(Circulation. 1997;95:1813-1821.)
© 1997 American Heart Association, Inc.
Articles |
Origin of Respiratory Sinus Arrhythmia in Conscious Humans
An Important Role for Arterial Carotid Baroreceptors
From the Department of Cardiovascular Medicine (M.P., P.S., J.J.), John Radcliffe Hospital, University of Oxford, UK, and the Dipartimento di Medicina Interna (S.L., F.V., G.S., C.P., L.B.), IRCCS S. Matteo, University of Pavia, Italy.
Correspondence to Peter Sleight, MD, Department of Cardiovascular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
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Abstract |
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Background We investigated whether respiratory sinus arrhythmia (RSA) in healthy humans originated from central neuronal oscillations or from peripheral baroreceptors responding to respiratory changes in venous return.
Methods and Results During subjects' controlled breathing we used sinusoidal neck suction to influence RSA (spectral analysis of RR interval). In 11 subjects, 20-second apnea greatly reduced RSA, which was restored by neck suction at the frequency of respiration. Counteracting the respiration-induced cycles of carotid blood pressure decreased RSA in 13 subjects (from 2136±682 to 1372±561 ms2, P<.01). The critical phase of this neck suction was constant for each subject at around the phase shift (with regard to respiration-related fluctuations of blood pressure) best for smoothing respiratory (mechanical) changes in blood pressure. Suction of a nonbaroreceptor area (the thigh) did not affect RSA. In 4 subjects, to separate the effects of peripheral baroreceptor afferents from respiration-entrained central oscillation (15 breaths/min), we cycled the neck suction at 12 cycles/min. Increasing neck suction from -7 to -30 mm Hg increased the ratio of the power of the 12 cycles compared with the 15-cycle RSA oscillation in RR interval spectral analysis from 0.26 to 2.57. A 12-cycle/min suction of an area other than the neck had little effect on the RR interval spectrum.
Conclusions RSA can be mimicked or reduced by stimulation of arterial baroreceptors with cycles of appropriately phased neck suction at the frequency of respiration. This suggests an important influence of the arterial baroreceptors in the generation of RSA in conscious humans.
Key Words: blood pressure • arrhythmia • respiration • baroreceptors
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Introduction |
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Respiration-related variations in cardiovascular parameters have been increasingly studied not only as indices of autonomic activity but also because they convey information about pathophysiological processes and their prognosis. For example, in healthy1 and diabetic2 subjects, respiration-related fluctuations in RR-interval RSA are used as an index of the gain of the baroreceptor cardiac vagal reflex responses. Acute reductions of fetal RSA during labor predict fetal death,3 and chronic reductions of HR variability after myocardial infarction are a marker for subsequent sudden cardiac death.4 5
Central to this problem is the origin of RSA. Several theories have been proposed. According to some studies, mostly animal-based,6 7 8 9 RSA originates from respiration-entrained oscillations in medullary neuron firing rates ("central oscillator")10 ; this medullary neuronal network shows regular oscillations in firing rates even when all afferent input is interrupted.11 12 These oscillations, when entrained by afferent stimuli from receptors in the lungs and thoracic wall in time with respiration, may result in an HR oscillation called an RSA.13
These autonomic changes may also be due to baroreflex stimulation caused by changes in arterial pressure due to the regular inspiratory increase in venous return to the heart.14 15 16 17 In addition, other reflexes originating from the cardiopulmonary receptors may be implicated in the origin of RSA.13 18 Whether and to what extent all these reflexes contribute to RSA is still controversial. From a practical point of view, RSA is a relatively simple index of the gain of the arterial baroreflex19 20 that can give important predictive clinical information.3 4 5
The aim of the present study was to establish the role played by the arterial baroreceptors in the origin of RSA in conscious humans. We posed three questions. (1) During apnea, can RSA be mimicked by stimulating the carotid baroreceptors by rhythmic neck suctions cycled at the frequency of the previous respiration? (2) Is it possible to reduce RSA by neck suction phased so as to smooth out the BP waves caused by respiration? (3) Is it possible to separate the effects of respiration from those of carotid baroreceptor input by examination of RR variability when neck suction is applied at a frequency close to, but distinct from, the respiratory frequency? We show below that the answers to all three questions were affirmative.
Arterial baroreceptors can be selectively stimulated by pressure changes in an applied neck chamber21 and can cause reflex RR interval changes: this methodology has been used in healthy subjects22 23 and patients.15 Neck suction has been used to assess the presence and type of delayed reinnervation in human heart transplant recipients.24 In the present study, we used the neck chamber to test for reflex HR and BP responses in normal humans.
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Methods |
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Subjects and Measurements
The study was approved by the local ethics committees; the participants gave written informed consent. The study group comprised 13 healthy male volunteers aged 27.5±5.9 (range, 22 to 43) years. Because the studies were performed in two different centers, Oxford and Pavia, the men were not all subjected to the full protocol. All subjects were familiarized with the laboratory, all the equipment, and the measurement technique before the actual day of investigation; however, in order not to influence their behavior during the recordings, they were unaware of the specific aims of the study. They were studied in the sitting position after a 10- to 15-minute rest, when recordings of ECG (lead II), respiration, noninvasive BP, and neck chamber pressure were obtained. The respiratory signal was obtained simultaneously from thorax ECG electrodes (modified Frank system) by means of an electrical impedance pneumograph (with a flat frequency response from 0 to 25 Hz) designed in our laboratory.25 Noninvasive BP recordings were obtained by using a Finapres unit (Model 2300, Ohmeda) and a conventional sphygmomanometer technique. The neck-suction technique was applied by means of a molded lead collar connected with a vacuum cleaner whose power was modulated by a function generator (Krohn-Hite model 5200) to generate a sinusoidal suction. Neck pressure was continuously monitored by a Statham P23d pressure transducer. During all recordings the controlled respiration was maintained at 0.25 Hz (15 breaths/min) by visual synchronization with an oscilloscope displaying a sinusoidal waveform. The subjects were instructed to maintain a steady, quiet respiration and to avoid hyperpnea: this was visually checked by the supervisor of the test to minimize any intrasubject change in tidal volume, as this parameter was not controlled.
Protocols
Three sets of experiments were performed.
Spontaneous RR Interval Fluctuations and Induction of RSA
During Apnea
First, spontaneous RR interval fluctuations during apnea and
induction of RSA-like HR changes ("SA") during apnea caused by
neck suction were analyzed in 11 subjects. After a 2-minute recording
of controlled breathing the subject held his breath for 20 seconds
starting at end expiration. The breath-hold maneuver was then repeated
but with continuous sinusoidal neck suction set at the same frequency
as the respiration, for the period before, during, and 2 minutes after
apnea. The neck pressure swing was from 0 to -15 mm Hg. Finally,
the recordings were repeated with the neck suction only during apnea,
starting at the onset and ending when the subject resumed
respiration.
Suppression of RSA by Varying Phase of Neck Suction
Next, suppression of RSA was obtained by varying the phase of
neck suction in 13 subjects. After a 4-minute baseline recording
obtained, as before, during quiet, controlled breathing, recordings
were taken for 2 minutes while the neck suction was set at the same
frequency as that of respiration, swinging from 0 to -15 mm Hg.
Four recordings were obtained in each subject at progressive phase
differences between respiration and neck suction, ie, with neck suction
in phase with respiration and then with progressive 90° shifts out of
phase with inspiration. The phase shift (in 90° steps) that maximally
suppressed RSA was then noted. In order to determine that this phase
was also the phase that best smoothed out respiratory BP fluctuations,
in 10 subjects we measured the phase relationship between neck suction
and Finapres BP (we assumed Finapres BP bears a constant phase relation
with carotid BP).
To assess the reproducibility of this test, 6 of the 13 subjects repeated the same protocol 1 month and 24 months later. To exclude a nonspecific effect of suction (ie, not mediated by the baroreflex) in suppressing RSA, suctions from 0 to -30 mm Hg of a nonbaroreflex area (thigh or leg) were performed in 6 subjects: four recordings were performed in each subject following the same protocol (above) to suppress RSA.
Baroreceptor- Versus Respiration-Induced SAs
Finally, baroreceptor- versus respiration-induced SAs were
compared in four subjects. While respiration was maintained at 0.25 Hz
(15 breaths/min), neck suction was set at a similar but distinct
frequency, ie, 0.20 Hz (12 cycles/min). The carotid baroreceptor
stimulation lasted 2 minutes, during which recordings were obtained.
Three sets of recordings were obtained by setting the pressure within
the neck to swing from 0 to -7 mm Hg, from 0 to -15
mm Hg, and from 0 to -30 mm Hg. As a control for nonbaroreflex
stimulation, suction from 0 to -30 mm Hg was also applied to the
thigh or leg at 0.20 Hz in the same four subjects during controlled
breathing at 0.25 Hz.
Data Acquisition and Analysis
The data were digitized on line by a 12-bit analogue-to-digital
converter (NB-MIO-16 board, National Instruments) at a sampling rate of
500 samples/s for each channel. The converter was connected to a
Macintosh II computer (Apple Inc). A C language program identified all
the QRS complexes in each sequence and then located the peak of each R
wave. The RR interval, SBP, DBP, neck suction, and respiration time
series were obtained from these data. The respiratory time series was
obtained from the thoracic impedance signal that occurred at the peak
of the R wave and was expressed in arbitrary values. For each step of
the protocol, all the RR intervals obtained were analyzed. The very few
premature beats were interactively identified and corrected by linear
interpolation with the previous and following beats. The original
signals and RR interval data were then stored for further analysis,
including mean RR interval and HR variability (evaluated as the
variance of RR interval).
PS Analysis
We applied PS analysis to RR interval, respiratory, SBP, DBP,
and neck-suction signals by using an autoregressive
model.25 In most cases a model order of 11 to 13 was
adequate. Spectral components were obtained by using a decomposition
method to measure the area below each spectral peak. According to the
autoregressive model, each peak identifies the presence of an
oscillatory component; however, to distinguish between signal and
noise, components below 5% of total variability were ignored. Two
frequency bands were considered: the so-called LF band (from 0.03 to
0.15 Hz) and the HF band around the respiratory frequency (from 0.18 to
0.35 Hz). Because the HF oscillations are due to the effect of
respiration, in the present study the respiration-related oscillations
in the RR interval spectrum (index of RSA) were more precisely
identified by their correspondence with the oscillations in the
respiratory spectrum by using coherence analysis. During the 0.20-Hz
neck-suction stimulation (experiment 3), the HF band was further
divided into two components: the respiratory component at 0.25 Hz
(identified by significant coherence with respiration, as in the rest
of the study) and the neck-suction component at 0.20 Hz (identified by
coherence with the neck-suction signal and absence of coherence in
frequency with the respiratory signal).
Analysis of Apnea by Time-Varying PS Analysis
The insertion of a necessarily short period of apnea in a
recording introduces several practical problems in the estimation of
variability. Spectral analysis, which is the method of choice, assumes
there are no changes during the period of recording and so is no longer
valid. One applicable method uses so-called time-varying spectral
analysis algorithms. The Wigner-Ville transform allows continuous
measurement of the spectral components for each beat of
recording26 and can be plotted in three-dimensional
figures to show time-varying changes in the various spectral components
(see "Results"); average power can be obtained for each
band.27 We obtained moving windows of 128 heartbeats and
used a 5-beat moving average of the spectra to remove the
"interference artifacts" inherent in the Wigner-Ville
transform.28 The results are summarized as average LF and
HF power before apnea, during the first and second half of apnea, and
after apnea.
Statistical Analysis
All results are given as mean±SEM. A paired t test
was used to evaluate the differences within tests; when more than one
trial was performed, repeated-measures ANOVA was used. As we were
interested in the absolute amount of RSA and not the relative
proportion of RSA with respect to other sources of variability (as in
terms of sympathovagal balance), we did not feel it appropriate to
evaluate RSA in relative or normalized (percent) units.
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Results |
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The subjects completed the tests without discomfort. In particular, they did not present any difficulty in performing the apnea or during the controlled respiration.
Analysis of Spontaneous RR Interval Fluctuations and Induction of
RSA During Apnea
No changes were observed in the mean RR interval during apnea
tests. During undisturbed apnea, SA (HF) was much reduced and at a
rhythm similar to, but generally slower than, that of respiration
before apnea (Table 1
). After the apnea, RSA increased
as a result of the initial compensatory increase in ventilation. During
the first part of undisturbed apnea the LF components of the RR
interval were markedly decreased, but during the second half they
increased above resting values. As a result, the LF components did not
show any significant differences with respect to baseline (Table 1). In
addition, the BP fluctuations at the respiratory frequency were
reduced, which accounted for the decreases in RR interval fluctuations
during apnea. These patterns were evident on both the time series (Fig 1) and in the three-dimensional continuous spectral
plots (Wigner-Ville transforms) (Fig 2). When the apnea
was performed during neck suction and cycled at the same frequency as
the prior respiration, SA remained unchanged, and the onset and end of
the apnea were almost indistinguishable in the RR interval patterns
(Fig 3) or in the Wigner-Ville plots (Fig 4). SA also remained unchanged when the neck suction was
delivered only during apnea. In the pressure signals the HF
fluctuations persisted during apnea with neck suction but were
attenuated (Figs 3 and 4).
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Analysis of Suppression of RSA by Varying Phase of Neck
Suction
In all subjects we were able to reduce RSA by cycling the neck
suction with the phase shifted but at the same frequency as
respiration. The phase difference between respiration and neck suction
that best reduced RSA differed among the subjects. Repetition of the
maneuver in six subjects after 1 and 24 months yielded similar results,
ie, RSA could be reduced only if the individuals' specific phase
relationship was chosen. HF was reduced from 1152±594 to 602±284
ms2 after 24 months (P<.01). An in-phase
relationship (shift 0°) was effective in 3 of 13 subjects, in-phase
opposition (shift 180°) was effective in 5 of 13 subjects, a 270°
phase shift between neck suction and respiration was effective in 5 of
13, and a 90° phase shift was effective in none. RR variance was
reduced, and the LF component of the RR interval variability was also
slightly but significantly reduced. The mean RR interval was unchanged
during the test. No significant changes were observed in BP
oscillations, although there was a trend to reduction in all values
(Table 2). Fig 5 shows, in a
representative subject, the considerable suppression of the RR interval
fluctuations (particularly HF) induced by counteracting baroreceptor
activity with neck suction. Suction of a nonbaroreflex area (thigh or
leg) at 0.25 Hz did not affect any of the PS analysis parameters with
respect to baseline. Changing the phase relationship of the
nonbaroreflex area suction with respect to respiration did not affect
the power of the RSA (whereas in the neck, a specific phase shift was
more influential in counteracting RSA). In particular, suction on the
leg timed at the individuals' specific phases that reduced RSA when
performed on the neck produced the following results: HF 1152±594
(baseline) versus 1652±1117 (suction) ms2 and LF 551±352
(baseline) versus 703±290 (suction) ms2
(P=NS).
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When we examined in 10 subjects the phase relationship between neck
suction at 0.25 Hz and BP, we observed that the optimal phases for
counteracting RSA were suction around 0° phase shift (Fig 6A). At this phase we would expect the neck suction to
augment baroreceptor activity at a time when it was falling due to a
trough in the BP caused by the mechanical variations in venous return
due to respiration (Fig 6B and 6C). We did not expect an exact match
with 0° phase shift, since our 90° steps in phase change were
relatively coarse. In addition, there would also be a small individual
correction for the pulse wave transmission between the Finapres BP
(measured in the finger) and the earlier pressure wave at the
carotid.
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0° the decreased baroreceptor firing
during a BP trough would be counteracted by a stretch of the carotid
sinus by neck suction (B and C).
Comparisons of Baroreceptor- Versus Respiration-Induced
SAs
Neck suction at 0.20 Hz induced a distinct oscillation in the RR
interval PS, the amplitude of which was proportional to the degree of
suction, whereas the respiration-induced 0.25-Hz component remained
unaffected (Table 3). As a consequence, the ratio of the
two components increased from 0.26±0.04 to 0.78±0.10 to 2.57±0.45 as
the neck-suction amplitude was increased from 7 to 15 to 30 mm Hg
(P<.001, ANOVA for repeated measures): ie, at 15
mm Hg neck suction the two components were approximately similar in
power, but at 30 mm Hg the baroreceptor-induced component was
largely predominant (Fig 7). The mean RR interval did
not change significantly during the different phases of the test. Thigh
or leg suction at 0.20 Hz induced only a small effect on RR interval
spectrum, which was only 13% with respect to the respiration-induced
0.25-Hz component: 84±155 (at 0.20 Hz) versus 644±218 (at 0.25 Hz)
ms2 (P<.05). As previously noted, RSA was not
altered by thigh or leg suction at 0.25 Hz.
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Discussion |
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Background
Despite many past studies, the precise mechanisms of respiration-induced SA are still debated. Two main theories have been proposed that are not mutually exclusive. The peripheral or "baroreflex" theory postulates that mechanically induced respiratory BP fluctuations stimulate the arterial baroreceptors to produce reflex changes in the circulation.14 15 Inspiratory augmentation of venous return, which is delayed and damped during passage through the lungs, leads to a regular rise and fall of peripheral arterial pressure; these respiration-related changes in venous return to the right atrium induce changes in left ventricular volume that are sufficient to reduce or increase stroke volume. Moreover, inspiration "afterloads" the left ventricle (by decreasing intrathoracic pressure) and momentarily decreases cardiac output and BP. This cycle of BP change is sensed by the arterial baroreceptors, which then modulate HR and determine RSA. This hypothesis is supported by evidence in humans that shows that respiration-induced changes in central hemodynamics elicit reflexes that control HR.18 However, to our knowledge, no direct evidence of the role of the arterial baroreceptors in RSA has been presented.
According to the "central" theory, RSA originates from respiratory oscillations in medullary neuron firing rates. This old hypothesis,29 30 which has been adopted by several authors,6 7 8 9 11 31 is supported by animal experiments, mostly performed in paralyzed or open-chest animals,7 9 which show that RSA may persist in the absence of any respiratory movements and that HR acceleration is still related to inspiratory activity in the phrenic nerve.7 8 32 These studies also show that the amplitude of RSA is positively correlated with the PCO2 level of the arterial blood.7 The "central" theory is also sustained by the evidence of the LF and HF components in the discharge variability of brain stem neurons recorded in cats with sinoaortic deafferentation.33 However, studies on humans that aimed to separate respiratory movements from central nervous respiratory activity by assisting ventilation (external intermittent negative pressure ventilation) and that measured changes in arterial PCO2 failed to identify any central origin of RSA.17 The discrepancy with animal work has been ascribed to species difference, but more probably might be due to the fact that the animals were anesthetized.7 32
Other theories have been proposed. Taha et al13 have suggested that RSA could result from reflexes other than the baroreflex, eg, cardiopulmonary reflexes, including those from lung stretch reflexes. Studies investigating the relationship between lung expansion and the amplitude of RSA, independent of simultaneous changes of intrathoracic pressure, have excluded the role of reflexes from the lungs or the thoracic wall.18 Another hypothesis is that local stretch of the sinus node causes changes in the spontaneous depolarization rate.34 This seems unlikely during physiological pressure conditions because RSA is dependent on an intact vagus nerve,30 35 36 and the SA seen in transplanted (denervated) hearts is of very small amplitude.13 24
Practical Considerations on the Genesis of RSA
Most of these theories have experimental support, so it is likely
that most or all of these mechanisms contribute to RSA. Thus,
redundancies may explain why it has been so difficult to identify which
specific mechanism is actually generating RSA. Indeed, it seems likely
that any mechanism, either central or peripheral, could entrain other
structures, such as a medullary cardiorespiratory neuronal network,
making it virtually impossible to identify a real "origin" of
RSA. Nevertheless, the relative importance of different factors can be
investigated by using suitable methodology. We performed three
different experiments devised to evaluate the relative contribution of
different mechanisms.
Observations on Simple Apnea
If RSA were mainly due to a respiration-entrained central
oscillator, it should persist despite respiratory apnea, especially at
first; conversely, if respiration acting at any level were the main
source of RSA, then RSA would be abolished by apnea. In fact, during
apnea not only is respiration stopped, but other complex changes occur
that involve chemoreceptors and cardiopulmonary receptors. After 15 to
20 seconds of apnea an increase in sympathetic efferent activity is
often observed in microneurographic recordings.37 38 As a
consequence, the RR interval is not fixed during apnea but shows a
rather complex pattern in which both LF and very LF oscillations are
evident. A new methodology for computing a time-varying spectrum
analysis (Wigner-Ville transform) allowed us to study the pattern of
change of these fluctuations during apnea. We found that the
respiratory BP fluctuations were reduced, thus accounting for the
decreases in RR interval fluctuations. In fact, RSA was markedly
reduced yet did not disappear completely, and it was at a rhythm slower
than that of respiration before apnea. This suggests that RSA is mainly
due to the peripheral activity of respiration and its influence on BP,
but even in the absence of respiration a small amount of RSA persists;
this persistence favors the presence of a central
oscillator.8 Other fluctuations, although reduced, were
evident during apnea, and occasionally, the slow (0.1-Hz) rhythm
increased toward the end of apnea (Figs 1
and 2): this may be related
to the increase in sympathetic traffic.16 37 38 An
important baroreflex contribution of this 0.1-Hz fluctuation has been
proposed by De Boer et al14 from a mathematical model and
has more recently been demonstrated in our laboratory by damped
persisting oscillations in BP.39 However, since these
oscillations were more obvious at the end than at the beginning of
apnea, they might be evidence of an additional coexisting central
neuronal oscillator.33 40
If RSA were due to baroreceptor-sensed respiratory changes in BP, then
a respiration-like modulation of the carotid sinus should result in
"RSA" despite apnea. The neck-suction technique is an ideal
method to stimulate the carotid baroreceptors selectively, without any
respiratory or hemodynamic effect other than reflex. Although in most
applications the stimulation has been given as a sudden decrease in
neck pressure, and the response has been evaluated simply in terms of
reflex bradycardia,24 the technique can be made far more
flexible. We have built a servomechanism able to continuously vary the
pressure within the neck chamber and that can be modulated by any
predetermined signal. A sinusoidal signal was used at the same
frequency as normal breathing, ie, 15 breaths/min, or 0.25 Hz. We found
that if the subject suddenly stopped breathing during such neck
suction, RSA continued unchanged, so that respiration (and other
possible related mechanisms, such as cardiopulmonary reflexes) appeared
unnecessary for the generation of RSA, provided that the carotid
baroreceptors were sensing an oscillation of similar frequency and
magnitude to that of the BP effects of respiration. Similar results
were obtained whether the neck suction became operative only during the
period of apnea and stopped thereafter or whether it was continuously
cycled before, during, and after apnea. This experiment suggests that
the arterial baroreceptors may contribute to the generation of RSA
(Figs 3 and 4). We cannot assume from this experiment alone that the
baroreflex is the only mechanism responsible for RSA, since we cannot
exclude the possibility that neck suction might have entrained a
central nervous oscillator normally entrained by respiratory afferent
stimuli.
The persistence of the HF fluctuations, although attenuated, in the BP signals during apnea with neck suction supports the theory of a mechanical origin of these respiratory oscillations.
Potentiation or Suppression of RSA by Changing the Phase of
Neck Suction
We next argued that if a central oscillator did play an important
role in generating RSA, then this oscillator should be entrained by the
neck suction regardless of the phase relationship between neck suction
and respiration. Thus, if this hypothesis were correct, by summing up
the effect of the centrally entraining neck suction and that of
respiratory entrainment, we should have obtained a potentiation of RSA.
Conversely, if RSA were the result of a baroreflex response to
respiration-induced changes in BP, then the effects of these BP
fluctuations on carotid distension and hence baroreceptor firing could
have been counteracted by specifically timed counterpressure induced by
neck suction that was out of phase with the respiration-induced BP
fluctuations. So by finding a suitable phase shift between respiration
and neck suction we might observe either a reduction or a potentiation
of RSA.
Our experimental data indicate that in all the subjects RSA could be reduced by at least 50% by neck suction timed at the same frequency as respiration but with an appropriate phase shift. This delay was consistent and specific in timing in the same subject when tested 1 month or 2 years later but was different from subject to subject, probably because of differences in the time necessary for the increased venous return generated by inspiration to pass from the right heart to the systemic arteries, and hence to the carotid baroreceptors. It is possible also that differences in pulmonary damping and capacitance and differences in circulatory delay through the pulmonary and left heart vessels could explain the interindividual variability. We excluded a nonspecific effect of suction (not mediated by the baroreflex) by suctioning a nonbaroreflex area (thigh or leg), which did not counteract RSA but did produce some nonsignificant changes in the PS.
The neck pressure swing able to obtain the maximum RSA suppression
ranged from 8 to 15 mm Hg, ie, a plausible and physiological
respiratory pressure swing. Complete suppression of RSA was not
expected, since it was not possible with this technique to exactly
counterbalance the respiratory BP fluctuations in the neck arteries,
nor was it possible to suppress afferent influences from other
noncarotid receptors in the aorta or heart (Fig 5). It seems unlikely
that the specific (for each individual) phase shift we found to
optimally suppress RSA was caused by a central nervous "gating"
mechanism. In fact, the phase shift necessary was not the same in each
subject, ie, did not bear a fixed relation to respiration, as might be
expected for a central nervous "gating" mechanism.41
Furthermore, the phase shift of neck suction was related more closely
to BP than to the respiration phase. The most simple explanation for
these results is that arterial pressure fluctuations in the neck region
play a major role in the generation of RSA in conscious humans through
the action of the carotid baroreceptors.
Comparison Between Pure Baroreflex-Induced and `Natural'
RSA
In the above two experiments the neck suction and respiration were
set at the same frequency, so the effect of pure baroreceptor
stimulation was mixed with that of respiration. We therefore examined
separately the pure baroreceptor effect and that of the "natural"
RSA (ie, including the baroreceptors together with all other possible
causes of RSA) by setting the respiration and the neck suction at two
close but distinct frequencies, ie, 0.25 and 0.20 Hz, respectively.
Saul et al42 have convincingly shown that the activities
of both the sympathetic and the vagus are frequency dependent;
therefore, to avoid differences due to the different frequencies of
stimulation, the two stimuli were set at the closest possible
frequency. At 0.20 and 0.25 Hz, two distinct peaks could be easily
observed in all the subjects studied. The power of the
"baroreceptor" peak was lower than the normal respiratory peak if
the neck suction swing was 7 mm Hg, was in the same range of
magnitude with a 15–mm Hg swing, and was two to three times greater
with 30 mm Hg. These results point to the importance of the
arterial baroreceptors in generating RSA. Suction applied to the leg or
thigh cycled at 0.20 Hz induced a small effect, suggesting that other
afferents could exert a central effect, but much less than neck suction
and without any specific phase where the effect was greater or
less.
Taylor and Eckberg43 have studied the origin of RSA in humans after elimination of RR interval fluctuations by atrial pacing: arterial pressure oscillations were increased in the 40° tilt position but decreased in the supine position. The authors concluded that RSA seemed to buffer the BP fluctuations in the upright but not the supine position. To override the sinus rhythm, Taylor and Eckberg needed to pace the heart at significantly higher rates than the control SA, with consequent reductions in stroke volume. This and the probable discomfort from esophageal electrical pacing could have altered baroreflex afferent discharge and/or the central gain of the reflex arc when comparing the fixed (paced) rate with the normal sinus rhythm. A major role of body position in the relationship between HR and BP has been reported.42 Our results, obtained in sitting subjects, may be at least partially consistent with the hypothesis that RSA buffers respiratory arterial pressure oscillations in a partially upright position.
Study Limitations
Like all models, the model we used may be subjected to criticism.
A system that normally works in closed-loop conditions is forced with
an external input in such a way that what is analyzed becomes an
input-output open-loop relationship: therefore baroreflex forcing
should be as brief as possible. However, the sinusoidal stimuli used
have the advantage of minimizing baroreceptor
adaptation.10 22
The RR interval response induced by baroreflex stimulation during apnea (SA) cannot really be described as natural RSA, but the similarity between the "natural" and the neck suction–induced responses suggests the possibility of a contribution of the carotid baroreceptors. Furthermore, animal experiments32 also suggest an important baroreceptor influence on RSA in normocapnic animals with intact vagus compared with vagotomized animals with increased central drive due to hypercapnia (when the "central" influence is dominant).
As this is a study of respiration, the measurement of tidal volume and/or end-tidal CO2 could have provided interesting information, but in our laboratory preliminary tests have shown that the concomitant presence of the collar around the neck and the mouthpiece for measurement of respiratory gases was poorly tolerated.
However, during the first set of experiments we evaluated whether the neck collar had induced any changes in ventilation by calculating the modifications of the spectrum of the respiratory signal during controlled breathing (15 breaths/min) without and during continuous sinusoidal neck suction set at the same frequency as the respiration. Five subjects (50%) did not show any changes or even reduced their respiration, but the other five increased their ventilation. Therefore, at least in some cases, the neck suction may have affected the RSA, perhaps by stimulating the carotid chemoreceptors or baroreceptors, or as a consequence of an alerting stimulus. No significant changes, however, were observed between the different recordings with the neck suction.
In this study we did not try to examine all other possible causes of RSA, nor were the differential roles of the aortic with respect to the carotid baroreceptors assessed. By definition neck suction affects only the neck region, and thus a counterresponse by the aortic baroreceptors to the changes induced by the neck was to be expected. This, together with the relatively crude phase changes, might explain why carotid countersuction was unable to suppress RSA totally. Nevertheless, our results indicate that the carotid input was important.
Conclusions
The present investigation suggests a substantial role for the
carotid baroreceptors in the origin of RSA in conscious humans.
However, the observations that conscious animals with chronic
sinoaortic deafferentation9 or during apnea8
show a clear RSA support the hypothesis of a multiple genesis of RSA
under particular conditions. Our present finding does not exclude the
presence of a central oscillator: the small RSA observed during
undisturbed apnea actually suggests that a central oscillator is
operative, although at a slower rate than either the normal or the
controlled ventilation that we used (Fig 2). It is possible to envisage
a more complex system for the generation of RSA that would involve both
the baroreflex and central oscillator mechanisms (and perhaps other
mechanisms). We have shown that during normal respiration, in healthy
subjects, the baroreflex is the major system for generating both HF
(RSA) and also slow oscillations of HR and BP39 : this
suggests that during normal respiration the less powerful central
rhythm can be masked. On the other hand, when respiration ceases during
apnea or when the baroreflex sensitivity is depressed (either in
physiological, such as exercise, or pathological conditions), the
contribution of the central and/or other oscillators to the generation
of the RR oscillations, which we generally found to occur at a slower
frequency than the normal RSA, can be observed.40
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Selected Abbreviations and Acronyms |
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Received August 13, 1996; revision received November 12, 1996; accepted November 19, 1996.
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References |
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