(Circulation. 2000;102:2076.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Sympathetic Neural Burst Amplitude Distribution
A More Specific Indicator of Sympathoexcitation in Human Heart Failure
From the Departments of Clinical Neurophysiology (Y.B.S., M.E.) and Cardiology (B.R.) and the Research Center for Endocrinology and Metabolism (G.J.), Sahlgren University Hospital, Göteborg, Sweden.
Correspondence to Dr Yrsa Bergmann Sverrisdóttir, Institute for Clinical Neuroscience, Department of Clinical Neurophysiology, Sahlgren University Hospital, S-41345 Göteborg, Sweden. E-mail yrsa.sverrisdottir{at}neuro.gu.se
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Abstract |
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Background—Human muscle sympathetic nerve activity (MSNA) is usually measured as the number of pulse-synchronous bursts in multiunit mean voltage recordings. We recently suggested burst amplitude distribution as a more sensitive indicator of altered MSNA in congestive heart failure (CHF). Here, we test whether this distribution can discriminate between different conditions with increased MSNA burst frequency and whether it reflects single vasoconstrictor fiber firing intensity.
Methods and Results—We analyzed resting multiunit MSNA in 36 CHF patients (24 with mild to moderate CHF, 12 with severe CHF investigated before and after heart transplantation), 14 patients with pituitary deficiency, 25 matched healthy control subjects, and an additional 56 healthy men with a wider age range (21 to 71 years). Pituitary deficiency was associated with increased MSNA burst frequency (60 versus 37 bursts/min in control subjects), equivalent to that in mild to moderate CHF (61 bursts/min). However, burst amplitude distribution in hypopituitary patients (median burst amplitude, 37%) did not deviate from matched control subjects (36%), whereas amplitudes increased with disease severity in CHF (43% in mild to moderate, 52% in severe) and normalized after transplantation (36%). In the larger healthy group, MSNA burst frequency increased with age, and burst amplitude distribution remained unaffected. In 8 CHF patients, single-unit firing frequency showed a close positive relationship to multiunit burst amplitude distribution (r=0.82, P<0.01) but none to burst frequency (r=0.39, P=0.3).
Conclusions—Muscle vasoconstrictor fiber activity is better reflected by multiunit MSNA burst amplitude distribution than by burst frequency, at least in CHF. This distribution can discriminate between conditions with increased burst frequency.
Key Words: nervous system, autonomic • heart failure • hormones • aging
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Introduction |
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Human muscle sympathetic nerve activity (MSNA) arises from vasoconstrictor fibers directed to the muscle vascular bed1 and is involved mainly in dynamic blood pressure regulation. An inhibitory influence from arterial baroreceptors provides a dominating control mechanism for MSNA, resulting in cardiac rhythmicity and an inverse relationship to diastolic blood pressure variations. Quantification of MSNA in intraneural recordings is usually based on counting the neural bursts identified by inspection of a mean voltage neurogram. Burst area or amplitude can be measured to evaluate relative changes in MSNA within a recording session, but absolute measures of burst size cannot be used for interindividual comparisons for technical reasons.2 3 Thus, interindividual or group comparisons of resting MSNA are usually based on burst counts over time (burst frequency) or, when differences in heart rate are accounted for, on bursts per 100 heartbeats (burst incidence). Because of the large interindividual variability of these 2 quantitative measures in healthy subjects,4 moderate differences in MSNA between groups of subjects in cross-sectional studies are difficult to identify.5 However, a recent study from our laboratory6 of patients with mild to moderate congestive heart failure (CHF) indicated that the relative burst amplitude distribution is shifted toward larger bursts before the occurrence of a significantly augmented burst frequency, suggesting that analysis of MSNA burst amplitude distribution may provide a more sensitive indicator of altered sympathetic discharge in early stages of CHF.
In the present study, we tested the hypothesis that MSNA burst amplitude distribution may also discriminate between conditions with increased MSNA burst frequency by comparing amplitude distributions in multiunit MSNA recordings from 3 conditions known to be associated with a high burst frequency. The first condition was CHF, in which increased MSNA burst frequency is a well-established finding7 8 considered to be at least partly elicited peripherally by malfunctioning baroreflex mechanisms.9 10 Because several studies have shown that the sympathoexcitation in CHF is normalized after orthotopic heart transplantation,11 12 13 14 15 we also analyzed the burst amplitude distribution before and after transplantation. The second group consisted of patients with pituitary deficiency and untreated growth hormone deficiency (GHD), a neuroendocrine disease recently shown to be associated with increased MSNA burst frequency, in all probability of central origin.16 The patient categories were compared with each other and an age-matched healthy control group. Finally, MSNA burst amplitude distribution was investigated in a larger group of healthy men with a wide age range because normal aging is related to an increased MSNA burst frequency.17
To test a second hypothesis, that multiunit MSNA burst amplitude distribution reflects intensity of muscle vasoconstrictor fiber discharge, the distribution was also compared with the activity of single muscle vasoconstrictor fibers previously reported from a subgroup of our CHF patients.18
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Methods |
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Subjects
The main study group consisted of 2 patient categories with marked augmentation of MSNA burst frequency and a group of healthy matched control subjects.
Cardiac Failure Patients
Twenty-four patients with mild to moderate cardiac failure (left
ventricular ejection fraction, 0.28±0.09) in NYHA II to
IIIA were investigated, 6 on the basis of coronary heart
disease and 18 with idiopathic dilated
cardiomyopathy. All the CHF patients and transplant
recipients (see below) were investigated without withdrawal of ongoing
medication (ACE inhibitors, digoxin, diuretics,
nitrates, standard triple immunosuppression, and calcium channel
blockers).
Pituitary-Deficient Patients
This group consisted of 14 patients with hypopituitarism caused
primarily by nonsecreting pituitary adenomas and its treatment. All
patients in this group had untreated GHD as verified by an insulin
tolerance test. When appropriate, the patients had received stable
replacement therapy with glucocorticoids (n=6), thyroxine (n=8), and
gonadal steroids (n=8) 
6 months before the study.
Control Subjects
Twenty-five healthy subjects matched for age, sex, and body mass
index (BMI) were recruited as MSNA control subjects for the mild to
moderate CHF and GHD patient groups (Table 1
).
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Cardiac Transplant Recipients
A separate study group consisting of 12 severe cardiac failure
patients (left ventricular ejection fraction, 0.18±0.08),
previously investigated before and after cardiac transplantation (HTx),
was reanalyzed to evaluate putative changes in burst amplitude
distribution related to the reduction in MSNA burst frequency that
occurs after HTx.15 The patients in the severe CHF group
were classified as being in NYHA functional class IIIB to IV, 5 with
coronary artery disease and 7 with idiopathic dilated
cardiomyopathy.
Aging
In addition to the main study group, we also reanalyzed
a larger group (n=56) of previously investigated normotensive (mean
arterial pressure, 91±10.7 mm Hg), normal-weight
(BMI, 24.4±2.5 kg/m2), healthy men (unpublished
data) with an age range of 21 to 71 years, (43±18 years) to evaluate
the effect of age on the different measures of MSNA.
Comparison With Single-Unit Discharge
Of the above CHF patients, 8 were previously used in a study of
the firing characteristics of single muscle vasoconstrictor nerve
fibers.18 These data are in the present study compared
with the burst amplitude distribution and burst frequency of a
multiunit MSNA recording performed in the same experimental
session as the previously reported single-unit data. In subjects in
whom >1 individual vasoconstrictor nerve fiber was recorded from
(2 fibers in 2 patients, 3 fibers in 3), data for 2 fibers were
averaged before comparison with multiunit data from that subject.
The Human Ethics Committee at the University of Göteborg approved the experimental procedures, and all subjects gave their informed consent to the procedure.
General Procedure
All nerve recordings were performed with the subjects in
the supine position in the postabsorptive state (2 hours after food
intake). Resting supine blood pressure was measured with a
sphygmomanometer from the left arm at the recording session
after 15 minutes of rest. Body weight was measured to the nearest 0.1
kg, and body height was measured barefoot to the nearest 0.01 m.
BMI was calculated as body weight in kilograms divided by height in
meters squared.
Nerve Recording
Multiunit recordings of efferent postganglionic
sympathetic nerve activity were obtained with a tungsten microelectrode
with a tip diameter of a few microns inserted into a muscle fascicle of
the peroneal nerve posterior to the fibular head. A low-impedance
reference electrode was inserted subcutaneously a few centimeters away.
When a muscle nerve fascicle had been identified, small electrode
adjustments were made until a site was found in which spontaneous
pulse-synchronous bursts of neural activity that increased during
voluntary apnea but did not respond to arousal stimuli (such as noise
or pinching) could be recorded. Details of the nerve
recording technique and criteria for MSNA have been reported
previously.2 The original nerve signal was amplified with
a gain of 50 000 and fed through a band-pass filter with a band width
of 700 to 2000 Hz and then through an integrating network with a time
constant of 0.1 second to obtain a mean voltage display of nerve
activity. Both the filtered and mean voltage neurograms were stored on
analog tape (Racal V-Store, Racal Recorders Ltd) and on a computer
(sampling frequency, 200 Hz), together with an ECG (via standard chest
leads) and respiratory movements (via a strain gauge attached to a
rubber strap around the chest). During the experiments, recorded
variables were also monitored on a storage oscilloscope (Tektronix
549, Tektronix Beaverton) and an ink-jet recorder (modified
Mingograph 800, Siemens-Elema Ltd).
Statistical Analysis
After a stable recording site was acquired, resting MSNA
was recorded for 15 to 20 minutes. Data from the last 5 minutes
were used for analysis. Bursts were identified by inspection of
the mean voltage neurogram, aided by computer software developed in the
laboratory, and MSNA was expressed as burst frequency (bursts per
minute) and burst incidence (bursts per 100 heartbeats). To obtain a
relative burst amplitude distribution, the amplitude of the largest
burst that occurred during the analyzed period was set to
100%, and other burst amplitudes were expressed as a percentage of the
maximal burst.6 17 19 20 From the burst amplitude
distribution, a median burst amplitude (the value at which 50% of the
burst amplitudes were larger and 50% were smaller) was extracted and
used for statistical analysis.
The results are presented as the mean±SD (range). Comparisons between the study groups were performed with the Kruskal-Wallis ANOVA median test followed by the Mann-Whitney U test when appropriate. Correlations were examined by calculating the Pearson linear correlation coefficient. P<0.05 was considered significant.
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Results |
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The subjects in the main study group did not differ in terms of age, sex, or BMI (Table 1
). The pituitary-deficient patients did
not deviate from the control subjects in heart rate but had
significantly higher mean arterial pressure
(P<0.05). In CHF patients, heart rate increased with
disease severity and was high in the denervated heart after HTx. Both
CHF groups and the HTx group had significantly higher heart rate than
the control subjects and the pituitary-deficient patient group. The
mean arterial pressure ranged from lower than that of
control subjects in the severe CHF (P<0.001), equal to that
of control subjects in mild to moderate CHF (P=0.2), to
higher than that of control subjects in the HTx group
(P<0.001; Table 1).
Differences in MSNA Between CHF and Hypopituitary Patients
Whereas MSNA burst frequency and incidence were increased to a
similar degree in both the mild to moderate CHF and hypopituitary
patient groups compared with control subjects (Table 1 and
Figure 1), the MSNA median burst
amplitude was increased only in the CHF patients (P<0.001),
and burst amplitude distribution in the hypopituitary patients did not
differ from the control subjects (P=0.97). In the CHF group
(mild, moderate, and severe), all MSNA parameters increased
with disease severity and were significantly reduced after HTx. MSNA
burst frequency and median burst amplitude in the HTx group did not
differ from the control subjects, whereas MSNA burst incidence was
significantly lower (P<0.01).
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) and median
burst amplitude (
) for different study groups. Note discrepancy
between GHD and mild to moderate CHF, in which MSNA burst incidence is
augmented to similar degree in both conditions, whereas median burst
amplitude is increased only in CHF. Results are mean±SEM; bars show
SD.
Age-Related Changes in MSNA
In the larger group of healthy subjects with an age range of 21 to
71 years, MSNA burst frequency and incidence showed a positive
relationship with age (r=0.65 and 0.64, respectively;
P<0.0005 for both). In contrast, MSNA median burst
amplitude remained unchanged throughout the age range (Table 2).
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Relationship Between Multiunit and Single-Unit MSNA
In 8 CHF patients in whom both single-unit18 and
multiunit MSNA was analyzed, multiunit burst amplitude
distribution was closely correlated to the firing frequency of
individual muscle vasoconstrictor nerve fibers (r=0.84,
P<0.01; Figure 2), whereas no
significant correlation was found between single-unit activity and
multiunit burst frequency (r=0.39, P=0.3).
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Discussion |
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The main findings of the present study are that (1) the distribution of multiunit MSNA burst amplitudes can discriminate between different conditions with a similar MSNA burst frequency augmentation and (2) the firing frequency of individual vasoconstrictor fibers is related more closely to MSNA burst amplitude distribution than to MSNA burst frequency. This indicates that burst amplitude distribution may be a more sensitive indicator of MSNA intensity, which can be used to distinguish between conditions with sympathetic nerve hyperactivity of different origin.
Burst Amplitude Distribution Illustrates Sympathoexcitation in
CHF
The sympathetic activation in CHF is well
established,21 22 with increased MSNA7 8
being paralleled by increased total body, renal, cardiac, and
central nervous system norepinephrine
spillover.13 23 24 25 26 Studies focusing on milder degrees
of CHF have found an increased27 or
unchanged26 number of MSNA bursts early in the disease. In
contrast to the previous study from our laboratory,26 the
present study also finds a significant augmentation of MSNA burst
number in mild to moderate CHF. This difference between 2 studies from
the same laboratory highlights the previously recognized
problem5 with a large interindividual variability of MSNA
burst number in group comparisons, making subject selection crucial. In
fact, the discrepancy between studies of mild CHF recently prompted our
first attempt to use MSNA burst amplitude distribution for group
comparisons. In agreement with the findings in our present mild to
moderate CHF group, the patients in the earlier study from our
laboratory26 were subsequently shown to have a greater
proportion of large bursts than healthy control subjects, despite not
differing in burst number,6 and we suggested that burst
amplitude distribution may be a more sensitive indicator of altered
discharge intensity than traditional burst counts. This notion is
strongly underlined by the present finding that the firing
frequency of individual vasoconstrictor fibers is closer related to
multiunit burst amplitude distribution than to burst frequency (see
also below) in a group of patients with CHF ranging from mild to
severe.
The underlying mechanisms for sympathetic hyperactivity in CHF are not fully elucidated, but impaired baroreflex control has been shown in severe9 28 and mild to moderate CHF.27 This impairment of baroreflex restraint of sympathetic neuronal outflow, whether caused by peripheral or central alterations,29 30 has therefore been proposed as one plausible mechanism for the sympathoexcitation characterizing this condition. However, sympathoexcitation as a compensatory response, elicited by still-functioning baroreceptors sensing an increasingly lowered blood pressure, may contribute. The improved hemodynamic situation and the normalization of baroreflex function within weeks after HTx31 could both be responsible for the rapid postoperative reduction in MSNA15 and the normalization of MSNA burst amplitude distribution shown in this study.
Ignoring the present findings concerning the relationship between single-unit firing frequency and multiunit burst amplitude distribution, we could argue that alterations in MSNA burst amplitude distribution are simply a consequence of the decreased beat-to-beat variability in blood pressure or heart rate known to be associated with CHF. Heart rate increases and its variability decreases32 with increasing severity of CHF, but our finding that the MSNA burst amplitude distribution was normalized after HTx, despite heart rate being high and less variable in the transplanted heart, clearly argues against heart rate per se being responsible for the change in MSNA burst amplitude distribution. The diastolic blood pressure variability (determined as the within-person SD) was significantly reduced in the severe compared with the mild to moderate CHF group (P<0.001) but did not differ between mild to moderate CHF and hypopituitary patients, making diminished blood pressure variations a less likely cause for the change in MSNA burst amplitude distribution. In fact, the increased proportion of large MSNA bursts in our mild to moderate CHF patients, despite a blood pressure variability similar to that in hypopituitary patients, may indicate that this change in distribution is reflecting the impairment of baroreflex control over sympathetic outflow.
Burst Amplitude Distribution Is Normal in Other Conditions With
High Burst Frequency
Both MSNA burst frequency and burst incidence are known to
increase with age,17 a development recently found to be
linked to the decrease in secretion of insulin-like growth factor-I
levels in somatopause (unpublished observations). Adults with
GHD and aging healthy subjects thus share a decline in insulin-like
growth factor-I and a rise in MSNA burst frequency.16 Our
present finding that MSNA burst amplitude distribution remains
unaffected during aging and in hypopituitary patients contrasts the
findings in CHF, clearly illustrating that this MSNA variable can
be used to discriminate between different conditions characterized by
increased MSNA burst frequency. This discrepancy between CHF and
aging/hypopituitarism may support the view of McAllen and
Malpas33 that sympathetic burst probability and burst
amplitude are controlled independently.
The notion that burst amplitude distribution could be maintained by baroreflex modulation agrees well with the fact that baroreflex control of MSNA has been shown to remain unchanged during aging.34 Hypopituitarism and untreated GHD are linked to a higher incidence of hypertension,35 but although our patients had a higher blood pressure than the matched control subjects, they were not hypertensive. Given that impairment of baroreflex function has also been found in hypertension, one could argue that hypopituitary patients (and those with other conditions) who develop significant hypertension eventually should alter their MSNA burst amplitude distribution, if this measure indeed reflects baroreflex modulation. However, in contrast to the impaired baroreflex control of heart rate, the baroreflex control of MSNA has been shown to remain intact in both primary and secondary hypertension.36 37 Thus, the difference in MSNA burst amplitude distribution between CHF and hypopituitary patients would probably persist even if the latter patient group developed hypertension.
Study Limitations
Given the possibility that baroreflex modulation governs MSNA
burst amplitude distribution (see above), the lack of a baroreflex test
is a limitation of the present study. However, reciprocal changes
in MSNA median burst amplitude and blood pressure during
pharmacological baroreflex provocations have been demonstrated in
normal subjects with intact baroreflex function.6 The
present data include reanalysis of several previous studies
from our laboratory,15 16 18 precluding the addition of a
baroreflex test, and we base our suggestion of baroreflex involvement
on the previously published evidence for decreased baroreflex control
of sympathetic outflow in CHF that is normalized after HTx and on the
evidence for normal sympathetic baroreflex control in aging. Baroreflex
control of MSNA is usually investigated with short-term pharmacological
interventions, raising blood pressure with phenylephrine
and/or lowering blood pressure with
nitroprusside.9 34 36 37 38 39 If future studies can
establish that the burst amplitude variation at rest is governed by
baroreflex modulation, analysis of MSNA burst amplitude
distribution may provide a less invasive, and thus safer, test of
baroreflex control of sympathetic outflow.
Our conclusion that multiunit MSNA burst amplitude distribution reflects the firing frequency of individual vasoconstrictor neurons, whereas multiunit burst frequency does not, is limited to CHF because no such comparisons were made in hypopituitary or aging subjects. However, in 2 previous reports by Macefield and coworkers on healthy subjects with low40 and high41 multiunit MSNA burst frequency, the average firing frequency of individual vasoconstrictor neurons was lower in the study group with higher multiunit burst frequency. Thus, the poor ability of multiunit MSNA burst frequency to predict the discharge intensity of individual vasoconstrictor fibers seems to be a general phenomenon.
Finally, the fact that ongoing pharmacological treatment was maintained in our CHF patients may be considered a limitation of the study. However, we chose this strategy to avoid rebound cardiovascular responses and associated baroreceptor-mediated effects on sympathetic nerve traffic.
In summary, muscle vasoconstrictor fiber activity is better reflected by multiunit MSNA burst amplitude distribution than by burst frequency. The amplitude distribution can discriminate between conditions with increased MSNA burst frequency of different origin.
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Acknowledgments |
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This study was supported by the Swedish Medical Research Foundation (grant 12170), the Swedish Heart and Lung Foundation, and the Medical Faculty of Göteborg. We thank Tomas Karlsson and Gun Bodehed-Berg for excellent technical assistance.
Received March 30, 2000; revision received May 19, 2000; accepted June 8, 2000.
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M. Ichinose, M. Saito, N. Fujii, N. Kondo, and T. Nishiyasu Modulation of the control of muscle sympathetic nerve activity during severe orthostatic stress J. Physiol., November 1, 2006; 576(3): 947 - 958. [Abstract] [Full Text] [PDF]
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M. Ichinose, M. Saito, T. Ogawa, K. Hayashi, N. Kondo, and T. Nishiyasu Modulation of control of muscle sympathetic nerve activity during orthostatic stress in humans Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2147 - H2153. [Abstract] [Full Text] [PDF]
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Y. Oda, H. Asanoi, H. Ueno, K. Yamada, S. Joho, T. Kameyama, T. Hirai, T. Nozawa, S. Takashima, and H. Inoue Pulse-synchronous sympathetic burst power as a new index of sympathoexcitation in patients with heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1821 - H1827. [Abstract] [Full Text] [PDF]
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D. S. Kimmerly and J. K. Shoemaker Hypovolemia and MSNA discharge patterns: assessing and interpreting sympathetic responses Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1198 - H1204. [Abstract] [Full Text] [PDF]
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