Anda di halaman 1dari 8

Curr Cardiol Rep

DOI 10.1007/s11886-012-0258-x

CONGESTIVE HEART FAILURE (J LINDENFELD, SECTION EDITOR)

The Role of Renal Denervation in the Treatment


of Heart Failure
Paul A. Sobotka & Henry Krum & Michael Bhm &
Darrel P. Francis & Markus P. Schlaich

# Springer Science+Business Media, LLC 2012

Abstract The heart and kidney interact in terms of hemo- angiotensin II that is mediated in part by renal sympathetic
dynamics and neurohumoral regulatory mechanisms, and activation has an effect on the central nervous system to
this helps to maintain circulatory homeostasis under normal further increase global sympathetic tone. Renal sympathetic
conditions. However, the normal regulatory mechanisms activity can be assessed clinically by renal norepinephrine
become inappropriate in the setting of congestive heart spillover, and an increase in renal norepinephrine spillover
failure (CHF), and significant renal dysfunction often devel- in CHF predicts reduced survival. In addition to efferent
ops in CHF patients. Activation of renal sympathetic effer- sympathetic activation, activation of renal sensory nerves in
ent nerves causes renin release, sodium and water retention, CHF may cause a reflex increase in sympathetic tone that
and reduced renal blood flow, all hallmarks of the renal contributes to elevated peripheral vascular resistance and
manifestations of CHF. An increase in plasma levels of vascular remodeling as well as left ventricular remodeling
and dysfunction. In animal models of heart failure, surgical
renal denervation has been shown to improve both renal and
ventricular function. Although surgical renal denervation
P. A. Sobotka
Medtronic, Vascular, has long been known to lower blood pressure and improve
Santa Rosa, CA, USA survival in patients with hypertension, the invasive nature of
this approach and its associated complications has limited its
H. Krum
appeal. However, a novel catheter-based device has recently
Centre of Cardiovascular Research and Education in Therapeutics,
Department of Epidemiology and Preventive Medicine, been introduced that specifically interrupts both efferent and
Monash University, afferent renal nerves, and there is significant interest in the
Melbourne, VIC, Australia use of this device to treat both hypertension and CHF.
Several ongoing clinical trials are investigating the safety
M. Bhm
Klinik fr Innere Medizin III, Universittsklinikum des Saarlandes, and efficacy of renal denervation in patients with CHF.
Homburg/Saar, Germany
Keywords Norepinephrine . Sympathetic . Angiotensin .
D. P. Francis
Kidney . Renal blood flow . Clinical trial . Renal denervation .
International Centre for Circulatory Health,
St Marys Hospital and Imperial College, Heart failure
59-61 North Wharf Road,
W2 1LA, London, UK
Introduction
M. P. Schlaich
Baker IDI Heart and Diabetes Institute,
Melbourne, VIC, Australia Renal dysfunction plays a seminal role in the development
and progression of congestive heart failure (CHF). The
P. A. Sobotka (*)
2015 Marywood Lane, West Street,
majority of patients hospitalized for acute decompensated
Paul, MN 55118, USA CHF have been shown to have some degree of renal dys-
e-mail: paul.a.sobotka@medtronic.com function [1]. The renal nerves are thought to play an
Curr Cardiol Rep

important role in the renal dysfunction that occurs in CHF, findings suggest that there exists a level of efferent renal
since renal sympathetic efferent activation causes renin sympathetic nerve activity that can directly affect renal
release, sodium and water retention, and reduced renal tubular sodium and water reabsorption independent of
blood flow (RBF) [2, 3]. Renal sympathetic activation changes in GFR, RBF, or the intrarenal distribution of blood
has important prognostic value in CHF patients, since flow. When the renal sympathetic nerves are directly stim-
increased renal norepinephrine spillover predicts reduced ulated at a frequency that is subthreshold for renal vasocon-
survival [4]. In addition to efferent sympathetic activation, striction, there is a reversible decrease in urinary sodium
activation of renal sensory nerves in CHF may cause a excretion without a change in renal perfusion pressure,
reflex increase in sympathetic tone that contributes to the GFR, RBF, or the intrarenal distribution of blood flow
progression of CHF [5]. (Table 1) [10]. This direct antinatriuretic effect of sympa-
Renal denervation has long been known to lower blood thetic activation appears to be mediated by 1-adrenergic
pressure and improve survival in patients with hypertension receptors.
[6], but the risks associated with the open surgery required In addition to neural influences on blood flow and tubular
to denervate the kidneys have limited its appeal. In the last secretion of sodium, the renal sympathetic nerves also
2 years, a novel catheter-based device has become available stimulate the release of renin from juxtaglomerular cells
that specifically interrupts both efferent and afferent renal (Table 1), which is thought to be meditated by activation
nerves [7], which might become an avenue of therapy for of 1-adrenergic receptors with a subsequent increase in
both hypertension and CHF. This review summarizes the cAMP [11, 12]. This mechanism of renin release is inde-
current information on the role of efferent and afferent renal pendent from but complementary to the release of renin
nerves in the pathogenesis and progression of CHF, and mediated by the vascular baroreceptor mechanism in the
describes ongoing clinical trials that will evaluate the safety afferent arterioles of the juxtaglomerular apparatus and the
and efficacy of catheter-based renal denervation in well- tubular macula densa mechanism that responds to the sodi-
defined CHF populations. um load in the distal tubule [12]. In addition, renal sympa-
thetic tone appears to modulate the expression of renin
mRNA in the kidney [13].
Functional Anatomy of the Renal Nerves Although efferent sympathetic activity mediates changes
in renal function, the kidney also has an extensive network
The efferent renal sympathetic nerves modulate renal func- of afferent unmyelinated fibers that transmit important sen-
tion through the release of local neurotransmitters. Although sory information to the central nervous system (CNS) [8,
immunofluorescent and immunocytochemical methods have 14]. Afferent fibers from the kidney have been shown to
identified a large number of substances in renal nerve ter- travel along with the sympathetic nerves at the level of the
minals, only neuropeptide Y and norepinephrine are thought kidney and then enter the dorsal roots and project to neurons
to act as true neurotransmitters [8]. These two substances are at both spinal and supraspinal levels. Most of the brainstem
released in response to renal nerve activation and bind to regions involved in cardiovascular control including the
specific post-junctional receptors in the kidney. Direct stim- hypothalamus receive inputs from the renal afferents. Renal
ulation of the renal sympathetic nerves results in frequency- afferents are thought to carry information to the CNS from
dependent renal vasoconstriction. Sympathetic activation renal chemoreceptors that respond to changes in the com-
causes greater constriction of afferent arterioles to the glo- position of the interstitial fluid environment, and mechanor-
merulus than efferent arterioles, causing a drop in glomeru- eceptors that monitor hydrostatic pressure changes within
lar pressure and glomerular filtration rate (GFR). In
addition, sympathetic activation reduces blood flow to both
Table 1 Changes in renal function at different frequencies of RNS
the renal cortex and medulla. The renal vasoconstriction
induced by sympathetic efferent stimulation results from Frequency of RNS, Hz Renin Na+ GFR RBF
norepinephrine acting predominantly on 1-adrenergic release excretion
receptors and neuropeptide Y acting on Y1 receptors [9].
0.25 NC NC NC NC
Since changes in renal sympathetic tone may influence
0.50 NC NC NC
RBF and GFR, which in turn influence sodium and water
1.00 NC NC
excretion, it is difficult to determine whether there is any
2.00
direct effect of renal nerve activity on the tubular handling
of salt and water. In animal models of sodium overload, Up arrow ()0increase; down arrow ()0decrease.
blockade of renal -adrenergic receptors or renal denerva- GFR glomerular filtration rate, NC no change, RBF renal blood flow,
tion increases urinary sodium excretion in the absence of RNS renal nerve stimulation.
changes in renal hemodynamic parameters [10]. These (Adapted from DiBona and Kopp [8].)
Curr Cardiol Rep

the kidneys. Mechanoreceptors are located both in the renal conscious sheep with pacing-induced heart failure, direct
cortex and in the renal pelvis, whereas chemoreceptive recordings of both renal and cardiac sympathetic nerve
nerve endings are found primarily in the submucosal layers activity showed increased discharge rates of both of these
of the renal pelvis [8, 14]. Direct electrical stimulation of the nerves compared with their discharge rates in control
renal afferent nerves in animals may produce both sympa- animals [19].
thoinhibitory and sympathoexcitatory reflexes, which There are multiple afferent inputs that regulate efferent
reflects the diverse functional nature of various populations renal sympathetic outflow from the CNS in CHF. There is a
of renal receptors [14]. Much less is known about the reduced sensitivity of both aortic and carotid baroreflexes
normal function of the renal afferent nerves than the efferent and this may play a role in increased central sympathetic
nerves, but there is evidence that renal afferents play a role outflow and efferent renal nerve activity [20, 21]. Further-
in the reflex increase in sympathetic tone that occurs in more, low pressure cardiopulmonary stretch receptors
hypertension [15, 16]. Presumably, the renal afferents also with vagal afferents have a reduced ability to modulate
mediate a reflex increase in sympathetic tone in CHF, but sympathetic tone in CHF [20, 21]. Enhanced sensitivity
this has not yet been confirmed in humans or experimental of peripheral and central arterial chemoreceptors may
animals. also contribute to an increase in sympathetic tone [22, 23].
Importantly, peripheral chemoreceptor hypersensitivity has
been shown to influence cardiovascular prognosis in patients
Efferent Renal Nerve Activation in CHF with CHF [23].
In addition to changes in reflex input to the CNS in CHF,
In CHF, the sympathetic nervous system is activated there appears to be a change in the CNS integration and
earlier than the renin-angiotensin-aldosterone system processing of afferent input that causes an increase in sym-
[17]. This increase in global sympathetic activity affects pathetic outflow [21]. It is likely that the direct effects of
all vascular beds, with preferential activation of sympa- angiotensin II on the CNS play an important role in medi-
thetic nerves to the heart and kidney, as demonstrated by ating the increase in sympathetic outflow in CHF [21]. The
a pronounced norepinephrine overflow from these two central effects of angiotensin II may function as part of a
organs to plasma [18]. The spillover of norepinephrine positive feedback cycle, where an increase in central sym-
from the kidney was shown to predict all-cause mortality pathetic outflow increases circulating levels of angiotensin
and the need for cardiac transplantation in CHF patients II that results in a further increase in sympathetic outflow.
[4]. Moreover, the predictive value of renal norepineph- The increase in sympathetic activity may start as a compen-
rine spillover was independent of overall sympathetic satory response to ventricular dysfunction and reduced car-
activity (total body norepinephrine spillover), GFR, and diac output, but may become part of a pathological positive
left ventricular ejection fraction (LVEF) (Table 2) [4]. In feedback cycle with the progression of CHF.
Although there is a global increase in sympathetic tone in
CHF that is due to CNS integration of all afferent input,
Table 2 The independent effect of renal NE spillover on the combined sympathetic outflow does not increase equally to all organs.
outcome of all-cause mortality and heart transplantation in patients Some vascular beds such as the renal vasculature receive
with HF
greater sympathetic activation than others in the presence of
Independent variable RR 95% CI P value CHF [15, 24]. A disproportionate increase in renal sympa-
thetic activity results in increased renal vascular resistance
HF etiology (ischemic vs nonischemic) 0.5 0.21.2 0.1 compared with other systemic vascular beds, and this results
Age 1.0 0.951.04 0.9 in increased plasma renin activity as well as sodium and
Below median GFR 1.7 0.74.2 0.2 water retention [25]. The disproportionate increase in renal
Below median LVEF 1.5 0.64.0 0.4 sympathetic activity may be an important mechanism that
Below median cardiac index 1.8 0.84.1 0.2 reduces GFR and prevents a compensatory natriuresis
Below median renal blood flow 1.4 0.63.6 0.5 during the progression of CHF [26].
Above median renal NE spillover 3.1 1.27.6 0.01
Above median total body NE spillover 1.5 0.73.4 0.3
Interventions that Reduce Renal Sympathetic Activation
Patients with HF (n061) were followed for a mean of 5.53.7 years.
The data were analyzed in a multivariate Cox regression model.
in CHF
CI confidence interval, GFR glomerular filtration rate, HF heart failure,
LVEF left ventricular ejection fraction, NE norepinephrine, RR relative Although bilateral renal denervation has little effect on
risk. kidney function in normal animals, several studies in animal
(Adapted from Petersson et al. [4].) models of heart failure have established the beneficial
Curr Cardiol Rep

effects of renal denervation. In a rat model of heart failure Although human studies of pharmacology and animal
induced by left anterior descending artery ligation, increased experiments with renal denervation suggest that reducing
sodium retention was abolished by surgical renal denerva- renal sympathetic tone would be beneficial in CHF, it must
tion [10]. Surgical renal denervation in dogs with an arte- be remembered that a trial of central sympathetic nervous
riovenous fistula and compensated high-output heart failure suppression with moxonidine to treat systolic CHF
improved the postprandial natriuresis in response to a sodi- (MOXCON [Sustained Release Moxonidine for Conges-
um load (125 mEq) [27]. The therapeutic value of renal tive Heart Failure]) was disappointing [35]. Prolonged-
denervation was demonstrated in two other rat models of release moxonidine, which acts on central imidazoline
heart failure induced by coronary ligation [28, 29]. Surgical receptors to reduce sympathetic tone, significantly in-
renal denervation was performed prior to coronary ligation creased mortality compared with placebo. Since moxoni-
and resulted in reduced ventricular filling pressures and dine causes a dose-dependent reduction in plasma
improved ventricular function after ligation compared to norepinephrine levels [36], it is possible that the dose
nondenervated control animals. Renal denervation was also of moxonidine used and the forced dose-titration protocol
shown to restore the diuresis and natriuresis in response to in the MOXCON trial may have reduced vital organ
exogenously administered atrial natriuretic peptide in rats perfusion because of too large a fall in global sympathet-
with heart failure induced by coronary ligation [30]. In a ic activity. Since multiple mechanisms are responsible for
rabbit model of pacing-induced heart failure, there was a the increase in sympathetic tone in CHF, it seems un-
decrease in RBF, an increase in renal vascular resistance, an likely that renal denervation will reduce sympathetic tone
increase in the expression of angiotensin II type 1 receptors to the same degree as high-dose moxonidine. Based on a
in renal cortical vessels, and a decrease in the expression of small number of studies in animals with heart failure,
angiotensin II type 2 receptors [31]. All of these changes bilateral renal denervation has not been associated with a
were prevented by renal denervation prior to the induction detectable increase in mortality [10, 2731].
of heart failure. Taken together, the results of these animal
studies suggest that renal denervation may be particularly
useful in the treatment of CHF in patients. Afferent Renal Nerve Activation in CHF
Although there is little information on the effects of renal
denervation in CHF patients, there is indirect evidence for In addition to acting as a target organ for efferent sympa-
the beneficial effects of interventions that reduce renal sym- thetic signals, the afferent nerves in the kidney may also
pathetic activation. The observation of a natriuresis in re- play a role in CHF. The precise population of afferent nerves
sponse to acute intrarenal -adrenergic blockade in CHF that are activated and the mechanisms responsible for their
patients supports a therapeutic role for reducing the effects activation are unknown. However, it is likely that increased
of increased renal sympathetic nerve activity on sodium and renal afferent nerve signals travel to the CNS and induce a
water retention [32]. Renin release from the kidneys is reflex increase in renal sympathetic tone (renorenal reflex),
influenced by 1-adrenergic receptors, and the administra- thereby causing renal vasoconstriction, renin secretion, and
tion of blockers without intrinsic sympathomimetic activ- sodium and water retention [37]. Moreover, increased renal
ity has been shown to reduce plasma renin activity in CHF afferent nerve signals that travel to the CNS may also cause
patients [33]. Furthermore, the beneficial effects of a reflex increase in sympathetic tone to other organs that
angiotensin-converting enzyme inhibitors and angiotensin have a dense sympathetic innervation, such as the heart and
II receptor blockers in CHF patients may be mediated in peripheral vasculature [15, 16]. The CNS in this case serves
part by reducing or attenuating the deleterious effects of as the central component of the reflex arc. It is possible that
renal sympathetic activation. Even the efficacy of loop a pathological positive feedback cycle at the level of the
diuretics may be influenced by renal sympathetic activity. kidney may exist, whereby an increase in renal efferent
A recent study showed that total urine volume and sodium sympathetic tone leads to an increase in renal afferent nerve
excretion were considerably greater when CHF patients activity, which further increases efferent sympathetic out-
received the same dose of furosemide while they were in a flow from the CNS (Fig. 1).
recumbent position for 90 min, as opposed to an upright Although several substances (nitric oxide, calcitonin
posture (sitting or walking on a treadmill) [34]. Plasma gene-related peptide, substance P, H+, adenosine) have been
norepinephrine and renin were higher with the upright postulated to stimulate chemosensitive renal afferents under
posture and these results suggest that the reduced response to various conditions [8, 14, 16], adenosine is of particular
furosemide was due to an increase in renal sympathetic tone. interest, since it is readily released by renal proximal tubular
These findings suggest that renal denervation may enhance cells directly into the tubular fluid during increased meta-
the efficacy of exogenous diuretics administered to CHF bolic activity [38]. Furthermore, intrarenal adenosine has
patients. been shown to be elevated in patients with CHF [39], and
Curr Cardiol Rep

Fig. 1 The effects of increased


sympathetic tone in CHF on the
kidneys, heart, and peripheral
vasculature. A positive
feedback cycle is proposed
whereby an increase in
sympathetic outflow from the
CNS results in an increase in
afferent renal traffic. This
increased afferent traffic travels
back to the CNS and leads to a
further increase in sympathetic
outflow from the CNS as part of
a reflex arc. This positive
feedback loop is interrupted
by renal denervation.
CHFcongestive heart failure;
CNScentral nervous system;
RAASrenin-angiotensin-
aldosterone system

it may activate renal afferents resulting in a reflex increase The invasive nature of nephrectomy or dorsal rhizotomy
in sympathetic tone. Studies in conscious dogs after has recently been superseded by the application of low-
unilateral nephrectomy have shown that the intrarenal power radiofrequency (RF) energy via an endovascular
infusion of adenosine elevates blood pressure and plasma catheter in the renal arteries to accomplish renal denerva-
norepinephrine, and these effects could be blocked by tion. This method of renal denervation has been used in
surgical interruption of renal afferents [16]. patients with hypertension resistant to pharmacologic thera-
Although studies of renal afferent activity in animals or py [44]. Following endovascular denervation, blood pres-
patients with CHF are limited, there is evidence of renal sure fell significantly, and elevated muscle sympathetic
afferent activation in other types of kidney dysfunction. nerve activity returned to normal levels [45, 46]. These
In a partial (5/6) nephrectomy rat model of renal failure findings in combination with a reduction in total body
and hypertension, bilateral dorsal rhizotomy prevented norepinephrine spillover in drug-resistant hypertensive
blood pressure elevation, indicating that afferent signal- patients without established renal disease suggest that there
ing to the CNS contributed to a rise in sympathetic tone may be increased renal afferent activity prior to ablation that
[40, 41]. In a rat model of one-kidney, one-clip Goldblatt causes a reflex increase in global sympathetic tone. In addi-
hypertension, bilateral dorsal rhizotomy significantly at- tion, since angiotensin II has a central action to increase
tenuated the rise in blood pressure; however, unilateral sympathetic tone, a reduction in circulating levels of angio-
rhizotomy on the side of the nephrectomy had no effect tensin II after renal denervation may also contribute to a
[42]. These findings suggest that the effect of dorsal reduction in central sympathetic outflow [21].
rhizotomy was specific for the renal afferents. In another
rat model where unilateral kidney injury was induced by
the intrarenal injection of phenol, surgical denervation of Evaluation of Renal Denervation in CHF Patients
the phenol-treated kidney prevented a rise in blood pres-
sure and an increase in norepinephrine turnover in the The dramatic reduction in renal sympathetic tone as well as
posterior hypothalamus [42]. In humans with end-stage sympathetic tone to other organs after catheter-based renal
renal disease, nephrectomy in patients with or without denervation in patients with drug-resistant hypertension
kidney transplantation had a similar effect [43]. Nephrec- suggests that this technique will also be useful in patients
tomy of the native non-functioning kidney resulted in a with CHF [7, 44, 45, 46]. Catheter-based renal denerva-
reduction of muscle sympathetic nerve activity and total tion involves femoral artery catheterization with the catheter
body norepinephrine spillover, confirming the role of tip placed in the distal renal artery. RF energy is then applied
renal afferents in mediating a reflex increase in sympa- to the endothelium, the catheter is pulled back 0.5 cm and
thetic tone. rotated circumferentially so that the RF energy is applied at
Curr Cardiol Rep

a different site. This is repeated four to six times in each stimulation. It will enroll a total of 100 patients with NYHA
renal artery. The procedure has been shown to very safe with class II to IV heart failure, LVEF less than 40%, estimated
minimal complications. Although patients may experience GFR greater than 35 mL/min, and on maximal tolerated
transient pain during the application of RF energy, this pain pharmacological therapy. They will have assessments at
is well managed by intravenous sedation. There has been no baseline and 6 months of symptom status, slope of ventilation
clinical evidence of either vessel thrombosis or kidney to carbon dioxide production on exercise (VE/VCO2 slope),
embolization, or renal artery dissection that is related to chemoreflex sensitivity, arrhythmia burden, and ambulatory
the application of RF energy. blood pressure.
Studies in rats subjected to renal surgical denervation Since CHF patients who are candidates for the
have shown that functional reinnervation of the renal vas- Simplicity-HF and REACH clinical trials should already
culature begins to occur between 14 and 24 days after be on optimal doses of -adrenergic blockers, and
denervation, with complete return of neural function by angiotensin-converting enzyme inhibitors or angiotensin II
8 weeks [47]. It is likely that some efferent sympathetic receptor blockers when they undergo renal denervation, it is
reinnervation occurs in patients after catheter-based renal possible that these drugs may attenuate some the beneficial
denervation, although the time course of this response is effects of renal denervation. However, the doses of these
unknown. Furthermore, it is difficult to clinically evaluate agents used are usually less than the doses needed to elim-
the amount of reinnervation, since there are no simple inate all stimulation of receptors and angiotensin II recep-
diagnostic tests that can evaluate the functional innervation tors; thus, these patients may still benefit from renal
of the kidneys. In contrast to efferent nerves, the afferent denervation. Furthermore, since pure 1-adrenergic agents
nerves may have less capacity to regenerate [48]. Thus, the are contraindicated in CHF patients because they expand
removal of renal afferent activity with renal denervation and extracellular and plasma volumes [50], renal denervation
the subsequent effects on central sympathetic outflow may should reverse the effects of increased -adrenergic tone
be sustained. This concept is supported by the finding of a on renal blood flow, tubular excretion of sodium, and sys-
continued reduction in blood pressure at 2 years of follow- temic vasoconstriction. In addition, renal denervation
up in a cohort of hypertensive patients [49]. should eliminate the release of other transmitters such as
A prospective clinical trial, Symplicity-HF (Renal Dener- neuropeptide Y that might also contribute to sympathetical-
vation in Patients with Chronic Heart Failure and Renal ly mediated renal vasoconstriction [9].
Impairment Clinical Trial), is currently underway to evalu-
ate the effects of catheter-based renal denervation in patients
with systolic CHF. The trial will enroll 40 patients who meet Conclusions
the following inclusion criteria: New York Heart Associa-
tion (NYHA) functional class II to III, LVEF less than 40%, Studies in animals and humans suggest that activation of both
estimated GFR of 30 to 75 mL/min/1.73 m2, and stable heart efferent and afferent renal nerves play a role in the pathogen-
failure medications including furosemide, angiotensin- esis and progression of disease states such as hypertension and
converting-enzyme inhibitors or angiotensin receptor CHF. Surgical renal denervation in animal models of heart
blockers, aldosterone antagonists and blockers. The failure has been shown to improve both cardiac and renal
primary end points of the study are focused on safety function. There are two ongoing clinical trials investigating
(adverse events) as well as efficacy, as assessed by cardiac the safety and efficacy of renal denervation in patients with
and/or renal physiological responses to the denervation. systolic CHF. The results of these clinical trials should provide
Specifically, ventricular function will be measured by important physiological information on the impact of renal
echocardiography at baseline, 6 months, and 1 year; denervation on renal and cardiac function, as well as informa-
and renal function evaluated by estimated GFR at baseline, tion that can be used to design other more definitive controlled
1, 3, 6 months, and 1 year. The first 10 patients enrolled will trials to determine whether there is therapeutic value of renal
have the following measurements at baseline, 6, and denervation in patients with CHF.
12 months: intracardiac pressures (right heart catheterization),
cardiac and renal norepinephrine spillover, heart rate
variability and arrhythmias (Holter monitoring), muscle
Disclosure Conflicts of interest: P.A. Sobotka: is an employee of
sympathetic nerve activity, and RBF (MAG3 imaging). Medtronic, Inc.; receives royalties based on Symplicity System sales;
Another trial, REACH (REnal Artery Denervation in and has stock/stock options in Medtronic, Inc.; H. Krum: has received
Chronic Heart Failure), is currently underway to compare grant support from Ardian/Medtronic; M. Bhm: is on the speakers
bureau for Medtronic.; D.P. Francis: has received grant support from
catheter-based renal denervation with sham procedure in
Medtronic; and has received travel/accommodations expenses covered
patients with systolic CHF. This trial is focusing on symptoms or reimbursed from Medtronic; M.P. Schlaich: has received grant
and ventilatory responses to exercise and chemoreceptor support from Ardian/Medtronic; has received a consulting fee or
Curr Cardiol Rep

honorarium from Ardian/Medtronic; has a board membership with 16. Katholi RE, Whitlow PL, Hageman GR, Woods WT. Intrarenal
Pharmaceutical; and has received grant support from the National adenosine produces hypertension by activating the sympathetic
Health and Medical Research Council. nervous system via the renal nerves in the dog. J Hypertens.
1984;2:34959.
17. Francis GS, Benedict C, Johnstone DE, et al. Comparison of
neuroendocrine activation in patients with left ventricular dysfunc-
References tion with and without congestive heart failure. A substudy of the
Studies of Left Ventricular Dysfunction (SOLVD). Circulation.
1990;82:17249.
Papers of particular interest, published recently, have been 18. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner
highlighted as: PI. Norepinephrine spillover to plasma in patients with congestive
heart failure: evidence of increased overall and cardiorenal
Of importance sympathetic nervous activity. Circulation. 1986;73:61521.
Of major importance 19. Ramchandra R, Hood SG, Denton DA, Woods RL, McKinley
MJ, McAllen RM, May CN. Basis for the preferential activation of
1. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran cardiac sympathetic nerve activity in heart failure. Proc Natl Acad
JR, Wynne J. High prevalence of renal dysfunction and its Sci USA. 2009;106:9248. This study was the first to directly
impact on outcome in 118,465 patients hospitalized with acute record renal sympathetic nerve activity in heart failure. Heart
decompensated heart failure: a report from the ADHERE database. failure was induced in sheep by 6 to 8 weeks of rapid ventricular
J Card Fail. 2007;13:42230. pacing, and there was a significant increase in integrated nerve
2. Napoli C, Casamassimi A, Crudele V, Infante T, Abbondanza C. activity in both the renal and cardiac sympathetic nerves.
Kidney and heart interactions during cardiorenal syndrome: a 20. Creager MA. Baroreceptor reflex function in congestive heart
molecular and clinical pathogenic framework. Future Cardiol. failure. Am J Cardiol. 1992;69:10G5G.
2011;7:48597. 21. Zucker IH. Novel mechanisms of sympathetic regulation in chron-
3. Wencker D. Acute cardio-renal syndrome: progression from ic heart failure. Hypertension. 2006;48:100511.
congestive heart failure to congestive kidney failure. Curr Heart Fail 22. Schultz HD, Li YL, Ding Y. Arterial chemoreceptors and
Rep. 2007;4:1348. sympathetic nerve activity: implications for hypertension and
4. Petersson M, Friberg P, Eisenhofer G, Lambert G, Rundqvist B. heart failure. Hypertension. 2007;50:613.
Long-term outcome in relation to renal sympathetic activity in 23. Ponikowski P, Chua TP, Anker SD, Francis DP, Doehner W,
patients with chronic heart failure. Eur Heart J. 2005;26:90613. Banasiak W, Poole-Wilson PA, Piepoli MF, Coats AJ. Peripheral
5. Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, chemoreceptor hypersensitivity: an ominous sign in patients with
Straznicky N, Esler MD, Lambert GW. Sympathetic activation chronic heart failure. Circulation. 2001;104:5449.
in chronic renal failure. J Am Soc Nephrol. 2009;20:9339. 24. Kon V. Neural control of renal circulation. Miner Electrolyte
6. Smithwick RH, Thompson JE. Splanchnicectomy for essential Metab. 1989;15:3343.
hypertension: Results in 1,266 cases. JAMA. 1953;152:15014. 25. Kirchheim H, Ehmke H, Persson P. Sympathetic modulation of
7. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, renal hemodynamics, renin release and sodium excretion. Klin
Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham Wochenschr. 1989;67:85864.
WT, Esler M. Catheter-based renal sympathetic denervation for 26. Shlipak MG, Massie BM. The clinical challenge of cardiorenal
resistant hypertension: a multicentre safety and proof-of-principle syndrome. Circulation. 2004;110:15147.
cohort study. Lancet. 2009;373:127581. This study was the 27. Villarreal D, Freeman RH, Johnson RA, Simmons JC. Effects of
first to demonstrate that catheter-based renal denervation renal denervation on postprandial sodium excretion in experimental
causes substantial and sustained blood pressure reduction heart failure. Am J Physiol. 1994;266(5 Pt 2):R1599604.
without serious adverse events in patients with drug-resistant 28. Nozawa T, Igawa A, Fujii N, Kato B, Yoshida N, Asanoi H, Inoue H.
hypertension. Effects of long-term renal sympathetic denervation on heart failure
8. DiBona GF, Kopp UC. Neural control of renal function. Physiol after myocardial infarction in rats. Heart Vessels. 2002;16:516.
Rev. 1997;77:76155. 29. Souza DR, Mill JG, Cabral AM. Chronic experimental myocardial
9. Eppel GA, Luff SE, Denton KM, Evans RG. Type 1 neuropeptide infarction produces antinatriuresis by a renal nerve-dependent
Y receptors and alpha1-adrenoceptors in the neural control of mechanism. Braz J Med Biol Res. 2004;37:28593.
regional renal perfusion. Am J Physiol. 2006;290:R33140. 30. Pettersson A, Hedner J, Hedner T. Renal interaction between
10. DiBona GF, Sawin LL. Role of renal nerves in sodium retention of sympathetic activity and ANP in rats with chronic ischaemic heart
cirrhosis and congestive heart failure. Am J Physiol. 1991;260(2 Pt failure. Acta Physiol Scand. 1989;135:48792.
2):R298305. 31. Clayton SC, Haack KK, Zucker IH. Renal denervation modulates
11. Zanchetti AS. Neural regulation of renin release: experimental angiotensin receptor expression in the renal cortex of rabbits with
evidence and clinical implications in arterial hypertension. Circu- chronic heart failure. Am J Physiol Renal Physiol. 2011;300:F319.
lation. 1977;56:6918. 32. Schrier RW. Pathogenesis of sodium and water retention in
12. Osborn JL, Dibona GF, Thames MD. Beta-l receptor mediation of high-output and low-output cardiac failure, nephrotic syndrome,
renin secretion. elicited by low-frequency renal nerve stimulation. cirrhosis, and pregnancy (1). N Engl J Med. 1988;319:106572.
J Pharmacol Exp Ther. 1981;216:2659. 33. Fung JW, Yu CM, Yip G, Chan S, Yandle TG, Richards AM,
13. Holmer S, Rinne B, Eckardt KU, Le Hir M, Schricker K, Kaissling Nicholls MG, Sanderson JE. Effect of beta blockade (carvedilol
B, Riegger G, Kurtz A. Role of renal nerves for the expression of or metoprolol) on activation of the renin-angiotensin-aldosterone
renin in adult rat kidney. Am J Physiol. 1994;266:F73845. system and natriuretic peptides in chronic heart failure. Am J
14. Stella A, Zanchetti A. Functional role of renal afferents. Physiol Cardiol. 2003;92:406.
Rev. 1991;71:65982. 34. Galiwango PJ, McReynolds A, Ivano J, Chan CT, Floras JS.
15. Katholi RE. Renal nerves in the pathogenesis of hypertension in Activity with ambulation attenuates diuretic responsiveness in
experimental animals and humans. Am J Physiol. 1983;245:F1 chronic heart failure. J Card Fail. 2011;17:797803. This study
F14. showed that an increase in sympathetic tone influences the response
Curr Cardiol Rep

to furosemide in patients with heart failure. Intravenous furosemide 44. Krum H, Sobotka P, Mahfoud F, Bhm M, Esler M, Schlaich M.
(75% of the usual oral morning dose) was administered to 9 patients Device-based antihypertensive therapy: therapeutic modulation of
with stable heart failure (NYHA class II-III, LVEF < 40%) in both the autonomic nervous system. Circulation. 2011;123:20915.
supine (90 minutes recumbency) and upright postures (90 minutes 45. Schlaich MP, Sobotka PA, Krum H, Lambert EA, Esler MD. Renal
sitting and treadmill walking). Sodium excretion and urine volume sympathetic nerve ablation for the treatment of uncontrolled
90 minutes after furosemide were attenuated in the upright hypertension. N Engl J Med. 2009;361:9324.
compared with the supine posture, whereas plasma norepinephrine 46. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE,
and renin activity were increased. Bhm M. Renal sympathetic denervation in patients with
35. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, treatment-resistant hypertension (The Symplicity HTN-2 Trial): a
Wiltse C, Wright TJ. MOXCON Investigators. Adverse mortality randomized controlled trial. Lancet. 2010;376:19039. In this very
effect of central sympathetic inhibition with sustained-release important multicenter, prospective, randomized trial, patients who
moxonidine in patients with heart failure (MOXCON). Eur J Heart had a baseline systolic blood pressure of 160 mm Hg despite
Fail. 2003;5:65967. treatment with three or more antihypertensive drugs were randomly
36. Swedberg K, Bristow MR, Cohn JN, Dargie H, Straub M, Wiltse allocated to renal denervation plus previous treatment (n052) or
C, Wright TJ. Moxonidine Safety and Efficacy (MOXSE) Inves- to a control group (n051) that maintained previous treatment alone.
tigators. Effects of sustained-release moxonidine, an imidazoline At 6 months of follow-up, office-based blood pressure measure-
agonist, on plasma norepinephrine in patients with chronic heart ments in the renal denervation group fell by an average of 32/
failure. Circulation. 2002;105:1797803. 12 mm Hg from a baseline of 178/96 mm Hg (P<0.0001),
37. Kopp UC. Renorenal reflexes: neural and functional responses. whereas it did not differ from baseline in the control group. The
Fed Proc. 1985;44:28349. results show that catheter-based renal denervation can safely
38. Rieg T, Vallon V. ATP and adenosine in the local regulation of be used to substantially reduce blood pressure in treatment-
water transport and homeostasis by the kidney. Am J Physiol resistant hypertensive patients.
Regul Integr Comp Physiol. 2009;296:R41927. 47. Kline RL, Mercer PF. Functional reinnervation and development
39. Funaya H, Kitakaze M, Node K, Minamino T, Komamura K, of supersensitivity to NE after renal denervation in rats. Am J
Hori M. Plasma adenosine levels increase in patients with Physiol. 1980;238:R3538.
chronic heart failure. Circulation. 1997;95:13635. 48. Arrowood JA, Goudreau E, Minisi AJ, Davis AB, Mohanty PK.
40. Campese VM. Neurogenic factors and hypertension in chronic Evidence against reinnervation of cardiac vagal afferents after human
renal failure. J Nephrol. 1997;10:1847. orthotopic cardiac transplantation. Circulation. 1995;92:4028.
41. Wyss JM, Aboukarsh N, Oparil S. Sensory denervation of the 49. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic
kidney attenuates renovascular hypertension in the rat. Am J denervation for resistant hypertension: Durability of blood pressure
Physiol. 1986;250:H826. reduction out to 24 months. Hypertension 2011;57:911917.
42. Ye S, Zhong H, Yanamadala V, Campese VM. Renal injury caused This study demonstrated the durability of blood pressure reduction
by intrarenal injection of phenol increases afferent and efferent after renal denervation. In patients with drug-resistant hypertension,
renal sympathetic nerve activity. Am J Hypertension. 2002;15:717 catheter-based renal sympathetic denervation results in a substantial
24. reduction in blood pressure that was sustained out to 2 years of
43. Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, follow-up, without significant adverse events.
Kisters K, Dietl KH, Rahn KH. Sympathetic nerve activity in 50. Grimm Jr RH, Flack JM. Alpha 1 adrenoreceptor antagonists. J
end-stage renal disease. Circulation. 2002;106:19749. Clin Hypertens. 2011;13:6547.