of a vagal nerve stimulator involves
(Table 2). The NECTAR-HF study enrolled 96 patients
the coordinated expertise of a surgeon and electro-
with symptomatic HF, depressed LVEF, and dilated
physiologist. Stimulation of the vagal nerve is
LV cavity and randomized patients in a 2:1 fashion
accomplished via an implantable stimulator system
using a sham-controlled design (83). VNS was
that delivers electrical impulses via a bipolar cuff
achieved via a vagal cuff lead (NCT lead, Boston
electrode around the vagus nerve in the neck
Scientific Corporation, Marlborough, Massachusetts)
approximately 3 cm below the carotid bifurcation
without use of a sensing right ventricular lead,
(Figure 2A). At this level, the vagus nerve comprises
and thus activation and inactivation were unrelated
791
792
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
879 to 882 pg/ml across study groups), suboptimal
F I G U R E 1 Anatomy of the Autonomic Nervous System
delivery of stimulation current (average of 1.4 mA,
which was lower than w4 mA current in trials
demonstrating
VNS
efficacy),
use
of
a
helical
bipolar electrode stimulating both afferent and
efferent vagal fibers (in contrast to the asymmetric,
preferential stimulation of efferent fibers utilized
previously), and suboptimal modulation of vagal
myocardial
inputs
(nonsignificant
changes
in
resting HR and variable improvement in indices of
HRV).
The ANTHEM-HF study was an open-label assessment of 60 patients with symptomatic HF and
reduced LVEF (<40%) randomized to right versus left
vagal nerve stimulation (84). VNS was accomplished
via the VNS Therapy System (Cyberonics, Houston,
Texas) using a pulse frequency lower than that used
in the NECTAR-HF study (10 vs. 20 Hz). Similar to the
NECTAR-HF study, and unlike the CardioFit system,
VNS was performed without intracardiac sensing and
was thus untimed to the cardiac cycle. In the entire
study population, there were modest, but significant,
improvements in the primary efficacy endpoints
of change in LVEF (þ4.5%) and reduction in LV
end-systolic volume (4.1 ml) at 6 months. NYHA
functional class improved in 77% of patients. ANS
surrogates were variably affected with improvement
in time-domain measures of HRV but no significant
change in resting HR or plasma NE and ATII. The
incidence of serious therapy-related adverse events
was very low (w2%). The ongoing INOVATE-HF study
is a multicenter phase III trial that aims to enroll 650
patients with symptomatic HF, dilated LV cavity, and
depressed LVEF (#40%) who will be randomized in a
(A) Anatomic organization of the extra-cardiac limbs of the autonomic nervous system
3:2 fashion to VNS or standard therapy (no implant)
(ANS)—the cardio-acceleratory sympathetic and cardio-inhibitory parasympathetic sys-
(85). The study will utilize the CardioFit VNS system,
tems. Reproduced with permission from Martini FH, Nath JL. Fundamentals of Anatomy and
delivering 1 to 2 pulses per cardiac cycle (timed via
Physiology. 8th ed. San Francisco, CA: Pearson, 2008. (B) Anatomic representation of the
epicardial neural plexus. Adapted with permission from Pauza et al. (8).
intracardiac sensing lead).
Taken together, the results and design of VNS
Continued on the next page
studies to date highlight several unanswered challenges in utilizing VNS in HF. Optimal patient selection is important to consider because patients with
to cardiac cycle. Preliminary 6-month follow-up
limited neurohormonal derangement (as seen in the
identified no significant difference in the primary
NECTAR-HF study) may not experience incremental
efficacy endpoint of change in LV end-systolic
benefit when compared with goal-directed medical
dimension, although patients undergoing VNS did
therapy. Furthermore, whether patients with baseline
demonstrate significant improvements in subjective
increased SNS activity are most likely to benefit re-
quality-of-life scores and improvement in New York
mains an open question. The range of stimulation
Heart Association (NYHA) functional class (62% vs.
sites (right vs. left), stimulation protocols (timed vs.
45% in the VNS vs. control groups, p ¼ 0.032). The
untimed to cardiac cycle, variability of current de-
lack of VNS efficacy in the NECTAR-HF study may be
livery), and lead design (asymmetric vs. symmetric
related to multiple factors, including enrollment of a
activation of afferent and efferent vagal fibers) frame
relatively “stable” HF population (baseline N-termi-
open questions and challenges in improving the
nal pro–B-type natriuretic peptide [NT-proBNP] was
efficacy of VNS in HF. Finally, given the protean
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
influences of VNS on intersecting pathway of HF
pathogenesis—from innate immunity and proin-
Autonomics in Heart Failure
F I G U R E 1 Continued
flammatory cytokines to NO signaling—additional
work elucidating the impact of VNS on these pathways will likely enhance patient selection and improve
the ability to assess the efficacy of different VNS
targeting strategies. For example, the ongoing NoSIRS
pilot study (Effects of Transvenous Vagus Nerve
Stimulation on Immune Response, NCT01944228) will
examine the impact of VNS on TNF-a expression
before and after exposure to endotoxin in healthy
volunteers (86).
CAROTID BARORECEPTOR STIMULATION
The carotid baroreflex arc plays a significant role in
sympathovagal balance and is implicated in the
regulation of blood pressure and HR (87,88). The
carotid body and carotid sinus are innervated by
both the PNS (vagus and glossopharyngeal fibers) and
SNS (via nearby cervical sympathetic ganglia), and
contain both chemoreceptors (predominantly in the
carotid body; responsive to oxygen and carbon dioxide tension, blood pH, hypoglycemia) as well as
stretch-sensitive mechanoreceptors (predominantly
in the carotid sinus; responsive to increase in blood
pressure) (89). Stimulation of the carotid sinus
mechanoreceptors results in afferent signals to the
dorsal medulla of the brainstem and, ultimately,
attenuation of SNS and augmentation of vagal
outflow reflected by reduction in system blood pres-
as favorable LV reverse remodeling (improved LVEF,
sure and HR (89–91). Stimulation of carotid body
reduced LV volumes) (94). CBS may further amelio-
chemoreceptors is associated with augmentation of
rate HF via reduction in plasma ATII levels (91,95)
SNS tone (17). Given the close relationship between
with related improvements in extracellular volume
carotid baroreceptor activation and blood pressure
regulation, endothelial function, and favorable ven-
modulation, there has been long-standing historical
tricular remodeling (17,98).
interest in the efficacy of carotid body stimulation
Renewed contemporary interest in CBS as a ther-
(CBS) in patients with hypertension (92). Initial
apy in HF has been catalyzed by technological ad-
enthusiasm nearly a half century ago was tempered
vances and improvement in implant techniques.
by technological limitations as well as the advent of
Implantation is performed under the direction of a
effective pharmacotherapy.
multi-disciplinary team of vascular surgeons, cardio-
In patients with HF, there is reduced sensi-
logists, and anesthesiologists. The most investigated
tivity of the normal inhibitory function of carotid
Rheos system (CVRx, Minneapolis, Minnesota) has 3
baroreceptors, related to primary alterations within
components: an implantable pulse generator, carotid
the carotid body as well as dysfunction of central
sinus leads, and an external programmer (Figure 3A).
nervous system processing, ultimately resulting in
Stimulation can be targeted to either or both carotid
excessive sympathetic tone (93–96). Additionally, the
sinuses (e.g., a newer-generation system [Barostim
neurohormonal (RAAS) activation associated with
neo, CVRx] consists of a single carotid sinus elec-
HF may further exacerbate SNS activity via ATII-
trode). Stimulation leads are typically targeted to the
mediated augmentation of carotid chemoreceptor
carotid sinus of the common carotid artery approxi-
sensitivity (96,97). Therapeutically, stimulation of the
mately 5 mm from the carotid bifurcation. Leads
carotid body in canine models of HF is associated with
are connected to an implantable pulse generator
normalization of ANS surrogates (reduced plasma NE,
that is placed within an infraclavicular pocket. The
normalized expression of cardiac b-receptors) as well
electrode is standardly tested for hemodynamic
793
794
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
T A B L E 1 Cardiac Autonomic Tests
Tests
Measurement Units
Description
Additional Information
Norepinephrine levels
Norepinephrine spillover
mol/min/m2
Plasma NE levels are a sensitive guide
to sympathetic nervous function
Limited availability and utility
Considerable variability in release and
uptake of catecholamines in various
tissues
Microneurography
Sympathetic nerve activity
in cutaneous or muscular
vasculature
burst/100 beats or
bursts/min
Commonly used to measure of nerve
activity using microelectrode nerves
such as in common peroneal nerve
Can be used to measure efferent multifiber
traffic in sympathetic nerves
Limited use. Low reliability and
logistically challenging
Scintigraphic imaging
123
Heart-to-mediastinum
ratio of cardiac
MIBG activity
Myocardial sympathetic imaging
Limited availability and standardization
May be useful in risk stratification
beats/min
Net influence of sympathetic and vagal
influence on sinus node
Predictive of morbidity and mortality
Total power
ms2
Total variance in heart rate pattern
Using for measuring sympathovagal
balance and in risk stratification
Low-frequency power
ms2
Sympathetic pattern
High-frequency power
ms2
Parasympathetic pattern
SDNN
ms2
SD of average RR interval
RMSs
ms2
RMSD of difference between adjacent
intervals
DPNN 50
Percentage
Number of pairs of adjacent RR intervals
differing by >50 ms/total RR intervals
DHR post-exercise
Reflects parasympathetic reactivation and
sympathetic withdrawal post-exercise
Predictive of arrhythmic mortality;
possibly modifiable by exercise
training
Index of baroreflex control of autonomic
outflow. Close relationship with cardiac
vagal tone
Estimated by changes in systolic arterial
pressure
Limited availability but useful in risk
stratification and post-myocardial
infarction prognostication
I-mIBG imaging
Resting heart rate
Heart rate variability
Frequency domain
Time domain
Heart rate recovery
(reference is either
peak or end-exercise)
Baroreflex sensitivity
Cardiovagal baroreflex
sensitivity
ms/mm Hg
DPNN ¼ differing proportion of normal to normal; HR ¼ heart rate; HRV ¼ heart rate variability; MIBG ¼
differences; SDNN ¼ standard deviation of normal to normal intervals.
123
Useful for risk stratification
Easily measured via implantable cardiac
devices (HRV footprint)
I-metaiodobenzylguanidine; NE ¼ norepinephrine; RMSD ¼ root mean square of successive
F I G U R E 2 Vagal Nerve Stimulation
(A) Examples of leads associated with available vagal nerve stimulation (VNS) systems. (B) Chest radiograph of patients with a vagal nerve stimulator (VNS) and
previously implanted implantable cardioverter-defibrillator. Highlighted is the sensing lead of the VNS system located in the right ventricle. CRT ¼ cardiac resynchronization therapy device.
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
T A B L E 2 Comparison of Randomized Controlled Comparisons of Vagal Nerve Stimulation in HF
n
NYHA functional class
Ejection fraction
LVEDD
QRS width
INOVATE-HF
(Ongoing)
ANTHEM-HF
NECTAR-HF
650
60
96 (87 with paired data)
III
II–IV
II–IV
#40%
#40%
#35%
50–80 mm
50–80 mm
$55 mm
<120 ms
<130 ms
#150 ms
Trial design
Randomized 3:2 (implant vs.
no implant)
Control
Optimal medical treatment
Device used
CardioFit System, BioControl
Medical, Israel
Side stimulated
Stimulation protocol
Intracardiac lead
Study duration
Primary efficacy endpoints
Primary efficacy endpoint met
Open label, randomized right vs.
left VNS
Right vs. left
Demipulse model 103, Cyberonics,
United States
Randomized 2:1 (VNS on vs. off)
Stimulation off
Precision, Boston Scientific,
United States
Right
Right and left
Right
Target output: 3.3–5.5 mA,
titrated on/off times to
maximum of 10 s on/30 s off
Target output 1.5–3.0 mA (average
achieved 2.0 mA), frequency
10 Hz, pulse width 130 ms,
14 s on/66 s off
Target output: maximal 4 mA
(average achieved 1.4 mA),
frequency 20 Hz, pulse
width 300 ms, 10 s on/50 s off
Yes
No
No
18 months
6 months
6 months
Death or HF hospitalization
(up to 5.5 years)
Trial ongoing
Change in LVESV and LVEF at
6 months
Yes, LVEF improvement of 4.5%
(95% CI: 2.4–6.6)
Change in LVESD from baseline
at 6 months
No
CI ¼ confidence interval; HF ¼ heart failure; LVEDD ¼ left ventricular end-diastolic dimension; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end-systolic
dimension; LVESV ¼ left ventricular end-systolic volume; NYHA ¼ New York Heart Association; VNS ¼ vagal nerve stimulation.
response utilizing an incremental voltage protocol.
CBS was associated with modest, but significant,
Similar to VNS, there are myriad stimulation param-
improvement in functional endpoints (e.g., 6-min
eters including sequence (continuous, burst) as well
walk distance, quality-of-life score, NYHA functional
as impulse duration and amplitude. Despite these
class), reduction in natriuretic peptide concentration,
technological advances, contemporary trials utilizing
and a trend to reduction in days of HF hospitalization.
these systems have been associated with adverse
There was no significant difference in LV reverse
events (surgical complications, hypoglossal nerve
remodeling between the 2 groups. Ongoing studies
injury, and respiratory complications), suggesting
involving CBS in HF include the Rheos Diastolic
need for further technological refinement (102).
Heart Failure trial (CVRx, NCT00718939) and the
The evaluation of efficacy of CBS in HF is in its
ongoing Rheos HOPE4HF (Hope for Heart Failure,
nascent stages. Recently, Gronda et al. (103) reported
CVRx, NCT00957073) trial, both of which are random-
a single-center, open-label evaluation of CBS in 11
ized controlled assessments of CBS in patients with
patients with symptomatic HF and depressed LVEF
relatively preserved LVEF ($40%) (105,106). End-
(<40%). Utilizing the Barostim neo system targeting a
points include major adverse cardiac events, changes
single carotid sinus, the study assessed a primary
in LV mass index, and safety. Alternative strategies to
efficacy endpoint of muscle sympathetic nerve ac-
carotid sinus stimulation including endovascular
tivity at 6 months. CBS was associated with signifi-
stimulation are being tested, for example, in the ACES
cant reduction in SNS activity in parallel with modest
II study (Acute Carotid Sinus Endovascular Stimula-
improvements in functional status, quality of life,
tion II Study, Medtronic, Minneapolis, Minnesota,
and LVEF. Extending these findings, the recently re-
NCT01458483) (107).
ported Barostim HOPE4HF study randomized 146
Although early efficacy assessments of CBS in HF
patients to goal-directed medical therapy alone
are promising, and technological evolution of the
versus the addition of CBS via the Barostim neo sys-
device and implant system has improved safety, there
tem (104). There was no standard dosing protocol,
remain significant questions regarding the role of
with device stimulation intensity incremented over a
unilateral versus bilateral stimulation, selection of
3-month period unless associated with excessive re-
patients with carotid baroreceptor dysfunction, and
ductions in HR or blood pressure. At 6-month follow-
optimization of stimulation protocols (impulse dura-
up, compared with patients with medical therapy,
tion, frequency, sequence).
795
796
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
SPINAL CORD STIMULATION
high-thoracic space (T1 to T3), set at 90% to 110% of
the paresthesia threshold, and delivering therapy
SCS is a well-established therapy for chronic pain
continuously (24 h/day). At 6-month follow-up,
syndromes and refractory angina (108). Implantation
SCS was associated with statistically significant
typically occurs under conscious sedation with
improvement
percutaneous insertion of a multipolar 8-electrode
scores, metrics of LV reverse remodeling (improved
lead into the epidural space at the mid-thoracic
LVEF, reduced LV volumes), and peak oxygen con-
level (109) (Figure 3B). Stimulation is applied typi-
sumption. The procedure was well tolerated, with no
cally at 90% of the motor threshold with a set
acute complications. In contrast to the favorable
of frequency (usually w50 Hz) and pulse width
results of the SCS HEART study, preliminary results
(usually w200 ms) for a prescribed duration of
of the single-blind, phase II efficacy study DEFEAT-
in
functional
class,
quality-of-life
time (either cyclic or continuously). For patients
HF (Determining the Feasibility of Spinal Cord
with implantable-cardioverter defibrillators, the po-
Neuromodulation for the Treatment of Chronic Heart
tential presence of SCS-induced myopotentials as
Failure, NCT01112579) were generally null (118). The
well as interference with ventricular fibrillation
DEFEAT-HF study randomized 66 patients with
detection warrant interrogation and, if needed,
symptomatic
reprogramming of the stimulator at the time of
dilated LV cavity in a 3:2 fashion to SCS for 12 h per
HF,
depressed
LVEF
(<35%),
and
implant.
day or no activation for 6 months. A single, 8-
SCS is thought to mediate cardioprotective effects
electrode lead (Medtronic lead model 3777) was uti-
via augmentation of parasympathetic tone through
lized at 90% of the motor threshold. There was no
an
include
significant improvement in the primary efficacy
modulation of higher-order PNS processing (110).
endpoint of LV end-systolic volume index, and no
Given the demonstrated influence of SCS on auto-
difference in secondary endpoints, which included
nomic function, there has been increasing interest in
peak oxygen consumption, change in NT-proBNP,
its role as a therapy for HF (111). Consistent with its
change in functional status, or major adverse cardiac
postulated effects on PNS tone, SCS has been shown
events (death, HF hospitalization).
unknown
mechanism
postulated
to
to increase atrial refractory period and decrease the
The neutral results of the DEFEAT-HF trial raise
inducibility of atrial fibrillation in a tachy-pacing
several questions regarding the implementation of
canine model (112). In addition, SCS has been
SCS in HF. Whether more continuous SCS exposure
shown to reduce the incidence of ventricular tachy-
(24 h in the SCS HEART study vs. 12 h in the
arrhythmias in several post-infarction animal models
DEFEAT-HF study) or multiple electrode poles are
(113,114). The most robust evidence of the efficacy of
associated with greater benefit is unknown. There
SCS in HF includes a randomized assessment of
remains no standardized “dose” of SCS in HF, and
thoracic SCS in a post-infarction canine model of HF
dose studies of electrode output in humans may be
(115). Over 10 weeks, SCS was performed at the T4
warranted. Finally, whether SCS benefits select pa-
level, 3 times a day for 2 h each, at 90% of the motor
tients with HF (e.g., ischemic cardiomyopathy, as
threshold.
SCS
was
associated
with
significant
was utilized in animal models) or whether efficacy
decrement in ANS surrogates (plasma NE) and
is related to duration of HF and degree of patho-
neurohormonal activation (reduced NT-proBNP), as
logical LV remodeling remain questions for future
well as significant improvement in LVEF. Stimula-
investigation.
tion at 60% of the motor threshold and at a higher
thoracic level (i.e., T1) was also shown to signifi-
RENAL DENERVATION
cantly reduce ambulatory HR in a similar canine
In patients with HF, there is bidirectional feedback
model (116).
The efficacy of SCS as HF therapy in humans has
between the ANS and RAAS. The reduced renal
been mixed (117). The SCS HEART (Spinal Cord
perfusion associated with HF leads to stimulation of
Stimulation for Heart Failure) study was an open-
the RAAS with ATII-mediated increases in central
label, nonrandomized assessment of safety and ef-
SNS output (14,15) as well as ATII-mediated modu-
ficacy of SCS in 22 patients (17 patients and 5 con-
lation of carotid body chemoreceptor sensitivity
trols
with
(16,17). Inversely, efferent sympathetic fibers in-
symptomatic HF, reduced LVEF (20% to 35%), and
nervating the renal cortex and terminating within
dilated LV cavity (118). The SCS device (Eon Mini
the glomerular arteriole lead to increased renin
Neurostimulation System, St. Jude Medical, Plano,
secretion
Texas) included 2 percutaneous leads covering the
and water (14,119). Additionally, renal afferents
who
did
not
consent
to
implant)
and
maladaptive
handling
of
sodium
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
F I G U R E 3 Carotid Baroreceptor Stimulation in Heart Failure
(A) Schematic diagram of patient with carotid body stimulation system. The top panel shows the location of the baroreflex activation lead and
implantable pulse generator. The lower panel shows the first-generation CVRx Rheos device (left) and the single-lead second-generation
Rheos device. Adapted, with permission, from Gassler et al. (99) and Karunaratne et al. (100). (B) Chest radiograph of patient with spinal cord
stimulator device (red arrow) and previously implanted biventricular pacemaker-implantable cardioverter-defibrillator. Adapted with
permission from Kang et al. (101).
responsive to renal hypoxemia and ischemia may
ventricular remodeling, increased peripheral vas-
directly trigger increased central SNS output (120).
cular resistance, and abnormal sodium and water
The synergistic relationship between autonomic and
homeostasis.
neurohormonal dysfunction in HF is thought to be
an important mediator of progressive pathological
Although
initially
assessed
in
patients
with
resistant hypertension, there has been growing
797
798
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
interest in the use of renal denervation as therapy
assessing the efficacy of renal denervation in pa-
in HF (121). Pre-procedural evaluation includes
tients with HF and preserved ejection fraction. Of
assessment of renal arterial anatomy and renal
interest, in previous trials of patients with resistant
function testing (122). The proceduralist must be
hypertension, regression of myocyte hypertrophy
experienced in renal angiography as well as man-
was only partly dependent on decrement in blood
agement of acute complications such as renal dis-
pressure, suggesting a more direct relationship be-
sections or perforation. Denervation is accomplished
tween autonomic modulation and HF pathogenesis
via circumferential, low-energy radiofrequency ap-
(129). The ongoing DIASTOLE trial (Denervation of
plications within the renal artery, typically posi-
the Renal Sympathetic Nerves in Heart Failure with
tioned just proximal to the origin of a second-order
Normal LV Ejection Fraction, NCT01583881) will
renal artery branch. In general, 4 to 8 applications
randomize 60 patients with HF and LVEF $50% to
are applied along the length of each renal artery,
renal denervation or continued optimal medical
although individual anatomy and catheter technol-
therapy. Efficacy endpoints include measures of LV
ogy affect the total number of lesions delivered.
remodeling (change in LVEF, LV mass) as well as
Given the recent demonstration of the lack of
multiple ANS surrogates (MIBG washout, HRV)
benefit associated with renal denervation in pa-
(130). Similarly, the ongoing SWAN-HF study (Renal
tients with resistant hypertension (123), there is
Sympathetic Modification in Patients with Heart
significant interest in the use of novel procedural
Failure, NCT01402726) will randomize 200 patients
approaches (e.g., more distal renal artery ablation;
with symptomatic HF (both reduced and preserved
increase in number of ablative lesions) as well
ejection fraction) to renal denervation or continued
as consideration of optimal patient selection and
medical therapy with a primary endpoint of com-
trial design. Procedural innovation in renal dener-
posite cardiovascular events (131). Finally, given the
vation includes the use of different ablation cath-
potential benefits of renal denervation on ventric-
eter designs (unipolar, bipolar, multipolar), balloon-
ular and atrial arrhythmias (132,133), glucose meta-
based application technology, use of alternative
bolism (134), and sleep apnea (135), there may be an
energy sources (cryo, laser, ultrasound), and alter-
additional role for this strategy in managing rele-
native ablative agents (ethanol) (123,124).
vant comorbidities implicated in the pathogenesis
Pre-clinical
models
of
HF
demonstrated
im-
and exacerbation of HF.
provements in sodium handling and cardiac output,
In summary, preliminary work suggests that renal
as well as decrease in angiotensin receptor density
denervation is safe and tolerated in patients with
following renal denervation (121). The first human
HF, although its ultimate efficacy and tolerability
demonstration of renal denervation safety and ef-
remains to be tested in larger studies. Sympathetic
ficacy in HF was in the REACH (Renal Artery
tone plays an important compensatory role in HF,
Denervation
pilot
and historic trials of nonspecific pharmacological
study (125). In 7 patients with symptomatic systolic
sympatholysis have been associated with increased
HF, depressed LVEF and normotension at baseline,
mortality
renal denervation was well tolerated as reflected
renal innervation and the presence of comorbid
by nonsignificant reduction in blood pressure, no
renal dysfunction in patients with HF will also need
episodes of syncope or hypotension, and no sig-
to be considered in the application of renal dener-
nificant change in renal function at 6 months. In
vation for this population.
in
Chronic
Heart
Failure)
(68,69).
Heterogeneity
of
sympathetic
this limited study, patients experienced significant
improvement in subjective quality-of-life measures
FUTURE STRATEGIES OF
and 6-min walk distance. These results in patients
NEUROMODULATION IN HF
with systolic HF remain to be validated in larger
randomized
studies
with
longer
follow-up,
There are several technologies on the horizon that
including the SYMPLICITY-HF study (Renal Dener-
may
vation
modulation in HF. First, there is expanding interest
in
Patients
with
Chronic
Heart
Failure
further
shape
the
landscape
of
neuro-
the
in the role of tragus stimulation as an alternative,
RSD4CHF trial (Renal Sympathetic Denervation for
less-invasive method of vagal nerve stimulation
Patients with Chronic Heart Failure, NCT01790906)
(136). In a pre-clinical model of post-infarction car-
(126,127).
diomyopathy, tragus stimulation was associated
and
Renal
Impairment,
NCT01392196)
and
Additionally, given the demonstrated relationship
with attenuation of ANS surrogates (plasma NE) and
between renal denervation and regression of LV
neurohormonal activation (NT-proBNP), as well as
hypertrophy
improvement in LV function (137). Similar efforts to
(128,129),
there
are
ongoing
trials
Chatterjee and Singh
JACC: HEART FAILURE VOL. 3, NO. 10, 2015
OCTOBER 2015:786–802
Autonomics in Heart Failure
stimulate the vagus nerve through less invasive
autonomic imbalance and novel transvenous pacing
means
include
(e.g.,
of the phrenic nerve (via axillary or subclavian vein
within
the
Second,
access of the left pericardiophrenic or right bra-
although the strategies discussed in the previous
chiocephalic vein) has been associated with a
text
have
endovascular
superior
focused
vena
stimulation
cava)
exclusively
(138).
on
extracardiac
promising efficacy in mitigating apneic episodes and
autonomic modulation, another area of intense
improving sleep apnea indices (141). The long-term
investigation involves modulation of the intrinsic
clinical impact of phrenic nerve pacing in HF
cardiac neural plexus that lies on the epicardial
patients remains to be proven.
surface of the heart as well as within the adventitia
of the great vessels between the ascending aorta
CONCLUSIONS
and pulmonary artery (9,12). Endovascular cardiac
plexus stimulation in preliminary pre-clinical work
The ANS plays a critical role in the pathogenesis of
was associated with augmented LV contractility and
HF. As acknowledged at the outset, the reductive
cardiac output without influence on vascular resis-
“yin-yang” formulation of the SNS and PNS com-
tances, central venous pressure, or HR (139). Given
ponents of the ANS does not reflect the complex
the anatomic organization of the intrinsic neural
and
plexus, the ability to selectively modulate compo-
function (extracardiac and intracardiac), neurohor-
nents of the intrinsic cardiac nervous system offers
monal activation, innate immune system activation,
the speculative possibility of truly targeted auto-
and
nomic modulation (e.g., sinoatrial node in sick sinus
Continued translational efforts focused on refining our
syndrome vs. ventricular myocardium in cardio-
understanding of the complex interactions between
myopathy). Third, given the ability of implantable
neurohormonal and ANS dysfunction, as well as
devices to measure surrogates of ANS function, we
insight into regional autonomic regulation, will only
anticipate the development of pacing and stimula-
augment the development of ANS targeting tech-
tion technologies dynamically responsive to ANS
nologies in HF. Experience to date with non-
tone. Finally, there is increasing evidence that HF is
pharmacological ANS therapy highlights ongoing
often accompanied by central sleep apnea (CSA),
challenges for improving patient selection, optimiza-
which in turn increases morbidity and mortality
tion of implant or denervation strategies, and refine-
(140). Mechanistically, CSA is mediated via the
ment of stimulation protocols. As technological
respiratory control center, which is sensitive to the
capabilities and scientific understanding converge,
increased sympathetic drive and overactive chemo-
effective modulation of the ANS may transform the
receptors observed in HF. The respiratory control
landscape of HF.
integrative
subcellular
relationships
functions
among
(e.g.,
NO
autonomic
signaling).
center regulates the blood CO2 and also sends signals to the diaphragm via the phrenic nerves to
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
control the pattern of breathing. Notably, every
Jagmeet P. Singh, Cardiac Arrhythmia Service, Mass-
episode of CSA also activates the SNS, perpetuating
achusetts General Hospital, Harvard Medical School,
the vicious cycle. Treating the CSA accompanying
55 Fruit Street, Boston, Massachusetts 02114. E-mail:
HF may in fact offset some of the accompanying
[email protected].
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KEY WORDS carotid baroreceptor,
heart failure, renal denervation,
spinal cord stimulation, vagal nerve
stimulation
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