Vol. 280, Issue 3, H1145-H1150, March 2001
Comparison of spontaneous vs. metronome-guided breathing on
assessment of vagal modulation using RR variability
Daniel M.
Bloomfield1,
Anthony
Magnano1,
J. Thomas
Bigger Jr.1,
Harold
Rivadeneira1,
Michael
Parides2, and
Richard C.
Steinman1
1 Division of Cardiology, Department of Medicine, and
2 Department of Biostatistics, School of Public Health,
Columbia University, New York, New York 10032
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ABSTRACT |
R-R interval
variability (RR variability) is increasingly being used as an index of
autonomic activity. High-frequency (HF) power reflects vagal modulation
of the sinus node. Since vagal modulation occurs at the respiratory
frequency, some investigators have suggested that HF power cannot be
interpreted unless the breathing rate is controlled. We hypothesized
that HF power during spontaneous breathing would not differ
significantly from HF power during metronome-guided breathing. We
measured HF power during spontaneous breathing in 20 healthy subjects
and 19 patients with heart disease. Each subject's spontaneous
breathing rate was determined, and the calculation of HF power was
repeated with a metronome set to his or her average spontaneous
breathing rate. There was no significant difference between the
logarithm of HF power measured during spontaneous and metronome-guided
breathing [4.88 ± 0.29 vs. 5.29 ± 0.30 ln(ms2), P = 0.32] in the group as a whole
and when patients and healthy subjects were examined separately. We did
observe a small (9.9%) decrease in HF power with increasing
metronome-guided breathing rates (from 9 to 20 breaths/min). These data
indicate that HF power during spontaneous and metronome-guided
breathing differs at most by very small amounts. This variability is
several logarithmic units less than the wide discrepancies observed
between healthy subjects and cardiac patients with a heterogeneous
group of cardiovascular disorders. In addition, HF power is relatively
constant across the range of typical breathing rates. These data
indicate that there is no need to control breathing rate to interpret
HF power when RR variability (and specifically HF power) is used to
identify high-risk cardiac patients.
heart rate variability; power spectral analysis; parasympathetic
nervous system; R-R interval
| |
INTRODUCTION |
RECOGNITION THAT THE
RESPIRATORY sinus arrhythmia was mediated by efferent vagal
activity acting on the sinus node led investigators to attempt to
quantify the fluctuations in R-R intervals that were related to
breathing. Power spectral analysis of R-R intervals permits calculation
of the amount of variance of a signal at a given frequency. Given that
vagal modulation of sinus node activity occurs at the respiratory
frequency (the respiratory sinus arrhythmia), measuring the variance
(or power) in the R-R interval time series at the respiratory frequency
provides a pure index of how much the vagus is modulating sinus node
activity. We measure high-frequency (HF) power as the area under the
power spectral curve between 0.15 and 0.40 Hz (quantifying the
respiratory sinus arrhythmia with breathing rates of 9-24
breaths/min) given that the majority of subjects have breathing rates
between 10 (0.17 Hz) and 20 (0.33 Hz) breaths/min.
However, a point of debate is whether vagal modulation is equivalent
during spontaneous breathing and controlled breathing, such as with a
metronome (6). During spontaneous breathing, breath-to-breath variation in the breathing rate causes HF power to be
spread out over a frequency range. During metronome-guided breathing,
there is little variation in the breathing rate, and HF power is
confined to a narrow peak at the respiratory frequency. The
recommendation that it is necessary to control breathing rate to
accurately measure vagal modulation using HF power (6) has important implications for the use of R-R interval variability (RR
variability) for physiological studies and clinical evaluations (where
metronome-guided breathing can be cumbersome or even impossible) and
thus deserves further evaluation.
Given that one of the most common and important uses of RR variability
is to identify patients at increased risk of cardiovascular morbidity
and mortality (16), we sought to evaluate the effect of
metronome breathing on HF power in normal subjects and in patients with
heart disease. This study design permits an assessment of the clinical
significance of the effect of metronome breathing on HF power in the
context of distinguishing high- and low-risk patients.
| |
METHODS |
Subjects.
Informed written consent was obtained from all patients and healthy
subjects. The study was approved by the Columbia-Presbyterian Medical
Center Institutional Review Board. A total of 45 subjects were
recruited, although 6 study participants were excluded because of
inability to complete the protocol (n = 2), tape
malfunction (n = 3), and discovery of systemic disease
in the healthy control group (n = 1).
Experimental protocol.
Studies were performed in the supine position in a quiet room. The
electrocardiogram (ECG) was monitored on an oscilloscope and
continuously recorded on a Holter recorder for the duration of the
study. An elastic respiratory belt (Pneumotrace respiration transducer
model 1130, UFI, Morro Bay, CA) was secured around the subject's chest
to measure breathing rate. The ECG and changes in thoracic
circumference were recorded using a digital acquisition analysis
program (Ponemah, version 1.21, Gould, Valley View, OH). Breathing
rates were measured by computer and overread manually during the study.
Study procedures.
Subjects were allowed to acclimate to their environment during a 10-min
rest period. HF power, a measure of RR variability, was measured during
this rest period. Each subject's average spontaneous breathing rate
was measured and then programmed into a digital metronome. Subjects
were instructed to breathe for 7 min, guided by the metronome at their
average spontaneous breathing rate, while the measurement of HF power
was repeated. In the second part of our study, we evaluated HF power
during a randomized sequence of metronome-set breathing rates (6, 9, 10, 12, 14, 16, 18, and 20 breaths/min) for 7 min each. HF power was
determined during each of these additional metronome-guided segments.
Analysis of Holter ECG recordings.
All Holter tapes (~1.5-h duration) were analyzed with a scanner
(model 8000, Marquette) running the Marquette analysis program (version
5.8) to identify and label each QRS complex. After the computer had
automatically detected and labeled each QRS complex, a frequency
histogram of the normal R-R (N-N) intervals was displayed, and the ECGs of the intervals in both tails of the N-N
distribution were reviewed by a technician. After they were edited, the
labeled QRS data stream was moved by means of a high-speed interface to a Sun 4/75 microcomputer, where a second stage of editing was performed
using algorithms developed at Columbia University to find and correct
any remaining QRS labeling errors that adversely affect measurement of
RR variability.
Power spectral analysis of N-N intervals.
Power spectral analysis of RR variability can be used to quantify
parasympathetic modulation of sinus node activity. We computed R-R
interval power spectra on the final 5-min segment of each 7-min segment
of the study. The methods used for spectral analysis have been
described previously (2, 5). A continuous function was
derived from the discrete N-N intervals, filtered, and then sampled at 1,024 samples per 5-min segment to produce a time series for
spectral analyses. The average N-N interval was subtracted from the time series, and a fast Fourier transform was performed to
resolve the frequency components of cyclic activity in the time series
of N-N intervals. Because the average N-N
interval was subtracted from the time series of N-N
intervals, changes in average N-N interval between different
treatment periods should not affect the power spectral analyses.
Total power between 0.003 and 0.40 Hz was calculated. This approximates
the total variance of the signal for a 5-min interval. Power in two
bands of this power spectrum were quantified: 0.15-0.40 Hz (HF
power) and 0.04-0.15 Hz [low-frequency (LF) power]. HF power is
a pure parasympathetic signal reflecting respiratory sinus arrhythmia
(1, 13); LF power reflects sympathetic and parasympathetic
modulation of R-R intervals and is strongly influenced by baroreflex
activity (1, 12, 13).
Statistical analysis.
The replicate measures allowed each subject to serve as his or her own
control. HF power was transformed to its natural logarithm for
statistical analysis because of its positively skewed distribution. The
logarithmic transformation succeeded in producing approximately normal
distributions and thus allowed the use of parametric statistics. Values
are means ± SE unless otherwise stated.
t-Tests were used to assess the statistical significance of
differences for HF power under spontaneous and metronome-guided breathing at the same rate. The effects of the rate of metronome-guided breathing, presence of heart disease, and their interaction on the
natural logarithm of HF power were examined using repeated-measures ANOVA. We adopted a univariate approach to the repeated-measures analysis, adjusting the degrees of freedom for the tests of the effect
of metronome-guided breathing rate and its interaction with group with
the Geiser-Greenhouse correction (9). In addition, we
estimated the slope of the natural logarithm of HF power on metronome-guided breathing rate for each subject and assessed through
least-squares regression the relationship between these slopes and
metronome-guided breathing rate adjusting for presence or absence of
heart disease. To determine whether the relationship between HF power
and metronome-guided breathing rate is affected by the baseline
spontaneous breathing rate, we also included the baseline rate of
spontaneous breathing (in one model as a continuous variable and in
another model dichotomized at 16 breaths/min) in the regression analyses.
On the basis of expectations for the mean HF power and its standard
deviation from pilot data, we determined prospectively that a sample
size of 40 subjects would provide >80% power at 
= 0.05 for
detecting a 10% increase in the mean of the logarithm of HF power
(based on mean = 6.5 units and SD = 1).
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RESULTS |
Characteristics of the subjects.
Of the 39 subjects included in the study, 19 were patients with cardiac
disease and 20 were healthy adults. Of the 19 cardiac patients, 15 were
men and 4 were women, with a mean age of 59 ± 11 yr. All patients
had supporting clinical and laboratory documentation of cardiac
disease: 58% known coronary artery disease, 58% reduced ejection
fraction, and 32% hemodynamically significant valvular disease. We
excluded subjects with atrial fibrillation, pacemakers, extensive
atrial or ventricular ectopy, or known peripheral neuropathic disorders. Of the 20 healthy subjects, 10 were men and 10 were women,
with a mean age of 32 ± 11 yr. None of the healthy subjects had
known cardiovascular or other systemic disease, and none was receiving medications.
Comparison of healthy subjects with cardiac patients.
As expected, cardiac patients had significantly lower HF power than
healthy subjects [3.55 ± 1.27 vs. 6.14 ± 1.31 (SD)
ln(ms2), P < 0.0001]. As a group, the
cardiac patients were significantly older than healthy subjects, but
the difference in HF power between healthy subjects and cardiac
patients was much greater than the expected decline in HF power with
age (4).
Spontaneous vs. metronome-guided breathing.
Mean spontaneous breathing rates were 18.9 ±0.95 and 14.5 ±0.90
breaths/min for patients and healthy subjects, respectively (Fig.
1). There was no significant difference
between HF power measured during spontaneous breathing and during
metronome-guided breathing in the group as a whole or when patients and
healthy subjects were examined separately (Fig.
2). The mean difference in the logarithm
of HF power between spontaneous and metronome-guided breathing was
0.42 ± 0.94 ln(ms2), which was not significantly
different from zero (P = 0.32). Even though there was
no significant difference in HF power when subjects were breathing
spontaneously or with a metronome, the shape of the power spectrum did
change during metronome-guided breathing (Fig.
3). When the subjects breathe
spontaneously, the HF power spectrum is broader, because there is
greater variability in the breath-to-breath interval. The variability
in the breath-to-breath interval is significantly reduced when the
subject's breathing is guided by a metronome, and the HF peak is
correspondingly narrower.
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Fig. 2.
Comparison of mean values for the logarithm of
high-frequency (HF) power measured while subjects were breathing
spontaneously and while subjects were breathing according to a
metronome set to their average spontaneous breathing rate. Mean values
are presented for the entire group and separately for healthy subjects
and for patients with heart disease. The differences in HF between
spontaneous and metronome-guided breathing are extremely small,
especially compared with the large differences between HF power in
healthy subjects and patients with heart disease.
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Fig. 3.
Comparison of spontaneous (top) and
metronome-guided breathing (bottom) from data from 1 healthy
subject with a breathing rate of 15 breaths/min (0.25 Hz). R-R interval
tachograms are displayed for 5 min (left), and corresponding
power spectra are presented (middle and right).
Middle: actual fast Fourier transform from which all
calculations were made. Right: an autoregressed power
spectrum, which is shown to facilitate the visual appreciation of the
power spectra. During spontaneous and metronome-guided breathing, the
HF power peak occurs at the same frequency, because the mean breathing
rates are identical during these 2 type of breathing. However, the
shapes of the 2 spectra are different: the HF peak during spontaneous
breathing is broader, representing greater variability in the
breath-to-breath interval. Because the variability in the
breath-to-breath interval is significantly reduced during
metronome-guided breathing, the HF power peak is narrower. The
magnitude of HF power (the area under the curve between 0.15 and 0.40 Hz) in these 2 conditions is similar, and the effect of disease is much
greater than the effect of metronome-guided breathing.
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There appeared to be greater HF power during metronome-guided than
during spontaneous breathing (the mean difference is negative), which
may have been related to larger tidal volumes associated with
metronome-guided breathing. We did not measure tidal volume quantitatively. However, we did monitor changes in thoracic
circumference with a strain gauge, which provides an index of tidal
volume. In Fig. 4, changes in thoracic
circumference using the strain gauge are displayed for a subject in
whom HF power was greater during metronome than during spontaneous
breathing. Even though the breathing rate was similar for both stages,
the depth of breathing appeared greater during metronome-guided
breathing than during spontaneous breathing.
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Fig. 4.
Change in thoracic circumference estimated by a strain
gauge during spontaneous and metronome-guided breathing. Depth of
breathing appears greater during metronome-guided than during
spontaneous breathing.
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Effect of breathing rate on HF power.
To assess the effect of metronome-guided breathing rates on HF power,
we examined HF power over the expected range of normal breathing
rates (9-20 breaths/min) that are reflected by HF power in the
frequency range of 0.15-0.40 Hz. HF power decreased from 5.84 ±0.30 ln(ms2) at a breathing rate of 9 breaths/min to 5.26 ±0.26 ln(ms2) at 20 breaths/min (Fig.
5). Using repeated-measures ANOVA, we controlled for the presence of heart disease, since it had a large effect on HF power independent of breathing rate
(F1,37 = 49.89, P < 0.001). This repeated-measures ANOVA of all subjects, controlling for
the presence of heart disease, indicated a significant decrease in HF
power with increasing metronome-guided breathing rates
(F8,280 = 6.18, Geiser-Greenhouse 
= 0.5244, adjusted P < 0.001). The effect of
metronome-guided breathing rate on HF power tended be smaller in
patients with heart disease than in healthy subjects, although the
interaction between the presence of heart disease and metronome-guided
breathing rate was not significant (F8,280 = 1.87, adjusted P = 0.12). Whereas the decrease in HF
power due to changes in the rate of breathing was statistically
significant, it was quite small. The average decrease in HF power was
only 9.9% from baseline and occurred more or less steadily from 9 to 20 breaths/min.
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Fig. 5.
Comparison of mean values for the logarithm of HF power
measured while healthy subjects and cardiac patients were breathing
cued to a metronome at different breathing rates. HF power was measured
in all subjects at all metronome-guided breathing rates. There is a
slight drop in HF power at higher breathing rates that is small
compared with the large differences in HF power between healthy
subjects and cardiac patients.
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Given this slight but significant tendency for HF power to decrease
with increasing metronome-guided breathing rates, we evaluated whether
this decrease in HF power was related to the subject's spontaneous
breathing rate. We hypothesized that subjects with lower spontaneous
breathing rates may have been more uncomfortable breathing at the
higher metronome-guided breathing rates, which may have accounted for
the reduction in HF power. To evaluate this possibility, we regressed
HF power measured at each metronome-guided breathing rate against that
rate for each subject. The average slope (HF power vs. metronome-guided
breathing rate) for the 39 subjects was 0.0578 ± 0.0750 (SD).
This small decrease in HF power with increasing metronome-guided
breathing rates was only weakly related to the subject's baseline
spontaneous breathing rate (r = 0.31).
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DISCUSSION |
Spontaneous vs. metronome-guided breathing.
On the basis of a study in nine normal subjects, it was suggested that
the estimation of vagal modulation using RR variability requires
control of the rate of breathing (6). Despite this recommendation, most studies have utilized RR variability without regulation of breathing rate. The purpose of this study was to compare
the estimation of vagal modulation during spontaneous and
metronome-guided breathing. Our data demonstrate that there is no
significant difference in HF power measured during spontaneous and
metronome-guided breathing at the same rate. In addition, the magnitude
of any possible difference in HF power between spontaneous and
metronome-guided breathing is much less than the differences in HF
power between healthy subjects and patients with cardiac disease. Our
data agree with those of Hayano et al. (10), who also
demonstrated in a small study of normal subjects that there was no
difference between HF power measured during spontaneous and
metronome-guided breathing at the same rate.
Whereas the differences between HF power during spontaneous and
metronome-guided breathing were small and not statistically significant, we did notice a trend toward increased HF power during metronome-guided breathing. It has been previously shown that increased
depth of breathing, or tidal volume, is associated with a small
increase in HF power (6). Among our subjects, the tidal volume associated with metronome-guided breathing tended to be larger
than the tidal volume associated with spontaneous breathing (Fig. 4),
although we did not quantify tidal volume.
Pagani et al. (12) reported differences in the measurement
of HF power (using normalized units) during spontaneous and
metronome-guided breathing. The measurement of HF power used by Pagani
et al. utilizes the amplitude of the peak HF component of the power
spectrum, which is different from measurement of HF power used in this
study, which used the area under the power spectral density curve
between 0.15 and 0.40 Hz. The measurement of HF power utilizing the
amplitude of the peak of the HF component is extremely dependent on the shape of the power spectrum. This is extremely important in the context
of this study, because the shape of the power spectrum is dependent on
variability in the rate of breathing. Variability in rate of
spontaneous breathing is reflected in a lower-amplitude and broader
peak at the mean respiratory frequency. In other words, RR variability
is "spread out" over a range of respiratory frequencies. During
metronome-guided breathing, the precisely regular respiratory oscillations are reflected by a single high-amplitude peak in the
spectrum with a narrow base. With this in mind, a comparison of HF
power during metronome-guided and spontaneous breathing using a
measurement of HF power that utilizes the peak of the HF component
would be much less reliable than a measurement of HF power that is
based on the area under the power spectral density curve.
Effect of increasing breathing rate on HF power.
The relationship between increasing breathing rate and HF power during
metronome-guided breathing revealed a trend toward a small decrease in
HF power with increasing breathing rate. This trend was more pronounced
in the healthy subjects than in the patients with cardiac disease. An
inverse relationship between breathing rate and HF power has been
previously reported (6, 7, 10, 11). However, within the
range of normal breathing frequencies (9-20 breaths/min), the
magnitude of the effect is small. In this study, HF power fell by
~0.5 log units through the range of normal breathing rates, an
extremely small effect compared with the large difference
(~2.5-3 log units) between cardiac patients and healthy
subjects. These data suggest that correcting HF power for breathing
rate is unnecessary. In addition, a consensus paper written by an
international group of experts on the use of RR variability did not
suggest such a correction (16). Further studies are needed
to examine the use of RR variability as a measure of vagal modulation
in subjects with breathing rates outside the physiological range.
The recommendation that the rate of breathing must be controlled to
estimate vagal modulation was made by Brown et al. (6) using a measurement of RR variability referred to as "respiratory frequency R-R interval power." In this small study, nine healthy subjects were asked to breathe at seven frequencies from 6 to 24 breaths/min. Brown et al. measured respiratory frequency R-R interval
power as the area under the peak at the measured breathing frequency at
the subjects' breathing rate rather than within the fixed frequency
bandwidths used in this and many other studies (HF power = 0.15-0.40 Hz). Respiratory frequency R-R interval power appeared
to vary significantly at different breathing frequencies, and the
authors concluded that the rate of breathing must be controlled if RR
variability is to be used to estimate vagal modulation.
There are a number of important problems, however, with the study by
Brown et al. (6) and its interpretation. First, there is
no comparison with spontaneous breathing: all data were collected during metronome-guided breathing. Second, the differences in respiratory frequency R-R interval power at different breathing rates
occurred primarily because of a 10-fold increase in respiratory frequency R-R interval power at a breathing rate of 6 breaths/min (corresponding to a frequency of 0.10 Hz). Estimation of vagal modulation from RR variability from a subject breathing at 6 breaths/min (0.1 Hz) is problematic, because at this frequency, R-R
intervals are modulated by the parasympathetic nervous system (at the
ventilatory frequency of 0.1 Hz) and by the sympathetic nervous system
(at the Mayer wave frequency of 0.1 Hz). In trying to estimate vagal modulation in a subject breathing at 6 breaths/min, the problem that
occurs with the measurement used by Brown et al., the respiratory frequency R-R interval power, is that the measurement includes sympathetic and parasympathetic influences on the sinus node. It is not
surprising that RR variability measured at the subject's breathing
rate (as is done by Brown et al.) would be markedly reduced when a
subject's breathing rate is increased from 6 to 12 breaths/min, since
the measurement at 6 breaths/min includes the influence of the
sympathetic nervous system on RR variability and the measurement at 12 breaths/min does not include these sympathetic influences.
Besides being cumbersome, metronome-guided breathing has other problems
that complicate the interpretation of HF power. The proponents of
metronome-guided breathing to measure vagal modulation base their
recommendation on the potential problem of comparing HF power between
different individuals with different breathing rates. However, in our
data, the association between spontaneous breathing rate and HF power
measured during spontaneous breathing was relatively weak
(r = 0.32 and 0.42 for healthy subjects and
patients with heart disease, respectively), suggesting that breathing
rate by itself is not an important determinant of HF power. In
addition, the intervention of metronome-guided breathing introduces
other biases into the measurement. Breathing to a metronome requires a
certain amount of mental concentration that tends to decrease HF power
(15). Metronome-guided breathing also tends to be deeper
(i.e., larger tidal volumes), which has also been shown to affect
autonomic balance and increase HF power (6). Finally, De
Meersman et al. (7) demonstrated convincingly that interventions that control and modify breathing rate and tidal volume
are associated with significant levels of subject discomfort and a
reduction in HF power. Although our data suggest that the sum of these
effects is small, these various effects of metronome-guided breathing
add error to the estimation of vagal modulation using RR variability.
Potential mechanisms.
The small decrease in HF power with increasing breathing rates may
reflect true changes in autonomic modulation. However, several reports
suggest that sinus node behavior may be influenced by
ventilatory-mediated effects that do not involve changes in sympathetic
and parasympathetic nerve firing. Hayano et al. (10) studied seven healthy male medical students in the setting of 
-adrenergic blockade and found that as the rate of
metronome-controlled breathing increased from 0.10 to 0.33 Hz, HF power
decreased while mean R-R intervals remained the same. This finding
suggests that the effects of increased breathing rates may produce
changes in the power spectral components that do not necessarily
reflect alterations in cardiac parasympathetic modulation. Further
evidence for changes in RR variability that do not involve changes in
autonomic nerve activity has been found in patients after heart
transplants. In denervated hearts where there are no vagal influences
in RR variability, small oscillations in R-R intervals are observed at
breathing frequencies (3).
The mechanism of this type of effect of breathing on RR variability is
poorly understood. Saul et al. (14) suggested that there
are mechanical changes in the thorax associated with breathing that may
result in mild stretching of the sinus node, which may in turn alter
its properties in firing behavior. Eckberg (8) suggested,
on theoretical considerations, that the kinetics of the sinus node
responses to ACh may be different during increased breathing rates when
ACh released during expiration may not have time to be completely
expressed before the next breath, resulting in an attenuated change in
R-R intervals. Importantly, although the existence of this type of
ventilatory-mediated modulation of R-R intervals that is independent of
autonomic nervous activity is an interesting phenomenon, the magnitude
of this effect is extremely small.
Conclusion.
HF power during spontaneous breathing and that during metronome-guided
breathing are significantly different at the same breathing rates. In
addition, HF power is relatively constant across the range of typical
breathing rates. The relatively small decline in HF power at higher
breathing rates is 2 log units less than the large discrepancies
observed between healthy subjects and many samples of patients with
cardiovascular disorders. As discussed above, our data indicate that
there is no need to control breathing rate to interpret HF power when
RR variability (and specifically HF power) is used to identify
high-risk cardiac patients.
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ACKNOWLEDGEMENTS |
This research was supported in part by National Heart, Lung, and
Blood Institute Grant HL-03466 and was conducted in the Irving Center
for Clinical Research supported by National Institutes of Health Grant
5 M01 RR-00645.
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FOOTNOTES |
Address for reprint requests and other correspondence: D. M. Bloomfield, College of Physicians and Surgeons, PH 3-342, 630 West
168th St., New York, NY 10032.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 August 1999; accepted in final form 18 October 2000.
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Copyright © 2001 the American Physiological Society
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