1. health and fitness
2. disease

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2006, 57, Suppl 11, 79–92
www.jpp.krakow.pl
M. SINSKI , J. LEWANDOWSKI , P. ABRAMCZYK , K. NARKIEWICZ , Z. GACIONG
1
1
1
2
1
WHY STUDY SYMPATHETIC NERVOUS SYSTEM?
Department of Internal Diseases, Hypertension and Vascular Disease, Warsaw Medical University,
1
Warsaw, Poland,
Department of Hypertension and Diabetology, Medical University of Gdansk,
2
Gdansk, Poland
Cardiovascular diseases are the most frequent causes of morbidity and mortality
around the world. However, during last decades, an improvement was made in
diagnosis and therapy of cardiovascular diseases, there was still a need for better
understanding of their pathophysiology. Among neurohormonal systems, SNS plays
a central role in cardiovascular regulation in both health and disease. Involvement of
SNS in pathogenesis of hypertension, coronary artery disease or heart failure is well
known
and
proved.
Methods
such
as
and
its
microneurography,
direct
catecholamine
measurements, heart rate variability or baroreflex sensitivity assessment allowed
studying
sympathetic
activity
influence
on
cardiovascular
disorders.
Although introduced into scientific practice methods of SNS evaluation are not
commonly used in the clinic. However, two of the methods: analysis of heart rate
variability
(HRV)
and
baroreflex
sensitivity
(BRS)
were
recommended
as
the
diagnostic tools and can be found in clinical guidelines as basic assessment methods.
Key
w o r d s : sympathetic nervous system, noradrenaline, microneurography, HRV, BRS
INTRODUCTION
The aim of this article is to summarize the role of sympathetic nervous system
(SNS) in cardiovascular pathophysiology and describe how methods for studying
sympathetic activity influence clinical practice. There is no doubt about the great
increase in the knowledge on neuroregulation of cardiovascular system during
last
3
decades.
Methods
such
as
microneurography,
direct
catecholamine
measurements, heart rate variability or baroreflex sensitivity assessment allowed
studying pathophysiology of cardiovascular diseases. What is most important,
80
data obtained using those methods changed clinical practice. Some of them were
also introduced into clinic as a diagnostic tool.
Studies on SNS changed clinical practice
Cardiovascular diseases are the most frequent causes of morbidity and mortality
around the world. However, during last decades, an improvement was made in
diagnosis and therapy of cardiovascular diseases, there was still a need for better
understanding
of
their
pathophysiology.
Among
neurohormonal
systems,
SNS
plays a central role in cardiovascular regulation in both health and disease (1 - 5).
Activation of SNS can increase peripheral vascular resistance and cardiac output to
raise blood pressure. Arteriolar vasoconstriction, as well as sympathetic mediated
venoconstriction
with
consequent
central
redistribution
of
blood,
both
acts
to
increase blood pressure. Cardiac sympathetic chronotropic and inotropic effects
also
increase
blood
pressure,
particularly
in
the
setting
of
increased
vascular
resistance. Thus, increased sympathetic traffic to the peripheral vasculature and
sympathetic discharge to the heart exert complementary effects on blood pressure.
Activation of SNS may also contribute to blood pressure levels in the long term by
other
mechanisms.
Effects
of
sympathetic
activation
on
the
kidney,
renin-
angiotensin system, blood vessel growth and permeability as well as resetting of the
arterial baroreflex should be mentioned.
In a few past decades, convincing data were collected to support theory that
enhanced
sympathetic
cardiovascular
activity
diseases.
was
Numerous
involved
data
in
pathogenesis
from
various
of
many
observations
overwhelmingly attest to the importance of the SNS in essential hypertension,
particularly in its early stages (2, 3). Increased sympathetic tone was also proved
to promote development and progression of hypertension related complications
that led to increased cardiovascular morbidity and mortality. Different techniques
were involved to quantify sympathetic cardiovascular effects in humans with
essential hypertension. First, tachycardia is the simplest and probably the most
reliable marker of sympathetic overactivity in humans with hypertension. An
association of tachycardia with higher blood pressure has been found in numerous
investigations and both a simultaneous elevation of the heart rate and plasma
catecholamines
were
reported
in
hypertensives.
In
some
observations,
it
was
described that in normotensive subjects tachycardia might predict development of
future hypertension. Also, an association of tachycardia and increased cardiac
output
was
found
as
a
characteristic
feature
of
early
stages
of
essential
hypertension. Secondly, important information regarding sympathetic activity in
hypertension has come from techniques that assay in a sensitive fashion plasma
level of sympathetic neurotransmitter - noradrenaline. Although a number of early
comparisons between normotensive and hypertensive individuals led to equivocal
results, a meta-analyses of published data did show that essential hypertensive
patients displayed greater plasma noradrenaline values than normotensives (6).
81
Thirdly,
other
biochemical
and
neurophysiological
approaches,
such
as
the
noradrenaline radiolabeled technique and the microneurography, have provided
further evidence of sympathetic overactivity in hypertensive individuals. In some
studies,
use
of
the
noradrenaline
-
radiolabeled
tracer,
which
estimates
the
secretion of noradrenaline from the sympathetic nerve terminals, confirmed a
greater sympathetic activity in young hypertensive subjects as compared to agematched normotensive individuals (7). An introduction of the microneurography
to
scientific
routine
has
provided
further
data
that
showed
an
increase
of
sympathetic drive in essential hypertension. Microneurography was also used to
demonstrate sympathetic enhancement during subsequent stages of hypertension.
It was confirmed that sympathetic activity might be increased in normotensive
subjects with a family history of hypertension and especially in subjects with
borderline hypertension as compared to normotensive subjects (8, 9) and might
progressively
increase.
In
addition,
an
increase
in
sympathetic
traffic
was
presented also in older patients with isolated systolic hypertension (10).
Knowledge regarding enhanced sympathetic activity in patients with essential
hypertension has many practical implementations and is currently employed in
daily
clinical
routine.
Common
use
of
antiadrenergic
agents
in
therapy
of
hypertension might be an example.
Apart of hypertension, sympathetic overactivity has been implicated in the
pathogenesis of other diseases as metabolic disorders, coronary artery disease,
cardiac
arrhythmias
or
heart
failure.
Studies
using
microneurography
have
consistently shown increased muscle sympathetic nerve activity in obese subjects.
Earlier data based on plasma catecholamine measurements and whole-body and
regional noradrenaline release revealed inconsistient results (11, 12). However,
recent observations suggest that obesity in humans is associated with increased
sympathetic outflow and that body fat is a major determinant of sympathetic neural
discharge. Moreover, sympathetic overactivity is also involved in pathogenesis of
metabolic
syndrome.
Primarily
enhanced
sympathetic
drive
can
produce
vasoconstriction, diminish the regional blood flow and tissue glucose delivery, and
thus generate insulin resistance, a key phenomenon in pathogenesis of many
metabolic and cardiovascular disorders. Some other mechanisms of sympathetic
influence
on
insulin
resistance
are
also
described.
Activation
of
adrenergic
peripheral ß-receptors changes proportion between slow and fast twitch muscle
fibers and decreases number of small blood vessels in the skeletal muscles (13).
Increased sympathetic drive in hypertensive subjects may be independently
implicated in atherosclerotic vascular disease, especially coronary artery disease
and associated fatal cardiovascular events. Although coronary artery disease has
a multifactorial origin sympathetic overdrive can be crucial for its development.
Increased
sympathetic
activity
induces
vascular
and
cardiac
hypertrophy,
produces coronary vasoconstriction and increases cardiac oxygen consumption.
Procoagulative
endothelial
state,
activation
dysfunction
are
of
also
platelets,
well
increased
recognized
hematocrit
results
of
level
and
sympathetic
82
overactivity
(13).
parasympathetic
electrolytes
In
addition
system
may
as
exert
well
an
as
imbalance
between
sympathetically
proarrhytmic
action
sympathetic
mediated
and
induce
and
disturbances
life
in
frightening
arrhythmias. Another evidence for a role of sympathetic overactivity in ischemic
heart disease is the efficacy of pharmacological ß-blockade in decreasing cardiac
death
in
showed
patients
that
after
myocardial
sympathetic
activity
infarction
was
(14).
more
Numerous
pronounced
studies
after
clearly
myocardial
infarction than after unstable angina, while sympathetic activity in patients with
stable angina did not differ from that in control subjects (15). This observation
may at least in part explain why patients with both myocardial infarction and
unstable ischemic syndromes are at increased risk of sudden cardiac death.
There is also a growing body of evidence that elevated sympathetic activity
plays an important role in the pathophysiology of congestive heart failure. Early
studies has shown an increased plasma noradrenalin concentration and total,
cardiac and renal noradrenaline spillover in patients with congestive heart failure
(16). Later studies demonstrated that prognosis in cardiac failure was directly
linked to the level of activation of the SNS and most strongly with that in the high
sympathetic outflow to the heart (17, 18). Finally, one of the major advances in
cardiology of the past years has been the successful introduction of ß-adrenergic
drugs to the therapy of cardiac failure, which has substantially improved the
clinical outcome in patients with congestive heart failure.
METHODS OF EVALUATION OF THE SYMPATHETIC NERVOUS SYSTEM
Measurements of urine and plasma noradrenaline
Traditionally, activity of the SNS was assessed using measurements of urine
noradrenaline and adrenaline or their precursors and metabolites. However, this
"static" approach cannot provide reliable assessment of short-term changes in
sympathetic activity and, therefore, has been replaced by measurement of plasma
noradrenaline concentration. These measurements provide useful information,
but
also
have
significant
limitations
(19).
First,
circulating
noradrenaline
represents only a small fraction (5 - 10%) of the amount of neurotransmitter
secreted
from
influenced,
nerve
in
terminals.
addition
to
the
Second,
level
plasma
of
levels
sympathetic
of
noradrenaline
neural
outflow,
are
by
prejunctional modulation of neurotransmitter release, as well as the clearance,
metabolism
and
uptake
of
noradrenaline
from
the
circulation.
Thus,
plasma
measurements do not allow discrimination between central (increased secretion)
and
peripheral
(reduced
clearance)
mechanisms
of
inreased
levels
of
the
neurotransmitter (5). Third, the use of plasma noradrenaline is based on the
assumption
Contrary
to
that
this
these
measurements
assumption,
there
reflect
are
"overall"
profound
sympathetic
regional
activity.
differences
in
the
activity and control of sympathetic function. Furthermore, the reproducibility and
83
sensitivity
of
plasma
noradrenaline
values
are
lower
than
those
of
microneurographic recordings (20).
Value of plasma catecholamines measurement is increased if it is combined
with assessment of responses to adrenergic antagonists and agonists. Using this
approach, it has been shown that mildly hypertensive individuals had elevated
plasma
noradrenaline
response to
estimated
levels,
α-adrenergic
by
augmented
decreases
in
blockade, and no increase in
responses
to
noradrenaline
(21).
vascular
α-receptor
This
study
resistance
in
sensitivity as
demonstrated
augmented sympathetic vasoconstrictor activity in young mildly hypertensive
humans,
suggesting
that
increased
sympathetic
vasoconstriction
results
from
enhanced sympathetic neural release of noradrenaline, and not from augmented
α-adrenergic response to the neurotransmitter.
Noradrenaline spillover rate measurements
The noradrenaline radiolabeled method is based on intravenous infusion of
small amounts of tritiated noradrenaline, which allows tissue clearance of this
substance to be subtracted from plasma noradrenaline values and to make the
remainder a marker of the neurotransmitter "spillover" from the neuroeffector
junctions. This "spillover" in steady-state conditions mirrors the secretion of
noradrenaline
"spillover"
from
technique
the
sympathetic
avoids
the
nerve
terminals.
confounding
influence
The
of
noradrenaline
neurotransmitter
clearance and permits assessment of noradrenaline release from specific target
organs
(22).
Hypertension,
in
particular
"early"
hypertension,
may
be
characterized by increased sympathetic traffic not only to the heart and blood
vessels, but also to the kidneys. Using measurements of noradrenaline spillover,
Esler et al. (23) found that noradrenaline release was elevated in hypertensive
patients, particularly in young hypertensives, and that the increased spillover
occurred mainly from the heart and kidneys.
Using jugular vein noradrenaline spillover measurements, Ferrier et al. (24)
have reported that higher sympathetic activity in hypertension may be explained
by increased cerebral noradrenaline release, mostly from subcortical forebrain
regions. The same group of investigators subsequently reported that subcortical
noradrenaline release was linked with both total body noradrenaline spillover as
well as renal noradrenaline spillover (25). Since the forebrain is involved in the
emotional responses (especially the defense reaction) it has been suggested that
increased noradrenaline spillover from certain subcortical regions may represent
a neurochemical manifestation of stress.
Quantitative
demonstrated
assessment
impairment
of
of
tritiated
noradrenaline
noradrenaline
transporter
uptake
from
function
in
plasma
essential
hypertension (26). The potential role of impaired neuronal noradrenaline reuptake
can
be
directly
desipramine
assessed
(27).
by
Finally,
infusion
of
noradrenaline
the
noradrenaline
stores
in
the
transport
human
heart
inhibitor
could
be
84
estimated by quantifying the processing inside sympathetic nerves of tritiated
noradrenaline to its intraneuronal metabolite, dihydroxyphenylglycol (DHPG),
coupled with measurement of DHPG in coronary sinus plasma (28, 29).
Microneurography
Direct intraneural recordings using microneurography provide a moment-tomoment
measure
of
central
sympathetic
neural
outflow
independent
of
the
influence of the neuro-effector junction. This technique involves the recording of
multiunit
sympathetic
nerve
discharge
from
a
peripheral
nerve,
usually
the
peroneal nerve (30, 31). Sympathetic nerve activity is recorded using tungsten
microelectrodes (shaft diameter 200 µm, tapering to an uninsulated tip of 1 - 5
µm)
inserted
selectively
into
muscle
or
skin
fascicles.
Recently,
micronuerographic approach allowed also quantification of single-fibre muscle
sympathetic nerve traffic (32, 33).
Microneurography permits separate recordings of sympathetic nerve activity
to muscle (MSNA) vessels or skin (SSNA). MSNA reflects the vasoconstrictor
signal to the skeletal muscle vasculature, is acutely sensitive to blood pressure
changes,
and
is
closely
regulated
by
the
arterial
and
cardiopulmonary
SSNA
7:
MSNA
7:
Fig. 1. Recordings of skin and muscle sympathetic nerve activity in a normal subject. Duration of
each muscle sympathetic nerve activity burst is limited by the cardiac cycle; skin sympathetic nerve
activity bursts are broad based and may extend over several cardiac cycles. Both Recordings were
performed in the young patient with essential hypertension.
85
Low MSNA
High MSNA
Fig. 2. Recordings of muscle sympathetic nerve activity illustrating low (top) and high (bottom)
activity. Recordings were performed in the young patient before and after 1minute apnea.
baroreflexes.
SSNA
baroreflexes.
At
vasomotor
activities
neural
present
is
rest,
not
in
traffic
(34).
a
to
altered
room
skin
MSNA
by
either
temperature
blood
and
vessels
SSNA
arterial
or
cardiopulmonary
environment,
SSNA
with
any
differ
little
if
markedly
with
reflects
sudomotor
regard
to
morphology (Fig. 1). SSNA bursts are broad based and may extend over several
cardiac cycles. The duration of each MSNA burst is limited by the cardiac cycle.
Measurement
of
sympathetic
nerve
activity
from
peripheral
nerves
in
humans has been shown to be safe, accurate, quantifiable and reproducible (35).
Also
important
is
that
simultaneous
measurements
of
sympathetic
nerve
activity from different limbs show identical profiles in terms of burst frequency
and
morphology. Thus, recordings in one limb can be reliably assumed to
reflect recordings of sympathetic nerve activity to the muscle vascular bed
throughout the body (36).
The neural signals are amplified, filtered, rectified, and integrated to obtain a
voltage display of sympathetic nerve activity. Sympathetic bursts are identified by
a careful visual inspection of the voltage neurogram or by dedicated software.
Muscle sympathetic nerve activity can be expressed as bursts per minute and
burst per 100 heart beats, which allows comparison of sympathetic discharge
between individuals (Fig. 2). The amplitude of each burst can also be determined
and sympathetic activity may be calculated as bursts/minute multiplied by mean
burst amplitude and expressed as units/minute. Measurements of nerve activity at
baseline before each intervention are expressed as 100%. Changes in integrated
86
MSNA
allow
evaluation
of
within
subject
changes
in
sympathetic
traffic
in
response to different stressors during the same recording session.
The introduction of microneurography has enabled a direct evaluation of the
reflex sympathetic neural response to chemoreflex stimulation. These studies
have documented that the peripheral and central chemoreflexes have powerful
effects on sympathetic activity in both health and disease and may contribute
importantly
to
disease
pathophysiology,
particularly
in
conditions
such
as
hypertension (37), obstructive sleep apnea (38) and heart failure (39).
Although
described
introduced
above
are
into
not
scientific
commonly
practice
used
in
methods
the
of
clinic.
SNS
evaluation
Limitations
and
disadvantages of the various techniques has been reviewed in greater details
elsewhere (19). However two of the methods: analysis of heart rate variability
(HRV) and baroreflex sensitivity (BRS) were recommended as the diagnostic
tools and can be found in clinical guidelines as basic assessment methods.
Heart rate variability
For more than 20 years spectral analysis of heart rate variability was used to
assess autonomic control of the heart (40). Assessment of heart rate variability
(HRV) is based on the analysis of consecutive sinus rhythm R-R intervals and
may provide quantitative information about the modulation of cardiac vagal and
sympathetic nerve activities. HRV measurements can be derived from short term
(2
to
5
minutes)
or
long-term
ECG
recordings
(24
to
48
hours).
It
can
be
quantified in a number of ways but techniques of conventional time domain
(statistical and geometrical) and frequency domain measurements (power spectral
density) remain predominantly utilized. Recently (41), analysis of heart rate
dynamics by methods based on non-linear system theory has been introduced,
which may be an alternative way for studying the abnormalities in heart rate.
In normal humans, short term RR interval variability occurs predominantly at
a low frequency (0.04 to 0.14 Hz) and a high frequency (±0.25 Hz, synchronous
with the respiratory frequency) (Fig. 3). The respiratory-related HF component is
attributed mainly to vagal mechanisms. By contrast, different hypotheses have
been proposed for the LF oscillation of RR interval variability. In several studies,
LF component was not related to rates of noradrenaline spillover from the heart
and or muscle sympathetic nerve traffic (19). Thus, while the LF/HF ratio may be
considered as a marker of sympatho-vagal balance, it is unjustified to consider the
low frequency power as a surrogate measure of sympathetic nerve firing.
HRV as an independent cardiovascular risk factor
The closely monitored elderly population from the Framingham Heart Study
was assessed using HRV calculated from 2-hour ambulatory ECG recordings. It
was found that HRV was significantly associated with all-cause mortality and
provided
additional
assessment
of
cardiovascular
risk
regardless
traditional
87
Fig. 3. Spectral analysis of simultaneous recordings of RR variability in a patient with heart failure
(low) and in a control subject (high). There is a relative predominance of the LF component over
the HF component of RR interval in the patient with heart failure.
cardiovascular
risk
factors.
A
later
study
showed
that
HRV
was
also
an
independent risk factor in the healthy cohort of the Framingham study (42).
HRV in sudden cardiac death (SCD) and coronary heart disease risk
assessment
HRV analysis was found useful in risk stratification for SCD in patients with
heart failure. High LF values obtained during controlled breathing were found
predictive of sudden cardiac death (43). HRV analysis was also classified as
recommendation Class I A for risk assessment by the Task Force on Sudden
Cardiac Death of European Society of Cardiology (44). It was also found that low
HRV predicts risk in coronary heart disease (45).
HRV in diabetes
Diabetic
autonomic
neuropathy
is
one
of
major
complication
of
diabetes
contributing significantly to the morbidity and mortality of the disease. Although
traditional
measures
and
symptoms
of
autonomic
function
like
resting
88
tachycardia,
exercise
gastroparesis,
intolerance,
erectile
orthostatic
dysfunction,
hypotension,
sudomotor
constipation,
dysfunction,
impaired
neurovascular function or hypoglycemic autonomic failure are able to document
the presence of neuropathy, usually they are abnormal when there is severe
clinical symptomatology. Thus by the time changes in function are evident, the
natural
course
of
autonomic
neuropathy
is
well
established.
HRV
analysis
determines the relative powers of the sympathetic and parasympathetic activities,
is
a
very
sensitive
and
early
measure
of
autonomic
neuropathy,
and
allows
monitoring of disease progression. American Diabetes Association recommends
HRV analysis as a part of the diagnosis of autonomic neuropathy (46).
Baroreflex sensitivity
Baroreflex sensitivity measurement is based on the principle that the increase
in blood pressure stimulates baroreceptors of the carotid sinus and aortic arch and
results in the activation of vagal fibers. As a result decrease in heart rate occurs.
Sensitivity of baroreflex is defined as proportion of heart rate decrease due to
blood
pressure
increase.
Impaired
baroreflex
sensitivity
is
characterized
by
decreased HVR and increased BP variability. As a result, normal buffering of BP
increases by HR decreases is lost.
In last decades neck suction (47) or pharmacological stimulation (48) were
used to activate baroreceptors and evoke heart rate changes. Advances in beat-bybeat
blood
pressure
(BP)
monitoring
methods
have
now
made
possible
noninvasive estimation of baroreflex sensitivity from the RR interval changes
associated with spontaneous fluctuations in BP. This new methodology offers
clear
advantages
A
over
traditional
techniques
of
assessing
baroreflex
control.
B
Fig. 4. Two methods of baroreflex sensitivity analysis-spectral (A) and sequence (B). Recordings
were made in the young patient with high-normal blood pressure.
89
Noninvasive estimates of baroreflex sensitivity are obtained from beat-to-beat BP
and heart rate recordings by one of two methods to extract concordantly changing
systolic BP (SBP) and RR interval. Power spectral analysis provides a baroreflex
estimate
based
on
the
RR
interval
changes
associated
with
rhythmic
BP
oscillations over a range of frequencies reported to be associated with baroreflex
function (Fig. 4). Second, recently developed method extracts covarying pressure
and
RR
interval
based
on
the
magnitude
of
the
changes
occurring
across
sequential beats. In this technique, beat-by-beat BP and RR interval recordings
are scanned for sequences in which SBP and RR interval concurrently increase or
decrease
for
assessed
from
at
least
the
three
consecutive
beats.
relationship
between
correlation
sequences
(Fig.
4).
Positive
sensitivity
estimates
obtained
by
the
SBP
was
Baroreflex
and
RR
reported
sensitivity
interval
between
frequency-domain-based
is
across
then
these
baroreflex
and
sequence
method and from pharmacological manipulations of BP and RR interval (49).
Spontaneous
baroreflex
sensitivity
is
a
very
important
marker
for
risk
stratification particularly in patients who suffered from myocardial infarction (50
- 53). A low BRS in patients with ischemic heart disease and impaired left
ventricular function is the important prognostic parameter (54, 55). The Task Force
on Sudden Cardiac Death of European Society of Cardiology also classified BRS
analysis as a recommendation Class I A for cardiovascular risk assessment (44).
CONCLUSIONS
This brief review indicates that SNS is involved in pathophysiology of many
cardiovascular disorders and points out an importance of its investigation for both
clinical and experimental research. Many aspects of the role of sympathetic system
are still controversial or remain a matter of debate. However, wider implementation
of objective methods like microneurography, may contribute to better understanding
of the role of SNS in cardiovascular disease and translate into better patient care.
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chronic
heart
failure,
clinical
and
hemodynamic
correlates
and
prognostic
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Circulation 1997; 96: 3450-3458.
Received:
November 21, 2006
A c c e p t e d : November 24, 2006
Author’s address: Zbigniew Gaciong, Department of Internal Diseases, Hypertension and
Vascular
Disease,
Medical
University
of
Warsaw,
Banacha
1a,
02-097
Warsaw,
Phone: + 48 22 599 2828, Fax: + 48 22 599 1928; e-mail: zgaciong@hotmail.com
Poland.