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Metabolic syndrome: a sympathetic disease?

Markus Schlaich, Nora Straznicky, Elisabeth Lambert, Gavin Lambert

Metabolic syndrome is associated with adverse health outcomes and is a growing problem worldwide. Although Lancet Diabetes Endocrinol 2014
eorts to harmonise the denition of metabolic syndrome have helped to better understand the prevalence and the Published Online
adverse outcomes associated with the disorder on a global scale, the mechanisms underpinning the metabolic April 2, 2014
http://dx.doi.org/10.1016/
changes that dene it are incompletely understood. Accumulating evidence from laboratory and human studies S2213-8587(14)70033-6
suggests that activation of the sympathetic nervous system has an important role in metabolic syndrome. Indeed,
See Online/Comment
treatment strategies commonly recommended for patients with metabolic syndrome, such as diet and exercise to http://dx.doi.org/10.1016/
induce weight loss, are associated with sympathetic inhibition. Pharmacological and device-based approaches to S2213-8587(14)70072-5
target activation of the sympathetic nervous system directly are available and have provided evidence to support the Neurovascular Hypertension
important part played by sympathetic regulation, particularly for blood pressure and glucose control. Preliminary and Kidney Disease and Human
Neurotransmitters
evidence is encouraging, but whether therapeutically targeting sympathetic overactivity could help to prevent
Laboratories, Baker IDI Heart
metabolic syndrome and attenuate its adverse outcomes remains to be determined. and Diabetes Institute,
Melbourne, VIC, Australia
Introduction Sympathetic nervous activation in metabolic (Prof M Schlaich MD,
N Straznicky PhD, E Lambert PhD,
The large rise in incidence of obesity in both developed syndrome and obesity Prof G Lambert PhD);
and developing countries has led to a burgeoning in the Investigators have reported clear evidence that obesity and Department of Cardiovascular
incidence of risk factors associated with the development its metabolic eects are associated with a chronic Medicine, Alfred Hospital,
of cardiovascular disease and type 2 diabetes. Collectively activation of sympathetic nervous tone. Sympatho- Melbourne, VIC, Australia
(Prof M Schlaich); and Faculty of
termed metabolic syndrome, these risk factors can excitationas indicated by increases in urinary
Medicine, Nursing and Health
include a combination of abdominal obesity, increased noradrenaline and metabolite concentrations, eerent Sciences, Monash University,
triglyceride concentrations, reduced HDL cholesterol muscle sympathetic nerve activity, and increased rates of Melbourne, VIC, Australia
concentrations, high blood pressure, and hyperglycaemia spillover of noradrenaline to plasma, particularly in people (Prof M Schlaich, E Lambert,
Prof G Lambert)
(panel). Although various societies and interest groups with concomitant insulin resistancehas been recorded
Correspondence to:
initially provided their own criteria for the denition of in obese individuals. Additionally, sympathetic nervous
Prof Markus Schlaich,
metabolic syndrome (appendix),1 in 2009, an international responses to several physiologically relevant stimuli, such Neurovascular Hypertension and
task force proposed a single set of cuto points for all as changing energy states, food intake, glucose Kidney Disease Laboratory, Baker
components except waist circumference (for which they consumption, hyperinsulinaemia, and exposure to cold, IDI Heart and Diabetes Institute,
Melbourne, VIC 8008, Australia
recommended population and country specic are blunted in obese people.4 Blunted sympathetic
markus.schlaich@bakeridi.
denitions; appendix) to harmonise the denition of the responses could contribute to decient thermogenesis, edu.au
syndrome (panel).2 positive energy balance, and increased weight gain. By
A sedentary lifestyle, unfavourable diet, and genetic contrast, exaggerated responses to mental stress and See Online for appendix
predisposition are important factors that underlie increased resting sympathetic activity could predispose an
metabolic syndrome, but emerging evidence also individual to the development of insulin resistance,
indicates the importance of the sympathetic nervous hypertension, renal disease, and cardiac abnormalities
system in the development and progression of obesity- such as diastolic dysfunction and left ventricular
related illnesses. The sympathetic nervous system is hypertrophy.5
well recognised as being important for cardiovascular The exact mechanisms that link obesity and activation
control, but activation of the sympathetic nervous system of the sympathetic nervous system remain to be
also has substantial metabolic eects (gure 1). For
example, direct stimulation of the hepatic sympathetic
nerves3 induces a rapid and marked release of glucose Panel: Criteria for metabolic syndrome2
from the liver, whereas the stimulation of nerves that Increased waist circumference (population and
supply the pancreas is associated with reduced insulin country specic denitions; see appendix)
and increased glucagon concentrations in portal blood. Triglyceride concentration 150 mg/dL (17 mmol/L), or
Furthermore, activation of sympathetic bres that patient undergoing drug treatment for high triglycerides
innervate adipose tissue results in lipolysis and neurally HDL cholesterol concentrations of <40 mg/dL (10 mmol/L)
mediated vasoconstriction of the peripheral arterioles, in men, <50 mg/dL (13 mmol/L) in women, or patient
which is associated with impaired glucose uptake in undergoing drug treatment for low HDL cholesterol
skeletal muscle. These metabolic and sympathetically Systolic blood pressure 130 mm Hg, diastolic 85 mm Hg,
mediated eects are important in stressful situations of or both; or patient with a history of hypertensioan
short duration to cope with increased energy undergoing antihypertensive treatment
requirements; however, sustained sympathetic activation Fasting plasma glucose concentrations of 100 mg/dL, or
can result in adverse metabolic and cardiovascular patient undergoing drug treatment for high glucose
outcomes.

www.thelancet.com/neurology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70033-6 1

 Personal View

determined. Dierent investigators69 have proposed Mechanisms of sympathetic nervous activation

several theories to link overeating, obesity, insulin
resistance, adipokines, non-esteried free fatty acid
(NEFAs), and changes in -adrenergic responsiveness
with sympathetic activation, with their views diering
about whether sympathetic activation is a cause or a
result of metabolic alterations (gure 2). Each theory has
merit, but in this Personal View, our main aim is to focus
on the role of the sympathetic nervous activation in the
pathology associated with obesity in metabolic syndrome.
In their prospective study with a 10 year follow-up,
Masuo and colleagues10,11 noted that increased circulating
noradrenaline at baseline predicted future weight gain
and increases in insulin concentrations and blood
pressure, supporting a role of the sympathetic nervous
system in the generation of obesity and metabolic
syndrome. Researchers have reported similar ndings
that link plasma noradrenaline concentration at baseline
and increased weight gain12 after an approximate
20 year follow-up.
Sympathetic nervous system
Adipocytes Liver Pancreatic Skeletal
cells muscle
Lipolysis Gluconeogenesis Insulin release Impaired glucose Vasoconstriction;
uptake
Figure 1: Overview of the eect of an activated sympathetic nervous system on pathways that adversely
aect metabolic control
Landsberg and colleagues Reaven Grundy Julius and colleagues
Overeating Insulin resistance Increased visceral fat Sympathetic activation
Hyperinsulinaemia
Insulin acts to reduce hepatic production of glucose
through direct eects on the liver to reduce glycogenolysis
and through indirect eects, including inhibition of
lipolysis, reduction in glucagon, and modication of
hypothalamic signalling. Selective reduction of insulin
receptors in the medial area of the arcuate nucleus in
animals is associated with hyperphagia, increased fat
mass, and the rapid development of hepatic insulin
resistance.13 Furthermore, stimulation of hypothalamic
insulin signalling results in about a 40% inhibition of
glucose production. The central eect of insulin is
probably mediated, at least partly, by inhibition of
neuropeptide Y neurones in the arcuate nucleus of the
hypothalamus. Intra-cerebroventricular infusion of
neuropeptide Y in mice leads to the development of
insulin resistance to endogenous glucose production
through the activation of sympathetic drive to the liver.13
Although an undoubtedly important link exists
between insulin and sympathetic regulation, results of
studies in human beings indicate that the sympathetic
nervous response elicited by insulin is heterogeneous.
For example, muscle sympathetic nerve activity increases
in response to acute hyperinsulinaemia and this response
is blunted in obese people, whereas renal noradrenaline
spillover does not change.4 Consistent with no eect on
renal sympathetic outow, we have noted no association
between hyperinsulinaemia and the rate of renal
noradrenaline spillover to plasma in obese people.4 Given
that obesity and hypertension are accompanied by high
rates of noradrenaline spillover from the kidneys, the
mechanisms that underpin the increased sympathetic
outow in obesity in metabolic syndrome might not be
Skeletal muscle conned to hyperinsulinaemia.5,13 Indeed, Gentile and
arteriole colleagues14 examined the eect of weight gain in lean
people and noted that even a slight increase in weight in
rarefection
obese individuals was associated with increased
sympathetic nervous activity with no change in insulin
concentration. Similarly, we have noted an association
between discrete increases in abdominal fat mass and
increased muscle sympathetic activity in people with
metabolic syndrome during a period of overall weight
stabilisation.15

Obesity Hyperinsulinaemia Increased adipokines and Reduced muscle blood Increased adiposity and hyperleptinaemia
non-esteried fatty acids ow and glucose uptake
Body fat, particularly abdominal visceral fat,16 is a major
Insulin resistance
determinant of muscle sympathetic nerve activity.
Products of visceral fat such as NEFAs and leptin might
Sympathetic activation Insulin resistance Insulin resistance contribute to sympathetic activation and to the
Hyperinsulinaemia development of insulin resistance in people with
abdominal obesity. Antigens derived from perivascular
Sympathetic activation Hypertension Sympathetic activation Obesity
fat surrounding the aorta might promote the inltration
of leucocytes into the aorta, kidney, and central nervous
system, and lead to sympathetic activation and
Figure 2: Various theories postulated to link elements of metabolic syndrome and changes in -adrenergic
responsiveness with sympathetic activation hypertension development.17,18 High plasma NEFA
Concepts based on Lansberg and colleagues,6 Reaven,7 Grundy,8 and Julius and colleagues.9 concentrations have been associated with worsening

2 www.thelancet.com/neurology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70033-6


glucose tolerance.19 Studies in human beings have shown
a positive association between high blood pressure and
plasma concentrations of NEFAs,20 and investigators
note that acute increases in NEFA concentrations result
in an increase in 1-adrenoceptor-mediated pressor
sensitivity,21 a rise in blood pressure, and increased
muscle sympathetic activity.22 Although these studies
support the notion of an interaction between NEFAs and
the sympathetic nervous system, Grekin and colleagues23
noted that whole-body and renal noradrenaline spillover
tended to be reduced during fatty acid infusion, despite a
substantial increase in circulating NEFAs.
Researchers have noted a marked rise in muscle
sympathetic activity when healthy lean men are given
leptin.24 Although our own investigations have provided
some support for interactions between leptin and
activation of the renal sympathetic nervous system in
obese individuals,25 whether leptin elicits changes in
brain signalling and acts as a major driver of sympathetic
activation in patients with metabolic syndrome is not
known. However, casting doubt over the importance of
leptin, researchers reported that leptin gene expression
was higher in subcutaneous than in visceral adipose
tissue26 yet sympathetic activity in muscle was not
increased in people with subcutaneous obesity, even
though their plasma leptin concentrations were between
two to three times higher.27 Additionally, results of
longitudinal studies show that rises in plasma
noradrenaline concentrations preceded weight gain and
increases in blood pressure and plasma leptin
concentration.10,11
Hypothalamic-pituitary-adrenal axis activation
Glucocorticoid concentrations can increase in response
to chronic stress and have been linked with the onset of
metabolic disturbances, including hyperinsulinaemia,
insulin resistance, glucose intolerance, hyperlipidaemia,
increased visceral fat mass,28 and the development of
hypertension.29 Activation of the hypothalamic-pituitary-
adrenal axis in response to a stressful life event such as
family bereavement or job change can lead to a rapid and
pronounced increase in weight gain in premenopausal
women.30 Men with high stress and hostility scores are
more likely to have insulin resistance than are those with
very low scores.31 In the Whitehall II study, work-related
stress was related to risk of development of general and
central obesity32 and to about a two-times increase in risk
of development of type 2 diabetes in middle-aged
(3555 years) women.33 Increased 24 h urinary cortisol
and normetanephrine concentrations were noted in
individuals with metabolic syndrome, with behavioural
factors accounting for about 40% of the link between
sympathetic activation and metabolic syndrome.
Obstructive sleep apnoea
Obstructive sleep apnoea is common in obese individuals
and is independently associated with insulin resistance,
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high blood pressure, hyperinsulinaemia, increased
plasma triglyceride concentrations, and decreased HDL
cholesterol concentrations.34 Although muscle sympathetic
nerve activity is higher in people with metabolic syndrome
with obstructive sleep apnoea than in those without,35
sympathetic activity is also increased in lean people with
obstructive sleep apnoea (gure 3).36 Trombetta and
colleagues reported that the increase in sympathetic
activity in metabolic syndrome is at least partly due to
increased chemoreex sensitivity.35 Interestingly, con-
tinuous positive airway pressure reduced sympathetic
drive in obese patients with obstructive sleep apnoea,37
and it improved insulin sensitivity, blood pressure, and
the lipid prole in patients with both obstructive sleep
apnoea and metabolic syndrome.38 The improvement in
insulin sensitivity was greater in lean people than in obese
individuals, suggesting that insulin sensitivity is more
related to the degree of obesity rather than to obstructive
sleep apnoea.38
Results of sympathetic nervous activation in
obesity in metabolic syndrome
Hypertension
Risk estimations ascribe 6575% of the risk for primary
hypertension to overweight and obesity, but the
mechanisms that link obesity and high blood pressure
remain incompletely understood.39 Activation of the
sympathetic nervous system, particularly when directed
towards the kidneys as is commonly evident in obesity,
results in increased renal tubular sodium reabsorption,
*
80 *
*
70
*
*
Bursts per 100 heartbeats
60
50
40
30
Lean Lean with Obese Obese with
obstructive sleep obstructive sleep
apnoea apnoea
Patient groups
Figure 3: Muscle sympathetic nerve activity in lean and obese patients with
and without obstructive sleep apnoea
*p<001. Figure reproduced from reference 36, with permission of Wolters
Kluwer Health.
3
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changes in renal blood ow, and release of renin,
engaging the renin-angiotensin-aldosterone system. In
combination with obesity-induced physical compression
of the kidneys, which is likely to further aggravate
sympathetic stimulation, a blood pressure increase in
obese individuals is an obvious result.40 In obese
adolescents, high blood pressure is associated with
increased urinary catecholamine concentrations and an
unfavourable metabolic prole.41 Pharmacologically
blocking the autonomic system in obese individuals
shows that sympathetic nervous activation has an
important role in increasing blood pressure in obesity.42
In patients with morning hypertension, 1-adrenergic
blockade with doxazosin before sleep improved both
morning blood pressure and insulin resistance.43 Obesity-
related hypertension is characterised by activation of the
sympathetic nervous outows to the kidneys and skeletal
muscle vasculature,13 with recruitment of previously
silent bres the salient feature that characterises the
pattern of sympathetic activation.44 Importantly, although
this pattern of sympathetic activation could underpin the
pathophysiology of hypertension in obesity, activation of
the sympathetic nervous system is also evident in obese
normotensive people.44
Insulin resistance
The physiological association between insulin and
sympathetic nervous activation is complex. Increased
circulating insulin might drive a regional increase in
sympathetic activity, but, given that sympathetically
mediated vasoconstriction could antagonise insulins
eect on glucose uptake via a secondary eect on blood
ow in skeletal muscle, hyperinsulinaemia might be a
result rather than a cause of sympathetic activation in
obese people.5 It is not known whether blood ow in
skeletal muscle is reduced in obesity and contributes to
the development of insulin resistance. In young people
with metabolic syndrome, forearm blood ow is
increased despite increased muscle sympathetic
vasoconstrictor nerve activity and increased
2-adrenergic-mediated responsiveness.45 Raison and
colleagues46 noted increased blood ow in skeletal muscle
in obese hypertensive patients, whereas Ribeiro and
colleagues47 noted an association between degree of
sympathetic activation and reduction in forearm blood
ow in obese women.48 An acute increase in activation of
the sympathetic nervous system, within the normal
range of physiological responses, caused acute insulin
resistance in the forearm of healthy individuals.49
Hyperglycaemia
In the liver, noradrenaline-immunoreactive bres arise
from the coeliac and superior mesenteric ganglia and
project to hepatocytes.50,51 Direct electrical stimulation of
the splanchnic nerve leads to an increase in activity of
liver glycogen phosphorylase and glucose-6-phosphatase,
and a rapid and sustained increase in circulating glucose
4 www.thelancet.com/neurology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70033-6
concentrations.3 Data from studies in dogs indicate that
the hepatic sympathetic nerves inhibit liver glucose
uptake and that hepatic sympathetic denervation leads to
an increase in net hepatic glucose uptake in response to
hyperglycaemia.52 Impaired glucose tolerance and insulin
resistance are commonly noted in patients with liver
cirrhosis.53 After liver transplantation, glucose tolerance
and insulin sensitivity are markedly improved, largely
through improvements in hepatic glucose clearance and
peripheral glucose disposal.54 These results indicate that
therapeutically targeting the hepatic sympathetic outow
could provide clinical benet to patients with prediabetes
or type 2 diabetes.
Organ damage
In addition to metabolic eects, chronic activation of the
sympathetic nervous system favours the development
and progression of target organ damage. Of particular
importance is damage to the kidney, heart, and
vasculature.
Regional sympathetic activation, with evidence for
increased sympathetic nervous outow to the kidneys,
occurs in obese individuals and in patients with
hypertension.4 Obesity is independently associated with
the development of end-stage renal disease.55 Overweight
(BMI >25 kg/m) at age 20 years has been linked to about
a three times increased risk of development of chronic
renal failure later in life.56 Moreover, the presence of
obesity poses a large risk for progressive renal
impairment in patients with established renal disease.57,58
Researchers have described an increased prevalence of
microalbuminuria59 and diminished renal function60 in
individuals with metabolic syndrome. Proteinuria and
the progressive development of renal dysfunction in
obese individuals occurs even in the absence of severe
hypertension and diabetes.61 In obese people, high blood
pressure, glomerular hyperltration, neurohumoral
activation, and metabolic changes that persist might
initiate further renal injury. Other factors such as
activation of the renin-angiotensin system, compression
by fat accumulation within and around the kidneys, and
increased abdominal pressure could further aggravate
and worsen renal impairment.40
Studies have shown a detrimental eect of obesity on
cardiac structure and function. Obesity is an
independent predictor of left ventricular diastolic
dysfunction in the general population.62 Left ventricular
hypertrophy in people with metabolic syndrome can
occur irrespective of the magnitude of blood pressure
rise,63 indicating that other components of metabolic
syndrome could exert adverse trophic eects on the
heart. Insulin stimulates growth of vascular smooth
muscle cells in isolated human arterioles,64 and
structural alterations in the heart in normotensive
people are related to concentrations of triglycerides and
glucose.65 Our data show an increased sympathetic
activity after the transition from impaired glucose
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tolerance to type 2 diabetes that is associated with
cardiac enlargement, diastolic dysfunction,66 and
impairment in noradrenaline transporter function.67 In
patients with hypertension, development of left
ventricular hypertrophy is directly linked to the amount
of spillover of cardiac noradrenaline into plasma and to
reduced neuronal noradrenaline reuptake.68 In patients
with impaired glucose tolerance, a defect in sympathetic
innervation has been shown.69 Increased noradrenaline
concentrations might be linked to a reduction in the
expression of nerve growth factor, a molecule that is
essential for the viability of sympathetic nerves.70
Importantly, the eects of increased bodyweight on the
heart are evident even at young ages. Cardiac structure
has been associated with the degree of sympathetic
activation in young overweight and obese individuals
(gure 4).71 Wong and colleagues72 noted that overweight
people aged about 45 years had subclinical changes in
left ventricular structure and function, even after
adjustment for blood pressure, age, sex, and left
ventricular mass. Data from the Bogalusa Heart Study
indicated that the presence of obesity since childhood
was the only consistent and signicant determinant of
adverse cardiac remodelling.73 Signicant improvements
main driver in sympathetic neural adaptation. This
pattern of sympathetic activity and its association with
obesity might be aected by factors such as ethnic origin
and sex. In African Americans, sympathetic activation is
strongly associated with BMI in women, whereas in
men, increased muscle sympathetic activity is present in
lean people.81 Consistent with these ndings, diet-
induced weight loss in black women was associated with
a signicant reduction in leptin, abdominal fat mass, and
sympathetic activity, whereas in black men, despite the
loss of 11 kg and a diminution in plasma leptin and
visceral abdominal fat, sympathetic activity was
unchanged.82
Pharmacological therapy
In addition to weight reduction and exercise,
pharmacological inhibition of the sympathetic nervous
system might be a rational therapeutic approach for
Muscle sympathetic nerve activity Endothelial function
80 25
70
20

Peripheral arterial tonometry ratio

60
in cardiac structure and function have been reported
Bursts per 100 heartbeats

after surgically induced weight loss in severely obese 50

15

adolescents.74 Investigators have reported markers of
40
vascular damage, including arterial stiening,75
endothelial dysfunction,76 and increased carotid intima- 10
30
media thickness,77 in people with metabolic syndrome.
20
Some evidence exists for a link between sympathetic 05
activation and endothelial dysfunction.78 10

Therapeutic implications 0 0
The sympathetic nervous system as a target for therapy Creatinine clearance Left ventricular mass
At present, the main goal in treatment of patients with 250 150
metabolic syndrome is to control individual risk factors
such as overweight and obesity, high blood pressure, and
200
changes in glucose and lipid concentrations. We now
Creatinine clearance (mL/min)

Left ventricular mass index

examine the eects of common therapies for metabolic 100

syndrome on sympathetic activation, and then explore 150
*
the potential of direct modulation of activity of the
sympathetic nervous system as a therapeutic strategy.
100
50
Weight loss and exercise
Weight loss and exercise are key treatments for obesity 50
and metabolic syndrome. Short-term exercise training is
consistently associated with a reduction in sympathetic
0 0
nervous activity and an improvement in blood pressure. Lean individuals Overweight or obese Lean individuals Overweight or obese
In people with metabolic syndrome, weight loss after a individuals individuals

12 week dietary programme was accompanied by a
signicant reduction in sympathetic nervous activity and
an improvement in all components of metabolic
syndrome.79 A subsequent study showed that the addition
of moderate-intensity aerobic exercise training to a
hypocaloric diet did not have additional benets for
sympathetic tone,80 suggesting that weight loss was the
Figure 4: Markers of sympathetic nervous activation and subclinical organ damage in young obese people
Sympathetic overactivation is already evident in very early stages of obesity (mean age 226 years [SE 07] years;
BMI 308 kg/m [11]; range 261501 kg/m) compared with age-matched lean people (226 [07] years;
209 kg/m [04], 180247 kg/m) and is associated with early markers of subclinical organ damage. Comparisons
between young lean people and young overweight or obese people for muscle sympathetic nerve activity,
endothelial function, creatinine clearance (with evidence of hyperltration in overweight or obese patients), and
left ventricular mass index are shown. *p<005, p<001, p<0001. Reproduced from reference 71 with permission
of Wolters Kluwer Health.

www.thelancet.com/neurology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70033-6 5

 Personal View
metabolic syndrome. Rather than being secondary to or
reliant on weight reduction, benet associated with
sympatho-inhibition might be associated with a reduction
in end-organ damage. Several pharmacological approaches
can lower sympathetic inhibition. -adrenergic blockers
improve blood pressure levels and cholesterol and
triglyceride concentrations.83 Decisions about whether the
use of -blocker drugs are appropriate in obese people are
problematic. Investigations done from 1986 to 1998 clearly
indicated that blockers such as metoprolol, atenolol, and
propranolol were associated with weight gain (particularly
in the rst few months of use) and a worsening of insulin
resistance and lipid prole, thereby favouring the tendency
of metabolic syndrome patients to develop diabetes.84 By
contrast, use of carvedilol in the GEMINI trial did not lead
to substantial weight gain85 and was associated with an
improvement in lipid prole86 and insulin resistance,87 and
a large reduction in microalbuminuria.88
Statins are potent inhibitors of cholesterol biosynthesis
and their use is established for the primary and secondary
prevention of coronary artery disease. Statins improve
endothelial function, inammation, and oxidative stress in
patients with hypercholesterolaemia and atherosclerosis.
Additional pleiotropic eects of statins include an ability to
modulate sympathetic nervous activity.89 Investigators have
linked increased plasma cholesterol concentrations, even
in the high-to-normal range, to sympathetic nervous
activation and impaired endothelial function in young,
otherwise healthy, women.90 Clinical studies show that
simvastatin reduces muscle sympathetic activity.91,92 In
men with hypertension and hypercholesterolaemia, the
improvement in lipid prole that occurred after 8 weeks of
statin treatment was accompanied by a signicant
reduction in muscle sympathetic activity and increased
baroreex sensitivity.91 In patients with non-
hyperlipidaemic hypertension, simvastatin lowered
muscle sympathetic activity and improved endothelium-
independent vasodilation without aecting plasma lipids.92
Angiotensin-converting enzyme inhibitors and
angiotensin-receptor blockers protect the kidney and
heart.93,94 Whether these eects are mediated by interactions
between the renin-angiotensin and sympathetic nervous
systems is not known. Intracoronary infusion of
angiotensin 2 enhances, and intracoronary inhibition of
angiotensin-converting enzyme attenuates, sympa-
thetically mediated coronary vasoconstriction in patients
with mild to severe coronary artery disease,95,96 indicating
that the renin-angiotensin system might allow sympathetic
nerve ring. Contrary to this notion, researchers did not
show a signicant eect for angiotensin-receptor blockade
on muscle sympathetic nerve activity or the rate of spillover
of noradrenaline to plasma in hypertensive patients.97,98
Both candesartan and telmisartan similarly reduced blood
pressure in individuals with metabolic syndrome, but
telmisartan had a larger eect on endothelial function and
was associated with a reduction in circulating
noradrenaline concentrations.99
6 www.thelancet.com/neurology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70033-6
Imidazoline I1 receptor agonists act centrally, at the level
of the rostral ventrolateral medulla, to inhibit sympathetic
drive and reduce blood pressure. Drugs in this class, such
as moxonidine and rilmenidine, improve glucose
metabolism and insulin sensitivity100,101 and are associated
with a reduction in the progression of microalbuminuria
and renal dysfunction.102,103 Other benecial eects on end-
organ function include reduced left ventricular
hypertrophy104 and improved endothelial function.105
However, whether these drugs should be used
preferentially should be used preferentially over other
drug classes in patients with metabolic syndrome and
obesity-related hypertension remains to be shown.
Device-based therapeutic approaches
Catheter-based renal denervation is a novel approach to
more directly target the sympathetic nervous system.
Clinicians previously used surgical sympathectomy to
target sympathetic overactivity in patients with
uncontrollable high blood pressure, substantially
improving cardiovascular outcomes. Endovascular
catheter technology now allows selective denervation of
the human kidney using radiofrequency energy delivered
via the renal artery lumen.106 Investigators have done
clinical trials with this minimally invasive technique to
assess its safety and ecacy to lower uncontrolled blood
pressure in patients with resistant hypertension.
Additional potential benets have been described,
particularly improvements in glucose metabolism, in
line with the pathophysiological considerations described
earlier and the close interaction between the sympathetic
nervous system and glucose metabolism. Catheter-based
renal denervation not only lowers renal sympathetic
nerve activity, reducing renal noradrenaline spillover by
about 50%,106 but also reduces whole-body sympathetic
nerve activity and muscle sympathetic nerve activity.107
Increased sympathetic outow to the skeletal muscle
vasculature has an important role in glucose metabolism,
mainly through reduced skeletal muscle blood ow and,
as a result, diminished uptake of glucose, a hallmark of
insulin resistance.49
Data from patients that undergo renal denervation for
resistant hypertension provide evidence to suggest that
sympathetic inhibition with this approach can lower
blood pressure and benecially aects glucose
metabolism.108 Of 50 patients with resistant hypertension,
37 underwent renal denervation and 13 continued on
their medication regimen as a control group. In addition
to signicant reductions in blood pressure after
1 and 3 months, the investigators noted reduced fasting
glucose, insulin, C-peptide, and HOMA index, as well as
reduced 2 h glucose during an oral glucose-tolerance test,
in patients who underwent renal denervation. By contrast,
they reported no signicant changes in blood pressure or
metabolic markers in the control group (gure 5).
Researchers reported similar outcomes after a study of
renal denervation in ten patients with obstructive sleep
 Personal View

Fasting glucose Fasting insulin

175 p=0366 Renal denervation (n=33) p=0328
15
Control (n=14)
Change in fasting glucose concentration (mg/dL)

Change in fasting insulin concentration (U/mL)

125
10
75 p=0506
5
25 +12
+76 +74
0
68 130 77 89 21
25
5 p=0404
75

10
125 p=0011
p=0033
p=0033
175 p=0006 15

Fasting C-peptide HOMA-IR

20 5
p=0353 p=0143
Change in fasting C-peptide concentraion (ng/ML)

15 4
10
p=0944 3
05
Change in HOMA-IR (ng/mL)

+07 +01 2
00
20 21
05 1
+25
10 0
29 35 09
15 1
20
2 p=0308
25
p=0039 3
30 p=0007
35 4 p=0037
40 5 p=0003
1 month 3 months 1 month 3 months

Figure 5: Changes in fasting glucose, insulin, C-peptide, and HOMA-IR index, after renal denervation in patients with resistant hypertension
P values refer to dierence compared with baseline in same patients. HOMA-IR calculated from the product of fasting plasma glucose and insulin divided by 405.
HOMA-IR=homoeostasis model assessment for insulin resistance. Used from reference 108, with permission of Wolters Kluwer Health.

apnoea.109 Most patients had a decrease in the severity of activation of the sympathetic nervous system has been
obstructive sleep apnoea after renal denervation, and clearly documented both in animals and in human beings
they also had signicantly changed 2 h glucose with obesity and metabolic syndrome. Furthermore,
concentrations during an oral glucose-tolerance test, and disorders commonly associated with obesity and metabolic
reduced HbA1c after 6 months. Investigators using a syndrome, such as hypertension, diastolic dysfunction,
hyperinsulinaemiceuglycaemic clamp technique to and renal impairment, are modulated by the sympathetic
assess insulin sensitivity reported that two patients with nervous system. Mechanistically, sympathetic nervous
resistant hypertension and metabolic disturbances activation aects relevant aspects of the pathophysiology
associated with polycystic ovary syndrome had improved that underlies obesity and its metabolic eects, perhaps
insulin sensitivity associated with reductions in best shown by insulin resistance occurring in response to
sympathetic nerve activity induced by renal denervation.110 an acute increase in sympathetic drive. Although the exact
These data are promising, but preliminary; additional nature of the association between sympathetic activation
studies are needed to dene the mechanisms by which and the metabolic results of obesity remains to be
renal denervation can lower blood glucose and improve determined, some evidence suggests a key role for the
insulin sensitivity in patients with resistant hypertension sympathetic nervous system in the generation of obesity
or other cardiovascular diseases. and metabolic syndrome. Common metabolic syndrome
treatments such as weight loss and exercise have been
Conclusions and future directions associated with large reductions in the activity of the
Aside from its well described eects on cardiovascular sympathetic nervous system. To target the sympathetic
control, accumulating data from laboratory and clinical nervous system directlyeither with drugs or with novel
studies now provide compelling evidence for an important device-based interventionsseems to be a logical and
role for the sympathetic nervous system in obesity and attractive next step, particularly since many patients with
metabolic syndrome. With use of state-of-the-art methods, obesity and metabolic syndrome do not achieve sustained

www.thelancet.com/neurology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70033-6 7

 Personal View
Search strategy and selection criteria
We searched Medline and Embase with the terms
sympathetic, metabolic syndrome, diabetes,
dyslipidemia, insulin resistance, hypertension, and
obesity. We limited our search to articles written in English
and published between Jan 1, 2000, and June 30, 2013, but did
not exclude commonly referenced and highly regarded older
articles. We read the relevant papers and used their
bibliographies further to identify other works for inclusion.
weight loss. Although promising preliminary data exist,
further studies are needed to substantiate the role of the
sympathetic nervous system as a useful therapeutic target.
Contributors
All authors contributed to the conception and design, acquisition of data,
or analysis and interpretation of data for this Personal View; drafted or
revised the Personal View; and approved the nal version.
Declaration of interests
MS and GL receive research funding from the National Health and
Medical Research Council of Australia (NHMRC), Medtronic, Abbott
Pharmaceuticals, Servier Australia, and Allergan, and are supported by
NHMRC Research Fellowships. MS serves on scientic advisory boards
for Abbott Pharmaceuticals, Novartis Pharmaceuticals, and Medtronic,
and has received honoraria and travel support from Abbott, Servier,
Novartis, MSD, Boehringer Ingelheim, and Medtronic. GL has acted as a
consultant for Medtronic and has received honoraria or travel support
for presentations from Pzer, Wyeth Pharmaceuticals, Servier, and
Medtronic. NS receives research funding from the NHMRC, National
Heart Foundation, and Diabetes Australia. EL receives research funding
from the NHMRC.
Acknowledgments
The writing of this Personal View was supported by the NHMRC and, in
part, by the Victoria Governments Operation Infrastructure Support
Program.
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