Download Regression Analysis Between Heart Rate Variability and Baroreflex

1
Regression Analysis Between Heart Rate Variability
and Baroreflex-Related Vagus Nerve Activity in Rats
TERRY B. J. KUO, M.D., PH.D.,∗ ,†,‡ CHING J. LAI, PH.D.,∗ ,† YU-TING HUANG, M.S.,∗
and CHERYL C. H. YANG, PH.D.∗ ,†
From the ∗ Institute of Neuroscience and †Department of Physiology, Tzu Chi University; and ‡Department of Neurology, Tzu Chi
Buddhist General Hospital, Hualien, Taiwan
Heart Rate Variability and Baroreflex-Related Vagal Activity. Introduction: Many previous
studies have suggested that the high-frequency (HF) power of the heart rate variability may represent
cardiac vagal activity although direct evidence of a correlation between the HF and vagal neuronal activity is still lacking. In the present study, we performed a regression analysis of the HF and vagal neurograms.
Methods and Results: Experiments were carried out on adult male Sprague-Dawley rats anesthetized
with a continuous infusion of pentobarbital sodium. The baroreflex-related vagus neuronal activities were
obtained by nerve or single-fiber recordings. The transient baroreflex response was employed to alter vagus
neuronal activities using a bolus injection of phenylephrine (PE). On-line power spectral analysis of the
heart rate and a vagal neurogram was performed during the acute baroreflex response. During the test
period, systemic arterial pressure immediately increased in response to the PE injection, after which the
R–R interval (RR), HF (0.6–2.4 Hz), and vagus nerve and unit activities all dramatically increased. Both
nerve and unit activities exhibited good correlations (r ≥ 0.7 in all nerve recordings and r ≥ 0.6 in 91% of
single-fiber recordings) with the HF. There were insignificant differences between the right- and left-side
baroreflex-related vagus nerve recordings.
Conclusion: Our present study provides a direct linkage between the HF and vagus neuronal electrical
activity in anesthetized rats. (J Cardiovasc Electrophysiol, Vol. 16, pp. 1-6, August 2005)
heart rate variability, power spectral analysis, baroreflex, vagus nerve recordings, single-fiber recordings
Introduction
It is well known that the autonomic nervous system (ANS)
constantly controls and monitors many aspects of the body’s
functions. When humans are under stress or in a diseased
state, ANS disturbances may frequently occur.1 It has been
reported that myocardial infarction patients with severe vagal
withdrawal are prone to enter a vicious cycle that may result
in lethal tachyarrhythmia.2 Sustained depression of cardiac
vagal activity indicates that a patient could be living in a high
risk state. Monitoring of vagal function may prove beneficial
under certain conditions. Therefore, it is important to validate
whether current heart-rate-based techniques reliably detect
vagal function.
Frequency-domain analysis of heart rate variability is a
sophisticated and noninvasive tool for detecting ANS regulation of the heart. It has been well established that heart rate
variability can be categorized into high-frequency (HF) and
low-frequency components according to its oscillation frequency.3 The standard procedures for interpretation of heart
This study was supported by the National Science Council (Taiwan) through
grant NSC-93-2320-B-320-008 and Veteran General Hospital-Taipei Grant
VGH92-371-5.
Address for correspondence: Cheryl C. H. Yang, Ph.D., Department of Physiology, Tzu Chi University, No. 701 Chung Yang Road, Section 3, Hualien
970, Taiwan. Fax: +886-3-8580639; E-mail: [email protected]
Manuscript received 17 September 2004; Revised manuscript received 2
February 2005; Accepted for publication 4 February 2005.
doi: 10.1046/j.1540-8167.2005.40656.x
rate variability analyses were documented in 1996.3 Since
frequency-domain analysis is readily accessible, its use for
examining heart rate variability has gained in popularity with
broad application as a functional indicator of the ANS. A
number of studies have suggested that HF is a measure of
respiratory sinus arrhythmia and is considered to represent
vagal control of the heart rate.4 The HF has been used to
elucidate the pathophysiology of autonomic dysfunction in
a number of diseases.5,6 It has also been used to evaluate
the effects of various medications.7-10 In humans, it has been
demonstrated that HF is affected by gender,11 aging,11 sleep
stages,12 and hormone replacement therapy.13 Many kinds of
exercises14,15 and environmental changes14 may also affect
heart rate variability.
The concept that the HF represents cardiac vagal activity is
generally accepted and has been broadly used in thousands of
basic and clinical applications.3 Many animal and human experiments, including vagal denervation,16 muscarinic blockade17 and vagus nerve excitation,18,19 and recording20 have
suggested that a good relationship between HF and cardiac
vagal activity should exist. However, investigations of a direct relationship between HF and vagal neuronal activity appear to be lacking, except for one study which failed to find
such a relationship.21 The linkage between the HF and direct recordings of vagal neuronal activity should be explored
in more detail considering the growing application of heart
rate variability techniques. Thus the present study was designed to investigate the relationship of HF and both vagus
nerve and single-unit activities in order to test the hypothesis
that HF is correlated with vagal activity in the anesthetized
rat.
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Journal of Cardiovascular Electrophysiology
Vol. 16, No. 8, August 2005
Materials and Methods
Preparation of Animals
Experiments were carried out on 19 adult male SpragueDawley rats (National Laboratory Animal Breading and Research Center, Taiwan) weighing 300–430 g. As described
previously,22 animals were anesthetized with an induction
dose of pentobarbital sodium (50 mg/kg i.p.). Anesthetic
maintenance was provided by an i.v. infusion of the same
anesthetic at 20 mg/kg/hour. This anesthetic management offered maintained anesthesia while preserving the capacity
for cardiovascular regulation.22 The trachea was intubated
to facilitate ventilation, and both femoral veins were cannulated for intravenous infusion of pentobarbital and administration of drugs. Animals were placed supine on a heating pad
throughout the experiment. During the experiment, the animal was allowed to spontaneously breathe room air. Animals
were sacrificed at the end of the experiment by an overdose of
intravenous pentobarbitone. The experimental protocol was
approved by the Institutional Animal Care and Use Committee of Tzu Chi University.
Recording and Acquisition of Systemic Arterial Pressure
(SAP) and Electrocardiogram (ECG) Signals
The left femoral artery was cannulated with a PE-50
catheter filled with heparinized saline (200 U/mL). The arterial catheter was connected to a pressure transducer (Statham
P23XL) and in turn to a universal amplifier (Gould 13-661550) by means of which SAP signals were amplified and filtered. The lead II ECG was also amplified and filtered using a universal amplifier (Gould 13-6615-58). These signals
were acquired by an analog-digital converter (PCL-818HD,
Advantech), and a general-purpose personal computer was
Q1 used for acquisition of the neuronal discharge signals. The
SAP and ECG signals were synchronously digitized at different sampling rates (256 and 1,024 Hz, respectively). The
acquired data were analyzed online but were simultaneously
stored on a hard disk for subsequent off-line verification. Digital signal processing of the bioelectric signals was similar to
that in our previous studies.22,23 Preprocessing of the ECG
signals was designed according to the recommended procedures3 as detailed in our previous investigations.11,23 In brief,
the computer algorithm identified each QRS complex and rejected each ventricular premature complex or noise according
to its likelihood in a standard QRS template. Stationary R–R
intervals (RRs) were resampled and interpolated at a rate of
64 Hz to provide continuity in the time domain.
Recording and Analysis of Nerve and Single-Unit
Electrical Activities
Similar to our previous study,24 the neck of each rat was
opened along the midline, and the right or left vagus nerve
was separated from the carotid artery and sectioned as far
caudally as possible. The nerve was placed on a small dissecting platform, the sheath was removed, and the nerve was
covered with mineral oil. With the aid of a dissecting microscope, iridectomy scissors, and watchmaker’s forceps, onefifth of the efferent filament was teased from the vagus nerve
and placed on a platinum-iridium recording electrode in 12
rats. The baroreflex-related nerves were obtained and identified by baroreflex excitation.25,26 The doses of phenylephrine
(PE) used to induce the baroreflex were 10 or 20 µg/kg
dissolved in saline. This was injected intravenously within
10 seconds. If there was little or no change due to baroreflex excitation, another fifth of the vagus was separated and
recorded until nerve discharges responsive to the baroreflex
were found. In the remaining seven rats, the fine efferent filament was further subdivided until activity from only one
to three units was obtained. Additionally, the relation of the
single baroreflex-related vagal unit with respiration was identified.25,27 Neuronal signals were amplified and filtered with
a high-impedance preamplifier (WPI DAM70, AC recording,
band-width 300–3,000 Hz) and synchronously digitized with
the SAP and ECG signals at 10,240 Hz using the same analog
digital converter. Analysis of single-unit signals was similar
to that used in our previous study.28 These digitized signals
were first subjected to continuous, online, real-time processing by a computer algorithm developed in our laboratory29 for
concurrent extraction, discrimination and analysis of singleunit signals from adjacent units (when present). The spike
train thus extracted for each unit was subsequently analyzed
by constructing two-dimensional amplitude histograms over
time (Fig. 2A; for the purpose of the present study this display was used in an ancillary manner). The spike train was
processed with a wide bin width (8 seconds), which produced
the conventional display of mean spike frequency, which was
defined as the vagal unit activity (VUA).
Power Spectral Analysis of Heart Rate and Vagus Nerve
Signals
The RRs and nerve signals were truncated into successive 16-seconds (1,024 points) time segments (windows or
epochs) with an 8-second (50%) overlap. A Hamming window was applied to each time segment to attenuate the leakage effect.30 Our algorithm then estimated the power density
of the spectral components based on fast Fourier transformation. The resulting power spectrum was corrected for attenuation resulting from sampling and application of the Hamming
window. The neuronal signals were analyzed into successive
0.4-seconds (4,096 points) time segments without overlap.
Twenty successive neuronal spectra (for a total of 8 seconds) were averaged to achieve synchronization with the RR
spectra. For each time segment, the power between 0.6 and
2.4 Hz of the RR spectrogram (HF)23 and the power between
70 and 3,000 Hz of the neuronal spectrogram, defined as
vagus nerve activity (VNA), were quantified by the method
of integration, that is, calculation of the area of the power
spectral density between specified frequencies.
Statistical Analysis
The HF and VNA were logarithmically transformed.11
Paired Student’s t-test was used to compare differences between the maximal response and the baseline. Statistical significance was assumed for P < 0.05. Values are expressed as
the means ± SE.
Results
Effects of a Bolus Injection of PE on Vagus Nerve
Recordings
Figure 1A is a typical example representing the influence
of an intravenous bolus injection of PE on the SAP, the RR,
a vagal neurogram, and the corresponding autospectra of the
Kuo et al. Heart Rate Variability and Baroreflex-Related Vagal Activity
3
Figure 1. Continuous displays of systemic arterial
pressure (SAP), R–R intervals (RR), power spectral
density of RR (HPSD), the high-frequency power
of RR (HF), electroneurogram (ENG) of vagus
nerve recordings, power spectral density of ENG
(NPSD), and vagus nerve activity (VNA) from one
rat after i.v. bolus administration of phenylephrine
(20 µg/kg) at 0 minute. A: Range of frequency for
HF and VNA were denoted on right side of the spectrograms. B: Two-dimensional scattergram showing the correlation between the HF and VNA of first
2 minutes after i.v. bolus injection of phenylephrine
in this rat.
RR and neuronal signal. A single bolus dose of PE (20 µg/kg
i.v.) produced robust augmentation of the SAP. Thereafter,
the RR, heart rate variability, HF, the activity of the vagal
neurogram, neuronal spectrogram, and VNA dramatically
increased at the same time. Twelve successful baroreflex responses were achieved with the slower injection rate (around
10-seconds). Linear regression analysis within the first 2 minutes revealed a significant correlation between the HF and
VNA in this test (Fig. 1B). We analyzed the baseline and
maximal values in response to the bolus injection of PE and
results are given in Table 1. For both the right- and left-side
vagus nerve recordings, values of the mean arterial pressure
(MAP), RR, HF, and VNA significantly increased from the
pre-drug control. The correlation coefficients between the HF
and VNA of the right-side recording of eight rats and the leftside recording of four rats were ≥0.70, and P values were all
<0.05. The responses of the MAP, RR, HF, and VNA and the
correlation coefficient between the HF and VNA did not significantly differ between the right- and left-side vagus nerve
recordings.
RR, the autospectra of the RR, HF, firing spikes of the vagal unit, and the firing rate of the unit analyzed from the
firing spikes. A single bolus dose of PE (10 µg/kg i.v.) produced robust augmentation of the SAP. Thereafter, the RR,
heart rate variability, HF, and the firing rate of the unit dramatically increased. Linear regression analysis between the
HF and the firing rate of the unit within the first 2 minutes revealed a high and significant correlation (Fig. 2B).
We analyzed the baseline and maximal values in response
to a bolus injection of PE in Table 2. Values of the MAP,
RR, HF, and the firing rates of single units all significantly
increased from the pre-drug control. Ninety-five percentage
of all units showed a significant correlation (P < 0.05), and
91% of all units showed a good correlation (r ≥ 0.6) with the
HF (Table 3). After analyzing the time lag of the most significant cross-correlation coefficient, we found that the time
lag in 77% of units was ≤ 8 seconds as compared to the HF
(Table 3).
Effects of a Bolus Injection of PE on Vagal Single-fiber
Recordings
The transient pressor response from a bolus injection of
PE was used to evoke transient vagal activation. Our results demonstrated a high correlation between the HF and
vagal neuronal activity, and therefore, provide a direct linkage between them in the anesthetized rat. Our findings, in the
Figure 2A is a typical example representing the influence of an intravenous bolus injection of PE on the SAP,
Discussion
TABLE 1
Baseline and Response to a Bolus Injection of Phenylephrine on Vagus Nerve Activity
MAP (mmHg)
Right-side recordings (n = 8)
Baseline
Maximal response
Left-side recordings (n = 4)
Baseline
Maximal response
RR (msec)
HF [ln(msec2 )]
VNA [ln(µV2 )]
122.4 ± 3.4
166.5 ± 4.3∗
151.0 ± 4.6
235.9 ± 15.7∗
-0.2 ± 0.2
2.6 ± 0.4∗
6.2 ± 0.2
7.1 ± 0.4∗
127.8 ± 6.3
170.7 ± 2.9∗
162.3 ± 7.7
288.5 ± 28.1∗
-0.6 ± 0.5
3.9 ± 0.7∗
6.2 ± 0.3
7.0 ± 0.4∗
MAP = mean arterial pressure; RR = R–R intervals; HF = the high-frequency power of RR; and VNA = vagus nerve activity. Data are expressed as means
± SE, ∗ P < 0.05 versus baseline.
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Journal of Cardiovascular Electrophysiology
Vol. 16, No. 8, August 2005
Figure 2. Continuous displays of systemic arterial
pressure (SAP), R–R intervals (RR), power spectral
density of RR (HPSD), the high-frequency power
of RR (HF), spike trains of vagal unit recordings
(SPIKE), their amplitude histogram (AMP), and
vagal unit activity (VUA) during i.v. bolus administration of phenylephrine (10 µg/kg) at 60 seconds.
A: Range of frequency for HF and range of amplitude for the unit was denoted on right side of the
figure. B: Two-dimensional scattergram showing
the relationship between the HF and VUA of first
two min after i.v. bolus injection of phenylephrine
in this test.
anesthetized rat, support the use of heart rate variability as a
functional index of the vagus activity.
Selective atrial vagal denervation in anesthetized dogs16
and selective muscarinic blockade in conscious dogs17 and
rats were shown to eliminate the HF components. Those experiments provided the basic evidence of the contribution of
the vagus nerve to the HF. According to their broad-band
cardiac vagal nerve stimulation experiment, Berger et al.18
concluded that the sinoatrial node responds as a low-pass
filter to fluctuations in vagal tone. Bloomfield et al.19 demonstrated a good correlation between the HF and RR in healthy
humans using indirect stimulation of the cardiac vagal nerve
through baroreflex excitation. Importantly, the result showed
a positive correlation between a prolongation of the RR, indicating increases in vagal activity, and the HF. The vagal
activity-HF relationship demonstrated in the present study is
compatible with those previous findings.
Traditional analysis of electrophysiological signals is carried out by the method of integration or root mean square. By
contrast, this study applied a frequency-domain technique
to analyze the neurograms. The digitized neuronal signals
first underwent autospectral analysis. Then the power spec-
TABLE 2
Baseline and Response to a Bolus Injection of Phenylephrine on Vagal
Unit Activity
MAP
(mmHg)
RR
(msec)
HF
[ln(msec2 )]
Baseline 113.0 ± 1.4 163.6 ± 4.5
−0.3 ± 0.1
Maximal 155.1 ± 1.2∗ 246.8 ± 10.8∗
4.0 ± 0.1∗
response
VUA
(Hz)
6.1 ± 1.6
31.4 ± 4.2∗
MAP = mean arterial pressure; RR = R–R intervals; HF = the
high-frequency power of RR; and VUA = vagal unit activity. Data
are expressed as means ± SE, n = 43 for VUA, n = 33 for the other
parameters. ∗P < 0.05 versus baseline.
tral density within specific frequencies (70–3,000 Hz) was
integrated to obtain its power. The frequency range was selected according to observations of the original autospectrogram (Fig. 1A), and this simultaneously covered the neural
activity and avoided interference from AC power (e.g., 60
Hz). Such a methodology might offer a better signal-to-noise
ratio than traditional methods. In order to double check the
results of the nerve recordings, single-fiber recordings were
used. In comparison with the traditional window discriminator, our single-unit analysis applied software-based slopetriggered amplitude discrimination, which is also believed to
offer better accuracy.28,29
Although we applied these computer techniques, some
physiologically related problems still remain to be solved.
For example, some baroreflex-independent responses of the
vagus nerves have been observed, especially when the injection rate is fast (i.e., 2 seconds). However, when slowing
the speed of the PE injection (i.e., 10 seconds), we found
that the reaction might change to baroreflex-dependent excitation. After an analysis of these baroexcitation-related vagus
nerves, all results from the nerve recordings showed a positive relation, and the value of the correlation coefficient for
each analysis was ≥0.7. It should be noted that the significant
correlation during the pressor and reversed phases occurred
within 2 minutes of when the PE was injected. Similarly,
a good correlation coefficient and significant P values were
also found in most of the single-fiber recordings which were
processed with different time lags. Also, these analyses were
obtained from 2 minutes of data.
Without cutting the afferent end of the vagus nerve, Yambe
et al.21 recorded burst discharges from the whole vagus nerve
bundle in unanesthetized goats. They found that vagal nerve
discharges were synchronized with heart beat and respiration,
but there were no significant correlations between the “tonus”
of the vagus nerve and the HF when goats treated with a depressor agent. They suggested that the rhythm composition
(cardiac or respiratory) of vagus nerve activity is represented
Kuo et al. Heart Rate Variability and Baroreflex-Related Vagal Activity
TABLE 3
Cross-Correlation Coefficients (r), P Value, and Time Lag of the
High-frequency Power of R–R Intervals (HF) and Vagal Unit Activity
(VUA) Relationship During a Bolus Injection of Phenylephrine
r
P
Number of Units
Percentage
r ≥ 0.9
0.8 ≤ r < 0.9
0.7 ≤ r < 0.8
0.6 ≤ r < 0.7
0.45 ≤ r < 0.6
10
13
9
7
4
24
30
21
16
9
P < 0.0001
0.0001 ≤ P < 0.001
0.001 ≤ P < 0.05
P ≥ 0.05
17
8
16
2
39
19
37
5
0
+1
−1
+2
−2
<−2
18
3
12
1
2
7
42
7
28
2
5
16
Lag
Cross-correlation coefficients were calculated for lags −9 to +9 with each
lag corresponding to a 8-second interval. For negative lags, HF changes
precede VUA changes. Number of unites = number of baroreflex- and
respiration-related vagal single fiber, n = 43.
by the heart rate variability while the tonus composition is
not. In different experimental settings and with different animal species, this study demonstrated positive and significant
correlations between VNA and the HF and between VUA and
the HF during the acute pressor and reverse stages. But good
correlations were not found with longer analysis durations
or under depressor conditions (data not shown). It should
be noted that pentobarbital sodium may suppress ANS activity. Under a controlled continuous infusion, however, the
ANS capacity may be partially preserved.22 In our opinion,
multiple factors and modulators, including both baroreflexdependent and baroreflex-independent ones, may simultaneously influence the vagus nerve during normal and depressor conditions, but strong vagal excitation during the pressor
condition may mask the baroreflex-independent portions and
highlight the baroreflex-dependent portions. In addition, vagal neuronal electrical activity may be influenced by a greater
number of signals, especially sensory inputs, without cutting
the afferent end. These effects may be especially prominent
while animals are in an awake state.
In general, vagal activity is separated into sustained and
pulsatile components, the former is also known as tone, the
latter as modulation, fluctuation, or rhythm. Saul et al.31 reported that the HF does not change with either increases or
decreases in arterial blood pressure. Goldberger et al.32,33
demonstrated that an infusion of PE even decreased the HF in
healthy humans despite a significant prolongation of the RRs.
Hedman et al.34 showed that constant frequency vagal stimulation increased the cardiac interval but did not markedly
change the heart rate variability. These results indicate that
heart rate variability may measure the pulsatile component
rather than the sustained component of vagal activity. However, those reports were not supported by one other study.19
We did not discriminate the “tone” or “modulation” of vagal
activity, but used a simple VNA obtained every 8 seconds
from the power spectrogram of whole vagal bundle recordings. The VNA data were also easily compared with VUA
5
data obtained every 8 seconds from the firing rate of the
single-fiber recordings. Our conclusion is simple: the HF may
parallel vagal activity in anesthetized rats especially under
pressor conditions.
Applications of heart rate variability are still expanding.
Since this technique is noninvasive, it is a good choice for
autonomic examinations in human studies and clinical applications. Some animal studies dealing with unanesthetized
creatures have also applied this less-painful technique. Such
indirect autonomic measurements still lack the certainty of
directly recorded nerve activity. It should be noted that the
basal heart rate of rats is much higher than that of humans,
and so is the frequency range of HF. Although it may not be
suitable to extrapolate our data in rats to humans directly, our
results may provide a linkage between the indirect and direct
measurements of vagus nerve activity and offer some clues
for future studies and applications.
Acknowledgments: Terry B. J. Kuo and Ching. J. Lai contributed equally to
this work. We thank Ms. Yung-Chen Chiang and Ms. Yi-Chen Lee for their
excellent technical supports.
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Query
Q1 Author: Please provide location details for Advantech.