Download Independent Control of Skin and Muscle Sympathetic Nerve Activity

1794
Independent Control of Skin and Muscle
Sympathetic Nerve Activity in Patients
With Heart Failure
Holly R. Middlekauff, MD; Michele A. Hamilton, MD;
Lynne W. Stevenson, MD; Allyn L. Mark, MD
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Background Sympathetic excitation characterizes heart
failure, but the underlying mechanisms remain unknown.
Abnormal baroreflex restraint of sympathetic neural outflow
has been proposed, since baroreflexes are known to be abnormal in heart failure. The purpose of this study was to determine if sympathetic activation in humans with heart failure is
limited to regions governed by the baroreflexes or is generalized to other regions free from baroreflex control.
Methods and Results We report the first direct recordings of
skin sympathetic nerve activity (free from baroreflex control)
in humans with heart failure and compare simultaneous skin
and muscle (baroreflex-dependent) sympathetic peroneal
nerve activity in six patients with severe heart failure (mean
left ventricular ejection fraction, 0.19+0.06) and in six age-
matched normal control subjects. Although muscle sympathetic nerve activity was markedly increased in heart failure
patients (heart failure versus controls, 69+3 versus 21±2
bursts per minute; P<.001), skin sympathetic nerve activity
was not increased (heart failure versus controls, 12+1 versus
15±1 bursts per minute; P=NS).
Conclusions The finding that skin sympathetic nerve activity
in contrast to muscle sympathetic nerve activity is not increased
in heart failure supports the concept that an altered reflex
system, such as the baroreflexes, with nonuniform effects on
muscle and skin sympathetic nerve activity, underlies sympathoexcitation in heart failure. (Circulation. 1994;90:1794-1798.)
Key Words * heart failure * baroreceptors * reflex
Sympathetic activation in patients with heart failure was first recognized over 30 years ago,1 but
the mechanisms underlying this sympathoexcitation remain poorly understood.2-9 Initially adaptive,
activation of the sympathetic nervous system may lead
to adverse sequelae, including progressive heart failure
and increased mortality.2"10"11 Increased central sympathetic outflow in patients with heart failure has been
documented in skeletal muscle, cardiac, and renal beds,
each of which is subject to baroreflex control.3-6,12-16
These uniform findings of sympathetic activation directed to tissues governed by the baroreflexes have
prompted the concept that impaired baroreflex restraint
underlies sympathetic activation. It is unknown if increased sympathetic neural outflow in heart failure is
limited to regions governed by the baroreflexes or is
generalized to all tissues -a distinction with mechanistic implications.
Skin sympathetic nerves that mediate vasoconstriction and sweating differ from skeletal muscle, cardiac,
and renal sympathetic nerves in that they are not
governed by the baroreflexes but are subject to other
regulatory mechanisms such as thermoregulatory influ-
ences and central (or cognitive) stimuli.17- 9 The determination of sympathetic nerve activity directed to skin
would clarify whether sympathetic activation in heart
failure is limited to regions subject to baroreflex restraint or is more generalized, implicating a nonbaroreflex-mediated mechanism.
We report the first direct recordings of skin sympathetic nerve activity in humans with heart failure and
compare simultaneous skin and muscle sympathetic
peroneal nerve activity in patients with severe heart
failure and in age-matched normal control subjects.
Received April 25, 1994; revision accepted May 31, 1994.
From the Division of Cardiology (H.R.M., M.A.H.), Department of Medicine, University of California, Los Angeles; the
Cardiovascular Division (L.W.S.), Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School, Boston;
and the Cardiovascular Division (A.L.M.), Department of Medicine, University of Iowa, Iowa City.
Correspondence to Holly R. Middlekauff, MD, UCLA Department of Medicine, Division of Cardiology, 47-123 CHS, 10833 Le
Conte Ave, Los Angeles, CA 90024.
(3 1994 American Heart Association, Inc.
Methods
After written informed consent was obtained, six heart
failure patients and six age-matched normal control subjects
were studied. The study protocol was approved by the UCLA
Human Subjects Protection Committee. All studies were performed with subjects in the supine, postabsorptive state in a
quiet, semidark, thermoneutral room (22°C). Control subjects
were healthy as confirmed by normal physical examinations
and were not taking medications. In heart failure patients,
medications including vasodilators, diuretics, and digoxin were
discontinued 24 to 36 hours before the study. All heart failure
patients were hospitalized at the UCLA Medical Center for
heart transplantation evaluation, which included echocardiography, cardiopulmonary exercise testing, and pulmonary artery catheterization performed within 24 hours of the research
study.
Microneurography
Multiunit postganglionic sympathetic nerve activity was
recorded using tungsten microelectrodes inserted selectively
into skin or muscle fasicles of the peroneal nerve.'7-21 The
signals were amplified by a factor of 50 000 to 100 000 and
bandpass-filtered (700 to 2000 Hz) (Nerve Traffic Analyzer,
Middlekauff et al Sympathetic Activation in Heart Failure
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model 662C-3, University of Iowa, Bioengineering). For recording and analysis, nerve activity was rectified and integrated (time constant, 0.1 second) to obtain a mean voltage
display of sympathetic nerve activity that was recorded on
paper (EVR-16 recorder, PPG).
A recording of skin sympathetic nerve activity was acceptable when (1) weak electrical stimulation through the electrode produced paresthesias without muscle twitch and (2) the
mean voltage neurogram revealed broad-based bursts (signal
to noise ratio >2:1) that were not pulse synchronous and
increased during arousal stimuli (eg, loud noise).18,19,21
A recording of muscle sympathetic nerve activity was acceptable when (1) weak electrical stimulation through the
electrode produced muscle twitch without paresthesias and (2)
the mean voltage neurogram revealed narrow-based, pulsesynchronous bursts (signal to noise ratio >2:1) that showed
postextrasystolic potentiation but did not increase during
arousal stimuli.17'21 Mixed skin and muscle sympathetic recordings were not accepted for analysis.
Sympathetic bursts were identified by inspection of the
mean voltage neurogram. The data are presented as bursts per
minute. Since muscle (in contrast to skin) sympathetic nerve
bursts are pulse synchronous, exhibiting cardiac rhythmicity
(attributed to baroreflex influences), and patients with heart
failure tend to have a faster heart rate than healthy subjects,
muscle sympathetic nerve activity is also reported as bursts per
100 heartbeats.17-19,21
Protocol
Subjects rested in the supine position. ECG leads were
positioned on the chest, and an automated sphygmomanometer was placed on the upper arm (Dinamap, Criticon). The leg
was positioned for microneurography. After identification of
an acceptable skin or muscle sympathetic nerve recording site
and a 5-minute rest period, sympathetic nerve activity was
recorded for 5 to 10 minutes. Immediately after this recording,
the microelectrode was repositioned in a different nerve
fasicle innervating the other (skin or muscle) tissue bed, and
the recording procedure was repeated. Muscle and skin sympathetic recordings were obtained in random order.
Statistical Analysis
Statistical analysis was performed using unpaired Student's
t tests. Probability values of <.05 were considered statistically
significant. Values are presented as mean±SEM.
Results
Clinical Characteristics
Ages of heart failure patients and control subjects did
not differ significantly (heart failure patients versus
control subjects, 43±7 versus 35±6 years; P=NS). All
patients had advanced (New York Heart Association
class III-IV) heart failure. Etiology of heart failure was
coronary artery disease in three patients and idiopathic
dilated cardiomyopathy in three patients. As measured
by echocardiography (n=6), quantified mean left ventricular ejection fraction was 0.19±0.06 and mean left
ventricular end diastolic dimension was 79±6 mm.
Pulmonary artery catheterization (n=6) revealed mean
right atrial pressure of 8±3 mm Hg, mean pulmonary
wedge pressure of 24±8 mm Hg, mean cardiac index of
2.1±0.4 L/min/m2, and mean systemic vascular resistance of 1496±338 dyne/s/cm5. Mean peak oxygen consumption measured by cardiopulmonary exercise testing (n=5) was 11.7±1.7 mL/kg.
Microneurography Studies
Mean heart rate, blood pressure, and skin and muscle
sympathetic nerve activity are compared between heart
1795
Comparison of Hemodynamics and Sympathetic
Activity in Heart Failure Patients and Control Subjects
HF Control
P
Heart rate, beats per minute
89±4 66±3 .02
Mean arterial pressure, mm Hg
85±2 89±2 NS
Muscle SNA, bursts per minute
69±3 21± 1 <.001
Muscle SNA, bursts per 100 heartbeats 77±3 35±3 .003
Skin SNA, bursts per minute
12±1 15±1 NS
HF indicates heart failure; SNA, sympathetic nerve activity.
Values are mean+SEM.
failure and control groups in the Table. Heart failure
patients had higher resting heart rates compared with
control subjects.
Values for skin and muscle sympathetic nerve activity
in individual heart failure patients and control subjects
are displayed in Fig 1. Muscle sympathetic nerve activity was markedly increased in heart failure patients
compared with control subjects (heart failure patients
versus control subjects, 69±3 versus 21+2 bursts per
minute; P<.001). Similar results were found when muscle sympathetic nerve activity was calculated as bursts
per 100 heartbeats (Table). There was no overlap for
values of muscle sympathetic nerve activity between
heart failure patients and control subjects (Fig 1).
In marked contrast to muscle sympathetic nerve
activity, skin sympathetic nerve activity was not increased in heart failure patients compared with control
subjects (heart failure patients versus control subjects,
12±1 versus 15±1 bursts per minute; P=NS; Fig 1 and
Table). The minute-to-minute individual variation of
skin sympathetic nerve activity as estimated by the
standard deviation was low in both normal control
subjects (range, 2.1 to 4.7 bursts per minute) and heart
failure patients (range, 0.7 to 3.1 bursts per minute).
Representative skin and muscle neurograms from two
heart failure patients and two control subjects are
shown in Fig 2. During skin sympathetic recordings, an
arousal stimulus such as a loud noise reproducibly
Sympathetic activity(bursts/min)
120 - Muscle
SNA
100 _ P<0.OO1
80
x
60 -
3"
Skin
SNA
p=NS
40
20
X
-I-x
o(
HF C
HF C
FIG 1. Graph shows individual values of muscle and skin
sympathetic nerve activity (bursts per minute) directed to muscle
and skin compared in heart failure patients and in control
subjects. Muscle sympathetic nerve activity is markedly increased in heart failure patients compared with control subjects
(P<.001). In contrast, skin sympathetic nerve activity is not
increased (P=NS). C indicates control; HF, heart failure; and
SNA, sympathetic nerve activity.
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Circulation Vol 90, No 4 October 1994
Skin SNA
Muscle SNA
Control- 1
*
Control-2
*
.......
J
Heart
4.
A
*
Heairt
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Failure-2
2i--s
2s
FIG 2. Original records of muscle and skin neurograms. Simultaneous muscle and skin neurograms in two representative control
subjects (top two tracings) and two representative heart failure patients (bottom two tracings) are shown. Muscle sympathetic nerve
activity is markedly increased in heart failure patients compared with control subjects. In contrast, skin sympathetic nerve activity is not
increased. In both the control subject and the heart failure patient, a brief arousal stimulus (asterisks) elicited a burst of skin sympathetic
nerve activity. This response was reproducible and not obviously different between heart failure patients and control subjects. SNA
indicates sympathetic nerve activity.
elicited a burst of sympathetic neural activity in both
heart failure patients and in normal control subjects.
The ratio of muscle sympathetic nerve activity to skin
sympathetic nerve activity (bursts per minute) was
significantly greater in heart failure patients than in
control subjects (heart failure patients versus control
subjects, 6.8±0.5 versus 1.6+0.1; P=.01).
Discussion
The major new finding in this study was that skin
sympathetic nerve activity, in dramatic contrast to muscle sympathetic nerve activity, is not increased in patients with severe heart failure. This finding, which is
consistent with intact central partitioning of skin and
muscle sympathetic neural outflow in heart failure,
supports the concept that baroreflex dysfunction underlies the sympathoexcitation in heart failure.
In normal humans, arterial and cardiopulmonary
baroreflex regulation of skin and muscle sympathetic
nerve activity is independent: Muscle sympathetic
nerve activity is tightly controlled by the baroreflexes,
whereas skin sympathetic nerve activity is largely free
from baroreflex influences.17,20-24 Bini and colleagues23
reported that in normal subjects exposed to hyperthermic conditions, skin sympathetic nerve activity directed
to sweat glands exhibited cardiac rhythmicity, a characteristic generally attributed to baroreflex influences.
However, in further experiments in which the baroreflexes were engaged, no cardiac rhythmicity or baroreflex modulation of either skin sudomotor or vasomotor
sympathetic activity was detectable.23 The investigators
concluded that skin sympathetic nerve activity is not
influenced by the baroreflexes and speculated that a
common central pacemaker under certain conditions
may influence both the heart and skin sympathetic
activity. Vissing and colleagues24 investigated the cardiopulmonary baroreflex control of skin sympathetic
nerve activity in normal subjects. No cardiac rhythmicity or baroreflex modulation of skin sympathetic nerve
activity was observed, and these investigators concluded
that skin sympathetic nerve activity is not subject to
cardiopulmonary baroreflex regulation.24
Substantial evidence in humans and animals with
heart failure supports the concept that the baroreflexes
are impaired in heart failure.13'516 Our findings of
normal resting skin sympathetic activity but markedly
increased muscle sympathetic activity provide direct
evidence that sympathoexcitation in heart failure is not
generalized. These findings of regional differences in
sympathetic nerve activation in heart failure are in
agreement with norepinephrine kinetic data, which
show increased norepinephrine spillover in muscle, cardiac, and renal beds but not in the pulmonary bed in
patients with heart failure.4 Our results are consistent
with the concept of diminished baroreflex restraint
underlying the sympathetic excitation characteristic of
heart failure.
Although our findings support the hypothesis that an
impairment of the arterial and cardiopulmonary baroreflexes leads to sympathoexcitation in heart failure, other
reflex systems and humoral substances have nonuniform
effects on muscle and skin sympathetic nerve activity
and may also be contributory. For example, activation
of the metaboreflex during exercise increases sympathetic nerve activity directed to muscle but not to skin.19
Similarly, hyperinsulinemia increases muscle but not
skin sympathetic nerve activity.25 Skin and muscle sympathetic neural responses to other reflex systems such as
the lung inflation reflex, chemoreflexes, and visceral
reflexes or to other humoral substances such as angio-
Middlekauff et al Sympathetic Activation in Heart Failure
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tensin II are not fully delineated but may also be
nonuniform.9,22'26 Further studies are necessary to identify which reflex system(s) or humoral substances contribute significantly to resting sympathetic excitation in
heart failure.
Neurohormonal activation in heart failure appears to
occur in stages and grades, with sympathetic activation
preceding the activation of the renin-angiotensin system
and greater activation of the sympathetic nervous system correlating with greater severity of heart failure.3,27-29 We studied patients referred for heart transplantation who had severe heart failure as indicated by
their markedly abnormal resting hemodynamics, uniformly depressed left ventricular ejection fraction, New
York Heart Association functional class III-IV symptoms, and poor exercise capacity. Even in this population with advanced heart failure, skin sympathetic nerve
activation was not present.
Although skin sympathetic nerve activity is not increased at rest in normothermic heart failure patients, it
remains unknown whether underlying control mechanisms of skin sympathetic outflow are intact. We did
observe, however, that a brief arousal stimulus elicited a
burst of skin sympathetic activity, which was reproducible and not obviously different in heart failure patients
and normal control subjects.
In the present study, we made no attempt to determine if the skin sympathetic nerve activity is directed to
cutaneous blood vessels, sweat glands, or both. Further
investigations of these responses in heart failure would
be of interest, since the clinical impression of cutaneous
vasoconstriction in heart failure appears discrepant with
our findings of normal skin sympathetic nerve activity.
Possible explanations include an increased cutaneous
sensitivity to circulating norepinephrine in heart failure
or alternatively, nonsympathetically mediated mechanisms of cutaneous vasoconstriction in heart failure.
Nonetheless, the nature of the neuroeffector responses
do not impact on the implications of the findings in this
study, since neither cutaneous vasoconstrictor nor sudomotor sympathetic activity is subject to baroreflex influences in resting, normothermic individuals,23 24 and the
purpose of this study was to compare sympathetic nerve
outflow directed to tissues that normally exhibit independent sympathetic control. We recorded skin sympathetic nerve activity from one region, a nonacral area of
the lower extremity. It remains unknown whether our
finding of normal skin sympathetic nerve activity in
heart failure applies to all cutaneous regions.
Summary
Direct recordings of skin sympathetic nerve activity in
humans with heart failure provide strong direct evidence that sympathetic activation in humans with heart
failure is not uniform, sparing tissues free from baroreflex restraint. Identification and characterization of the
abnormalities of regulation of sympathetic nerve activity, with attention focused on reflex systems or humoral
substances that elicit nonuniform muscle and skin sympathetic neural responses, may provide further insights
into the underlying mechanism of resting sympathoexcitation in humans with heart failure.
1797
Acknowledgments
This study was supported by US Public Health Service grant
MO1-RR00865, a Grant-in-Aid from the American Heart
Association, Greater Los Angeles Affiliate; and the Committee on Research of the Academic Senate of the Los Angeles
Division of the University of California. The authors are
indebted to Robert F. Rea, MD, and Mary P. Clary for expert
technical instruction; to Leila Terada and Julie A. Walden,
MN, for facilitating patient enrollment; and to the nurses and
staff of the UCLA Clinical Research Center for excellent
patient care.
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Independent control of skin and muscle sympathetic nerve activity in patients with heart
failure.
H R Middlekauff, M A Hamilton, L W Stevenson and A L Mark
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
Circulation. 1994;90:1794-1798
doi: 10.1161/01.CIR.90.4.1794
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1994 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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