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Clinica Medica I, University of Milan, and Ospedale S. Gerardo, 20052 Monza; Istituto Scientifico Ospedale S. Luca, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano, 20149 Milan; and Laboratorio di Ricerche Cardiovascolari, Centro di Bioingegneria, IRCCS, Fondazione pro Juventute, 20148 Milan, Italy
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ABSTRACT |
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In animals and humans, baroreceptor modulation
of the sinus node in daily life can be studied by identification of the
number of sequences in which systolic blood pressure (SBP) and pulse interval (PI) linearly decrease or increase for several beats. It is
also studied by power spectral analysis of SBP and PI in regions where
their powers are coherent, although, in contrast to the sequence
method, whether this frequency-domain method specifically reflects the
baroreceptor-heart rate reflex has not been adequately tested. We
recorded intra-arterial BP for ~3.5 h in eight conscious cats, first
intact and then 7-10 days after sinoaortic denervation (SAD).
Sensitivity of baroreceptor-heart rate reflex was assessed in 120-s
segments by the square root of the ratio of PI and SBP spectral powers
(
) in the regions around 0.1 (MF) and 0.3 (HF) Hz, and coherence
between PI and SBP spectral powers in MF and HF regions was computed.
SAD increased overall SBP variability and reduced PI variability
throughout the frequency range examined. SAD markedly reduced
(P < 0.01) both
-MF
(
65.6%) and
-HF (
79.9%) and consistently reduced the
number of coherent segments [i.e., where coherence
(K2) > 0.5] and average coherence values in the MF region. In the HF
region, however, SAD did not alter the number of coherent segments, and
although average coherence value throughout the HF band was reduced, in
restricted portions of the band (different between animals), a high
coherence value survived denervation. No significant changes were seen
in any measured variables in five sham-operated cats. Thus the
frequency-domain method specifically reflects baroreflex modulation of
heart rate in the MF region only. In the HF region, in contrast,
baroreflex and nonbaroreflex influences on the sinus node both
contribute to a variable degree to determination of heart rate
responses to BP oscillations. If used to study baroreflex function in
daily life, this method should use the coefficient derived from MF data.
arterial baroreflex; blood pressure variability; heart rate variability; sequence analysis; spectral analysis
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INTRODUCTION |
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WE PREVIOUSLY SHOWED that in conscious animals and humans computer scanning of the intra-arterial systolic blood pressure (SBP) signal identifies a large number of sequences characterized by a progressive increase in SBP and a linearly related increase in pulse interval (PI) and/or a progressive reduction in SBP and a linearly related decrease in PI (3, 5, 18). We also showed that in animals the number of either type of sequence is strikingly reduced after sinoaortic denervation (SAD), indicating that their occurrence specifically reflects baroreceptor modulation of the sinus node in response to spontaneous blood pressure (BP) alterations (3) and that therefore this time-domain method can be used to study spontaneous baroreflex function in health and disease (9, 14, 18-23, 25, 28) without baroreceptor manipulation by vasoactive drugs or other "artificial" laboratory techniques.
Another method that has been proposed for the determination of spontaneous baroreflex function under daily life conditions is based on the relationship between the spectral powers of SBP and PI in the frequency region in which changes in these powers are coherent (1, 15). This frequency-domain method may allow much data to be collected during short lasting resting conditions in which clear-cut BP increases and reductions do not frequently occur (22). However, no information has ever been provided as to the dependence of coherent changes in SBP and PI powers on the baroreflex modulation, that is, as to whether this method also specifically reflects baroreceptor modulation of the sinus node, as is the case for the sequence method (3). We have addressed this question by a spectral analysis-derived estimate of the baroreflex in conscious cats before and after SAD. This estimate was compared in the same animals with the sequence-derived estimate of baroreflex sensitivity to determine whether there is any superiority of one method versus the other.
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METHODS |
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Our study was carried out in eight unanesthetized cats in which BP and PI were monitored for at least 3.5 h, first in the intact condition and then 7-10 days after SAD. BP was measured via a catheter (30-cm length; 1.14-mm internal diameter) aseptically inserted into the right or left femoral artery under ether anesthesia 1 or 2 days before each monitoring period. The distal end of the catheter was advanced to lie in the abdominal aorta, and the proximal end was passed through the paravertebral muscles to which it was secured by silk sutures. Once the catheter was implanted, we flushed it periodically with small amounts of heparinized solution (5 U/ml saline) to keep it patent throughout. The cat was placed in a Plexiglas box large enough to allow activities such as standing, eating, drinking, walking, etc. The box was kept in the laboratory to make the animal accustomed to the environment, and the catheter was connected via a rigid-walled polyethylene tube (1.14-mm internal diameter; 90-cm length) to a transducer (Statham P23 Dc, Spectramed, Oxnard, CA) placed outside the cage approximately at the heart level. The transducer signal was directed to an amplifier of a Grass polygraph (Grass Instruments, Quincy, MA) to be displayed on the polygraph chart and stored on a tape recorder (Racal Thermionic, Hythe, UK) for subsequent analysis (see Data analysis). The recording system was characterized by a linear response from 0 to 200 mmHg and no drift of the zero signal throughout the recording period. The catheter was removed under ether anesthesia after termination of the monitoring session.
SAD.
After the animal was anesthetized with ketamine (50 mg/kg body wt im),
the neck was aseptically incised along the midline. The internal and
external carotid arteries were freed from their connections with the
surrounding structures, and the carotid sinus nerves were cut by
severing all tissues between their enclosure in a double ligature. The
aortic nerves were separated from the vagi near the nodose ganglion and
cut. Additional aortic fibers possibly traveling outside the aortic
nerves were cut by isolating and stripping the common carotid arteries
over the entire neck and by sectioning the cervical sympathetic trunks
near the nodose ganglion (24). The effectiveness of SAD was shown by
the disappearance of the bradycardic response to the baroreceptor
stimulation induced by an intravenous bolus of phenylephrine capable of
increasing mean BP (diastolic BP +
of pulse pressure) by
20-25 mmHg. In the intact condition the bradycardia was
27.3 ± 7.2 beats/min, whereas after SAD it was
1.9 ± 0.4 beats/min. On visual inspection the animal's behavior
(grooming, drinking and eating habits, motion, etc.) after SAD was not
appreciably different than before SAD.
Sham-operated animals. In five additional cats BP was recorded first in the intact condition and then 7 days after a neck operation that consisted exclusively of the midline neck incision and the initial surgical approach to the carotid arteries and vagosympathetic trunks after ketamine anesthesia. The duration of the recording periods was similar to that described for the cats studied before and after SAD. As was the case for those cats, no apparent change in the animal's behavior was induced by the sham operation.
Data analysis. The BP signal stored on the magnetic tape recorder was replayed and sent to a personal computer, sampled at 200 Hz, digitized on a 12-bit analog-digital converter, and stored on another magnetic disk for further analysis. This consisted of 1) editing the signal from artifacts and pulse pressure dampening by an interactive procedure described in previous studies (11, 17) and 2) calculating SBP and PI for each pulse wave. PI was estimated from the interval between the systolic peaks of consecutive arterial waveforms. The time of occurrence of each peak was obtained by computing the maximum of the parabola interpolating the three samples having the highest pressure values in each pulse wave. Previous data indicate that this leads to a high time resolution and to results that are similar to those obtained by measuring the R-R interval by electrocardiogram (6, 17).
To assess the baroreceptor-heart rate reflex by the frequency-domain method we used the approach described in detail in previous studies (15, 19-22). Briefly, the SBP and PI time series were processed in a sequential fashion, as described previously (6, 17). Each time series was split into contiguous segments of 120 s. Power spectral densities of each segment were estimated after a 10% cosine tapering of the raw data using the standard fast Fourier transform (10). For each segment the power spectral densities of SBP and PI oscillations were calculated over a frequency region from 0.008 to 0.8 Hz. Across the same frequency region calculations were also made of the coherence between PI and SBP powers, i.e., the equivalent of the correlation coefficient in the time domain. In line with previous studies using the frequency-domain method (1, 15), the baroreflex sensitivity was expressed as the square root of the ratio between PI and SBP powers, computed within each segment over the spectral lines where the PI and SBP powers displayed a squared coherence modulus (K2) >0.5. This ratio was averaged separately in the region from 0.07 to 0.20 Hz (midfrequency or MF) and in the region from 0.20 to 0.8 Hz (high frequency or HF) and referred to as the
-MF and
-HF coefficients,
respectively. Coherence was also averaged separately in the two
regions. The PI and SBP signals were also automatically scanned to
identify when both variables increased progressively over four
consecutive beats (+PI/+SBP sequence) or decreased progressively over
four consecutive beats (
PI/
SBP sequence) with a
correlation coefficient (r) between
PI and SBP values
0.85. The threshold for a SBP and PI change was 1 mmHg and 6 ms, respectively. Further details on baroreflex analysis by
the sequence method are available elsewhere (3, 5, 18). The baroreflex
sensitivity estimates obtained by the
-coefficient in the MF and HF
regions were averaged in each cat separately for the intact and the SAD
or sham-operated conditions. This was also done for the percentage of
segments with coherent PI and SBP powers, for the low frequency (LF;
0.02-0.07 Hz), MF, and HF powers of SBP and PI, for the number and
slope of +PI/+SBP and
PI/
SBP sequences combined, and for
the SBP and PI values.
Comparisons between conditions were performed by Student's
t-test for paired observations. Linear
regression analysis was used to obtain the relationship between time-
and frequency-domain estimates of baroreflex sensitivity. A
P < 0.05 was taken as the level of
statistical significance. Unless otherwise stated, values are means ± SE.
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RESULTS |
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In confirmation of previous findings (3), cats in the intact condition
showed a large number of +PI/+SBP and
PI/
SBP sequences, the combined number being, on average, 1,378. The number of sequences was significantly and markedly reduced (
86.1%,
P < 0.001) after SAD. Table
1 shows that in the eight cats SAD was
accompanied by no significant alteration in mean SBP values. Overall
SBP variability increased markedly after SAD (Fig.
1), and so did SBP spectral powers in the
LF range. In contrast, the SBP powers in the MF range were
significantly reduced by SAD whereas those in the HF range were
affected in a more variable fashion and on average were slightly and
not significantly decreased. SAD was accompanied by a significant
reduction in mean PI values (i.e., tachycardia) and by a significant
and marked reduction in PI spectral powers throughout the frequency
range examined. An example of the changes in SBP and PI powers and in
their coherence observed after SAD in one cat is shown in Fig.
2.
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Figure 3,
B and
D, shows that in intact cats SBP and
PI powers were coherent in 82% of the 120 segments when considered in the MF region and in virtually all segments when considered in the HF
region. The number of coherent segments was significantly reduced after
SAD in the MF region, although the reduction was only ~35%. In
contrast, in the HF region the high number of coherent SBP and PI
segments was left unchanged by SAD. SAD, however, significantly and
markedly reduced the
-coefficient both in the MF region (from 9.3 ± 2.4 to 3.2 ± 0.6 ms/mmHg) and in the HF region (from 14.9 ± 4.5 to 3.0 ± 0.9 ms/mmHg) (Fig. 3,
A and
C).
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Figure 4 shows the absolute coherence
values between PI and SBP segments over the frequency range examined as
averages for each cat and for the group as a whole. In the MF region
the high coherence seen when the animals were intact was systematically reduced after SAD. In the HF band, however, the SAD-induced changes were more complex than those inferred from the simple comparison of the
coherent segments shown in Fig. 3D,
i.e., after SAD a high coherence was still found within a restricted
portion of the HF band, although the frequency at which coherence
survived was different in different animals. Furthermore, when averaged
for each individual frequency throughout the HF range, the coherence
value shown by the eight cats was also clearly reduced by SAD in the HF
band.
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Sham-operated cats.
SBP and PI mean values were similar before and after sham neck
operations. This was the case also for the SBP and PI powers in the LF,
MF, and HF bands, the number of sequences, the sequence-derived baroreflex sensitivity, the number of segments with coherent SBP and PI
powers in the MF and HF bands, the
-MF and
-HF coefficients, and
the number of PI/SBP sequences (Table 2).
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DISCUSSION |
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In our conscious cats SAD was accompanied by a striking reduction in the number of sequences characterized by linearly related changes in SBP and PI, confirming the specificity of this time-domain method in reflecting spontaneous modulation of the sinus node by the baroreflex.
The new finding of our study, however, is that the data provided by the
frequency-domain method for investigating the baroreceptor-heart rate
reflex in daily life, i.e., power spectral analysis of SBP and PI in
the frequency regions around 0.1 (MF) and 0.3 (HF) Hz, are of a more
complex interpretation. There is no question that in the MF region this
method provides a specific measure of the baroreflex modulation of the
sinus node, because after SAD the MF region showed a marked reduction
in the PI power and
-coefficient. Furthermore, after SAD there was a
consistent and clear reduction in the number of segments in which
coherence (K2)
between MF powers of SBP and PI was >0.5, i.e., the segments in which
these powers were linked to each other. Finally, in the MF region SAD
was also followed by a marked and consistent reduction in the average
coherence value (see Fig. 4). However, all this did not occur to the
same degree and consistency in the HF region, because, although SAD was
also associated in this region with a reduction in PI power,
-coefficient, and average PI-SBP coherence, in almost every animal a
high coherence persisted after SAD in restricted portions of the HF
range (Fig. 4), which caused calculation of the overall number of
coherent segments to be apparently unchanged (see Fig. 3). Thus in the
HF region the coupling between SBP and PI powers does not depend
exclusively on the baroreflex but also, at least over some of the
frequencies included in this region, on mechanisms of a different
nature. We can speculate that these mechanisms consist of reflex
modulation of the sinus node by airway receptors stimulated by changes
in pulmonary hemodynamics induced by BP changes, because in the HF
region respiratory modulation of the cardiovascular signals plays an
important role (12, 29). Other possibilities, however, such as a direct
effect on sinus node excitability by atrial stretching (originating
from changes in the afterload to the heart) cannot be ruled out (2).
Three other findings of our study deserve to be discussed. The first
finding is that SAD was accompanied by an equally pronounced reduction
in
-coefficient in the MF and HF regions, although its effect on
SBP-PI coherence was much more consistent and homogeneous through the
former than the latter frequency range. Thus the baroreflex may enhance
PI oscillations even when the PI-SBP coupling does not originate only
from the baroreflex itself. This may be accounted for by the fact that
baroreceptors can modify the excitability of the central autonomic
neurons to a variety of other stimuli (13) that thus interact with this
reflex mechanism in the control of circulation (12, 16, 26, 27, 29).
Baroreceptors have in particular been shown to operate synergistically,
at the brain stem level, with respiratory influences, which may serve
the purpose of amplifying heart rate variations in daily life (29).
The second finding is that in the MF region SAD was followed by a
marked reduction not only in the PI power and
-coefficient but also
in the SBP power, which means that in this frequency region SAD reduced
not only the reflex heart rate response to BP oscillations but also the
BP oscillations themselves. This may seem surprising because the
baroreflex is known to buffer BP variability, which is enhanced by its
inactivation (22, 24). It was shown recently, however, that
baroreceptors exert their buffering role on slow BP oscillations (7),
which is in line with the present finding that LF power of SBP
increased after SAD. Baroreceptors may, in contrast, have an amplifying
role on MF BP oscillations (7), possibly because of a resonance
phenomenon (4, 8, 30), which could explain why removal of baroreceptor influence can be followed by a reduction rather than an increase in MF
power of BP.
The third finding concerns the common procedure by which an average
coherence
0.5 between SBP and PI spectral components is generally
taken as the threshold value that guarantees a SBP and PI coupling of a
baroreflex origin (9, 15, 19). The observations made in the present
study, however, suggest that this is simplistic. First, the use of a
value of 0.5 for regarding SBP and PI as coupled is compatible with a
large number of the SBP and PI changes that are indeed not related to
each other. Second, coherence may be much greater than 0.5 in a portion
of the band analyzed but below 0.5 in another portion, which means that
an average coherence value may also include SBP and PI changes that are
not linearly coupled. Third, and most importantly, our data show that
within the HF band a high coherence could persist after SAD. Thus even
coherence values much greater than 0.5 do not guarantee a baroreflex
origin of the SBP and PI coupling. This emphasizes that the use of both
a relatively low threshold (0.5) and of an average coherence value to
investigate baroreflex coupling between PI and SBP powers in the HF
band has major limitations for identification of baroreflex modulation
of sinus node function in daily life by the frequency-domain method.
These limitations can be overcome, however, if the analysis is limited
to the MF band, in which a high coherence between PI and SBP powers
does reflect more specifically a baroreflex modulation of the sinus node.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. Mancia, Clinica Medica I, Università di Milano, Ospedale S. Gerardo, via Donizetti 106, 20052 Monza, Italy (E-mail: mancia.g{at}imiucca.csi.unimi.it).
Received 16 March 1998; accepted in final form 9 February 1999.
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D. Rubinger, R. Backenroth, and D. Sapoznikov Restoration of baroreflex function in patients with end-stage renal disease after renal transplantation Nephrol. Dial. Transplant., April 1, 2009; 24(4): 1305 - 1313. [Abstract] [Full Text] [PDF] |
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F. Cottin, C. Medigue, and Y. Papelier Effect of heavy exercise on spectral baroreflex sensitivity, heart rate, and blood pressure variability in well-trained humans Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1150 - H1155. [Abstract] [Full Text] [PDF] |
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J. M. Stewart, I. Taneja, and M. S. Medow Reduced central blood volume and cardiac output and increased vascular resistance during static handgrip exercise in postural tachycardia syndrome Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1908 - H1917. [Abstract] [Full Text] [PDF] |
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P. Castiglioni, M. Di Rienzo, A. Veicsteinas, G. Parati, and G. Merati Mechanisms of blood pressure and heart rate variability: an insight from low-level paraplegia Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1502 - R1509. [Abstract] [Full Text] [PDF] |
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J. M. Stewart, L. D. Montgomery, J. L. Glover, and M. S. Medow Changes in regional blood volume and blood flow during static handgrip Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H215 - H223. [Abstract] [Full Text] [PDF] |
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G. Parati, G. Mancia, M. D. Rienzo, P. Castiglioni, J. A. Taylor, and P. Studinger Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation J Appl Physiol, August 1, 2006; 101(2): 676 - 682. [Abstract] [Full Text] [PDF] |
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R. Fazan Jr., M. de Oliveira, V. J. Dias da Silva, L. F. Joaquim, N. Montano, A. Porta, M. W. Chapleau, and H. C. Salgado Frequency-dependent baroreflex modulation of blood pressure and heart rate variability in conscious mice Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1968 - H1975. [Abstract] [Full Text] [PDF] |
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G. Parati, M. Di Rienzo, P. Castiglioni, M. Bouhaddi, C. Cerutti, A. Cividjian, J.-L. Elghozi, J.-O. Fortrat, A. Girard, B. J.A. Janssen, et al. Assessing the Sensitivity of Spontaneous Baroreflex Control of the Heart: Deeper Insight Into Complex Physiology * Response Hypertension, May 1, 2004; 43(5): e32 - e34. [Full Text] [PDF] |
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F Conci, M Di Rienzo, and P Castiglioni Blood pressure and heart rate variability and baroreflex sensitivity before and after brain death J. Neurol. Neurosurg. Psychiatry, November 1, 2001; 71(5): 621 - 631. [Abstract] [Full Text] [PDF] |
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G. Nollo, A. Porta, L. Faes, M. Del Greco, M. Disertori, and F. Ravelli Causal linear parametric model for baroreflex gain assessment in patients with recent myocardial infarction Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1830 - H1839. [Abstract] [Full Text] [PDF] |
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