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This Review is in a thematic series on The Autonomic Nervous System and the Cardiovascular System, which includes
the following articles:
Role of the Autonomic Nervous System in Modulating Cardiac Arrhythmias [Circ Res. 2014;114:1004–1021]
The Autonomic Nervous System and Hypertension [Circ Res. 2014;114:1804–1814]
The Autonomic Nervous System and Heart Failure
Renal Denervation for the Treatment of Cardiovascular High Risk—Hypertension or Beyond?
The Autonomic Nervous System and Heart Failure
Viorel G. Florea, Jay N. Cohn
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Abstract: The pathophysiology of heart failure (HF) is characterized by hemodynamic abnormalities that result
in neurohormonal activation and autonomic imbalance with increase in sympathetic activity and withdrawal
of vagal activity. Alterations in receptor activation from this autonomic imbalance may have profound effects
on cardiac function and structure. Inhibition of the sympathetic drive to the heart through β-receptor blockade
has become a standard component of therapy for HF with a dilated left ventricle because of its effectiveness
in inhibiting the ventricular structural remodeling process and in prolonging life. Several devices for selective
modulation of sympathetic and vagal activity have recently been developed in an attempt to alter the natural
history of HF. The optimal counteraction of the excessive sympathetic activity is still unclear. A profound decrease
in adrenergic support with excessive blockade of the sympathetic nervous system may result in adverse outcomes
in clinical HF. In this review, we analyze the data supporting a contributory role of the autonomic functional
alterations on the course of HF, the techniques used to assess autonomic nervous system activity, the evidence
for clinical effectiveness of pharmacological and device interventions, and the potential future role of autonomic
nervous system modifiers in the management of this syndrome. (Circ Res. 2014;114:1815-1826.)
Key Words: autonomic nervous system
heart failure
ctivation of the sympathetic nervous system (SNS) and
inhibition of the parasympathetic system have long been
recognized as manifestations of the clinical syndrome of heart
failure (HF), presumably as a consequence of hemodynamic
changes associated with the alteration in cardiac function. The
possibility that this autonomic imbalance contributes directly
to the progression of the disease process was postulated in the
1990s with evidence that inhibition of the sympathetic drive
to the heart through β-receptor blockade favorably affected
the course of the disease. Numerous drugs and devices that
interfere with this activation pattern have since been studied
as therapeutic means to alter the natural history of HF. The
purpose of the present review is to re-explore the basic cellular
mechanisms of enhanced sympathetic activity, to examine the
data supporting a contributory role of these autonomic functional alterations on the course of HF, to evaluate the evidence
receptors, adrenergic
for clinical effectiveness of these pharmacological and device
interventions critically, and to consider the future role of autonomic nervous system modifiers in the management of this
increasingly common and lethal disease process.
The cardiac autonomic nervous system consists of 2
branches, the sympathetic and the parasympathetic systems,
that work in a delicately tuned, yet opposing fashion in the
heart. These branches differ in their neurotransmitters and
exert stimulatory or inhibitory effects on target tissue via adrenergic and muscarinic receptors. Both sympathetic and the
parasympathetic branches of the autonomic nervous system
are composed of afferent and efferent, as well as interneuronal
fibers. Sympathetic innervation originates mainly in the right
and left stellate ganglia. These fibers travel along the epicardial vascular structures of the heart into the underlying myocardium and end as sympathetic nerve terminals reaching the
Original received February 10, 2014; revision received April 29, 2014; accepted April 29, 2014. In March 2014, the average time from submission to first
decision for all original research papers submitted to Circulation Research was 12.63 days.
From the Minneapolis VA Health Care System, Section of Cardiology (V.G.F.) and Rasmussen Center for Cardiovascular Disease Prevention, Department
of Medicine (J.N.C.), University of Minnesota Medical School.
Correspondence to Jay N. Cohn, MD, Rasmussen Center for Cardiovascular Disease Prevention, University of Minnesota Medical School, 420 Delaware
St SE, Minneapolis, MN 55455. E-mail [email protected]
© 2014 American Heart Association, Inc.
Circulation Research is available at
DOI: 10.1161/CIRCRESAHA.114.302589
1816 Circulation Research May 23, 2014
Nonstandard Abbreviations and Acronyms
adrenergic receptor
baroreflex sensitivity
cardiac resynchronization therapy
G-protein–coupled receptor kinase
heart failure
heart failure with preserved ejection fraction
heart rate turbulence
heart rate variability
iodine 123 metaiodobenzylguanidine
left ventricular ejection fraction
sympathetic nervous system
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endocardium. Parasympathetic effects are carried by the right
and left vagus nerves, originating in the medulla. The vagus
nerve further divides into the superior and inferior cardiac
nerves, finally merging with the postganglionic sympathetic
neurons to form a plexus of nerves at the base of the heart,
known as the cardiac plexus.1
The 2 mediators of the SNS, norepinephrine and epinephrine, derive from 2 major sources in the body: the sympathetic
nerve endings, which release norepinephrine directly into the
synaptic cleft, and the adrenal medulla, whose chromaffin cells
synthesize, store, and release predominantly epinephrine and
norepinephrine on acetylcholine stimulation of the nicotinic
cholinergic receptors present on their cell membranes.2 Thus,
all of the epinephrine in the body and a significant amount of
circulating norepinephrine derive from the adrenal medulla,
and the total amount of catecholamines presented to cardiac
adrenergic receptors (ARs) at any given time is composed of
these circulating norepinephrine and epinephrine plus norepinephrine released locally from sympathetic nerve terminals.2
Norepinephrine is released into synaptic clefts in response to
neuronal stimulation through fusion of presynaptic storage
vesicles with the neuronal membrane. Norepinephrine stimulates presynaptic α2-ARs, which provide a negative feedback
on exocytosis,3 and the postsynaptic β-ARs. In the synaptic cleft, most norepinephrine undergoes reuptake into nerve
terminals by the presynaptic norepinephrine transporter and
recycles into vesicles or is metabolized in the cytosol by monoamine oxidase.4 A small fraction of ≈20% diffuses into the vascular space, where it can be measured in coronary sinus blood.5
Norepinehprine spillover can also be measured in the blood and
used to infer sympathetic outflow to the heart.6 Epinephrine is
released into the circulation by the adrenal medulla and affects
both the myocardium and the peripheral vessels.7
Adrenoceptors mediate the central and peripheral actions of
the primary sympathetic neurotransmitter—norepinephrine—
and the primary adrenal medullary hormone—epinephrine.
The ARs are divided into 3 families, the α1-ARs, the α2-ARs,
and the β-ARs, each of which is further subdivided in several
subtypes.8 In the heart, the 2 main ARs are the β-ARs, which
comprise ≈90% of the total cardiac ARs, and α1-ARs, which
account for ≈10%.9
Evidence from cell, animal, and human studies demonstrates
that α1-ARs mediate adaptive and protective effects in the
heart and activate pleiotropic downstream signaling to prevent
pathological remodeling in HF.9,10 These effects may be particularly important in chronic HF, when catecholamine levels
are elevated and β-ARs are downregulated and dysfunctional.10
It is now generally accepted that, in the human heart, β1and β2-ARs coexist; the existence of a third heart β-AR is to
date mainly supported by the anomalous pattern of nonconventional partial agonists.11 β1-AR is the predominant subtype
in the myocardium, representing 75% to 80% of total β-AR
density, followed by β2-AR.12 Activation of cardiac β-ARs
increases heart rate, myocardial contractility, impulse conduction through the atrioventricular node, and pacemaker activity
of the sinoatrial node.13
The interpretation of catecholamine effects has recently
been re-examined in light of the demonstration of the expression of the β3-AR in cardiovascular tissues in humans and
in several animal species.14 This isotype was known to mediate lipolysis and thermogenesis in adipose tissue. In the heart,
contrary to β1 and β2 isotypes, it mediates a negative inotropic effect when activated with high concentrations of agonist
ex vivo.15 Given its differential expression in cardiac tissue,
the β3-AR is an attractive target for therapeutic modulation in
several cardiomyopathies.15
The concept of biased agonism has recently been proposed
with the demonstration that G-protein–coupled receptors activate complex signaling networks and can adopt multiple
active conformations on agonist binding. As a consequence,
the efficacy of receptors, which was classically considered
linear, is now recognized as pluridimensional. Biased agonists
selectively stabilize only a subset of receptor conformations
induced by the natural unbiased ligand, thus preferentially activating certain signaling mechanisms. Such agonists reveal
the intriguing possibility that one can direct cellular signaling
with unprecedented precision and specificity and support the
notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects.16
Acetylcholine, the transmitter of the parasympathetic system, is stored in vesicles and is released by parasympathetic
stimulation, activating postsynaptic muscarinic, and preganglionic nicotinic receptors.17 These effects are terminated by rapid
degradation by acetylcholinesterase.18 Parasympathetic stimulation decreases heart rate by decreasing sinoatrial node discharge rate and atrioventricular node conduction velocity with
minimal or no effect on cardiac contractility.7 There is evidence
that stimulation of the local muscarinic receptors in the heart
inhibits norepinephrine release from adrenergic nerve terminals; therefore, cardiac muscarinic receptors may play a role in
the local modulation of cardiac sympathetic activity in HF.19,20
Alterations in autonomic function occur in several interrelated cardiac conditions, including hypertension, myocardial
ischemia, HF, cardiac arrhythmias, and sudden cardiac death.21
Autonomic Nervous System in HF
Most of the data about the role of the SNS in the development
and prognosis of HF were obtained from studies on subjects
with dilated ventricles and reduced ejection fraction (EF).22–27
One of the first responses to myocardial injury or to alterations
in cardiac loading is activation of the SNS, resulting in both
increased release and decreased uptake of norepinephrine at
Florea and Cohn Autonomic Nervous System and Heart Failure 1817
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adrenergic nerve endings. Sympathetic outflow from the central nervous system in HF affects several key organs, including the heart, the kidney, and the peripheral vasculature. In
the acute setting, catecholamine-induced augmentation of
ventricular contractility and heart rate help maintain cardiac
output. Increased sympathetic activity also leads to systemic
vasoconstriction and enhanced venous tone, both of which
initially contribute to maintenance of blood pressure by increasing systemic vascular resistance and ventricular preload.
Renal vasoconstriction (mediated primarily by angiotensin II)
occurs at the efferent arteriole, producing an increase in filtration fraction that allows glomerular filtration to be relatively
well maintained, despite a fall in renal blood flow. Both norepinephrine and angiotensin II stimulate proximal tubular sodium reabsorption, which contributes to sodium retention and
volume expansion characteristic of HF. The heart responds to
the increase in venous return with an elevation in end-diastolic
volume that results in a rise in stroke volume via the Frank–
Starling mechanism. Chronic sympathetic stimulation induces
myocyte enlargement, interstitial growth, and remodeling that
increase myocardial mass and may lead to enlargement of the
left ventricular (LV) chamber.28,29
The elevated SNS outflow and norepinephrine and epinephrine levels in chronic HF lead to chronically elevated
stimulation of the cardiac β-AR system, which has detrimental repercussions for the failing heart. Extensive investigations
during the past 3 decades have helped delineate the molecular
alterations afflicting the cardiac β-AR system that occur during
HF, and it is now well known that, in chronic human HF, cardiomyocyte β-AR signaling and function are significantly deranged and the adrenergic reserve of the heart is diminished.30–32
Cardiac β-AR dysfunction in human HF is characterized at the
molecular level by selective reduction of β1-AR density at the
plasma membrane (downregulation) and by uncoupling of the
remaining membrane β1-ARs and β2-ARs from G proteins
(functional desensitization).31 In addition, emerging evidence
suggests that β2-AR signaling in the failing heart is different
from that in the normal heart (ie, is more diffuse and noncompartmentalized and resembles the proapoptotic diffuse cAMP
signaling pattern of the β1-AR).33 Importantly, myocardial levels and activities of the most important, versatile, and ubiquitous G-protein–coupled receptor kinases (GRKs), GRK2 and
GRK5, are elevated both in humans and in animal models of
HF.34–38 The current consensus is that in chronic HF, the excessive amount of SNS-derived catecholamines stimulating
cardiac β-ARs extracellularly triggers the GRK2 upregulation
inside the cardiomyocytes, thus leading to a reduction in cardiac β-AR density and responsiveness and resulting in cardiac
inotropic reserve depletion.39,40 This GRK2 elevation possibly
serves as a homeostatic protective mechanism aimed at defending the heart against excessive catecholaminergic toxicity.
Thus, elevated SNS activity in chronic HF causes enhanced
GRK2–mediated cardiac β1-AR and β2-AR desensitization
and β1-AR downregulation, which leads to the progressive
loss of the adrenergic and inotropic reserves of the heart, the
hallmark molecular abnormality of this disorder.41
It has been known for many years that chronic exposure
to catecholamines is toxic to cardiac myocytes.42 Many studies demonstrated a high plasma norepinephrine concentration
concomitant with a depressed iodine 123 metaiodobenzylguanidine (123I-MIBG) reuptake in HF, and this phenomenon has
been explained as sympathetic denervation.43 In 1992, Mann
et al44 demonstrated that at the cellular level, adrenergic stimulation leads to cAMP-mediated calcium overload of the cell,
with a resultant decrease in cardiomyocyte viability. Kimura
et al45 have recently suggested that the cardiac sympathetic
nerve density is strictly regulated by the nerve growth factor
expression and demonstrated in an experimental rat model
that long exposure to high plasma norepinephrine concentration caused myocardial nerve growth factor reduction, followed by sympathetic fiber loss. It has been suggested that the
sympathetic nerve endings are probably damaged by norepinephrine-derived free radicals,46 and that antioxidant therapy
may prevent the toxic effects of norepinephrine on the sympathetic nerve terminals.46,47 Norepinephrine-mediated cell toxicity was also attenuated by β-AR blockade and mimicked by
selective stimulation of the β-AR, whereas the effects mediated by the α-AR were relatively less apparent.44
Communal et al48 examined the mechanism by which norepinephrine caused cell death in ventricular myocytes cultured from adult rat hearts. Exposure to norepinephrine for 24
hours caused DNA fragmentation consistent with apoptosis.
Norepinephrine-stimulated apoptosis was abolished by the βAR antagonist propranolol but not by the α1-AR antagonist
prazosin.48 Stimulation of β1-ARs increases apoptosis via a
cAMP-dependent mechanism, whereas stimulation of β2-ARs
inhibits apoptosis via inhibitory G-protein (Gi) pathway.49–52
Although hyperstimulation or overexpression of β1-ARs has
detrimental effects in the heart,51,53 there are new data suggesting chronic β-adrenergic signaling can be cardioprotective.54
Extensive research in the rat model of dilated cardiomyopathy after induction of myocardial infarction showed that
prolonged treatment with the β2-AR agonist, fenoterol, in
combination with the β1-AR blocker, metoprolol, is more effective than β1-AR blocker alone and as effective as β1-AR
blocker with angiotensin-converting enzyme inhibitor with
respect to survival and cardiac remodeling.55 This combined
regimen of a β2-AR agonist and a β1-AR blocker might be
considered for clinical testing as alternative or adjunct therapy
to the currently accepted HF arsenal.
Preclinical data point to protective effects of overexpressed
β3-ARs against LV remodeling in the setting of neurohormonal or postischemic stress. Theoretically, one could conceive the
benefit of using β3-AR agonists to prevent adverse remodeling in these conditions. Recently, a study showed preliminary
encouraging data using a β3 agonist, BRL37344, in mice submitted to transaortic constriction56 although the specificity of
this molecule as an agonist for the murine β3-AR is somewhat
disputed.57 Sorrentino et al58 have recently demonstrated in
a postinfarction murine model that nebivolol, a β2-AR, and
likely β1-AR biased agonist,59 which was previously shown to
activate β3-AR in the human ventricle,60 improves LV function
and survival early after myocardial infarction likely beyond the
effects provided by conventional β1-receptor blockade.58 The
Study of the Effects of Nebivolol Intervention on Outcomes and
Rehospitalisations in Seniors with Heart Failure (SENIORS)
trial demonstrated the effect of nebivolol on all-cause mortality
or cardiovascular hospitalization in elderly patients with HF.61
1818 Circulation Research May 23, 2014
Less is known about the role of the para-SNS in the pathophysiology of HF. Parasympathetic outflow to the heart is
reduced in patients with HF,62,63 resulting in increased heart
rate and decreased heart rate variability (HRV), both of which
are correlated with increased mortality.64 Muscarinic receptor
stimulation in the failing human left ventricle was shown to
have an independent negative lusitropic effect and at antagonize the effects of β-adrenergic stimulation.65
Autonomic Nervous System in HF With
Preserved EF
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Approximately one half of patients presenting with HF have
normal or near-normal LVEF.66,67 These patients with HF and
preserved EF (HFpEF) have been reported to experience an
overall prognosis and pattern of functional decline similar to
that of patients with HF and reduced LVEF.68 Patients with
HFpEF are, however, older, and their functional decline is
characterized by impaired ventricular relaxation and reduced
compliance of the ventricles. The resulting impairment of diastolic filling may in time lead to congestive HF.69,70 To date,
no established effective treatment strategies are known. Partly,
this can be explained by a lack of knowledge on mechanisms.
Various physiological mechanisms have been implicated in
the pathogenesis of HFpEF, including increased passive ventricular stiffness, because of enhanced extracellular collagen
deposition and intrinsic alterations in myocyte cytoskeletal
proteins,71 impaired active myocardial relaxation related to altered myocyte calcium handling and reduced myocardial energy reserve,72,73 abnormal ventricular–vascular coupling and
pulsatile load as a consequence of diminished aortic compliance,74 and impaired renal handling of salt and water because
of increased neurohormonal activation.75
Data on autonomic nervous system in HFpEF are limited.
In patients with hypertension, SNS hyperactivity may contribute to the development of LV diastolic dysfunction and thus
increase HF risk.76 Several preclinical and clinical studies
have shown a relationship between an elevated SNS activity
and the development of diastolic dysfunction or HFpEF.77–79
On the basis of the relationship between the SNS and
HFpEF, we have suggested that modulation of the SNS may
result in an improvement of the clinical status of patients with
HFpEF. Although there have been no randomized clinical trials investigating the role of β-blockers in patient with HFpEF,
the SENIORS trial enrolled subjects with both reduced and
preserved EF.61 In the subgroup of 752 patients with a LVEF
of ≥35%, treatment with nebivolol showed no significant
benefit on the primary end point of all-cause mortality or cardiovascular hospitalizations.80 The denervation of the renal
sympathetic nerves in HF with normal LVEF (DenervatIon of
the renAl Sympathetic nerves in hearT failure with nOrmal Lv
Ejection fraction [DIASTOLE]; Identifier
NCT01583881) will investigate whether renal sympathetic
denervation is an effective means to modulate the detrimental
effects of the SNS in patients with HF with normal EF.81
Techniques Used to Assess Autonomic Nervous
System Activity
The following techniques have been used to assess autonomic nervous system activity: analysis of heart rate and blood
pressure, measurement of norepinephrine spillover, microneurography, and imaging of cardiac sympathetic nerve terminals.
Analysis of Heart Rate and Blood Pressure
Heart Rate Variability
Beat-to-beat HRV can serve as a noninvasive marker of autonomic input to the heart. HRV is markedly reduced in patients
with HF, and the reduction in HRV is related to the severity of HF and its prognosis.82,83 The underlying physiological
mechanism of decreased HRV is likely to be an alteration in
the cardiac sympathetic–parasympathetic balance, characterized by a relative sympathetic dominance probably secondary
to reduced parasympathetic activity.84 The estimation of HRV
by ambulatory monitoring provides prognostic information
beyond that of traditional risk factors.85 Studies have shown
that HRV strongly predicts sudden cardiac death in patients
with chronic HF,86 and that β-blocker therapy with bisoprolol
induced a significant increase in HRV.87
Baroreflex Sensitivity
Baroreceptor-heart rate reflex sensitivity (BRS) assesses the
integrity of the carotid and aortic baroreceptors in response
to changes in blood pressure. Abnormalities in baroreceptor function are intrinsic to the pathophysiology of HF.88
Experimental89 and clinical62 studies demonstrated that the
carotid sinus baroreceptor sensitivity is diminished in HF. The
site or sites within the baroreflex arc that is responsible for the
depressed baroreflex in HF are not clearly identified. Patients
with HF were shown to exhibit reduced elevation in heart rate
when parasympathetic restraint is abolished by atropine and
diminished sensitivity of the baroreceptor reflex, characterized by a severe reduction in the heart rate slowing for any
given elevation of systemic arterial pressure.62 In contrast to
the increase in heart rate and plasma norepinephrine levels
during nitroprusside infusion in normal subjects, patients with
HF also exhibited neither an increase in plasma norepinephrine nor an increase in heart rate during nitroprusside infusion
(Figure 1).90 A depressed BRS conveys independent prognostic information that is not affected by the modification of autonomic dysfunction brought about by β-blockade.91
Heart Rate Turbulence
The phenomenon of heart rate turbulence (HRT) refers to
sinus rhythm cycle-length perturbations after isolated premature ventricular complexes. The physiological pattern of
HRT consists of brief heart rate acceleration (turbulence onset) followed by more gradual heart rate deceleration (turbulence slope) before the rate returns to the pre-ectopic level.
Physiological investigations confirm that the initial heart
rate acceleration is triggered by transient vagal inhibition in
response to the missed baroreflex afferent input caused by
hemodynamically inefficient ventricular contraction. A sympathetically mediated overshoot of arterial pressure is responsible for the subsequent heart rate deceleration through
vagal recruitment. Two large studies (UK-HEART [United
Kingdom Heart Failure Evaluation and Assessment of Risk]
trial and Muerte Subita en Insuficiencia Cardiaca [MUSIC]
study) investigated the prognostic role of HRT in patients with
HF.92,93 In the UK-HEART trial,93 abnormal turbulence slope
was an independent predictor of HF decompensation. In the
Florea and Cohn Autonomic Nervous System and Heart Failure 1819
MUSIC study,92 HRT predicted all-cause mortality and sudden death in patients with HF. The HRT pattern is blunted
in patients with reduced BRS.94 La Rovere et al95 analyzed
the relationship between measures of HRT and the BRS in
patients with HF, who also had a direct evaluation of their hemodynamic status by right heart catheterization and suggested
HRT might be regarded as a surrogate measure of BRS.
Norepinephrine Spillover
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Most norepinephrine released into the synaptic cleft of the AR
undergoes reuptake into nerve terminals by the presynaptic
norepinephrine transporter, where it recycles into presynaptic vesicles or is metabolized in the cytosol by monoamine
oxidase. A small amount of the transmitter escapes neuronal
uptake and local metabolism and diffuses or spills over into
the blood vessels, where it can be measured to infer the level
of sympathetic outflow.6
Depletion of cardiac norepinephrine content was the first
objective evidence of sympathetic derangement in HF. In
1963, Chidsey et al96 reported a significant diminution in
the myocardial norepinephrine concentrations observed in
patients with chronic congestive HF. They also reported increased plasma norepinephrine levels and urinary excretion of
norepinephrine in patients with HF.97,98 In 1984, Cohn et al99
reported that plasma norepinephrine levels provide a better
guide to prognosis in patients with chronic congestive HF than
other commonly measured indices of cardiac performance
(Figure 2). A more recent analysis of both plasma norepinephrine and plasma brain natriuretic peptide indicated that brain
natriuretic peptide had a stronger association with morbidity
and mortality than norepinephrine, and that changes in these
neurohormones over time are associated with corresponding
changes in morbidity and mortality.100 It should be noted that
measurement of plasma norepinephrine levels represents a
crude assessment of SNS activity as only ≈20% of norepinephrine released at the nerve terminals may enter the bloodstream where it undergoes clearance from the circulation.101,102
A higher plasma norepinephrine concentration in patients
Figure 1. Response of plasma norepinephrine (PNE) and
heart rate (HR) to nitroprusside (NP) infusion in 5 normal
subjects (▲) and 46 patients with congestive HF (CHF; ● ).
Symbols above the control columns (C) indicate a significant
difference between normal subjects and patients with CHF;
symbols in NP columns indicate significant changes from control
during NP infusion. *P<0.01, †P<0.05. Mean values±SEM are
shown. Reprinted from Olivari et al.90
with HF was shown to be secondary to both increased release
and reduced its clearance.24 In conditions, such as congestive
HF, where clearance is likely to be abnormal, the rate of spillover is a more accurate index of sympathetic activity than the
total plasma norepinephrine concentration.24
The analysis of plasma kinetics of norepinephrine can be used
to estimate sympathetic nervous activity for the body as a whole
and for individual organs. There is marked regional variation
in sympathetic nerve activity in patients with HF. Cardiac and
renal norepinephrine spillover are increased, whereas norepinephrine spillover from the lungs is normal.24 Adrenomedullary
activity is also increased in patients with HF.24 The finding of
increased cardiorenal norepinephrine spillover has important
pathophysiologic and therapeutic implications.
Microneurography uses metal microelectrodes to investigate
the neural traffic in myelinated and unmyelinated efferent and
afferent nerves directly.103 This technique has been used in
clinical neurophysiology to evaluate the neural mechanisms of
autonomic regulation, motor control, and sensory functions in
physiological and pathological conditions. Microneurography
has also been used to analyze the muscle sympathetic nerve
activity. Studies have shown that increased muscle sympathetic nerve activity is associated with increased mortality rate in
patients with HF.104
Imaging of Cardiac Sympathetic Nerve Terminals
The use of radiolabeled catecholamine analogs to image cardiac sympathetic nerve terminals dates back ≈30 years.105
Recently, several radiolabeled compounds have been proposed
for noninvasive imaging of cardiac neuronal function. The catecholamine analog 123I-MIBG is the tracer most commonly
used to map myocardial presynaptic sympathetic innervation
and activity.106–108 Cardiac neuronal distribution and function
can be imaged with standard γ-cameras and positron emission
Figure 2. Predicted survival curves based on initial measure­
ment of plasma norepinephrine. Reprinted from Cohn et al.99
Copyright 1984. Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
1820 Circulation Research May 23, 2014
tomography scanners.109 123I-MIBG cardiac imaging has been
shown to carry independent prognostic information for risk
stratification of patients with HF in a complementary manner
to more commonly used biomarkers, such as LVEF and brain
natriuretic peptide.110 β-blockade and renin–angiotensin–aldosterone system inhibition are associated with an increase in
I-MIBG uptake and a reduced washout.7 Imaging of the cardiac autonomic nervous system has recently entered large-scale
clinical trials and has supported a prognostic value in HF.111,112
Interventions Targeting the Autonomic
Nervous System in HF
Pharmacological Blockade of the SNS
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β-blockers reverse ventricular remodeling113,114 and reduce
mortality in patients with HF.115–117 The use of 1 of the 3 β
blockers proven to reduce mortality (eg, bisoprolol, carvedilol,
and sustained-release metoprolol succinate) is, therefore, recommended for all patients with current or previous symptoms
of HF with reduced EF.118
The association between the degree of sympathetic activation and mortality99,100 raised the possibility that more complete
adrenergic blockade might produce even greater benefit on
outcomes. Moxonidine, a mixed central agonist that stimulates
both α2- and imidazoline-receptors119 and which greatly reduces circulating catecholamines,120 was used to test this hypothesis in the Moxonidine in Congestive Heart Failure (MOXCON)
trial.121 The study had to be terminated early with only 1934 of
the planned 4533 patients randomized because of a 38% higher mortality in the moxonidine group. Hospitalizations for HF
and myocardial infarctions were also increased. The increase
in mortality and morbidity was accompanied by significant
decrease in plasma norepinephrine by moxonidine (–18.8%)
when compared with that by placebo (+6.9%).121
The MOXCON findings suggest that central inhibition of
the SNS may not be safe in patients with HF. It is conceivable
that receptor inhibition might be better tolerated than central
suppression of the cardiac stimulation and peripheral vasoconstrictor effects of the SNS.121 It is also possible that the pharmacological benefit of β blockade in HF is at least partly achieved
through a mechanism different than that resulting from a decrease in sympathetic nerve traffic. Renin inhibition by β1
receptor blockade with reduction in angiotensin II levels may
be an important mechanism for the efficacy of β blockers.122
Another possible reason for the failure of moxonidine in the
MOXCON trial might have been the reported α2-AR desensitization and downregulation that accompanies HF, which renders
α2-ARs dysfunctional, thus increasing sympathetic outflow and
limiting efficacy of α2-AR sympatholytic agonists.7,123
Another example of the association between marked sympatholytic effect and adverse outcomes was seen in the BetaBlocker Evaluation of Survival Trial (BEST),124 which is the
only β-blocker HF trial that failed to demonstrate mortality
benefit. In BEST, patients receiving bucindolol, who had a decrease in norepinephrine of >224 pg/mL from baseline to 3
months, had a 169% increase in mortality when compared with
patients who had no significant change in norepinephrine.125
β-blocker trials in patients with HF have demonstrated differences in outcomes by geographic region. In Metoprolol
Controlled-Release Randomized Intervention Trial in Heart
Failure (MERIT-HF), metoprolol succinate showed a significant
34% risk reduction in mortality when compared with placebo.115
This risk reduction was nearly identical to the significant mortality
risk reductions observed with bisoprolol in Cardiac Insufficiency
Bisoprolol Study (CIBIS)-II (34%) and carvedilol in Carvedilol
Prospective Randomized Cumulative Survival (COPERNICUS)
trial (35%), both were compared with placebo.116,117 In contrast,
BEST showed a nonsignificant 13% risk reduction in mortality
in patients treated with bucindolol versus placebo.124 MERITHF, CIBIS-II, and COPERNICUS were international trials with
the majority of recruitment outside the United States, whereas
BEST recruited only patients in the United States and Canada
(97.7% and 2.3%, respectively). The geographic diversity among
these trials created an opportunity to examine whether outcome
differences by region were present. A recent post hoc analysis
of large β-blocker trials suggested that a difference in response
to β-blocker therapy may exist between patients in the United
States and in other parts of the world.126 Among US patients, the
reduction in mortality associated with β-blocker therapy was of
lesser magnitude than that observed in the overall trial results,
and it was not statistically better than placebo. This geographic
difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease
management, or low power and statistical chance.
Questions remain as to the mechanism of the beneficial effect of β-blockers in patients with HF and whether they work
through diminishing sympathetic overactivity or exclusively
through cardiac slowing. In patients with mild to severe chronic HF, elevated resting heart rate is associated with an increased
risk of all-cause mortality and cardiovascular mortality.127,128
Similarly, investigators of the systolic HF treatment with the If
inhibitor ivabradine trial (SHIFT) study observed that patients
with chronic HF and in sinus rhythm who had the highest heart
rate were at a 2-fold greater risk of cardiovascular death or
hospitalization for HF when compared with patients with the
lowest heart rate.129 In this trial, treatment with ivabradine was
associated with an average reduction in heart rate of 15 bpm
from a baseline value of 80 bpm and a significant reduction of
the risk of cardiovascular death or hospital admission for worsening HF.130 Patients with heart rates higher than the median
were at increased risk of an event and received greater eventreducing benefit from ivabradine than did those with heart
rates lower than the median.130 These finding suggests that the
magnitude of benefit associated with ivabradine varies directly
with pretreatment heart rate. This conclusion is in line with
a meta-analysis of β-blocker trials in chronic HF, suggesting
that there is an association between the magnitude of heart rate
reduction and outcome.131 Although these findings support the
idea that heart rate plays an important part in the pathophysiology of HF and that heart rate modulation can interfere with the
progression of the disease, it is possible that the higher heart
rates represent a sicker population in which the benefit of the
drug would be easier to demonstrate.
Although SHIFT emphasized the importance of isolated
heart rate reduction on outcomes in patients with HF, several
β-blocker trials could not establish any relationship between
the baseline heart rate and the efficacy of β-blocker therapy
with either nonselective agents132,133 or selective agents.134,135
Florea and Cohn Autonomic Nervous System and Heart Failure 1821
In the MERIT-HF, metoprolol controlled release/extended
release significantly reduced mortality and hospitalizations independent of resting baseline heart rate, achieved heart rate, and
change in heart rate.135 The reduction in mortality with bisoprolol,
when compared with placebo, was not influenced by heart rate
changes in the CIBIS-II as well.136 It is likely that β-blocker therapy may counteract the deleterious effects of tachycardia in the
failing heart so that this variable loses its prognostic significance.
Effect of Cardiac Resynchronization Therapy on
Cardiac Autonomic Function
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Several studies have shown that cardiac resynchronization
therapy (CRT) improves sympathetic function in patients with
HF accompanied by reduced systolic function. Biventricular
pacing was shown to reduce muscle sympathetic nerve activity
when compared with right ventricular pacing137 or right atrial
pacing.138 These beneficial effects persisted ≤6 months after resynchronization therapy.139,140 Cha et al141 examined the effect of
CRT on neurohormonal integrity by studying cardiac presynaptic sympathetic function, as determined by nuclear cardiac
imaging modalities (123I-MIBG scintigraphy), in patients with
HF who received CRT and found that CRT reverses cardiac
autonomic remodeling by upregulating presynaptic receptor
function, as evidenced by increased 123I-MIBG heart/mediastinum ratio and attenuated heart/mediastinum washout rate, with
concomitantly improved HRV.141 Najem et al142 found that sympathetic inhibition induced by chronic CRT is acutely reversed
when patients are shifted from a synchronous to a nonsynchronous mode; this was observed only in patients who responded
to CRT, even more than a year after initiation of the therapy. The
mechanism by which CRT inhibits sympathetic activity is intriguing because correction of the electric and mechanical dyssynchrony with biventricular pacing does not directly block the
SNS. It is probable that biventricular pacing improves cardiac
function over time and thus reduces sympathetic drive.
Exercise Training and Autonomic Nervous System
in HF
Studies in experimental HF have shown that exercise training in animals improves cardiac β-AR signaling and function,
increases adrenergic and inotropic reserves of the heart, and
helps restore normal SNS activity/outflow and circulating catecholamine levels.143–145 Exercise training is known to increase
resting vagal tone and to decrease sympathetic drive in healthy
individuals. Coats et al146 showed that a similar beneficial
change could be induced in patients with HF. Exercise not only
improved peak oxygen uptake in patients with HF but also associated with a reduction in markers of SNS activation (norepinephrine spillover and HRV).146 In the HF: A Controlled Trial
Investigating Outcomes of Exercise Training (HF-ACTION)
trial, the largest randomized controlled trial of exercise training
in patients with HF and reduced LV function, exercise training
provided a nonsignificant reduction in the risk of the primary
end point of all-cause mortality or all-cause hospitalization.147
Use of Devices to Modulate Autonomic Nervous
System in HF
Renal Sympathetic Denervation
Sympathetic outflow to the kidneys is activated in patients
with essential hypertension.101 Efferent sympathetic outflow
stimulates renin release, increases tubular sodium reabsorption, and reduces renal blood flow.148 Afferent signals from the
kidney modulate central sympathetic outflow and thereby directly contribute to neurogenic hypertension.149–151
Recently developed endovascular catheter technology
enables selective denervation of the human kidney, with radiofrequency energy delivered in the renal artery lumen, accessing the renal nerves located in the adventitia of the renal
arteries. A first-in-man study of this approach performed in
a 59-year-old man with uncontrolled hypertension152 showed
reduction of sympathetic activity and renin release in parallel
with reductions of central sympathetic outflow. Muscle sympathetic nerve activity decreased from 56 bursts per minute at
baseline to 41 bursts per minute at 30 days and 19 bursts per
minute at 1 year. Furthermore, from baseline to 30 days, total
body norepinephrine spillover decreased by 42%, and renal
norepinephrine spillover decreased by 75% and 48% in the
right and left kidney, respectively. Finally, mean office blood
pressure decreased from 161/107 mm Hg at baseline to 141/90
at 30 days and 127/81 mm Hg at 1 year, despite the withdrawal
of 2 antihypertensive medications. This fall in blood pressure
was accompanied by a reduction in LV mass measured using
cardiac MRI.
A subsequent randomized controlled trial (SYMPLICITY
HTN-2 trial [renal sympathetic denervation in patients with
treatment-resistant hypertension])153 showed that catheterbased renal denervation can safely be used to reduce blood
pressure substantially in treatment-resistant patients with hypertension. Renal sympathetic denervation was also shown
to reduce LV hypertrophy and to improve cardiac function
in patients with resistant hypertension.154 The pivotal study,
the SYMPLICITY HTN-3 trial was, however, terminated
prematurely because it failed to achieve its primary efficacy end point of change in office systolic blood pressure at
6 months.155 The SYMPLICITY HTN-3 study was a singleblinded, randomized, designed to evaluate the safety and
effectiveness of renal denervation in patients with treatmentresistant hypertension. In this trial, people receiving the investigational treatment were compared with a sham-control
group that did not receive treatment.
Experimental studies suggested that renal denervation could
be beneficial for improving the neurohormonal dysregulation
of chronic HF.156,157 Davies et al158 have recently reported the
results of a pilot study of 7 patients with chronic systolic HF,
who underwent bilateral renal denervation and were followed
up for 6 months. The study found no procedural or postprocedural complications.158 A randomized trial with appropriate
concealment of treatment is required to address the potential
benefits of renal denervation in HF, and such a trial is currently underway in chronic systolic HF (REACH [Renal Artery
Denervation in Chronic Heart Failure study], ClinicalTrials.
gov Identifier NCT01639378).
Baroreflex Sensitization
Baroreflex sensitization devices have been commercialized
and are currently undergoing clinical testing. The Rheos
(CVRx, Minneapolis, MN) implantable carotid sinus stimulator has been studied in patients with severe hypertension refractory to drug therapy. Implantation involves both carotid
1822 Circulation Research May 23, 2014
sinuses being surgically exposed and electrodes being placed
around the carotid adventitial surface bilaterally. The leads
are subcutaneously tunneled and connected to an implantable
stimulation device placed in the subclavian subcutaneous position on the anterior chest wall. Electric baroreflex activation
is then initiated on both carotid sinuses simultaneously with
incremental voltage increases until the chronic stimulation
level is achieved.159
A recent European multicenter feasibility study showed
that the Rheos device sustainably reduces blood pressure
in patients with resistant hypertension, and that this unique
therapy offers a safe individualized treatment option for these
high-risk individuals.160 There are currently several trials underway examining the role of baroreceptor activation therapy
in patients with HF.161
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Vagal Nerve Stimulation
An approach that could further advance the neurohormonal
and autonomic imbalance hypothesis in HF is the improvement of autonomic regulatory function by vagal nerve stimulation. Reduced vagal activity is associated with increased
mortality in patients with HF,162 and many investigators have
shown that restoration of autonomic regulatory function by
vagal nerve stimulation improves survival in animal models
of HF.163–165 More recently, a multicenter, open-label phase
II safety and feasibility study was reported with the use of
right cervical vagal nerve stimulation synchronized to the
cardiac cycle (Cardiofit System; BioControl Medical, Yehud,
Israel).166 The Autonomic Neural Regulation Therapy to
Enhance Myocardial Function in Heart Failure (ANTHEMHF) study will use the Cyberonics vagal nerve stimulation
therapy system to provide additional information on the role
of autonomic regulation therapy in patients with LV dysfunction and chronic symptomatic HF.167
Future Directions
Despite remarkable insights into the role of the autonomic
nervous system in the syndrome of HF, several issues remain
poorly understood and in need of further investigation. The
issue of paramount importance is whether activation of the
autonomic nervous system is the driver of HF or merely a
consequence of the disease. Some other important questions
include (1) What is the optimal counteraction of the activation
of the SNS in chronic HF? (2) What is the mechanism of the
heterogeneity of response to β-blocker therapy? (3) Are there
new pharmacological mechanisms that could be exploited?
(4) If drugs are properly used, are devices still necessary? (5)
At what stage of the HF syndrome the adaptive sympathetic
activation becomes deleterious and begins playing a critical
role in the progression of the disease? (6) Could preventive
strategies at that stage be more effective? (7) What preventive strategy would be most effective? Prospective intervention studies are needed to reach a verified consensus on how
measurements and modulation of autonomic nervous system
should be incorporated into the diagnosis, risk assessment,
and treatment of patients with HF.
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The Autonomic Nervous System and Heart Failure
Viorel G. Florea and Jay N. Cohn
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Circ Res. 2014;114:1815-1826
doi: 10.1161/CIRCRESAHA.114.302589
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