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Renal sympathetic denervation


THOMAS F. LSCHER, ULF LANDMESSER, MATHIAS
WOLFRUM, GEORG NOLL, ISABELLA SUDANO

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SUMMARY
Arterial hypertension represents a significant global health issue. Despite lifestyle modification and pharmacological
approaches, worldwide, the achievement rates of blood pressure control remain unsatisfactory.
Both experimental and clinical studies have emphasised the important role of sympathetic nervous system activation in the
development and progression of arterial hypertension. Catheter-based renal denervation is a new therapeutic option to
reduce renal sympathetic nervous activation in experimental and human hypertension. The data so far obtained in patients
with drug-resistant hypertension has demonstrated that this procedure may reduce blood pressure effectively and safely.
Targeting the renal sympathetic nerves could also be an attractive future strategy for other diseases, where the activation
of the sympathetic nervous system plays an important pathophysiological role; such as in sleep apnoea syndrome, heart
failure, chronic kidney disease or polycystic ovary syndrome.

THE IMPORTANCE OF HYPERTENSION


HISTORICAL PERSPECTIVE
High blood pressure (systemic arterial hypertension) was only recognised as a clinical entity in the 20th century. In fact,
although the Reverend Stephen Hales had already measured blood pressure for the first time in a living horse in 1740,
using a glass cannula inserted into the carotid artery [1], it wasnt until 1896, when Scipione Rive-Rocci invented the
sphygmomanometer, that blood pressure could be easily and repeatedly determined in humans [2]. Initially, only systolic
blood pressure could be assessed using palpation of the radial pulse. Then Korotkoff (using the stethoscope introduced by
Ren Laenec in 1828) discovered arterial sounds and described the method in 1904 that is still used today [3].

Summary
The importance of hypertension
Aetiology of hypertension
The sympathetic nervous system and blood
pressure regulation
Renal nerves and blood pressure regulation
Renal sympathetic denervation
Future perspectives
Personal perspective - Thomas F. Lscher

About the authors


Thomas Lscher
Ulf Landmesser
Mathias Wolfrum
Georg Noll
Isabella Sudano

Table of contents
VOLUME I

It soon became apparent that blood pressure levels varied among individuals and patient groups, particularly those with

VOLUME II

renal disease. At first, high blood pressure was not recognised as a condition responsible for disease, although Richard
Bright had described in 1827 an association between shrunken kidneys and a thickened heart during autopsy. However,
until the beginning of the 20th century, hypertension was considered a compensatory phenomenon required to maintain
adequate perfusion of damaged kidneys (Erfordernishochdruck). It was in 1904 that Theodor Caldwell Janeway
published A clinical study of blood pressure, where he described for the first time end-organ damage induced by high
blood pressure [3]. Still, almost 40 years later in 1945 when US president Franklin D. Roosevelt died from a cerebral
haemorrhage, his personal physician Dr. Ross McIntyre insisted that the fatal bleeding was unexpected, although
Roosevelts blood pressure values had reached levels as high as 310/190 mmHg [4].

VOLUME III

The relationship of blood pressure to both stroke and myocardial infarction was eventually demonstrated in several
epidemiological studies (among them the Framingham Cohort begun in 1945) establishing hypertension as one of the
most important cardiovascular risk factors [5].

EPIDEMIOLOGY
Arterial hypertension is highly prevalent in the overall population, but particularly in adults and the elderly (
Figure 1 )
[6]. Systolic blood pressure especially increases with age due to a loss in elasticity of the vasculature and hence a loss of
the Windkessel Effect. In Western countries, around 20% of the adult population have elevated blood pressure values
(above 140/90 mmHg) making it one of the most important cardiovascular risk factors.

CLINICAL CONSEQUENCES
Hypertension per se does not cause symptoms, but rather, it represents a major risk factor for myocardial infarction and
stroke [7] (
Figure 2 ). Both major adverse cardiovascular events exhibit a linear relationship with the blood pressure
[8]. Although myocardial infarction is the more prevalent complication of hypertension, stroke is even more tightly linked to
blood pressure, and in particular to age (
Figure 3 ). Certainly at any age, increasing blood pressure levels are
associated with an increased risk of stroke [9]. Similarly, high blood pressure carries an increased risk of vascular
dementia [10].
In addition, it is a major cause of chronic renal failure leading to haemodialysis.

FOCUS BOX 1
Hypertension and cardiovascular disease
High blood pressure is highly prevalent in the overall population and represents a major risk factor for cardiovascular
diseases:
myocardial infarction

3.29 - Percutaneous interventions in mitral and


tricuspid stenosis and in failure of mitral and
tricuspid bioprostheses
3.30 - Percutaneous mitral valve repair
3.31 - Balloon aortic valvuloplasty
3.32 - Transcatheter aortic valve implantation
3.33 - Percutaneous pulmonary valvuloplasty
3.34 - Percutaneous pulmonary valve
implantation
3.35 - Atrial septal defect and patent foramen
ovale closure
3.36 - Ventricular septal defect closure
3.37 - Patent ductus arteriosus closure
3.38 - Left atrial appendage occlusion
3.39 - Coarctation of the aorta
3.40 - Interventions for congenital and acquired
pulmonary vein stenosis
3.41 - Percutaneous closure of paravalvular leaks
3.42 - Carotid artery stenting
3.43 - Subclavian, brachiocephalic and vertebral
interventions
3.44 - Thoracic and abdominal aortic disease
3.45 - Interventions in the reno-visceral
circulation
3.46 - Peripheral arterial occlusive disease
3.47 - Interventions for varicose veins
3.48 - Closure of arteriovenous fistulae and
malformations
3.49 - Alcohol septal ablation for hypertrophic
obstructive cardiomyopathy
3.50 - Alternative techniques to alcohol septal
ablation for hypertrophic obstructive
cardiomyopathy
3.51 - Renal sympathetic denervation
3.52 - Techniques of myocardial stem cell
delivery
3.53 - Cell-based regenerative therapy
3.54 - Pulmonary embolism and pulmonary
hypertension

VOLUME IV

peripheral artery disease


stroke
dementia
chronic renal failure

Recommended references

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Figure 1
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Figure 2
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Figure 3
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AETIOLOGY OF HYPERTENSION
In patients considered for renal sympathetic denervation, secondary forms of hypertension (
excluded prior to the procedure [11].

Table 1 ) must be

ESSENTIAL HYPERTENSION
In over 95% of the patients, no apparent cause for the elevated blood pressure values can be found, a condition which is
referred to as essential hypertension [12]. It is likely that this condition has a hereditary basis, as it is seen to run in
families. In fact, the risk of developing high blood pressure with advancing age increases three to fivefold if one or two
parents respectively are hypertensive [13]. Recently, it has been identified that genes themselves account for small
changes in blood pressure [14]. Furthermore, the condition is more prevalent in certain populations over others (the socalled low blood pressure populations) [15, 16].
Besides a genetic disposition, dietary factors such as sodium and potassium intake as well as obesity have been linked to
essential hypertension. Of note, an over-activation of the sympathetic nervous system is often associated with essential
hypertension.

RENOVASCULAR HYPERTENSION
Renovascular hypertension is the most common curable form of secondary hypertension. Its prevalence ranges from
between 1-3% in the hypertensive population, but is more common in referral centres [17]. Two forms of renovascular
hypertension can be distinguished: 1) Fibromuscular dysplasia and 2) atherosclerotic renal artery stenosis [18]. Both are
amenable to percutaneous renal angioplasty [19, 20, 21], and in the case of atherosclerotic lesions, to stenting as well
[22].

RENAL PARENCHYMAL HYPERTENSION


Most forms of chronic kidney disease involve both kidneys, and lead to a steady decline in renal function over years and
decades. Hypertension is associated with all forms of chronic kidney disease, in particular diabetic glomerulosclerosis
(characterised by Kimmelstiel-Wilson lesions on renal biopsy) and chronic glomerulonephritis [23]. Specific treatment
modalities are rarely available, although inhibitors of the renin-angiotensin system (i.e., ACE-inhibitors and AT1-receptor
antagonists) reduce proteinuria and delay the decay in kidney function over time [11, 24].

ENDOCRINE HYPERTENSION
In 1955 Jerome Conn described patients with hypertension, hypokalaemia and adenomas of the adrenal cortex (the socalled Conns syndrome) [25].
Mineralocorticoid hypertension is characterised by elevated plasma aldosterone levels and suppressed plasma renin
activity reflecting an autonomous aldosterone secretion by the adenoma [26]. Localisation of the adenoma is best
performed with computer tomography [15].
Patients with phaeochromocytoma typically experience palpitations, sweating and sometimes headaches due to sudden
releases of catecholamines from the tumour. The diagnosis involves either computer tomography or magnetic resonance
imaging [11, 27, 28]. Catecholamine levels in plasma or in urine (metanephrine, vanillinic acid) are typically elevated [29,
30].
Hypertension is one of the most distinguishing features of endogenous Cushings syndrome. The diagnosis is based on
clinical observations and laboratory parameters (i.e., morning plasma cortisol, 24 hour cortisol metabolites in urine) [11].
The latter often requires a cortisol-suppression test to distinguish Cushings syndrome from elevated cortisol values in
simple obesity.
True Cushings disease due to a pituitary adenoma producing ACTH should be distinguished from a cortisol-producing
adrenal adenoma or bilateral adrenal hyperplasia, primarily by using imaging techniques such as MRI and/or adrenal
scintigraphy. In the former clinical condition, removal of the tumour by transsphenoidal hypophysectomy is the treatment of
choice, whereas adrenal tumours are managed by unilateral adrenalectomy.

FOCUS BOX 2
Secondary hypertension
Determining possible secondary causes of hypertension is an important part in diagnosing patients with elevated blood
pressure. The following (including less common causes of hypertension) should always be excluded in severe
hypertension, resistant hypertension or those aged <40 before starting or continuing long-term conventional
pharmacological treatment:

renal parenchymal disease


renovascular disease
phaeochromocytoma
primary aldosteronism (Conns syndrome)
Cushings syndrome

31. Esler M. The 2010 Paton Lecture. The


sympathetic nervous system through the ages:
From Thomas Willis to resistant hypertension.
Exp Physiol. 2011;96:611-22.
34. Noll G, Wenzel RR, Schneider M, Oesch V,
Binggeli C, Shaw S, Weidmann P, Lscher TF.
Increased activation of sympathetic nervous
system and endothelin by mental stress in
normotensive offspring of hypertensive parents.
Circulation. 1996;93:866-9.
39. DiBona GF. Functionally specific renal
sympathetic nerve fibers: role in cardiovascular
regulation. Am J Hypertens. 2001;14:163S-170S.
47. Schlaich, MP, Sobotka PA, Krum H, Lambert
E, Esler MD. Renal sympathetic-nerve ablation
for uncontrolled hypertension. N Engl J Med.
2009;361:932-4.
48. Krum H, Schlaich M, Whitbourn R, Sobotka
PA, Sadowski J, Bartus K, Kapelak B, Walton A,
Sievert H, Thambar, Abraham WT, Esler M.
Catheter-based renal sympathetic denervation for
resistant hypertension: a multicentre safety and
proof-of-principle cohort study. Lancet.
2009;373:1275-81.
49. Symplicity, H.T.N.I., Esler MD, Krum H,
Sobotka PA, Schlaich MP, Schmieder RE, Bhm
M. Renal sympathetic denervation in patients
with treatment-resistant hypertension (The
Symplicity HTN-2 Trial): a randomised controlled
trial. Lancet. 2010;376:1903-9.
50. Krum H, Barman N, Schlaich M, Sobotka P,
Esler M, Mahfoud F, Bohm M, Dunlap M,
Sadowski J, Bartus K, Kapelak B, Rocha-Singh
KJ, Katholi RE, Witkowski A, Kadziela J,
Januszewicz A, Prejbisz A, Walton AS, Sievert H,
Id D, Wunderlich N, Whitbourn R, Rump LC,
Vonend O, Saleh A, Thambar S, Nanra R, Zeller
T, Erglis A, Sagic D, Boskovic S, Brachmann J,
Schmidt M, Wenzel UO, Bart BA, Schmieder RE,
Scheinert D, Brgel J, Straley C. Catheter-Based
Renal Sympathetic Denervation for Resistant
Hypertension: Durability of Blood Pressure
Reduction Out to 24 Months. Hypertension.
2011;57:911-7.
51. Czernichow S, Zanchetti A, Turnbull F, Barzi
F, Ninomiya T, Kengne AP, Lambers Heerspink
HJ, Perkovic V, Huxley R, Arima H, Patel A,
Chalmers J, Woodward M, MacMahon S, Neal B;
Blood Pressure Lowering Treatment Trialists
Collaboration. The effects of blood pressure
reduction and of different blood pressurelowering regimens on major cardiovascular
events according to baseline blood pressure:
meta-analysis of randomized trials. J Hypertens.
2011;29:4-16.
55. Mahfoud F, Schlaich M, Kindermann I, Ukena
C, Cremers B, Brandt MC, Hoppe UC, Vonend O,
Rump LC, Sobotka PA, Krum H, Esler M, Bhm
M. Effect of Renal Sympathetic Denervation on
Glucose Metabolism in Patients With Resistant
Hypertension: A Pilot Study. Circulation.
2011;123:940-1946.
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coarctation of the aorta


thyroid dysfunction (hypo or hyperthyroidism)
primary hyperparathyroidism

acromegaly
obstructive sleep apnoea
drug/toxin-induced
monogenic renal tubular syndromes
pre-eclampsia
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Table 1
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THE SYMPATHETIC NERVOUS SYSTEM AND BLOOD PRESSURE REGULATION


The cardiovascular system is neurally governed by the sympathetic and parasympathetic (vagal) neuronal afferents and
efferents, which act as opposing mechanisms to activate and deactivate the heart and blood vessels. While the former is
used in fight or flight reactions, the latter is active postprandially as well as during rest and sleep. Changes in blood
pressure are closely linked to changes in sympathetic outflow as assessed by microneurography, heart rate variability
and/or catecholamine levels [31, 32].
The sympathetic nervous system originates in the cardiovascular centres of the brain stem and activates the organs of the
body via cholinergic neurones which, within the paravertebral ganglia, synapse with efferent adrenergic neurones which
Figure 4 ) [33].
reach out to blood vessels, the kidney and other organs (
Of note, offspring of hypertensive parents who are normotensive exhibit a marked overactivity of muscle sympathetic
nerve activity during episodes of mental stress (
Figure 5 ) [34]. Similarly, particularly in young hypertensives, renal
norepinephrine overflow, an index of renal sympathetic nerve activity, is markedly upregulated, an effect that becomes
less pronounced in ageing hypertensives (
Figure 6 ) [35].

FOCUS BOX 3
The sympathetic nervous system
Hyperactivity of the sympathetic nervous system is one of the pivotal players in the pathogenesis of arterial
hypertension
The sympathetic nerve fibres are distributed ubiquitously within the heart, the blood vessels, the kidney, and
major peripheral baroreceptor sites, a finding that suggests a direct effect on:
- fluid balance
- cardiac output
- peripheral vascular resistance
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Figure 5
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Figure 6
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RENAL NERVES AND BLOOD PRESSURE REGULATION


The kidneys play a key role in long-term pressure regulation. In fact, the degree of water and salt excretion (pressure
diuresis) at any given level of blood pressure determines the long-term homeostasis of the circulation [36]. The
sympathetic nervous system has: 1) direct effects on renal vascular resistance via efferent adrenergic nerve endings
activating alpha-receptor on smooth muscle cells of the circulation of the kidneys; and 2) activates renin release in
juxtaglomerular cells via beta-receptors (
Figure 7 ) [37, 38]. This in turn leads to the formation of angiotensin I and II
and aldosterone, all important regulatory hormones for blood pressure which act upon both the resistance of the arteries
as well as within the kidneys.
Sympathetic renal blood pressure regulation involves efferent and afferent nerves. The former transmit sympathetic
outflow to the kidney, while the latter provide feed-back information from the kidney to the cardiovascular centres (
Figure 7 ) [38, 39]. The neurones of both systems form a dense network within the adventitia of the main renal artery and
its branches. The concept of detaching the regulatory organs implicated in blood pressure, such as the kidneys and
muscles from the influence of the sympathetic nervous system was based on a large series of animal experiments and
already applied clinically in the 1950s. This was reported by Smithwick in 1953 (
Figure 8 ) [40]. Surgical
sympathectomy, however, was not very selective and (although it reduced blood pressure and diminished the
consequences of hypertension in those surviving the procedure) was associated with severe complications; in particular,
orthostatic hypotension and an unacceptably high operative morbidity and mortality. Similarly, antihypertensive drugs such
as the ganglion blocker guanethidine, introduced at the same time in the management of hypertension, were associated
with marked side effects [41, 42, 43].

FOCUS BOX 4
Renal nerves and hypertension
The kidneys play a key role in long-term pressure regulation through efferent and afferent nerves
The surgical and pharmacological blockade of the renal nerves were found to be effective in reducing blood
pressure, but were also associated with an increase in marked side effects

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RENAL SYMPATHETIC DENERVATION


Surgical renal denervation has been shown to reduce norepinephrine spillover and to prevent or reverse hypertension in
different animal models (
Figure 9 ) [44, 45]. This technique is much more selective than the surgical sympathectomy
used in the 1950s, and appeared suitable for clinical development [44, 45]. The fact that muscle sympathetic nerve activity
as well as renal norepinephrine spillover was seen to be elevated in human hypertension (
Figure 5 ) [35], led to the
development of a catheter-based renal denervation procedure using radiofrequency ablation by Murray Esler and his coworkers similar to that used in the ablation of arrhythmias [46]. In a proof-of-concept study, renal nerve ablation reduced
muscle sympathetic activity in the peroneal nerve (
Figure 10 ) and renal norepinephrine spillover in hypertensive
patients from 72 and 79 ng/minute in the left and right kidney to 37 and 20 ng/minute and total body norepinephrine
spillover by 42% [47].
Currently the most commonly used system has been developed by Ardian Inc., which was commercially acquired by
Medtronic Inc. in 2010 (Ardian Inc.,a division of Medtronic, Mountain View, CA, USA). The system comprises an ablation
Figure 11 ). Similar systems from other manufacturers are currently under development.
catheter and a power source (
Although conventional ablation catheters used to treat arrhythmias might in principle be suitable as well, the energy used
in these procedures is several times higher than that used to ablate renal sympathetic nerves (30-55 vs. 5-8 Watt).

CURRENT INDICATIONS
Currently, renal nerve ablation is considered in patients with treatment-resistant hypertension, i.e., a blood pressure >
140/90 mmHg despite the use of at least 3 to 4 antihypertensive drugs. Furthermore, the patients must have a suitable
renal anatomy, i.e., renal arteries >4 mm in diameter, and preferably only a single renal artery supplying each kidney (
Table 2 ).

PATIENT PREPARATION
After informed consent, the patient is brought to the catheterisation laboratory and premedication is applied intravenously.
As the ablation of the afferent nerves during application of the radiofrequency energy is very painful, premedication with
midazolam (Dormicum 2-6 mg IV) and morphine (4-10 mg IV) is required. Alternatively, Remifentanil (0,0250,2 g/kg/min
IV) might be used. The disadvantage of morphine is the long time required to take effect, as well as side effects such as
nausea and vomiting, particularly with higher dosages. Ideally, an anaesthetist should assist during the procedure.
Unfractionated heparin is given intravenously at a dose aimed at reaching an activated clotting time (ACT) of > 250
seconds. In addition, 100 g nitroglycerine must be introduced through the guiding catheter before the procedure in order
to avoid vasospasm.

TECHNIQUE AND COMPLICATIONS


The first generation system required an 8 Fr sheath and guiding catheter introduced at a femoral puncture site. Depending
on the anatomy, either a right coronary (with a more or less 90 branching angle of the main renal artery) or an internal
mammary artery catheter (with a downward directed angle of the main renal artery) was employed. Using a 0.014 Fr
guidewire, a 6 Fr straight tip catheter was advanced into the right renal artery close to the bifurcation. Then, the ablation
catheter was advanced and the guiding catheter pulled back. Six ablations were then applied in a spiral fashion starting
from the distal part of the renal artery up to its origin from the aorta, after which the guidewire was removed and the
guiding catheter placed in the left renal artery where the same procedure was repeated in a similar fashion.
The second-generation system allows for direct advancement of the ablation catheter through a 6 Fr guiding catheter
without the use of a guidewire and a straight tip guiding catheter. The catheter can be flexed, pushing a lever towards the
back or front of the handle and turned with a handle rotator at the tip of the body of the shaft of the catheter (
Figure
11 ). A power unit provides radiofrequency energy. It is important to turn the catheter in such a way as to obtain optimal
wall contact. Extensive force, however, should be avoided, as should small side branches of the renal artery. Before and
during the ablation procedure, the renal artery should be continuously flushed with cold (21C) saline solution using a
pressure cuff around the solution package. Continuous temperature monitoring assures that the power unit detects any
overheating of the arterial wall and the application of energy interrupted immediately. Commonly, 5-8 watts are applied for
2 minutes at each of the six ablations sites. Impedance may be used to assure good wall contact (optimal range: 300
350 ).
Renal artery spasm may occur during the ablation procedure, particularly in smaller vessels, and/or when flushing with
cold saline is not performed adequately. If spasm occurs, nitroglycerine (100-200 u.g. ia) and/or verapamil (2-10 mg ia)
should be applied through the guiding catheter. After each ablation, a characteristic notch is seen angiographically at the
ablation site reflecting the oedema that formed in response to the energy and the local heating (

Figure 12 ).

Complications of the procedure involve renal artery dissection and bleeding at the femoral puncture site. In a series of
around 100 patients in the HTN-1 [48] and HTN-2 [49], renal artery dissection occurred in 1 patient, and femoral artery
pseudoaneurysms were observed in 2 patients. With the current use of a 6 Fr system, both complications should further
decrease in frequency.
Long-term complications could potentially involve iatrogenic renal artery stenosis, persistent hypotension and orthostatic
hypotension. Renal artery stenosis was assessed in most patients using either follow-up angiography or renal Duplex
studies, and so far was not observed in the several hundred patients treated with an observation period of up to 18
months. Obviously, the number of patients studied is too small to draw any final conclusions at this point, and large
registries will be required to further document the safety of this procedure.

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Symptomatic hypotension, and in particular orthostatic hypotension, does not seem to occur after renal nerve ablation (at
least in the series of currently treated patients with resistant hypertension in which antihypertensive drugs are commonly
withdrawn in a stepwise manner when blood pressure falls).

EFFECTS ON BLOOD PRESSURE


Renal nerve ablation leads to a long-lasting decrease in blood pressure in the range of 30/12 mmHg up to 18 months after
the intervention (
Figure 13 ) [50]. Of note, the initial decrease in blood pressure immediately after the procedure is
small, suggesting that the partial denervation of the kidneys leads to a slowly developing re-setting of the neurohumoral
control of water, salt excretion and, in turn, blood pressure.
An additional trial, the Simplicity HTN-3, is currently under way in the US, with 500 patients randomised at different centres
in a 2:1 fashion to renal nerve ablation or a sham procedure. Follow-up is at 3 months, and the results will probably
become available in 2012 or 2013.
Whether or not larger outcome trials are required to establish the clinical relevance of renal nerve ablation remains
debatable. Even the Federal Drug Administration in the United States accepts blood pressure as a surrogate endpoint for
the registration of antihypertensive drugs. Furthermore, a close correlation exists between blood pressure lowering and
Table 3 ).
the reduction of cardiovascular events during pharmacological treatment of hypertension [51] (

EFFECTS ON RENAL FUNCTION


Renal function remains unchanged in most patients despite the profound lowering of perfusion pressure.

METABOLIC EFFECTS
Hypertension is associated with an impaired glucose metabolism and insulin resistance [52, 53, 54]. Activation of the
sympathetic nervous system is believed to contribute to this condition. In a recent study, renal nerve ablation led to a
reduction in fasting and plasma glucose, insulin and C-peptide levels as well as a reduction in the HOMA-index (
Figure 14 ) [55]. Furthermore, plasma glucose levels 2 hours after a glucose challenge were similarly decreased. These
preliminary results strongly suggest that sympathetic activation is causally involved in the changes in glucose metabolism
in hypertension, and that renal nerve ablation may offer a novel treatment strategy for the metabolic syndrome.
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FUTURE PERSPECTIVES
THE MANAGEMENT OF HYPERTENSION
Currently, renal nerve ablation is used exclusively in patients with treatment-resistant hypertension and those with multiple
drug intolerance. From a pathophysiological point-of-view, however, it appears that renal sympathetic nerve activity is
particularly elevated in younger hypertensives with a more recent onset of high blood pressure (
Figure 5 ) [35].
Whether renal nerve ablation will prove as effective in this patient population, or even in those with borderline
hypertension, remains to be determined by future studies.

OBSTRUCTIVE SLEEP APNOEA


This condition is characterised by abnormal breathing patterns at night and severe intermittent hypoxia. Hypoxia markedly
activates sympathetic outflow (
Figure 13 and
Figure 14 ) [34, 56, 57] and in turn causes severe increases in blood
pressure. This explains why obstructive sleep apnoea is associated with an increased incidence of stroke, even in the
absence of daytime hypertension.
The patient suffering from obstructive sleep apnoea would thus be an ideal candidate for renal nerve ablation, which might
prevent nocturnal hypertension and possibly correct the abnormal breathing pattern in these patients as well. In fact, a
preliminary report in 12 patients suggest an improvement in the Apnoea Hypopnea Index or the Respiratory Disturbance
Index after renal nerve ablation [58]. Future studies are required to confirm these preliminary findings.

POLYCYSTIC OVARY SYNDROME


In women, polycystic ovary syndrome represents an unrecognised cardiovascular risk factor affecting between 6-10% of
all females in the reproductive age [59, 60]. The syndrome is associated with obesity, ovarian dysfunction and
hypothalamic pituitary abnormalities. These abnormalities lead to its typical clinical presentation with obesity, hirsutism,
infertility, insulin resistance and hypertension. Of note, it has recently been shown that polycystic ovary syndrome is
associated with an increased activity of the sympathetic nervous system [61]. A preliminary report in two patients suggests
that renal nerve ablation lowers blood pressure and improves insulin resistance in the absence of changes in body weight
over a 3 month follow-up in this condition [62].

CHRONIC HEART FAILURE


Chronic heart failure is the end stage of many forms of cardiovascular disease, most notably of coronary heart disease. It
is characterised by dyspnoea, exercise intolerance, elevated levels of brain natriuretic peptide and cardiac dysfunction
[63]. Cardiac dysfunction may involve a reduction in systolic and/or diastolic function. Specifically, the former is associated
with marked neurohumoral activation, in particular, of the sympathetic nervous system (
Figure 15 ) [64]. The latter is

also of great prognostic importance (


these patients [66].

Figure 16 ) [65], and beta blockade has been shown to improve outcomes in

The kidneys are involved in chronic heart failure; of note, renal function is commonly impaired, sodium and water retention
along with peripheral and lung oedema is a common feature of the disease process. Thus, chronic heart failure might
represent a suitable disease for the use of renal nerve ablation, although studies are just in their planning phase at this
point in time. Important safety concerns which need to be considered are the degree of renal nerve ablation and the
danger of inducing persistent hypotension.

CHRONIC KIDNEY DISEASE


Sympathetic nervous system hyperactivity is observed in patients with renal injury, renovascular hypertension, chronic
kidney disease and end-stage renal disease [67, 68, 69].
Elevated sympathetic nervous activity is an important mechanism, possibly contributing to the onset and maintenance of
renal injury at least in part through its concomitant adverse effects in patients with chronic renal disease. Understanding
the contribution of sympathetic nervous hyperactivity to the onset and maintenance of chronic kidney disease might aid in
its prevention and therapy. Moreover, as suggested by experimental studies [70, 71, 72, 73], renal sympathetic
denervation could be a potentially novel therapeutic strategy in patients with renal injury, chronic kidney disease and endstage renal disease. However, data on the effects of renal nerve ablation are currently lacking in these conditions. In
particular, the number of ablations and the energy applied needs to be reconsidered in these patients who suffer from
reduced renal blood flow and smaller renal arteries.

FOCUS BOX 6
Potential future applications
Further studies are needed to evaluate whether renal nerve ablation could be a therapeutic option in patients
with hypertension other than resistant hypertension
Moreover, renal nerve ablation has the potential to benefit patients with other diseases characterised by an
increased sympathetic activation, such as:
- sleep apnoea syndrome
- heart failure
- chronic kidney disease
- metabolic syndrome
- obesity
- chronic liver disease
- polycystic ovary syndrome
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Figure 13
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Figure 14
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Figure 15
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Figure 16
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PERSONAL PERSPECTIVE - THOMAS F. LSCHER


Since the fatal cerebral haemorrhage of Franklin D. Roosevelt on the 13th of April 1945, the diagnosis and
management of arterial hypertension has made huge progress. Today, we are able to easily diagnose essential
hypertension as well as a variety of secondary forms of hypertension. Furthermore, lowering of blood pressure with
either drugs, balloon angioplasty or tumour excision has become common practice and highly effective. Indeed, we
now have a large series of potent antihypertensive drugs available such as beta blockers, diuretics, inhibitors of the
renin-angiotensin system, mineralocorticoid-receptor antagonists as well as calcium antagonists. Depending on the
severity of hypertension, blood pressure can be easily normalised in most patients, using either one drug or a
combination of up to four drugs. Also, most of these drugs are well-tolerated by the patients. However, although blood
pressure lowering reduces stroke by about 50 percent and heart attacks by about 25 percent over the years, lifelong
medical treatment is required and the cure of hypertension is only feasible in a small percentage of patients with either
renal artery stenosis or renal tumours. The challenge of compliance with lifelong antihypertensive therapy has
dampened the success of medical progress in real life clinical practice. Therefore, a cure for essential hypertension
remains a dream, which has come closer to realisation with the development of renal nerve ablation. Although, today,
this new technology is reserved for patients with severe treatment resistant hypertension, it is conceivable that ablation
of renal sympathetic nerves may be particularly effective in early stages of hypertension where sympathetic activation
is rather strong, or may even prevent hypertension in those prone to it with documented increased activity of the
sympathetic nervous system.

PCR CLASSIFICATION
INTERVENTIONS FOR HYPERTENSION & HEART FAILURE

Specific "risks" subset

INTERVENTIONS FOR HYPERTENSION & HEART FAILURE

Sub anatomy subset

Renal insufficiency
Renal artery stenosis

INTERVENTIONS FOR HYPERTENSION & HEART FAILURE

Access

INTERVENTIONS FOR HYPERTENSION & HEART FAILURE

Specific technique/treatment

INTERVENTIONS FOR HYPERTENSION & HEART FAILURE

Complication

Access site

INTERVENTIONS FOR HYPERTENSION & HEART FAILURE

Complication

Renal occlusion

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Renal sympathetic denervation

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