Chemohypersensitivity and Autonomic Modulation of Venous Capacitance in the Pathophysiology of Acute Decompensated Heart Failure

Abstract

Heart failure is increasing in prevalence around the world, with hospitalization and re-hospitalization as a result of acute decompensated heart failure (ADHF) presenting a huge social and economic burden. The mechanism for this decompensation is not clear. Whilst in some cases it is due to volume expansion, over half of patients with an acute admission for ADHF did not experience an increase in total body weight. This calls into question the current treatment strategy of targeting salt and water retention in ADHF. An alternative hypothesis proposed by Fallick et al. is that an endogenous fluid shift from the splanchnic bed is implicated in ADHF, rather than an exogenous fluid gain. The hypothesis states further that this shift is triggered by an increase in sympathetic tone causing vasoconstriction in the splanchnic bed, a mechanism that can translocate blood rapidly into the effective circulating volume, generating the raised venous pressure and congestion seen in ADHF. This hypothesis encourages a new clinical paradigm which focuses on the underlying mechanisms of congestion, and highlights the importance of fluid redistribution and neurohormonal activation in its pathophysiology. In this article, we consider the concept that ADHF is attributable to episodic sympathetic hyperactivity, resulting in fluid shifts from the splanchnic bed. Chemosensitivity is a pathologic autonomic mechanism associated with mortality in patients with systolic heart failure. Tonic and episodic activity of the peripheral chemoreceptors may underlie the syndrome of acute decompensation without total body salt and water expansion. We suggest in this manuscript that chemosensitivity in response to intermittent hypoxia, such as experienced in sleep disordered breathing, may explain the intermittent sympathetic hyperactivity underlying renal sodium retention and acute volume redistribution from venous storage sites. This hypothesis provides an alternative structure to guide novel diagnostic and treatment strategies for ADHF.

Full text

1 23
Current Heart Failure Reports
ISSN 1546-9530
Curr Heart Fail Rep
DOI 10.1007/s11897-013-0135-y
Chemohypersensitivity and Autonomic
Modulation of Venous Capacitance in the
Pathophysiology of Acute Decompensated
Heart Failure
Amy E.Burchell, Paul A.Sobotka,
Emma C.Hart, Angus K.Nightingale &
Mark E.Dunlap

1 23
Your article is protected by copyright and all
rights are held exclusively by Springer Science
+Business Media New York. This e-offprint is
for personal use only and shall not be self-
archived in electronic repositories. If you
wish to self-archive your work, please use the
accepted author’s version for posting to your
own website or your institution’s repository.
You may further deposit the accepted author’s
version on a funder’s repository at a funder’s
request, provided it is not made publicly
available until 12 months after publication.

PATHOPHYSIOLOGY: NEUROENDOCRINE, VASCULAR, AND METABOLIC FACTORS (SD KATZ, SECTION EDITOR)
Chemohypersensitivity and Autonomic Modulation of Venous
Capacitance in the Pathophysiology of Acute Decompensated
Heart Failure
Amy E. Burchell &Paul A. Sobotka &Emma C. Hart &
Angus K. Nightingale &Mark E. Dunlap
#Springer Science+Business Media New York 2013
Abstract Heart failure is increasing in prevalence around the
world, with hospitalization and re-hospitalization as a result of
acute decompensated heart failure (ADHF) presenting a huge
social and economic burden. The mechanism for this decom-
pensation is not clear. Whilst in some cases it is due to volume
expansion, over half of patients with an acute admission for
ADHF did not experience an increase in total body weight.
This calls into question the current treatment strategy of
targeting salt and water retention in ADHF. An alternative
hypothesis proposed by Fallick et al. is that an endogenous
fluid shift from the splanchnic bed is implicated in ADHF,
rather than an exogenous fluid gain. The hypothesis states
further that this shift is triggered by an increase in sympathetic
tone causing vasoconstriction in the splanchnic bed, a mech-
anism that can translocate blood rapidly into the effective
circulating volume, generating the raised venous pressure
and congestion seen in ADHF. This hypothesis encourages a
new clinical paradigm which focuses on the underlying mech-
anisms of congestion, and highlights the importance of fluid
redistribution and neurohormonal activation in its pathophys-
iology. In this article, we consider the concept that ADHF is
attributable to episodic sympathetic hyperactivity, resulting in
fluid shifts from the splanchnic bed. Chemosensitivity is a path-
ologic autonomic mechanism associated with mortality in
patients with systolic heart failure. Tonic and episodic activity
of the peripheral chemoreceptors may underlie the syndrome of
acute decompensation without total body salt and water expan-
sion. We suggest in this manuscript that chemosensitivity in
response to intermittent hypoxia, such as experienced in sleep
disordered breathing, may explain the intermittent sympathetic
hyperactivity underlying renal sodium retention and acute vol-
ume redistribution from venous storage sites. This hyp othesis
provides an alternative structure to guide novel diagnos-
tic and treatment strategies for ADHF.
Keywords Heart failure .Venous capacitance .Splanchnic .
Chemosensitivity .Chemoreceptor .Sympathetic .Sleep
disordered breathing .Baroreflex
Introduction
Heart failure is increasing in prevalence around the world
[1–3]. This is as a result of improvements in survival from
acute myocardial infarction, the rise in risk factors for both
heart failure with preserved (HFpEF) and reduced (HFrEF)
ejection fraction such as diabetes and hypertension, and the
A. E. Burchell :E. C. Hart :A. K. Nightingale
Bristol CardioNomics Group, Bristol Heart Institute, Bristol Royal
Infirmary, Bristol, BS2 8HW, UK
P. A. Sobotka
Paul A. Sobotka, The Ohio State University, Columbus, OH, UK
M. E. Dunlap (*)
Heart and Vascular Center H350, MetroHealth Campus of Case
Western Reserve University, 2500 MetroHealth Dr.,
Cleveland, OH 44109, USA
e-mail: mdunlap@metrohealth.org
A. E. Burchell
School of Clinical Sciences, University of Bristol,
Research Floor Level 7, Queens Building,
Bristol Royal Infirmary, Marlborough Street,
Bristol, BS2 8HW, UK
E. C. Hart
School of Physiology and Pharmacology,
University of Bristol, Medical Sciences Building,
University Walk, Bristol, BS8 1TD, UK
A. K. Nightingale
Cardiology Department, Bristol Heart Institute,
University Hospitals Bristol NHS Foundation Trust,
Bristol, BS2 8HW, UK
Curr Heart Fail Rep
DOI 10.1007/s11897-013-0135-y
Author's personal copy

aging population demographic [4]. Hospitalization and
re-hospitalization as a result of acute decompensated heart
failure (ADHF) continue to present a huge social and eco-
nomic burden: in the UK, the annual cost of heart failure
accounts for 2 % of the NHS budget, 70 % of this attributed
to inpatient hospital care [2]. Readmissions are common, with
24 % of patients returning to hospital within 12 weeks [5], and
the mortality rates of those patients hospitalized with conges-
tion and renal dysfunction remain high [6••]. Importantly,
neither diuretics nor mechanical ultrafiltration have signifi-
cantly altered the prognosis of congested patients with heart
failure and cardiorenal syndrome [6••]. Under appreciated is
that half of hospitalized patients with heart failure and con-
gestion have not experienced significant increases in total
body weight prior to admission [7], suggesting that total body
volume expansion may not explain the underlying pathology
and raising questions as to the utility and safety of therapy
targeting reduction of total body salt and water.
The traditional paradigm for ADHF is based predominant-
ly on salt and water retention due to a change in diet or
medication, and/or a reduction in cardiac output caused by
triggers such as ischemia, arrhythmia and concurrent infection
[8]. Diuretics are the mainstay of treatment, along with inter-
ventions targeting any precipitating factors of worsening ven-
tricular performance [4,8]. Predicated on the assumption that
weight gain and total body volume expansion underlie epi-
sodes of decompensation, there has been considerable effort
put into tools to facilitate the identification of total body
volume overload, such as meticulous attention to weight
management, salt intake restrictions and generous use of home
diuretics linked to weight changes. Unfortunately, these strat-
egies, even associated with telemonitoring [9••] and home
health care, have not proven routinely valuable.
The CARRESS-HF trial demonstrated that the presence of
worsening renal insufficiency in the presence of clinical con-
gestion was associated with an extraordinary mortality rate,
not different between diuretic and ultrafiltration treatment
strategies [6••]. The mortality rate associated with the cardi-
orenal presentation of congestion may certainly imply a worse
prognosis or, alternatively, that the strategies targeting a
reduction in total body volume are themselves contributing
to rehospitalizations and excess mortality.
An alternative hypothesis proposed by Fallick et al. is that an
endogenous fluid shift from the splanchnic bed is implicated in
ADHF, rather than an exogenous fluid gain [10•]. The hypoth-
esis states further that this shift is triggered by an increase in
sympathetic tone causing vasoconstriction in the splanchnic
bed, a mechanism that can translocate blood rapidly into the
effective circulating volume, generating the raised venous pres-
sure and congestion seen in ADHF. This hypothesis suggests a
new clinical paradigm, which focuses on the underlying
mechanisms of congestion, and highlights the importance
of fluid redistribution and neurohormonal activation in its
pathophysiology [11]. In this article we consider the concept
that ADHF is attributable to episodic sympathetic hyperactivity
resulting in fluid shifts from the splanchnic bed.
Chemosensitivity, a marker of hypersympathetic response
to chemo stimulants such as hypoxia, is associated with in-
creased mortality in patients with systolic heart failure [12,
13]. We hypothesize that sleep disordered breathing, causing
tonic hyperactivity of the chemoreceptors, and episodic hyp-
oxia, causing incremental surges of sympathetic activity,
underlies both chronic renal sodium retention and acute redis-
tribution of volume. This hypothesis therefore provides an
alternative paradigm to guide diagnostic and treatment strate-
gies for ADHF and prevention of recurrence.
Changes in Venous Capacitance: Fluid Shift
as an Explanation for Congestion in Heart Failure
Total intravascular fluid comprises only 5 % of total body
weight (see Fig. 1)[
10•]; 70 % of this intravascular fluid is
located in the venous system [14], with the majority (~60 %)
located in the splanchnic bed, comprising the veins and ven-
ules of the abdominal viscera which feed into the portal vein
Fig. 1 Distribution of water throughout the body. Body composition is
approximately 60 % water by weight, and is distributed in proportion to
the areas of the different boxes shown. Total intravascular fluid comprises
5 % of total body weight, and only 12 % of total body water. TBW
indicates total body water; ICF intracellular fluid; ECF extracellular fluid;
ISF interstitial fluid; IVF intravascular fluid. From Fallick C, et al.,
“Sympathetically mediated changes in capacitance: redistribution of the
venous reservoir as a cause of decompensation,”Circ Heart Fail.2011
Sep;4(5):669–75, with permission from Wolters Kluwer Health
Curr Heart Fail Rep
Author's personal copy

[15]. In comparison to the arterial circulation, venous endo-
thelial function is preserved in heart failure and responsive to
local and systemic factors [16,17]. Veins, 30 times more
compliant than arteries, are exquisitely sympathetically inner-
vated, and thus the large venous capacity and its dynamic
changes in compliance give provision for a significant venous
fluid reservoir [14]. The high level of compliance seen in the
splanchnic capacitance vessels under resting conditions means
that relatively small increases in venous vasomotor tone can
significantly mobilize this reservoir [15].
Fluid held in this venous reservoir does not form part of the
effective circulating volume which lies predominantly within
the arterial circulation and directly relates to central venous
pressure and preload [18]. As much as 800 ml of whole blood
may be moved from splanchnic reservoir into the effective
circulation following sympathetic-mediated reduction of
splanchnic venous capacitance [19]. Indeed, it is this rapid
mobilization that protects against orthostasis and provides a
preload boost to cardiac output in response to standing, exer-
cise, stress, and trauma. However, sympathetically mediated
emptying of this reservoir in a patient with either HFpEF or
HFrEF would be expected to raise pulmonary pressures and
contribute to extravasation of fluid into the lungs or dependent
interstitial tissues.
A rapid shift in fluid caused by vasoconstriction in venous
capacitance vessels would mirror the clinical course seen in
ADHF. This process does not require the addition of exogenous
fluid. Moreover, the renal-based salt and water accumulation is
likely a minor contributor to acute expansion of effective
arterial volume, because incremental exogenous salt and water
accumulation distributes rapidly throughout all of the body’s
fluid compartments, resulting in a relatively small contribution
to increases of effective arterial circulating volume. The auto-
transfusion of whole blood from the venous capacitance reser-
voirs would both immediately and significantly increase
effective arterial volume. Diastolic ventricular interaction is
another mechanism whereby shifts to the central compartment
may destabilise cardiac function [20]. Thus endogenous fluid
shift provides a mechanism for ADHF without significant
weight gain, manifested by an increase in effective circulating
volume and pulmonary congestion (Fig. 2).
Autonomic Dysfunction in Heart Failure
Autonomic imbalance including raised sympathetic tone is
present in HF [21], as well as in several other chronic
conditions [22]. The relationship between excessive sympa-
thetic nerve activity (SNA) and the development and pro-
gression of hypertension [23], insulin resistance, chronic
renal disease [24–26] and heart failure [27,28] has been
demonstrated in both preclinical and human experiments
[29,30]. Chronic elevation in SNA contributes to
circulatory pathology through numerous mechanisms, in-
cluding: reduction of venous capacitance, increased arterial
resistance, reduced arterial compliance and increased pulse
wave velocity (an estimate of arterial stiffness) [31]. In
addition, increased aortic stiffness and peripheral vascular
resistance contribute to renal microvascular damage [32].
Elevated SNA has an adverse effect on the heart (hypertro-
phy, arrhythmias and ischaemia), vasculature (vasoconstric-
tion, increased vascular resistance, hypertension and
atherosclerosis) and kidney (increased renin release, sodium
retention and renal vascular resistance); all of which have a
significant negative impact in HF [33•]. Tonic and episodic
increases in SNA are both driven by alterations in the
feedback received from key autonomic reflexes.
Heart failure patients demonstrate increased sensitivity of
the peripheral chemoreceptors [34,35], and have exaggerated
increases in respiratory drive and sympathetically mediated
reflex increases in BP when stimulated with hypoxia [36–38].
The peripheral chemoreceptors respond to acute hypoxia,
increased arterial carbon dioxide tension (pCO2), acidic pH
and hypoperfusion.
In a rabbit model of pacing-induced heart failure, Schultz
demonstrated that HF rabbits have higher resting levels of renal
sympathetic nerve activity (RSNA), a marker of sympathetic
Fig. 2 The more conventional concepts leading to congestion are
shown on the right, with renal and dietary mechanisms leading to
sodium and water retention causing increased effective circulatory
volume, mechanisms that occur relatively slowly, over a period of days
to weeks. Depicted on the left are the dynamic processes that can occur
rapidly and involve a relatively minor increase in sympathetic outflow
acting on the splanchnic reservoir of blood resulting in a shift of
volume from the capacitance vessels into the systemic circulation,
increasing effective circulatory volume and causing congestion. From
Fallick C, et al., “Sympathetically mediated changes in capacitance:
redistribution of the venous reservoir as a cause of decompensation,”
Circ Heart Fail. 2011 Sep;4(5):669–75, with permission from Wolters
Kluwer Health
Curr Heart Fail Rep
Author's personal copy

hyperactivity, and increased peripheral chemoreceptor sensitiv-
ity (with a significant increase in RSNA and minute ventilation
in response to hypoxia) when compared with animals without
heart failure [39•]. Inhalation of 100 % oxygen resulted in
simultaneous inhibition of carotid body activity and reduction
of RSNA, proving the neuro-link between chemosensitivity
and sympathetic activation, in particular renal efferent sympa-
thetic activity. Underlying this increase in peripheral chemo-
reflex sensitivity may be alterations in blood flow to the carotid
body in heart failure, inflammation or periodic episodes of
hypoxia that condition the carotid body to higher tonic activity.
In spontaneously hypertensive rats (SHR), which exhibit
elevated sympatho-excitatory responses to peripheral chemo-
receptor stimulation relative to normotensive control animals,
the peripheral chemoreceptors exert a tonic excitatory influence
on sympathetic activity [40••,41]. Denervation of the carotid
body in these rats resulted in a reduction in BP and sympathetic
vasomotor tone, an effect not seen in normotensive rats [40••].
Critically, carotid body activity directly inhibits the protective
activity of the mechano-baroreceptors [42]. Thus, excess tonic
and episodic carotid body activity may underlie the profound
autonomic imbalance observed in heart failure.
Peripheral chemoreceptor hypersensitivity has been shown
to be an independent indicator of poor prognosis in ambulatory
patients with HF [12]. This chemo-hypersensitivity also acts to
drive the elevated SNA seen in this population; exposure to a
hypoxic stimulus causes a greater increase in muscle SNA in
HF patients than in controls [43]. In heart failure patients, there
is a deleterious relationship seen between these alterations in
baroreflex and peripheral chemoreflex response; chemo-
hypersensitivity inhibits baroreflex gain, and impaired barore-
flex activity fails to attenuate the peripheral chemoreceptor
stimulation of SNA [42]. Despas et al.. have demonstrated this
interaction in HF patients [44••]; baseline muscle sympathetic
nerve activity (MSNA) was elevated and sympathetic barore-
flex function impaired, in HF patients with high peripheral
chemosensitivity. Administration of 100 % oxygen resulted in
a significant decrease in MSNA and an increase in sympathetic
baroreflex gain in HF patients with chemo-hypersensitivity, but
not in HF patients with normal chemosensitivity. They
hypothesise that the blunted baroreflex function and raised
MSNA in HF patients with high chemosensitivity may explain
the poor prognostic implications of peripheral chemoreflex
hypersensitivity.
Sympathetic Overdrive and Chemoreflex
Hypersensitivity in Sleep Disordered Breathing
and ADHF
The intermittent hypoxia seen in heart failure and as an inherent
component of either central or obstructive sleep apnoea is
sufficient to increase chemosensitivity [36,45]. However,
excessive gain in this reflex can have a negative effect by
triggering excessive ventilation in response to exercise and by
increasing sympathetic tone. Similarly, the sleep disordered
breathing seen in heart failure may be attributed to sympathetic
hyperactivity; central apnea as a consequence of underlying
hyperpnea, and obstructive apnea related to orthopneic conges-
tion of the oral airway.
Narckiewicz et al. have demonstrated that patients with
OSA have elevated MSNA, and that offloading of the
peripheral chemoreceptors by the administration of 100 %
oxygen causes a reduction in MSNA and mean arterial
pressure [45]. These findings are consistent with tonic acti-
vation of the peripheral chemoreflex in OSA, a process that
is likely to be driven by chronic exposure to intermittent
hypoxia. Cutler et al. tested this hypothesis in healthy vol-
unteers, in whom exposure to intermittent hypoxia altered
the chemoreflex control of MSNA [36].
Patients with heart failure have a high prevalence of sleep
disordered breathing (SDB) consisting of both central and
obstructive sleep apnoea, ranging from 45–82 % of patients
studied [46,47]. Untreated SDB can worsen ADHF and delay
recovery by increasing inflammation and oxidative stress,
increasing blood pressure, and promoting arrhythmias [48].
OSA, with upper airway collapse and concurrent marked
negativity of intrathoracic pressure, causes increased cardiac
afterload and work simultaneous to arterial oxygen desatu-
ration and sympathetic hyperactivity and tone. Not surpris-
ingly, OSA is associated with increased cardiovascular risk,
and may be particularly detrimental in patients with heart
failure [49]. Data from the Sleep Heart Health Study indi-
cates that OSA is an independent risk factor for self-reported
heart failure [50], and untreated OSA is an independent
predictor for mortality in HF patients [51]. Treating OSA
in patients with heart failure using continuous positive air-
way pressure (CPAP) to splint the upper airways can result
in a decrease in heart rate, blood pressure, left ventricular
end-systolic dimension and sympathetic nerve activity, with
associated improvement in left ventricular ejection fraction
[52] and quality of life [53]. Observational studies also
report an improvement in hospitalisation-free survival and
mortality following treatment with CPAP in patients with
OSA and HF, but large scale randomized controlled trials
are still required to confirm this finding [54].
Central sleep apnoea (CSA) describes patients with repet-
itive nocturnal central hypopneas, and is associated with an
increased risk of arrhythmia and a higher cardiac mortality in
patients with HF [47]. Periodic breathing (PB) is a related
phenomenon observed both during sleep and during activities
of daily living. When PB is associated with apnoeas, it is
better known as the centrally disordered breathing pattern of
Cheyne-Stokes respiration (CSR). CSR has been shown to
decrease oxygen saturation and increase MSNA in patients
with HF [55].
Curr Heart Fail Rep
Author's personal copy

We suggest that the intermittent hypoxia in patients with
heart failure is sufficient to initiate a cascade of events stem-
ming from the hypoxia induced chemosensitivity, including
sympathetic storm, resulting in changes in splanchnic capaci-
tance leading to acute congestion and so triggering ADHF.
HF patients commonly exhibit disordered breathing pat-
terns with episodes of apnoea or hypopnea causing brief
periods of hypoxia. Less well appreciated is the critical role
of intermittent hypoxia as an underlying cause of chemo-
sensitivity. The intermittent hypoxia is sufficient to cause
peripheral chemoreceptor hypersensitivity resulting in an
exaggerated sympathetic response when activated by hyp-
oxemia. The resulting SNA storm can cause venoconstric-
tion in the splanchnic capacitance bed, displacing fluid into
the effective circulation. This fluid shift increases the effec-
tive circulating volume, with an associated rise in right atrial
pressure (preload). The problem is compounded by the fact
that HF patients have tonic elevation of SNA with impaired
baroreceptor sensitivity [56]. Consequently, they are less able
to buffer any volume and blood pressure changes or changes in
renal sympathetic nerve activity [57]. Raised sympathetic tone
will also increase peripheral vascular resistance (afterload) and
heart rate, and therefore myocardial work. These summative
factors, occurring over a relatively short time scale, can explain
the rapid development of pulmonary oedema without weight
gain seen in ADHF. Once activated, this mechanism self-
propagates, with the pulmonary oedema exacerbating fluctua-
tions in hypoxia, and chemohypersensitivity increasing the
gain in the hypoxia/SNA/ventilatory feedback loop. Thus,
intermittent hypoxia is sufficient to cause the tonic increases
in chemosensitivity underlying the autonomic imbalances seen
in HF, and hypoxic mediated sympathetic storms trigger the
shifts in volume seen in ADHF that occur without weight gain.
Conclusions
Impact: Identification of Patients at Risk of ADHF
This hypothesis changes the paradigm for identification and
treatment of patients at risk for ADHF. Previous ‘early-warn-
ing’systems have focussed on monitoring patients for weight
gain, including remote telemonitoring techniques. These have
notprovedtobesuccessful,possiblyexplainedbythefactthat
half of patients do not have a rise in weight prior to presentation
with ADHF. Devices designed to monitor changes in right atrial
pressure (HOMEOSTASIS) [58], pulmonary arterial pressure
(CHAMPION) [59•], intrathoracic impedance (FAST,
COMPASS-HF) [60•,61] or changes in blood flow in a vascu-
lar bed, may have a role to play, although clinical results have
been variable [60•]. Rises in pressure in the absence of weight
gain suggest predominant capacitance changes, whereas rises in
pressure associated with weight gain will reflect renal based salt
and water retention and probable capacitance changes.
Therefore, identification of patients with chemohypersensitivity
(exaggerated ventilatory response on exposure to hypoxic/
hyperoxic conditions) or those with concurrent HF and periodic
or sleep disordered breathing (overnight oximetry screening,
full polysomnography), defines a high-risk group for ADHF
and may explain the half who present without weight gain.
Treatment of the decompensation and prevention of recurrent
ADHF episodes would then focus on fluid redistribution, and
therapies targeting the sympathetic nervous system.
Importantly, therapy that reduces chemosensitivity may result
in acute benefit and prevention of ADHF recurrence. Moreover,
the identification of these patients may prevent iatrogenic ill-
ness associated with overzealous volume reduction [62].
Impact: Management and Prevention of ADHF
Defining the autonomic phenotype for an individual patient
should help to guide clinical practice. Changing our thinking
to incorporate strategies that target fluid shifts as well as fluid
gain may bring acute and chronic benefits. Treatment for
ADHF with congestion will then focus on the importance of
capacitance underlying congestion, and the prevention of
ADHF will target identification of those patients with elevated
sympathetic tone and chemosensitivity. It is assumed that all
patients with HF are receiving therapeutic beta blockade, so
pharmacologic strategies are limited to consideration of addi-
tional alpha blockade (and potentially beta-2 agonists) to
prevent sympathetically mediated splanchnic redistribution.
In addition, identifying sleep disordered breathing, adrenergic
excess or chemosensitivity in these patients may guide spe-
cific prevention therapy. Prevention of hypoxemia with sleep
support in those with sleep disordered breathing may reduce
chemosensitivity and ameliorate sympathetic hyperactivity.
Alternatively, direct modulation of the autonomic nervous
system through the use of device-based therapies such as renal
sympathetic denervation, carotid body modulation, vagal
nerve stimulation or carotid sinus stimulation could attend to
the underlying pathology.
Conflict of Interest Amy E. Burchell declares she has no conflict of
interest.
Paul A. Sobotka has received compensation for serving as Chief
Medical Officer of Cibiem, Inc.; compensation for serving as a consultant
for Medtronic, Inc.; payment for lectures including service on speakers
bureaus from Medtronic, Inc.; compensation for patents from Cibiem, Inc.
(device to modulate the carotid body) and Medtronic, Inc. (applications
related to renal denervation); royalties from Medtronic, Inc. for the
Symplicity Renal Denervation System; compensatory stock options from
Cibiem, Inc., Rox, Inc., and Ardelyx, Inc. for services rendered; reimburse-
ment for travel/accommodations/meeting expenses from Medtronic, Inc.
Emma C. Hart has received compensation from Cibiem, Inc. for
serving as a consultant in a clinical trial associated with developing a
new intervention for improving prognosis of heart failure.
Curr Heart Fail Rep
Author's personal copy

Angus K. Nightingale has received compensation from Novartis for
serving as a member of the United Kingdom Advisory Board on
Serelaxin; supported by a grant from Cibiem, Inc. for a study on carotid
body modulation in hypertension; payment for lectures including ser-
vice on speakers bureaus from Servier; reimbursement for travel/ac-
commodations/meeting expenses from Novartis and Servier; payment
to Bristol Heart Institute from Medtronic, Inc. for training of physicians
and other staff in renal denervation.
Mark E. Dunlap has received compensation for serving as a consultant
for Medtronic/Ardian, Inc.; supported by grants from BioControl
Medical, Inc. and Medtronic/Ardian, Inc.; payment for lectures including
service on speakers bureaus from BioControl Medical, Inc.
References
Papers of particular interest, published recently, have been
highlighted as:
•Of importance
•• Of major importance
1. McCullough PA, Philbin EF, Spertus JA, Kaatz S, Sandberg KR,
Weaver WD. Confirmation of a heart failure epidemic: findings
from the Resource Utilization Among Congestive Heart Failure
(REACH) study. J Am Coll Cardiol. 2002;39(1):60–9.
2. NICE. CG108 Chronic heart failure: NICE guideline [Internet].
NICE. [cited 2013 Jan 14]. Available from: http://www.nice.org.uk/
3. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD,
Borden WB, et al. Heart disease and stroke statistics–2012 update:
a report from the American Heart Association. Circulation.
2012;125(1):e2–220.
4. Greenberg B. Acute decompensated heart failure - treatments and
challenges. Circ J. 2012;76(3):532–43.
5. Cleland JGF, Swedberg K, Follath F, Komajda M, Cohen-Solal A,
Aguilar JC, et al. The EuroHeart Failure survey programme–a survey
on the quality of care among patients with heart failure in Europe. Part 1:
patient characteristics and diagnosis. Eur Heart J. 2003;24(5):442–63.
6. •• Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM,
Bull DA, et al. Ultrafiltration in decompensated heart failure with
cardiorenal syndrome. N Engl J Med. 2012;367(24):2296–304.
The CARRESS-HF trial randomised patients with ADHF and
cardiorenal syndrome to treatment with stepped pharmacological
(diuretic) therapy or ultrafiltration. The patients who received
ultrafiltration had a similar weight loss to those treated with
diuretics, but a significantly greater deterioration in renal function
and rate of adverse events.
7. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM.
Patterns of weight change preceding hospitalization for heart fail-
ure. Circulation. 2007;116(14):1549–54.
8. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS,
Ganiats TG, et al. 2009 focused update incorporated into the ACC/
AHA 2005 Guidelines for the Diagnosis and Management of Heart
Failure in Adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines: developed in collaboration with the International
Society for Heart and Lung Transplantation. Circulation. 2009;119
(14):e391–479.
9. •• Lyngå P, Persson H, Hägg-Martinell A, Hägglund E, Hagerman I,
Langius-Eklöf A, et al. Weight monitoring in patients with severe
heart failure (WISH). A randomized controlled trial. Eur J Heart Fail.
2012;14(4):438–44. Patients with severe heart failure were rando-
mised to either self-directed weight monitoring or intensive weight
measurement using an electronic scale with the results transmitted to
a heart failure centre. Intensive weight monitoring did not reduce
hospitalisations or death in these patients.
10. •Fallick C, Sobotka PA, Dunlap ME. Sympathetically mediated
changes in capacitance: redistribution of the venous reservoir as a
cause of decompensation. Circ Heart Fail. 2011;4(5):669–75. This
review article puts forward the hypothesis that the congestion seen
in ADHF is predominantly due to a rapid shift in fluid from
splanchnic venous capacitance beds, and that this mechanism is
driven by sympathetic over-activity.
11. Cotter G, Metra M, Milo-Cotter O, Dittrich HC, Gheorghiade M.
Fluid overload in acute heart failure–re-distribution and other
mechanisms beyond fluid accumulation. Eur J Heart Fail.
2008;10(2):165–9.
12. Ponikowski P, Chua TP, Anker SD, Francis DP, Doehner W,
Banasiak W, et al. Peripheral chemoreceptor hypersensitivity: an
ominous sign in patients with chronic heart failure. Circulation.
2001;104(5):544–9.
13. Giannoni A, Emdin M, Bramanti F, Iudice G, Francis DP, Barsotti
A, et al. Combined increased chemosensitivity to hypoxia and
hypercapnia as a prognosticator in heart failure. J Am Coll
Cardiol. 2009;53(21):1975–80.
14. Gelman S. Venous function and central venous pressure: a physi-
ologic story. Anesthesiology. 2008;108(4):735–48.
15. Fink GD, Arthur C. Corcoran Memorial Lecture. Sympathetic
activity, vascular capacitance, and long-term regulation of arterial
pressure. Hypertension. 2009;53(2):307–12.
16. Nightingale AK, Blackman DJ, Ellis GR, Schmitt M, Morris-
Thurgood JA, Jones EA, et al. Preservation of venous endothelial
function in the forearm venous capacitance bed of patients with
chronic heart failure despite arterial endothelial dysfunction. J Am
Coll Cardiol. 2001;37(4):1062–8.
17. Schmitt M, Broadley AJM, Nightingale AK, Payne N, Gunaruwan
P, Taylor J, et al. Atrial natriuretic peptide regulates regional
vascular volume and venous tone in humans. Arterioscler
Thromb Vasc Biol. 2003;23(10):1833–8.
18. Brunner MJ, Shoukas AA, MacAnespie CL. The effect of the
carotid sinus baroreceptor reflex on blood flow and volume redis-
tribution in the total systemic vascular bed of the dog. Circ Res.
1981;48(2):274–85.
19. Gelman S, Mushlin PS. Catecholamine-induced changes in the
splanchnic circulation affecting systemic hemodynamics.
Anesthesiology. 2004;100(2):434–9.
20. Atherton JJ, Thomson HL, Moore TD, Wright KN, Muehle GW,
Fitzpatrick LE, et al. Diastolic ventricular interaction: a possible
mechanism for abnormal vascular responses during volume
unloading in heart failure. Circulation. 1997;96(12):4273–9.
21. Kishi T. Heart failure as an autonomic nervous system dysfunction.
J Cardiol. 2012;59(2):117–22.
22. Parati G, Esler M. The human sympathetic nervous system: its
relevance in hypertension and heart failure. Eur Heart J. 2012;33
(9):1058–66.
23. Goldstein DS. Plasma catecholamines and essential hypertension.
An analytical review. Hypertension. 1983;5(1):86–99.
24. Grassi G, Quarti-Trevano F, Seravalle G, Arenare F, Volpe M,
Furiani S, et al. Early sympathetic activation in the initial clinical
stages of chronic renal failure. Hypertension. 2011;57(4):846–51.
25. Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H,
Kisters K, et al. Sympathetic nerve activity in end-stage renal
disease. Circulation. 2002;106(15):1974–9.
26. Penne EL, Neumann J, Klein IH, Oey PL, Bots ML, Blankestijn
PJ. Sympathetic hyperactivity and clinical outcome in chronic
kidney disease patients during standard treatment. J Nephrol.
2009;22(2):208–15.
27. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et
al. Plasma norepinephrine as a guide to prognosis in patients with
Curr Heart Fail Rep
Author's personal copy

chronic congestive heart failure. N Engl J Med. 1984;311(13):819–
23.
28. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner
PI. Norepinephrine spillover to plasma in patients with congestive
heart failure: evidence of increased overall and cardiorenal sym-
pathetic nervous activity. Circulation. 1986;73(4):615–21.
29. Schlaich MP, Hering D, Sobotka P, Krum H, Lambert GW,
Lambert E, et al. Effects of renal denervation on sympathetic
activation, blood pressure, and glucose metabolism in patients
with resistant hypertension. Front Physiol. 2012;3:10.
30. Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum
H. Sympatho-renal axis in chronic disease. Clin Res Cardiol.
2011;100(12):1049–57.
31. Brandt MC, Reda S, Mahfoud F, Lenski M, Böhm M, Hoppe UC.
Effects of renal sympathetic denervation on arterial stiffness and
central hemodynamics in patients with resistant hypertension. J
Am Coll Cardiol. 2012;60(19):1956–65.
32. Hashimoto J, Ito S. Central pulse pressure and aortic stiffness deter-
mine renal hemodynamics: pathophysiological implication for micro-
albuminuria in hypertension. Hypertension. 2011;58(5):839–46.
33. •Paton JFR, Sobotka PA, Fudim M, Engleman ZJ, Hart ECJ,
McBryde FD, et al. The Carotid Body as a Therapeutic Target
for the Treatment of Sympathetically Mediated Diseases.
Hypertension. 2013;61(1):5–13. This review article focuses on
the pathological effects of chemo-hypersensitivity in sympatheti-
cally mediated diseases, and considers the potential clinical ther-
apeutic role of carotid body removal.
34. Narkiewicz K, Pesek CA, Van de Borne PJ, Kato M, Somers VK.
Enhanced sympathetic and ventilatory responses to central chemo-
reflex activation in heart failure. Circulation. 1999;100(3):262–7.
35. Chua TP, Ponikowski P, Webb-Peploe K, Harrington D, Anker SD,
Piepoli M, et al. Clinical characteristics of chronic heart failure
patients with an augmented peripheral chemoreflex. Eur Heart J.
1997;18(3):480–6.
36. Cutler MJ, Swift NM, Keller DM, Wasmund WL, Burk JR, Smith
ML. Periods of intermittent hypoxic apnea can alter chemoreflex
control of sympathetic nerve activity in humans. Am J Physiol
Heart Circ Physiol. 2004;287(5):H2054–60.
37. Leuenberger UA, Brubaker D, Quraishi S, Hogeman CS,
Imadojemu VA, Gray KS. Effects of intermittent hypoxia on
sympathetic activity and blood pressure in humans. Auton
Neurosci. 2005;121(1–2):87–93.
38. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic
nerve responses to hypoxia in borderline hypertensive subjects.
Hypertension. 1988;11(6 Pt 2):608–12.
39. •Ding Y, Li Y-L, Schultz HD. Role of blood flow in carotid body
chemoreflex function in heart failure. J Physiol (Lond). 2011;589
(Pt 1):245–58. In this study rabbits with pacing-induced heart
failure were seen to have a reduction in carotid body blood flow.
When carotid body blood was reduced to a similar degree in non-
paced rabbits by carotid artery occlusion, a similar increase in
peripheral chemoreflex sensitivity was seen; the chemo-
hypersensitivity seen in chronic heart failure is therefore likely
due to poor carotid body perfusion.
40. •• Abdala AP, McBryde FD, Marina N, Hendy EB, Engelman
ZJ, Fudim M, et al. Hypertension is critically dependent on the
carotid body input in the spontaneously hypertensive rat. J
Physiol (Lond). 2012;590(Pt 17):4269–77. Carotid body dener-
vation in spontaneously hypertensive rats resulted in a reduc-
tion in the development and maintenance of hypertension, with
an associated reduction in sympathetic vasomotor tone and an
improvement in baroreflex sensitivity. These findings are con-
sistent with the knowledge that chemoreceptor activation causes
a reflex increase in sympathetic tone and, importantly, demonstrate
that abolition of this sensory input can reverse autonomic pathology
such as hypertension.
41. Siński M, Lewandowski J, Przybylski J, Bidiuk J, Abramczyk P,
Ciarka A, et al. Tonic activity of carotid body chemoreceptors
contributes to the increased sympathetic drive in essential hyper-
tension. Hypertens Res. 2012;35(5):487–91.
42. Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Peploe K,
Harrington D, et al. Augmented peripheral chemosensitivity as a
potential input to baroreflex impairment and autonomic imbalance
in chronic heart failure. Circulation. 1997;96(8):2586–94.
43. Alves MJ, dos Santos MR, Nobre TS, Martinez DG, Pereira
Barretto AC, Brum PC, et al. Mechanisms of blunted muscle
vasodilation during peripheral chemoreceptor stimulation in heart
failure patients. Hypertension. 2012;60(3):669–76.
44. •• Despas F, Lambert E, Vaccaro A, Labrunee M, Franchitto N,
Lebrin M, et al. Peripheral chemoreflex activation contributes to
sympathetic baroreflex impairment in chronic heart failure. J
Hypertens. 2012;30(4):753–60. This trial looked at muscle sympa-
thetic nerve activity (MSNA) and baroreflex sensitivity in patients
with chronic heart failure. Only in those patients with chemohyper-
sensitivity did offloading of the chemoreceptors with 100 % oxygen
result in a significant decrease in MSNA and an increase in sympa-
thetic baroreflex gain. The blunted baroreflex and raised sympathetic
tone may explain the worse prognosis seen in heart failure patients
with peripheral chemoreflex hypersensitivity.
45. Narkiewicz K, Van de Borne PJ, Montano N, Dyken ME, Phillips
BG, Somers VK. Contribution of tonic chemoreflex activation to
sympathetic activity and blood pressure in patients with obstruc-
tive sleep apnea. Circulation. 1998;97(10):943–5.
46. Vazir A, Hastings PC, Dayer M, McIntyre HF, Henein MY, Poole-
Wilson PA, et al. A high prevalence of sleep disordered breathing in
men with mild symptomatic chronic heart failure due to left ventric-
ular systolic dysfunction. Eur J Heart Fail. 2007;9(3):243–50.
47. Lanfranchi PA, Somers VK. Sleep-disordered breathing in heart
failure: characteristics and implications. Respir Physiol Neurobiol.
2003;136(2–3):153–65.
48. Jelic S, Le Jemtel TH. Sleep-disordered breathing in acute decom-
pensated heart failure. Curr Heart Fail Rep. 2009;6(3):169–75.
49. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras
A, et al. Sleep apnea and cardiovascular disease: an American
Heart Association/american College Of Cardiology Foundation
Scientific Statement from the American Heart Association
Council for High Blood Pressure Research Professional
Education Committee, Council on Clinical Cardiology, Stroke
Council, and Council On Cardiovascular Nursing. In collaboration
with the National Heart, Lung, and Blood Institute National Center
on Sleep Disorders Research (National Institutes of Health).
Circulation. 2008;118(10):1080–111.
50. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto
FJ, et al. Sleep-disordered breathing and cardiovascular disease:
cross-sectional results of the Sleep Heart Health Study. Am J
Respir Crit Care Med. 2001;163(1):19–25.
51. Wang H, Parker JD, Newton GE, Floras JS, Mak S, Chiu K-L, et
al. Influence of obstructive sleep apnea on mortality in patients
with heart failure. J Am Coll Cardiol. 2007;49(15):1625–31.
52. Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al.
Cardiovascular effects of continuous positive airway pressure in
patients with heart failure and obstructive sleep apnea. N Engl J
Med. 2003;348(13):1233–41.
53. Mansfield DR, Gollogly NC, Kaye DM, Richardson M,
Bergin P, Naughton MT. Controlled trial of continuous posi-
tive airway pressure in obstructive sleep apnea and heart
failure. Am J Respir Crit Care Med. 2004;169(3):361–6.
54. Kasai T. Sleep apnea and heart failure. J Cardiol. 2012;60(2):78–85.
55. Van de Borne P, Oren R, Abouassaly C, Anderson E, Somers VK.
Effect of Cheyne-Stokes respiration on muscle sympathetic nerve
activity in severe congestive heart failure secondary to ischemic or
idiopathic dilated cardiomyopathy. Am J Cardiol. 1998;81(4):432–6.
Curr Heart Fail Rep
Author's personal copy

56. Grassi G, Seravalle G, Cattaneo BM, Lanfranchi A, Vailati S,
Giannattasio C, et al. Sympathetic activation and loss of reflex
sympathetic control in mild congestive heart failure. Circulation.
1995;92(11):3206–11.
57. Al-Hesayen A, Parker JD. Impaired baroreceptor control of renal
sympathetic activity in human chronic heart failure. Circulation.
2004;109(23):2862–5.
58. Ritzema J, Troughton R, Melton I, Crozier I, Doughty R, Krum H, et
al. Physician-directed patient self-management of left atrial pressure
in advanced chronic heart failure. Circulation. 2010;121(9):1086–95.
59. •Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo
MR, Stevenson LW, et al. Wireless pulmonary artery haemody-
namic monitoring in chronic heart failure: a randomised controlled
trial. Lancet. 2011;377(9766):658–66. In the CHAMPION study
daily measurement of pulmonary artery pressures using an im-
plantable device resulted in a significant reduction in heart failure-
related hospitalisations.
60. •Bourge RC, Abraham WT, Adamson PB, Aaron MF, Aranda
Jr JM, Magalski A, et al. Randomized controlled trial of an
implantable continuous hemodynamic monitor in patients with
advanced heart failure: the COMPASS-HF study. J Am Coll
Cardiol. 2008;51(11):1073–9. In the COMPASS-HF study re-
mote haemodynamic measurements (right ventricular pressure,
heart rate, body temperature, patient activity and estimated
pulmonary arterial diastolic pressure) using an implantable
Chronicle device did not significantly reduce heart failure-
related events.
61. Abraham WT, Compton S, Haas G, Foreman B, Canby RC, Fishel
R, et al. Intrathoracic impedance vs daily weight monitoring for
predicting worsening heart failure events: results of the Fluid
Accumulation Status Trial (FAST). Congest Heart Fail. 2011;17
(2):51–5.
62. Dunlap ME, Sobotka PA. Efficiently doing the wrong thing. J Am
Coll Cardiol. 2012;60(17):1713. author reply p. 1713–1714.
Curr Heart Fail Rep
Author's personal copy