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Am J Physiol Heart Circ Physiol 291: H2864-H2874, 2006. First published July 21, 2006; doi:10.1152/ajpheart.01024.2005
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Time course analysis of baroreflex sensitivity during postural stress

Berend E. Westerhof,1 Janneke Gisolf,2 John M. Karemaker,2 Karel H. Wesseling,1 Niels H. Secher,4 and Johannes J. van Lieshout3

1BMEYE, and Departments of 2Physiology and of 4Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; and 3Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Submitted 27 September 2005 ; accepted in final form 17 July 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Postural stress requires immediate autonomic nervous action to maintain blood pressure. We determined time-domain cardiac baroreflex sensitivity (BRS) and time delay ({tau}) between systolic blood pressure and interbeat interval variations during stepwise changes in the angle of vertical body axis ({alpha}). The assumption was that with increasing postural stress, BRS becomes attenuated, accompanied by a shift in {tau} toward higher values. In 10 healthy young volunteers, {alpha} included 20 degrees head-down tilt (–20°), supine (0°), 30 and 70 degrees head-up tilt (30°, 70°), and free standing (90°). Noninvasive blood pressures were analyzed over 6-min periods before and after each change in {alpha}. The BRS was determined by frequency-domain analysis and with xBRS, a cross-correlation time-domain method. On average, between 28 (–20°) to 45 (90°) xBRS estimates per minute became available. Following a change in {alpha}, xBRS reached a different mean level in the first minute in 78% of the cases and in 93% after 6 min. With increasing {alpha}, BRS decreased: BRS = –10.1·sin({alpha}) + 18.7 (r2 = 0.99) with tight correlation between xBRS and cross-spectral gain (r2 ~ 0.97). Delay {tau} shifted toward higher values. In conclusion, in healthy subjects the sensitivity of the cardiac baroreflex obtained from time domain decreases linearly with sin({alpha}), and the start of baroreflex adaptation to a physiological perturbation like postural stress occurs rapidly. The decreases of BRS and reduction of short {tau} may be the result of reduced vagal activity with increasing {alpha}.

blood pressure regulation; tilt; sequential and spectral analysis; vagal and sympathetic tone

INFORMATION on human cardiovascular function can be obtained from oscillations in arterial pressure and R-R intervals. These oscillations and their relationships can be studied by a physiological perturbation like postural stress that profoundly affects autonomic neural outflow (14). Postural circulatory stress elicits baroreceptor unloading, and cardiac baroreflex sensitivity (BRS) can be quantified by time-domain sequential methods (1, 11) and frequency-domain analysis (8, 49). Algorithms based on spectral analysis generally require steady state and an observation window of preferably several minutes unless sophisticated methodologies are applied (17, 30). Time-domain sequential algorithms require not more than a few heartbeats to obtain BRS. A possible disadvantage is that only a small number of values becomes available per minute, and with such methods a transient within that time frame might not be well described. A new sequential BRS method (20, 21, 56) requires only a 10-s window and generates values at a much higher rate than earlier methods, close to one value per 2 s. Additionally, the method provides information about the delay between changes in systolic blood pressure (SBP) and interbeat interval (IBI), called {tau}. We applied this method to analyze the effects of the circulatory challenge of postural stress on BRS.

Considering that during passive head-up tilt muscle sympathetic nerve activity increases linearly with the sine of the tilt angle, reflecting the body axis component of gravity (6, 14, 24), we determined time- and frequency-domain BRS function during graded progressive orthostatic stress. Orthostatic stress was expressed as sin({alpha}), in which {alpha} corresponds to the angle of body position, representing the vertical component of the fluid column on which the gravitational forces are exerted. {alpha} was increased stepwise from –20° to 90°. We traced the alterations in BRS and analyzed the dynamic changes in distribution of the time domain-determined IBI-to-SBP delay, {tau}. We considered that the frequency-domain phase lag should augment with increasing postural stress (6) and evaluated whether BRS becomes attenuated by a reduction in its vagal component with a shift in {tau} toward higher values.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We studied 10 healthy volunteers (22–39 yr; 9 men and 1 woman). They were nonsmokers, had normal physical fitness without sports training, had no history of orthostatic fainting, and used no medication. Informed consent was obtained from all participants, and the study was approved by the ethics committee of Copenhagen (KF01–120/96) and performed in accordance with the guidelines laid down in the Declaration of Helsinki. After instrumentation the subjects rested in the supine position for 30 min. Participants were subjected to a standing (90°) and tilt protocol including 20 degrees head-down tilt (–20°) and 30 and 70 degrees head-up tilt (30° and 70°) preceded and followed by a period of supine rest (0°). The 90° period differed in that it was active, while the other periods were passive. However, the passive tilts were performed with foot support (not with a saddle) for best comparability (1). The –20°, 30°, and 90° lasted 10 min; 70° lasted 60 min but was interrupted earlier when presyncopal symptoms and signs occurred, or at the request of the test subject. Three of the 10 participants experienced presyncopal symptoms or requested to be brought back to the supine position in the 70° period as well as in the 90° period.

Instrumentation and Data Processing

Noninvasive finger pressure was recorded with a TNO Finapres model 5 and sampled at 100 Hz. The TNO Beatfast software was used to reconstruct brachial pressure from finger pressure (4, 22, 57) and to determine beat-to-beat variables. IBI and systolic, diastolic, and mean arterial pressures were analyzed, as well as parameters determined from arterial pressure, using a model (25, 55) that calculates stroke volume, cardiac output, and total peripheral resistance (Fig. 1). SBP and IBI were used for subsequent analysis with BRS software (20, 21, 56).


Figure 1
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  		Fig. 1. Hemodynamic data. Pressure traces are systolic (top trace), mean (middle trace), and diastolic blood pressures (bottom trace). HR, heart rate in beats/min (BPM). TPR, total peripheral resistance in medical units (MU; mmHg·s/ml). xBRS, cross-correlation baroreflex sensitivity. Moving averages with 12 s window.

 
Period Selection

Sections of 6 min before and 6 min after each change in {alpha} were selected for analysis. Starting from –20°, this resulted in seven transients (Fig. 2). Periods before and after tilt were compared to determine the difference in BRS and {tau} distribution. To quantify the dynamic BRS response to a change in tilt angle, the 6-min periods following a transient were subdivided in 120-s sections for statistical evaluation. Running averages were calculated using a 120-s window for plotting.


Figure 2
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  		Fig. 2. xBRS baroreflex sensitivity results of one participant. Each dot represents a baroreflex sensitivity result. Drawn horizontal lines represent period averages. Geometric running averages trace the transients. Note the overshoot in baroreflex sensitivity after tilt-back from 70° and in 0° position after 90°.

 
BRS was related to –20° and 0° (Fig. 2, top right) and to 30°, 70°, and 90° using periods following an increase in {alpha} (Fig. 2, left). Periods immediately following an increase in {alpha} were used as opposed to the periods just before a decrease, to exclude the effects of fainting.

BRS

For time-domain analysis of BRS, the cross-correlation method was used (20, 21, 56) assuming an open-loop model to approach the SBP-IBI relation. Beat-to-beat SBP and IBI data were fitted with cubic spline functions and resampled at 1-s intervals. The cross-correlation between 10-s series of SBP and IBI samples were computed for delays {tau} in IBI of 0–5 s. The combination with the {tau} giving the highest cross-correlation was selected if significant at P = 0.05. The regression slope was recorded as one xBRS value together with the {tau}. Subsequently, the process was repeated for series of SBP and IBI samples 1 s later. Theoretically, one xBRS value can be obtained each second. This technique produces approximately three times as many BRS values as existing sequential techniques and with a reduced scatter between subsequent values (56). To determine to which extent the successive results of the xBRS method were correlated, we calculated the coefficient of correlation between uninterrupted series of 20 xBRS values and the same series but shifted in time from 0 to 10 s.

For frequency analysis, beat-to-beat SBP and IBI time series were detrended and Hanning windowed. Power spectral density and transfer gain of the cross-spectra of SBP and IBI (8, 49) were computed using discrete Fourier transform (9). The 10-s rhythm band from 0.06 to 0.15 Hz, called "s10", and the respiratory band from 0.15 to 0.5 Hz, called "Resp" were selected; transfer gain and phase were computed for coherence >0.5.

Performance

An analysis was performed to determine computational precision of xBRS and the sensitivity to varying signal-to-noise ratios. Model data comprised records of 2,000 beats with a constant systolic pressure of 125 mmHg and a constant interval of 700 ms, to a total duration of 1,400 s or ~23 min. Pressure and interval were modulated with sinusoids and with random noise. Sinusoids were generated at 0.04 Hz (thermoregulation), 0.1 Hz (10-s rhythm), and 0.25 Hz (respiration), with or without delay between pressure and interval, and with sinusoids of two frequencies superimposed. Gaussian noise was obtained from a pseudorandom sequence with its uniform distribution transformed to normal with zero mean and prescribed variance (58). To simulate a BRS of 10 ms/mmHg, pressure was modulated with a 10-mmHg amplitude, interval with a 100-ms amplitude, and in the same ratio for noise standard deviations. With noise added to a sinusoid, the signal-to-noise ratio is traditionally defined as the ratio of their variances. The variance of a sinusoid is 0.5 times the amplitude squared. The variance of a noise signal is the square of the standard deviation. Thus a sinusoid with an amplitude of 10 has a variance of 50 (0.5 x 10 x 10) and Gaussian noise with standard deviation 7 also has a variance of 50; consequently, their signal-to-noise ratio equals 1. Random noise with standard deviations increasing from 0 to 11 mmHg in steps of 1 mmHg, and from 0 to 110 ms in steps of 10 ms, was added to sinusoids at respiratory frequency (0.25 Hz) with amplitude 10 and standard deviation 7 mmHg. Each noise level resulted in a file separately evaluated with xBRS. xBRS should find almost 1,400 values at 10 ms/mmHg. Since the interval sinusoid was delayed 1 s with respect to pressure, a best delay {tau} of 1 s should result.

Statistics

Distributions of xBRS values are best described as log-normal (56); therefore, geometric averages were used. Within-subject differences were tested with the Mann-Whitney U-test. Differences in BRS and hemodynamic parameters were evaluated for the group by parametric repeated-measures ANOVA. BRS values before and after a change in {alpha} were compared, and BRS values representing each {alpha} were compared separately to investigate BRS values as a function of sin ({alpha}). Histograms of the distributions of {tau} were plotted and compared by the {chi}2 test after normalizing of data. The number of estimations in the {chi}2 test was set to the group average number of estimations for each period.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
With increasing {alpha}, diastolic (76 to 89 mmHg) and mean pressure (96 to 106 mmHg) and total peripheral resistance (1.2 to 1.4 mmHg·s/ml) increased (Fig. 1), while IBI (1.1 to 0.75 s) and stroke volume (95 to 61 ml) decreased.

Time Domain

xBRS during transients in {alpha} is given in Figs. 2 and 3. In one case, data from tilt back from 70° was not available; in another case the transient from 90° to 0° was not available. For the total of 68 tilt transients, in 63 cases (93%) BRS had altered in the 6 min following a change in {alpha}, and this difference was present in 78% after 1 min and in 85% after 2 min. BRS was significantly different between the 30°, 70°, and 90° in all but one subject. BRS at –20° was not significantly different from 0°, and at 70° not different from 90°. The averaged values of BRS for each {alpha} are given in Table 1. Averaged BRS related to {alpha} [xBRS = –10.1·sin ({alpha}) + 18.7; r2 = 0.99; Fig. 4].


Figure 3
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  		Fig. 3. Running averages of xBRS baroreflex sensitivity results of all participants and group average (heavy line).

 

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  		Table 1. Effects of axis of body angle {alpha} on time-domain and frequency-domain baroreflex sensitivity

 

Figure 4
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  		Fig. 4. xBRS baroreflex sensitivity and transfer gain and phase as a function of the tilt angle. Data are means ± SE. Note that in the regressions of phase on the sine of tilt angle, the –20° periods are excluded. Gs10 and Ps10, transfer gain and phase for 10-s band, respectively; Gresp and Presp, transfer gain and phase for respiratory band, respectively.

 
The number of xBRS results increased with tilt angle (Table 1). Expressing the number of xBRS results per minute gives 28 ± 12, 31 ± 9, 35 ± 11, 45 ± 8, and 45 ± 11 for {alpha} increasing from –20° to 90°.

From 36 uninterrupted series of 20 xBRS values, the coefficient of correlation between each series and the same but time-shifted series was calculated. An example is given in Fig. 5: the coefficient of correlation is no longer significant for a shift of 3 s. Similarly, in the other series, there were no longer any significant correlations for shifts of 4 s and higher.


Figure 5
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  		Fig. 5. A series of xBRS values taken from the subject represented in Fig. 2 (90° period) plotted against the same series for delays from 0 to 4 s. The correlation coefficients are no longer significant when the series of xBRS values are shifted more than 3 s. NS, not significant.

 
Distribution of {tau}

The distribution of delays between SBP and IBI determined from the strongest cross-correlation also related to {alpha} (Fig. 6). With increasing {alpha}, the distribution moved toward more {tau} of 1 s and less {tau} of 0 s; –20° was not significantly different from 0°, and 70° was not significantly different from 90°.


Figure 6
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  		Fig. 6. Distributions of delays (cubic spline fit). x-axis: delay {tau} (s) corresponding to the best cross-correlation between blood pressure and interbeat interval variations; y-axis: the percentage of incidence. In 0° and –20°, the 0-s {tau} dominates, while in 30° the 1-s {tau} is more frequent. In 70° and 90°, the 1-s {tau} dominates even more.

 
Frequency Domain

Spectral gain and phase for 10-s band and respiratory band are given in Table 1 and in Fig. 4. xBRS and spectral gain were tightly correlated for both the 10 s band (Gs10 = 0.88·xBRS – 0.40; r2 = 0.98) and respiratory band (Gresp = 1.48·xBRS – 3.65; r2 = 0.97). The phase in the respiratory band tended to lower values (P = 0.07) for higher {alpha}, corresponding to the xBRS-determined shift in {tau} (Fig. 6).

Transients

The rate of change in BRS depended on the change in {alpha} and was asymmetrical for an increase vs. a decrease (Fig. 3). From 70° to tilt back and from 90° to 0°, there was a BRS overshoot (P < 0.05).

Figure 7 shows the changes in {tau} distributions vs. response time to an increase in {alpha}. At 30° the {tau} distribution shifted toward a modest dominance of 1-s {tau}. At 70°, 1-s {tau} progressively increased, while in 90° the 1-s {tau} immediately dominated.


Figure 7
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  		Fig. 7. Distribution of delay {tau} over time after the change from 0° to 30°, to 70°, and to 90°. In 30°, {tau} of 0 s and 1 s are equally distributed; then there is a slight increase of 1 s {tau}s. In 70°, 1-s {tau} progressively increases. In 90°, the distribution immediately shifts to mainly 1-s {tau}, and this situation is maintained throughout the analyzed period.

 
The same subjects that fainted in the 70° period did so in the 90° period. They had kept their eyes open at both occasions. In the frequency domain, gain for fainters vs. nonfainters tended to be lower in 70° (5 ± 4 vs. 9 ± 2, P = 0.08 and 4 ± 1 vs. 12 ± 6, P = 0.08 for Gs10 and Gresp, respectively) and was comparable for other {alpha}s (P > 0.1). In the fainters, during 70° phase Ps10 was lower (–62 ± 6 vs. –46 ± 9, P = 0.03) and phase Presp tended to be lower (–70 ± 29 vs. –21 ± 24, P = 0.09). xBRS in fainters tended toward lower values (70°: 6 ± 4 vs. 10 ± 3, P = 0.09; 90°: 6 ± 1 vs. 11 ± 5, P = 0.1). At 70 and 90°, the {tau} distribution in fainters vs. nonfainters had shifted more to 1-s {tau} (P < 0.05, Fig. 8) within 2 min.


Figure 8
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  		Fig. 8. Distribution of delay {tau} in nonfainters (top) vs. fainters (bottom), with same axes as in Fig. 4, after the change from 0° to 30°, 0° to 70°, and 0° to 90. The fainters have more delays of 1 s. Note that the distribution –20° and 0° of the fainters is similar to the distribution at 30° of the nonfainters.

 
Performance

Constant pressure and interval. Constant pressure and interval data contain no events, and xBRS generated no output. Neither did xBRS generate output with modulation added to only one of the signals.

Sinusoids with and without interval delay. Sinusoidal variability at any of the three frequencies and with any two frequencies superimposed resulted in the correct xBRS value of 10.0 ms/mmHg. Delaying the interval sinusoids by 1 or 2 s resulted in xBRS {tau} of 1 or 2 s. Delays of 1.5 and 3.5 s resulted in an averaged xBRS {tau} of 1.48 and 3.48 s. With 1,366 estimates, typically 712 estimates were at the lower {tau} and 654 at the higher {tau}, and none of the other possible {tau}s was found. With two sinusoids superimposed and the interval sinusoid of only one frequency delayed, the resultant {tau} was that of the lower frequency. This supports that an oscillation period does not have to fit in a single window but may be wider or narrower and shows that nonintegral delays are accommodated.

Random noise. Several runs of independent random noise added to the constant pressure and interval data caused some 40–45 detections in 17–19 clusters over the 1,400-s period with a mean BRS of 10.2 ± 5.9 ms/mmHg and a mean best delay of 2.7–3.1 s. A value of 2.5 is expected since each delay is equally likely. The higher values that were found are probably due to best delays longer than 5 s that are not accommodated but could still be significantly correlated at the incorrect 5-s delay. A small proportion of false detections is expected in the noise since the probability level for a random detection was placed at 0.01. This shows relative but not absolute insensitivity for uncorrelated noise. In uncorrelated noise there is a tendency toward 3-s delay values.

Sinusoids and random noise. Figure 9 presents the results as a function of noise amplitude. With increasing noise, xBRS (Fig. 9, top) remained within ±5% of the correct value up to noise amplitude 9, where the signal-to-noise ratio falls below 0.6. The number of significant xBRS estimates (Fig. 9, middle) decreased rapidly from 1,367 for the 1,400-s period down to 134. {tau} (Fig. 9, bottom) increased from 1 s, the correct value, to ~3 s with increasing noise amplitude.


Figure 9
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  		Fig. 9. xBRS values (% of the correct value), number of xBRS results (N), and delay {tau} values (s) on 0.25-Hz sinusoids for increasing amounts of added noise. At noise amplitude 7, the signal-to-noise ratio is 1. True BRS is 10 ms/mmHg; true delay is 1 s. RMS, root mean square.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The main findings of this study are that 1) during gravitational stress the sensitivity of the cardiac baroreflex obtained from time domain decreases linearly with the sine of the angle of the vertical body axis, and 2) the dynamic baroreflex adaptation to a physiological perturbation like postural stress starts rapidly, i.e., within 1 min in the majority of subjects.

With a posture change or with application of subatmospheric pressure to the lower part of the body [lower body negative pressure (LBNP)], the shift of blood from the chest to the lower parts of the body reduces central venous pressure and stroke volume (10, 54), modifying arterial pulsatility and with concomitant activation of vestibulosympathetic reflexes (48). The posture-induced carotid baroreceptor unloading evokes an increase in efferent sympathetic vasoconstrictor activity. The result of the ongoing cardiovascular reflex activity is parasympathetic withdrawal and sympathetic activation with an increase in heart rate (HR) (45). In humans, the degree of arterial and cardiopulmonary baroreflex involvement cannot be ascertained; for instance, even mild LBNP reduces aortic dimensions contesting selective low pressure area receptor activation (53). The finding that following carotid deafferentation the adjustment of arterial pressure to orthostatic stress is impaired during the early phases of circulatory stabilization is in accordance with the notion that carotid baroreceptor input dominates the cardiovascular reflex changes involved in the maintenance of postural normotension (19, 50).

Postural baroreceptor unloading also demonstrated by Cooke et al. (6) and Iwase et al. (24) has been proposed to account for the reduced BRS (18, 26). This is not at variance with data presented by Pawelczyk and Raven (44). They found that a reduction in central venous pressure by LBNP augmented BRS and concluded that the inhibitory influence of pressure- or volume-sensitive cardiopulmonary receptors was removed by central hypovolemia. Of note, in that study the subjects remained supine, and gravitational unloading of the carotid baroreceptors did not play a role. However, in tilt studies using pulsed neck suction and pressure (15, 16) protocols to determine BRS, no decrease (7) or an increase in the cardiac baroreflex has been found (38), while in studies using sequential BRS methods, a decline in sensitivity in reaction to tilt has been established (1, 27, 28, 32, 39, 52). The discrepancy between the findings with sequential (1, 11) methods, using spontaneous variations in blood pressure (BP) and HR on the one hand, and the neck cuff stimulation (15, 16) on the other, has received little attention. Data from experiments gauging the separate arterial and cardiopulmonary baroreflex gains suggest that the arterial component remains equivalent during tilt while the cardiopulmonary contribution decreases (34). Neck suction obviously assesses only the arterial component and thus would remain equal with tilt, corroborating this finding. However, these observations challenge the suggestion that unloading of the carotid baroreceptors is involved, in which case BRS is expected to be reduced as shown in this study.

The IBI and the high-frequency amplitude of HR variability decrease progressively with tilt angle (36). The finding that cardiac BRS decreased linearly with the sine of the angle of the vertical body axis complements the observation by Cooke et al. (6) and Iwase et al. (24) that muscle sympathetic nerve activity increases linearly with the sine of the angle during passive head-up tilt.

Posture-induced changes in autonomic activity not only affect baroreflex responsiveness but also have a major influence on the latency of the vagally mediated carotid baroreceptor-HR reflex (31). The finding of a shift toward longer delays between SBP and IBI supports the suggestion that the decrease of BRS is a result of the vagal withdrawal associated with larger postural stress (28, 45). The linear relationship between angle of body axis and cardiac baroreflex as found in this study does not reveal direct information on its vagal vs. sympathetic constituents.

The distribution of the delay between variations in BP and IBI may provide additional insight in the performance of the sequential methods for BRS assessment. We found that the distribution of delays shifted toward longer delays with increasing tilt angle. The observed reduction in BP to IBI delays of 0 s suggests acute withdrawal as the fast efferent parasympathetic branch to the sinus node. The phase as determined by spectral analysis (6) similarly implicates increasing delay. We consider that if it is indeed vagal control of the heart that we are describing, the use of IBI/BP is acceptable. Instead, when addressing baroreflex control of BP (cardiac output x total peripheral resistance), the use of HR/BP as the gain measure would be preferable (37). Katona and Jih (29) suggested that the degree of respiratory sinus arrhythmia, thus using only heart period, may reflect parasympathetic cardiac control. More recently, Julu et al. (27) found a decrease during tilt as well using a different approach to assess cardiac vagal tone in humans.

As an opposing view, the shift in {tau} distribution may be interpreted as an effect of increasing HR. For low HRs, the effect of efferent vagal activity on HR becomes apparent within the same beat (3). It was shown that the vagal effect on HR can be described by 0-s delay when IBI is greater than 775 ms (46) or HR lower than 77 beats/min. For higher HRs, the effect of efferent vagal activity becomes apparent only in the next beat expressed as 1-s delay. Thus at higher HRs the decrease of 0-s delay in itself is therefore no proof for reduced vagal activation. However, with the body axis at 30°, the average interval was 969 ms, corresponding to 62 beats/min, allowing one to attribute the shift in the delay distribution to a decrease in vagal tone.

In the measurement of BRS, customarily the immediate effect of systolic pressure on the duration of the ongoing heart period (51) has been equated to the "open-loop" gain. Along this line of reasoning, the latency of sympathetic effectors is too large (>3 s) to exert an appreciable effect on the computed value for the pressure-to-vagal effectiveness. Accordingly, we have restricted the estimated gains to a maximum delay of 5 s.

An increase in peripheral resistance during graded tilt up conforms to increased sympathetic vasomotor tone. Similarly, forearm vascular resistance (7) and muscle sympathetic nerve activity (39) as indication of sympathetic efferents are found to increase with tilt. Postural stress is a complex physiological intervention with baroreceptor unloading that may provoke both parallel and reciprocal changes of vagal and sympathetic nerve activity (14). Evidently the issue whether sympathetic and vagal nerve activities change reciprocally remains unsettled as long as knowledge on changing cardiac vagal neural traffic is lacking. We do consider that tracking of dynamic changes in BRS together with changes in the distribution of HR to BP delays as obtained from time-domain analysis has the potential to reveal information on the vagal contribution.

In the subjects who presented with presyncopal signs during 70° and 90°, the faster and more pronounced shift toward longer delays with increasing tilt angle was already apparent in the first 2 min of 70° and 90°, compatible with early sympathetic activation. We acknowledge the limited number of observations of fainting, which prevents us from generalizing directly from the data presented. Gulli et al. (23) found a less negative phase shift in the high-frequency range in the 2–3 min before syncope. Combining these findings, fainters appear to engage earlier in sympathetic activation but to disengage earlier as well. We found no significant differences in BRS values in our group; Pitzalis et al. (47) described a large population in which BRS was enhanced in those with tilt induced vasovagal syncope.

In HR variability and BP variability signals of healthy individuals, the presence of apparent noise (fractal or otherwise characterized) is a prominent feature. When viewed over a longer time scale, for instance a 24-h period, the variability signals show so-called "one-over-f" behavior, i.e., that spectral intensity increases with decreasing frequency (5). Within this noise, sensitivity of the baroreflex on heart interval is estimated. In the xBRS sensitivity analysis, this has been approached by the addition of Gaussian noise to a deterministic signal with xBRS correctly detecting BRS values only when truly present. Also, when reducing the signal-to-noise ratio to 1, correct BRS values were established but with a reduction in number of results. Thus the abrupt changes in BRS as shown in Fig. 2, particularly in the supine position, are likely to be a result of physiological signals. Comparable jitter in BRS was shown earlier by Di Rienzo et al. (13) and endorsed by their findings using an {alpha} coefficient BRS determination. Inherent to the complex ongoing functional integrative adaptation of autonomic neural activity is that it is subject to influences from several sides, resulting in outcomes for BRS that vary from moment to moment. Against this background, nonetheless, a progressive decline in levels of BRS as result of an increase in the angle of body axis can be recognized.

xBRS values might be assumed as being correlated over the width of the window within which SBP are IBI are analyzed (10–15 s), but they emerge not so (Fig. 5), with no significant correlations for shifts beyond 4 s. This implies that the xBRS results are not correlated over the length of the window. Likewise the variability in Fig. 2 can be interpreted to indicate a lack of correlation between successive xBRS values in a supposedly stable recording. Similarly, Eckberg and Kuusela (17) recently showed wide short-timed fluctuation. This holds true for the transfer from BP to R-R interval, representing the vagal arm of the reflex, as well as for BP to muscle sympathetic nerve activity, representing the sympathetic arm. The stochastic nature of the nerve signals involved seems a basic property of the baroreflex system. Thus, stating that a different BRS value is reached soon after a change in the angle of body axis does not imply that the new BRS level is stable.

The increasing number of xBRS data with tilt can be explained in several ways. It could be interpreted as the effect of increased baroreflex effectiveness (12), proposed as a complementary measure of baroreflex function, or as less effective suppression of oscillations due to decreased BRS with mathematically a larger number of correlations. The finding that the number of baroreflex results decreased substantially with the prescribed significance level of the SBP-IBI regression slope of the xBRS method, but values for BRS remained unaffected (Table 2), indicates that the number of results is method dependent, but BRS level is not.


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  		Table 2. Baroreflex sensitivity and number of results as a function of P value required for the xBRS result to be accepted

 
In the present study, we did not formally compare the xBRS method with previously reported methods in the time domain (1, 11), as well as in the frequency domain (8, 49). However, Parati et al. (42) have discussed the xBRS method in the context of other methods for the determination of BRS presently in use.

The practical value of BRS assessment from spontaneous BP and HR variability analysis as opposed to the pharmacological approach has been the issue of recent discussions in the literature (33, 35, 40, 41). They indicate that the methods, although valid from a theoretical and basic scientific point of view, still require more clinical application to show their value. Of relevance, it has been shown that spontaneous and pharmacologically determined BRS are complementary (43). We consider that the xBRS method may contribute to examine baroreflex circulatory control in greater detail.

In summary, in healthy subjects the sensitivity of the cardiac baroreflex obtained from time domain decreases linearly with the sine of the angle of the vertical body axis, and the dynamic baroreflex adaptation to a physiological perturbation like postural stress occurs rapidly. The shift toward longer delays between BP and IBI variations with increasing body axis angle suggests that the decrease of BRS with tilt results from reduced vagal activity and increased sympathetic cardiac tone.


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 DISCUSSION
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B. E. Westerhof was in part supported by a research grant of Finapres Medical Systems, The Netherlands, for this investigation. J. Gisolf was supported by a grant from Space Research Organization Netherlands, Project MG-052.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. E. Westerhof, BMEYE, Academic Medical Centre, Suite K2–245, Univ. of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands (e-mail: berend.westerhof{at}bmeye.com)

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.


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