Inconsistent link between low-frequency oscillations: R-R interval ...

J Appl Physiol 90: 1559–1564, 2001.

Inconsistent link between low-frequency oscillations: R-R interval responses to augmented Mayer waves J. W. HAMNER, RAYMOND J. MORIN, JAMES L. RUDOLPH, AND J. ANDREW TAYLOR Laboratory for Cardiovascular Research, Research and Training Institute, Hebrew Rehabilitation Center for Aged, Boston 02131; and Division on Aging, Harvard Medical School, Boston, Massachusetts 02131 Received 18 July 2000; accepted in final form 20 October 2000

Hamner, J. W., Raymond J. Morin, James L. Rudolph, and J. Andrew Taylor. Inconsistent link between low-frequency oscillations: R-R interval responses to augmented Mayer waves. J Appl Physiol 90: 1559–1564, 2001.—Low-frequency oscillations in arterial blood pressure (Mayer waves) and R-R interval are thought to be linked through the arterial baroreflex. To delve into this relationship, we applied low (10 mmHg) and moderate (30 mmHg) lower body negative pressure (LBNP) in 10-s cycles to 18 healthy young male subjects. They showed no change in average blood pressure with this oscillatory stimulus but did show a significant decrease in R-R interval (P ⬍ 0.05) during both levels of LBNP. In addition, we succeeded in augmenting low-frequency blood pressure oscillations in a graded response to oscillatory LBNP level (P ⬍ 0.05) while significantly increasing low-frequency R-R interval oscillations (P ⬍ 0.05). However, cross-spectral coherence between these increased oscillations was highly variable across individuals and stimulus level. Although nearly all subjects showed significant coherence during basal conditions (n ⫽ 17), only seven subjects maintained significant coherence during both levels of LBNP. These results suggest that a complex interaction of regulatory mechanisms determines the link between low-frequency oscillations and the responses to even low levels of LBNP.

in arterial blood pressure (Mayer waves) and heart period have long been researched, yet there is no universally accepted theory regarding their source. Theories suggest that oscillations in blood pressure could originate from various mechanisms, including endogenous central rhythms (13, 17), negative-feedback system engagement (10, 19), or vascular autorhymicities (18). Cross-spectral phase and gain relationships, as well as coherence, have shown a relatively close link between low-frequency arterial pressure and heart period oscillations (3). Consequently, arterial baroreflex engagement in response to pressure oscillations is most commonly cited as the cause for corresponding low-frequency oscillations in cardiac interval (2, 5, 20). However, the

variable nature of the waves themselves may indicate a more complex relationship than can be easily explained by the baroreflex. Unlike respiratory frequency oscillations, arterial pressure Mayer waves spontaneously appear without any seeming consistency. Power spectra of heart period and blood pressure have shown that the frequency of oscillation differs between and within subjects, with oscillations occurring across a range of frequencies from 0.07 to 0.15 Hz (although they are generally centered at 0.1 Hz) (15). In addition, standard power spectral indexes show a relatively high degree of dayto-day variability in average amplitudes of low-frequency heart period and blood pressure oscillations (6, 9). There are also interpretive issues in understanding the link between these low-frequency oscillations. For example, magnitude may not correlate with standard baroreflex gain measures (27), and elimination of low-frequency heart period oscillations, through atrial pacing, increases low-frequency blood pressure oscillations in only upright, and not supine, humans (23). Thus some data suggest that heart period oscillations do not buffer pressure consistently through the baroreflex. In our study, we sought to augment low-frequency oscillations in humans to delve further into the relationship between arterial pressure and cardiac interval fluctuations. To accomplish this, we used two levels of lower body negative pressure (LBNP) oscillating at 0.1 Hz. Low (10 mmHg) and moderate (30 mmHg) LBNP were used, because the former does not generate a heart period response, whereas the latter does (12, 16, 28). We hypothesized that the fluctuations in cardiac filling with low-level oscillatory LBNP would be offset appropriately, resulting in unchanged Mayer wave amplitude but a lowered cross-spectral coherence to heart period. That is, preferential engagement of a noncardiogenic response would dissociate arterial pressure and cardiac interval fluctuations. We further hypothesized that fluctuations in cardiac filling with moderate oscillatory LBNP would generate an appropriate arterial baroreflex-mediated heart period response, leading

Address for reprint requests and other correspondence: J. A. Taylor, Laboratory for Cardiovascular Research, HRCA Research and Training Institute, 1200 Centre St., Boston, MA 02131 (E-mail: [email protected]).

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arterial blood pressure; power spectral analysis; oscillatory lower body negative pressure

LOW-FREQUENCY OSCILLATIONS

http://www.jap.org

8750-7587/01 $5.00 Copyright © 2001 the American Physiological Society

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spectral densities derived with the same parameters used to estimate power spectra. Coherence was calculated from the cross-spectral and power spectral measures to determine whether a significant relationship existed between the variables at the frequencies of interest. Many researchers consider a coherence of 0.5 to be significant; however, it can be exactly calculated on the basis of the number of data points and window parameters (22). For our desired level of significance (P ⬍ 0.10) and our nine degrees of freedom, a coherence of ⱖ0.49 indicated a significant relationship between variables. If a significant relationship existed, the transfer function phase and magnitude were determined from the standard cross spectrum normalized by the input’s (systolic blood pressure) power spectrum. Frequency ranges for the examination of Mayer waves were dependent on subject and experimental condition. For basal conditions, the range of maximal coherence between 0.05 and 0.15 Hz corresponding to the peaks in the power spectrum of R-R interval and systolic pressure was used to define the low-frequency oscillations (on average 0.0872 ⫾ 0.004 to 0.1113 ⫾ 0.003 Hz). For oscillatory LBNP, the range of maximal coherence between 0.05 and 0.15 Hz corresponding to the peaks in the power spectrum of tank pressure and systolic pressure was highly significant for all subjects and was used to define the range of oscillatory LBNP: from 0.0853 ⫾ 0.001 to 0.1056 ⫾ 0.001 Hz (low oscillatory LBNP) and from 0.0852 ⫾ 0.001 to 0.1054 ⫾ 0.001 Hz (moderate oscillatory LBNP). For all conditions, the frequency range for respiration was simply defined as 0.2– 0.3 Hz. Mean powers for low-frequency and respiratory oscillations over these defined ranges were calculated for systolic and diastolic pressure and R-R interval, while crossspectral and transfer function indexes were derived for systolic blood pressure to R-R interval. We chose to use average values, rather than sums of power, to allow comparison among low-frequency ranges that differed between experimental conditions. Logarithmic transformations were applied to spectral powers to provide normal distributions for application of standard Gaussian statistics; however, for ease of interpretation, all values are reported in standard units. Logarithmic transformations ensured normality in all cases, except respiratory power. Effects of oscillatory LBNP on average R-R intervals and arterial pressures were evaluated by repeated-measure ANOVA with a Student-NewmanKeuls post hoc correction to identify significant differences. For measures not normally distributed, a nonparametric ANOVA on ranks with a Student-Newman-Keuls post hoc correction was applied. Differences were considered significant at P ⬍ 0.05. Values are means ⫾ SE.

to unchanged or increased Mayer wave amplitude and an augmented cross-spectral coherence relationship. We found that increased low-frequency arterial pressure oscillations resulted from both low and moderate levels of oscillatory LBNP that were accompanied by increased low-frequency heart period oscillations. Surprisingly, the strength of the cross-spectral coherence between low-frequency oscillations was highly unstable, within and among subjects, across the levels of oscillatory LBNP. This inconsistent coherence relationship may belie mutable engagement of the multiple-feedback system responsible for generating blood pressure Mayer waves. METHODS

Subjects. Eighteen healthy young men, aged 22–32 yr (body mass index 23.3 ⫾ 0.497), gave their informed consent to participate in the study. The subjects were free from heart and neurological disorders and were not taking any cardioactive medications. All the participants were normotensive nonsmokers who refrained from alcohol and caffeine ingestion during the 24 h before the study. The experimental protocol was approved by the Clinical Investigations Committee of the Hebrew Rehabilitation Center for Aged. Protocol and measurements. Subjects were studied while supine with their lower body sealed in an LBNP tank. A vacuum pump with timing mechanism set to control suction intervals to produce a 0.1-Hz oscillation was used. A manual bleed-off valve, in conjunction with a pressure gauge, was used to control tank pressure. The experimental protocol consisted of three 5-min measurement periods at LBNP levels of 0 mmHg, oscillatory LBNP of 10 mmHg, and oscillatory LBNP of 30 mmHg in random order. For all experimental conditions, breathing was paced at 0.25 Hz; a 3-min acclimation period preceded the 5 min of data acquisition. Electrocardiogram lead II, beat-by-beat photoplethysmographic arterial pressure (Finapres, Ohmeda), respiration (Respitrace, Ambulatory Monitoring), and tank pressure were recorded continuously throughout each period. The signals were digitized at 500 Hz and stored for later analysis using commercial hardware and software (Windaq, Dataq Instruments, and Matlab, The Mathworks). Data analysis and statistics. Electrocardiogram R waves and arterial pressure peaks and valleys were identified to provide beat-by-beat R-R intervals and systolic and diastolic pressures. Means and SDs were calculated from beat-by-beat values. The time series of R-R interval, systolic pressure, and diastolic pressure were linearly interpolated to provide a 1,500-point signal for frequency analysis. The power spectral estimate of each signal was calculated via Welch’s averaged, modified periodogram method (26). First, the interpolated signals were divided into five equally overlapping segments of 500 points each. Each individual window was then linearly detrended, smoothed via a Hanning window, and fast Fourier transformed to produce its magnitude squared. Cross-spectral estimates between variables were calculated from cross-

RESULTS

Mean R-R interval and arterial pressures. Table 1 lists average R-R intervals and arterial pressures for all experimental conditions. Oscillatory LBNP resulted in lower average R-R intervals than basal measures (P ⬍ 0.05). These R-R interval changes corresponded to a significant difference in heart rate only at moderate

Table 1. Average hemodynamic variables across subjects

Basal Low OLBNP Moderate LBNP

R-R Interval, ms

Systolic BP, mmHg

Diastolic BP, mmHg

Mean BP, mmHg

Pulse Pressure, mmHg

1,074 ⫾ 41 1,044 ⫾ 38* 1,027 ⫾ 37*

127 ⫾ 4 126 ⫾ 4 125 ⫾ 4

67 ⫾ 2 67 ⫾ 2 66 ⫾ 3

87 ⫾ 2 87 ⫾ 3 86 ⫾ 3

60 ⫾ 3 58 ⫾ 2 59 ⫾ 3

Values are means ⫾ SE. OLBNP, oscillatory lower body negative pressure; BP, blood pressure. * P ⬍ 0.05 vs. basal.

OSCILLATORY LBNP AND MAYER WAVES

Fig. 1. Thirty seconds of low-level (10 mmHg) oscillatory lower body negative pressure (LBNP) response from subject 11. Top: R-R interval in tachogram form; middle: arterial pressure; bottom: oscillations in tank pressure.

LBNP: 57.3 ⫾ 2.18 (basal) vs. 59.7 ⫾ 2.28 (moderate oscillatory LBNP, P ⬍ 0.05). Oscillatory LBNP did not, however, cause any change in average systolic, diastolic, or mean pressure. Spectral characteristics. Figure 1 shows 30 s of representative raw data from one subject collected during oscillatory LBNP of 10 mmHg at 0.1 Hz. Figure 1 shows the consistency of the generated LBNP wave as well as the resulting oscillations in blood pressure. This subject also shows a large corresponding 0.1-Hz response in R-R interval. Even with low-level oscillatory LBNP, low-frequency oscillations in systolic pressure, diastolic pressure, and R-R interval were significantly larger than corresponding oscillations during 0 mmHg LBNP (Table 2, Fig. 2). With moderate oscillatory LBNP, systolic and diastolic pressure powers in the low-frequency range were significantly greater. The higher level of oscillatory LBNP did not alter R-R interval oscillations further (P ⫽ 0.17). Oscillations at the respiratory frequency were largely unaffected by oscillatory LBNP, except for

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Fig. 2. Average spectral powers of all subjects at each oscillatory LBNP (OLBNP) level from 0.04 to 0.3 Hz. Low-frequency oscillations in systolic pressure were significantly different between all stimulus levels (P ⬍ 0.05) and, in R-R interval, were significantly different between oscillatory LBNP and basal conditions (P ⬍ 0.05).

small effects on systolic and diastolic pressure oscillations with 30 mmHg: 0.69 ⫾ 0.23 and 0.10 ⫾ 0.02 (basal) vs. 0.80 ⫾ 0.21 and 0.21 ⫾ 0.06 (moderate oscillatory LBNP, P ⬍ 0.05). The first step of our cross-spectral analysis, for each subject, is shown in Fig. 3. The minimum coherence value necessary for significance (0.49) is shown; during 0 mmHg all but one subject is above this minimum value (and this subject is very close, 0.46). During either level of oscillatory LBNP, the entire group average coherence was not significantly changed (Table 2). However, simple group means masked highly variable inter- and intraindividual differences in coherence from basal measures. For example, 5 of 18 subjects lacked coherence at the lower level of LBNP; 2 of these subjects did not have coherence at the higher level of LBNP, 3 subjects regained significant coherence, and 5

Table 2. Low-frequency average spectral variables

Basal Low OLBNP Moderate OLBNP

R-R Interval, ms2

Systolic BP, mmHg2

Diastolic BP, mmHg2

R-R Interval-Systolic BP Coherence

291 ⫾ 65 496 ⫾ 96.6* 836 ⫾ 259*

1.79 ⫾ 0.82 3.09 ⫾ 0.718* 5.70 ⫾ 1.300*†

0.658 ⫾ 0.178 2.41 ⫾ 0.533* 6.57 ⫾ 0.915*†

0.68 ⫾ 0.024 0.61 ⫾ 0.058 0.63 ⫾ 0.061

Values are means ⫾ SE. * P ⬍ 0.05 vs. basal. † P ⬍ 0.05 vs. low OLBNP.

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four times the systolic blood pressure power (5.52 ⫾ 2.1 vs. 1.40 ⫾ 3.83, P ⫽ 0.0543), and four times the change in R-R interval power (935 ⫾ 372 vs. 142.5 ⫾ 3.83, P ⬍ 0.05). Figure 4 shows the changes in the logarithmically transformed low-frequency powers from basal conditions to moderate oscillatory LBNP. All subjects with significant coherence showed increases in both systolic pressure and R-R interval power, while five of the seven subjects who did not have significant coherence showed an increase in systolic pressure power coupled with a decrease in R-R interval power. DISCUSSION

Fig. 3. Low-frequency coherence between systolic blood pressure and R-R interval for all subjects at each oscillatory LBNP level. Dashed line, coherence necessary for significance at 0.49. Only 7 of 18 subjects maintained significant coherence for all 3 conditions.

others lost coherence. Among subjects with significant coherence at all levels (n ⫽ 7), transfer function gain and phase between systolic blood pressure and R-R interval were not affected by oscillatory LBNP (P ⫽ 0.79 and 0.273, respectively). In addition, there were no significant differences in basal gain between the group that maintained coherence and the group that did not (P ⫽ 0.49). There were no significant differences in low-frequency basal powers or powers during low-level oscillatory LBNP between these two groups. However, examination of those subjects with and without coherence during moderate oscillatory LBNP showed some significant differences in spectral powers. Those with coherence between systolic blood pressure and R-R interval power had almost four times the R-R interval power (1,170 ⫾ 390 vs. 307 ⫾ 120, P ⬍ 0.05),

Fig. 4. Change in low-frequency R-R interval power vs. change in low-frequency systolic blood pressure power between moderate oscillatory LBNP and basal conditions. Change scores represent logarithmically transformed powers.

We found that low and moderate oscillatory LBNP augment low-frequency pressure oscillations in a graded fashion without affecting average blood pressure. We also observed subtle, yet significant, reductions in average R-R intervals during even low-level oscillatory LBNP and profound increases in low-frequency R-R interval oscillations during both levels. Despite the fact that the forced oscillations in blood pressure and cardiac interval were large in magnitude and centered within a narrow frequency band, the relationship between the two was highly inconsistent, between subjects and across conditions. Our data have implications for commonly accepted notions of hemodynamic regulation on two fronts. First, low levels of LBNP can alter arterial pressure, supporting previous evidence implicating arterial baroreflex engagement. Second, the simple linear input-output relationship between low-frequency blood pressure and R-R interval oscillations may not be maintained across individuals and conditions, indicating a level of complexity commonly overlooked. Effects of oscillatory LBNP. In agreement with previous work, low-level LBNP had no effect on average blood pressures (12, 16, 28). However, in contrast to previous studies, our subjects did not demonstrate any

OSCILLATORY LBNP AND MAYER WAVES

change in average blood pressure during moderate LBNP and demonstrated significant shortening of R-R interval during both LBNP levels. The lack of change in average blood pressure may not be surprising, however, inasmuch as the stimulus we used includes an acute response and brief recovery from LBNP during a very short period of time (10 s). The acute response may involve the expected depression of blood pressure, followed by an overshoot during the recovery period, resulting in no change in average blood pressure. The changes in R-R interval did not necessarily correspond to a hemodynamic response to low-level LBNP; changes in heart rate were not significant. However, the linear relationship between R-R interval and vagal outflow would suggest an autonomic response (8, 21). Our subjects also showed a graded increase in lowfrequency blood pressure oscillations with oscillatory LBNP accompanied by an increase in low-frequency R-R interval oscillations (which were not graded, however). Cross-spectral coherence, although significant during basal conditions, showed high inter- and intraindividual variability during oscillatory LBNP. Among subjects with significant coherence across all LBNP levels (n ⫽ 7), there was no change in transfer function magnitude during oscillatory LBNP. During moderate, but not low, oscillatory LBNP, a decrease in R-R interval power from basal conditions generally indicated lack of a significant coherence relationship between systolic blood pressure and R-R interval. This may reflect a differential engagement of blood pressure regulatory mechanisms that is not uniform across subjects and between conditions. It is possible that a mechanistic heterogeneity explains the range of responses that were demonstrated. Oscillations in tank pressure could have uncovered a transient arterial baroreflex response to LBNP onset or could have entrained the cardiopulmonary response. A sudden drop in stroke volume at the onset of LBNP would reduce the pulsatile stretch in baroreceptive arteries and decrease arterial pressure (24). An acute arterial baroreflex-mediated R-R interval response, dictated by the pressure change, could generate a synchronous oscillation in cardiac interval. Another possibility is that the response is caused by a synchronization of cardiopulmonary receptor activity to the 0.1-Hz stimulus. Oscillating changes in central venous pressure could cause oscillations in sympathetic nerve activity, which could result in systemic resistance and, hence, arterial pressure fluctuations. Thus cyclic cardiopulmonary activation could generate arterial pressure oscillations. Nonetheless, the response could not be a purely cardiopulmonary one, since there was a significant R-R interval change, indicating arterial baroreflex engagement. The oscillations in cardiac filling could also have activated the Bainbridge reflex, further complicating the regulatory landscape. At high levels of cardiac filling, the Bainbridge reflex purportedly stimulates vagal withdraw, thereby increasing R-R interval (11). If the reverse were true at low levels of cardiac filling induced by LBNP, the corresponding decrease in R-R interval would work to counteract the

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regulatory actions of the arterial baroreflex. It seems most likely that no single reflex was responsible but that multiple regulatory systems were engaged and that nonlinear interactions explain the lack of coherence between arterial pressure and R-R interval oscillations. It should be noted that a lack of significant coherence does not necessarily indicate that any single reflex is behaving in a nonlinear fashion, only that, in a broad assessment of blood pressure’s effect on R-R interval, the linear single input-output model is insufficient to describe their relationship. However, independent of any mechanism, our data clearly show that low-level LBNP can generate changes in arterial pressure and R-R interval. Links between low-frequency oscillations. Our data raise questions about assumptions commonly made regarding relationships between low-frequency oscillations in arterial pressure and heart period. We were able to generate large and consistent low-frequency oscillations in arterial pressure and R-R interval during oscillatory LBNP. Significant coherence was evident in all but one subject during basal conditions but in only seven subjects during both levels of oscillatory LBNP. The lack of R-R interval coherence to consistent-amplitude arterial pressure oscillations may have implications for the interpretation of spectral data. Disappearance of cross-spectral coherence may indicate nonlinearities arising from interplay between blood pressure-buffering mechanisms. For example, a mechanical damping of central venous pressure changes by the heart may reduce coherence between arterial pressure and R-R interval during LBNP (25). In addition, there is a state dependency in arterial pressure buffering by R-R interval at the Mayer wave frequency (23), which suggests that an alterable interaction of cardiac and vascular mechanisms is responsible for arterial pressure fluctuations. Moreover, inconsistency between and among subjects demonstrates heterogeneous responses in a presumably homogenous population. Thus the engagement of these nonlinearities may be state and trait dependent. Cross-spectral analysis requires linearity between input and output, which may not hold for arterial pressure and R-R interval in all conditions. Nonetheless, significant coherence tended to occur when R-R interval and arterial pressure oscillations changed in parallel. Limitations. Dependency on standard spectral techniques limited the amount of information we could glean from this study. We had no reason to suspect that cross-spectral analysis would prove ineffective at examining the relationship between pressure and R-R interval. Time-varying estimates of spectral power, such as the Wigner distribution, spectrograms, and scalograms, show how a signal’s frequency characteristics change with time, and time-varying cross spectra show the interaction of multiple variables with time (7). These techniques, however, are most suited to characterize transients and to eliminate nonstationarities associated with changing experimental and/or behavioral conditions. The nature and consistency of the arterial pressure oscillations would limit these analy-

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ses, such that they would be unlikely to shed additional light on the interactions between R-R interval and blood pressure. Time domain modeling has proven to be very effective at examining cardiovascular systems; unfortunately, lengthy physiological recordings are required for proper analysis, and extreme care must be taken to produce interpretable parameters (1, 4, 5, 14). Spectral techniques are a valuable scientific tool, but perhaps too limited to properly examine the underlying physiology of nonstationary cardiovascular variables. Another limiting factor is our inability to assess the effect of the sympathetic nervous system during oscillatory LBNP. If sympathetic nerve recordings had been obtained or sympathetic blockade achieved, we could more accurately discern the physiological impact of our stimulus. However, these limitations do not undermine the implications of our present findings; they merely give direction for further study. Conclusions. The fact that subjects showed a shorter average R-R interval during oscillatory LBNP challenges the notion that low-level LBNP cannot affect R-R interval. In addition, we successfully enhanced low-frequency oscillations in blood pressure and R-R interval, which is significant in several respects. Oscillatory LBNP provides a stimulus that is reliably able to create repeated drops in arterial pressure for the examination of a myriad of pressure regulatory systems. Specifically, we sought to illuminate the R-R interval response to these repeated drops in arterial pressure. However, we found that the simple linear arterial baroreflex model incorporated into cross-spectral analysis cannot explain blood pressure regulation across conditions. Although standard frequency domain techniques are a powerful tool, ultimately, scientists may have to move to nonlinear and/or time-varying analysis methods to further understand cardiovascular regulation of beat-by-beat oscillations. This study was supported by The American Federation for Aging Research and National Institute on Aging Grants R29 AG-14376 (J. A. Taylor) and R01 AG-14420-01. REFERENCES 1. Abbiw-Jackson RM and Langford WF. Gain-induced oscillations in blood pressure. J Math Biol 37: 203–234, 1998. 2. Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, and Cohen RJ. Hemodynamic regulation: investigation by spectral analysis. Am J Physiol Heart Circ Physiol 249: H867– H875, 1985. 3. Baselli G, Cerutti S, Civardi S, Liberati D, Lombardi F, Malliani A, and Pagani M. Spectral and cross-spectral analysis of heart rate and arterial blood pressure variability signals. Comput Biomed Res 19: 520–534, 1986. 4. Cavalcanti S and Belardinelli E. Modeling of cardiovascular variability using a differential delay equation. IEEE Trans Biomed Eng 43: 982–989, 1996. 5. De Boer RW, Karemaker JM, and Strackee J. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am J Physiol Heart Circ Physiol 253: H680–H689, 1987. 6. Dimier-David L, Billon N, Costagliola D, Jaillon P, and Funck-Brentano C. Reproducibility of non-invasive measurement and of short-term variability of blood pressure and heart rate in healthy volunteers. Br J Clin Pharmacol 38: 109–115, 1994.

7. Di Virgilio V, Barbieri R, Mainardi L, Strano S, and Cerutti S. A multivariate time-variant AR method for the analysis of heart rate and arterial blood pressure. Med Eng Phys 19: 109–124, 1997. 8. Eckberg DL, Cavanaugh MS, Mark AL, and Abboud FM. A simplified neck suction device for activation of carotid baroreceptors. J Lab Clin Med 85: 167–173, 1975. 9. Girard A, Laude D, and Elghozi JL. [Reproducibility of shortterm variability indicators of blood pressure]. Arch Mal Coeur Vaiss 87: 1079–1082, 1994. 10. Guyton AC and Harris JW. Pressoreceptor-autonomic oscillation: a probable cause of vasomotor waves. Am J Physiol 165: 158–166, 1951. 11. Hakumaki MO. Seventy years of the Bainbridge reflex. Acta Physiol Scand 130: 177–185, 1987. 12. Johnson JM, Rowell LB, Niederberger M, and Eisman MM. Human splanchnic and forearm vasoconstrictor responses to reductions of right atrial and aortic pressures. Circ Res 34: 515–524, 1974. 13. Kruger K. Ist der Sinus caroticus bei der Entstehung der Blutdruckwellen hoherer Ordnung beteiligt? Z Biol 94: 135–149, 1933. 14. Ottesen JT. Modelling of the baroreflex-feedback mechanism with time-delay. J Math Biol 36: 41–63, 1997. 15. Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell’Orto S, Piccaluga E, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 59: 178–193, 1986. 16. Pawelczyk JA and Raven PB. Reductions in central venous pressure improve carotid baroreflex responses in conscious men. Am J Physiol Heart Circ Physiol 257: H1389–H1395, 1989. 17. Preiss G and Polosa C. Patterns of sympathetic neuron activity associated with Mayer waves. Am J Physiol 226: 724–730, 1974. 18. Rothlin E and Cerletti A. Uber die Koppelung von Atmung und Kreislauf. Schweiz Med Wschr 80: 1394–1399, 1950. 19. Sagawa K, Carrier O, and Guyton AC. Elicitation of theoretically predicted feedback oscillation in arterial pressure. Am J Physiol 203: 141–146, 1962. 20. Scheffer GJ, TenVoorde BJ, Karemaker JM, and Ros HH. Effects of epidural analgesia and atropine on heart rate and blood pressure variability: implications for the interpretation of beat-to-beat fluctuations. Eur J Anaesthesiol 11: 75–80, 1994. 21. Smyth HS, Sleight P, and Pickering GW. Reflex regulation of arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity. Circ Res 24: 109–121, 1969. 22. Taylor JA, Carr DL, Myers CW, and Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation 98: 547–544, 1998. 23. Taylor JA and Eckberg DL. Fundamental relations between short-term RR interval and arterial pressure oscillations in humans. Circulation 93: 1527–1532, 1996. 24. Taylor JA, Halliwill JR, Brown TE, Hayano J, and Eckberg DL. “Non-hypotensive” hypovolaemia reduces ascending aortic dimensions in humans. J Physiol (Lond) 483: 289–298, 1995. 25. Triedman JK and Saul JP. Blood pressure modulation by central venous pressure and respiration. Buffering effects of the heart rate reflexes. Circulation 89: 169–179, 1994. 26. Welch PD. The use of fast Fourier transform for the estimation of power spectra: a method based on time averaging over short modified periodograms. IEEE Trans Audio Electro Eng 15: 70– 73, 1967. 27. Williams TD, O’Mahony D, Green A, and Taylor JA. Spontaneous baroreflex indices do not correlate to carotid pulsatile elasticity (Abstract). FASEB J 12: A688, 1998. 28. Zoller RP, Mark AL, Abboud FM, Schmid PG, and Heistad DD. The role of low pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 51: 2967–2972, 1972.