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1Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Osaka; 2Core Laboratory, Nagoya City University Graduate School of Medical Sciences, and 3Department of Autonomic Neuroscience, Research Institute of Environmental Medicine, Nagoya University, Nagoya; and 4Department of Cardiovascular Medicine, Kyusyu University Graduate School of Medical Sciences, Fukuoka, Japan
Submitted 6 October 2004 ; accepted in final form 31 May 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP (finger photoplethysmography) variability during a 15-min 60° HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability (index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope.
autonomic nervous system; baroreflex; blood pressure; heart rate variability; hemodynamics
0.1-Hz) oscillation of sympathetic nerve activity (SNA) (1, 5). Tilt maneuvers of 75° and 80° greatly increase the LF oscillatory patterns of muscle SNA (MSNA), which mirrored similar changes in LF oscillation of AP (1, 5). However, LF oscillation of SNA has been investigated only in the steady-state orthostatic condition, when AP remains well maintained. It remains unclear whether LF oscillation of SNA changes during development of orthostatic neurally mediated syncope. Syncope is a common and potentially dangerous clinical syndrome (18). Under this condition, a major cause of hypotension is paradoxical withdrawal of sympathetic outflow to resistance vessels, because MSNA is greatly inhibited during hypotension (16–18), in addition to cardiac vagal excitation. Inasmuch as sympathetic activation is known to be accompanied by an increase in LF oscillation of SNA (1, 5, 15, 20, 24), it is possible that the increase in LF oscillation of SNA during orthostatic stress is not sustained during sympathetic withdrawal in the course of development of orthostatic neurally mediated syncope. Therefore, we hypothesized that LF oscillation of SNA decreases during development of orthostatic neurally mediated syncope. Because detailed characteristics, including LF oscillations of SNA during development of syncope, have not been studied in detail, we examine this phenomenon and attempt to explain the mechanism involved on the basis of current theories.
To test the hypothesis, we analyzed MSNA (by microneurography) and AP in 10 healthy male volunteers who manifested orthostatic neurally mediated syncope during the head-up tilt (HUT) test. Because sympathetic and cardiovascular changes during development of syncope are sudden and time dependent, traditional spectral methods, including autoregressive and fast Fourier transform power spectral analyses, cannot be used to assess these parameters. We therefore used the complex demodulation technique (8, 9, 13) to investigate dynamic changes in amplitudes of LF and respiratory high-frequency (HF, 0.25-Hz) oscillations of MSNA before and during tilt-induced orthostatic neurally mediated syncope.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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Measurements. AP was measured continuously using a finger photoplethysmograph (Finapres, model 2300, Ohmeda, Englewood, CO). Systolic, diastolic, and pulse pressures were measured from the continuous pressure wave. Mean pressure was calculated by averaging pressure within a pulse wave. Finger pressure was confirmed to match intermittent (every minute) brachial AP measured by an automated sphygmomanometer (model BP203MII, Nippon Colin, Komaki, Japan). Electrocardiogram (chest lead II) and thermistor respirogram were also recorded continuously.
MSNA was measured as reported previously by our laboratory (14). Briefly, a tungsten microelectrode (model 26-05-1, Frederick Haer, Bowdoinham, ME) was inserted percutaneously into the muscle nerve fascicles of the tibial nerve at the right popliteal fossa without anesthesia. Nerve signals were fed into a preamplifier (Kohno Instruments, Nagoya, Japan) with two active band-pass filters set between 500 and 5,000 Hz and monitored with a loudspeaker. MSNA was identified according to the following discharge characteristics: 1) pulse-synchronous and spontaneous efferent discharges, 2) afferent activity evoked by tapping calf muscles, but not in response to a gentle skin touch, and 3) enhancement during phase II of the Valsalva maneuver.
Protocols.
Subjects were instructed to refrain from eating for 3 h before the experiments, which were conducted in an air-conditioned (26°C) room. Each subject was required to remain supine on a tilt bed set at 0° horizontally. After the microneurographic MSNA signal was detected, the subject remained at 0° supine and at rest for 
20 min; then baseline MSNA, blood pressure, electrocardiogram, and respiration were recorded for 6 min. Thereafter, the tilt table was inclined to 60° in a passive manner and fixed for 15 min. The HUT was terminated and the table was returned to the 0° horizontal position when any of the following findings was observed: development of presyncope symptoms such as nausea, sweating, yawning, gray out, and dizziness and progressive reduction in systolic blood pressure to <80 mmHg. All variables were continuously monitored.
Data analysis. The full-wave-rectified MSNA signal was fed through a resistance-capacitance low-pass filter at a time constant of 0.1 s to obtain the mean voltage neurogram, which was resampled at 200 Hz, together with other cardiovascular variables. MSNA bursts were identified, and their areas were calculated using a custom-built (by our laboratory) computer program. MSNA was expressed as the rate of integrated activity per minute (burst rate) and total activity by integrating individual burst area per minute (total MSNA). Because burst area and, hence, total MSNA were dependent on electrode position, they were expressed as arbitrary units (AU) normalized by the individual baseline value at 0° supine rest (average of total MSNA per minute during 6 min of 0° supine rest was given an arbitrary value of 100 AU). The area of each burst during HUT was normalized to this value.
Time-dependent changes in amplitudes of LF (0.04–0.15 Hz) and HF (0.15–0.35 Hz) components of MSNA, mean AP, and R-R interval variability were assessed continuously by complex demodulation using a custom-designed computer program (8, 9, 13). The complex demodulation technique is a nonlinear time-domain method of time series analysis suitable for investigation of nonstationary/unstable oscillations within an assigned frequency band (8, 9, 13). This method provides instantaneous amplitudes and frequency of LF and HF component variables as a function of time (8, 9, 13). For example, for a signal with 0.09- and 0.22-Hz oscillations at a given moment, this method calculates the instantaneous frequency of the LF and HF components as 0.09 and 0.22 Hz, respectively. In addition, the method provides the instantaneous amplitude of each oscillation. All neural and cardiovascular variables and their LF and HF components were averaged every 2 min during 0° supine rest and every 20 s during 60° HUT.
The squared coherence function was calculated as the square of the cross-spectrum normalized by the product of the spectra of the two different signals in the LF and HF bands (13). The periods analyzed were 0° supine (6 min), early HUT (first 5 min of HUT), from 100 to 60 s before onset of syncope, and from 60 s before to onset of syncope. The coherence function quantifies the amount of linear link between oscillations with the same frequency contained in two different signals. Coherence values >0.5 were considered significant.
Statistical analysis. Values are means ± SE. Repeated-measures analysis of variance was used to compare variables for time (every 2 min at 0° supine rest and every 20 s at HUT) and group (syncopal and nonsyncopal subjects). When the main effect or interaction term was significant, post hoc comparisons were made with Scheffé's F test. P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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0.09 and 0.25 Hz, respectively (Figs. 2–5).
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From 100 s before onset of syncope, AP (systolic, diastolic, and mean) started to decrease, and LF oscillation of MSNA weakened, as shown in the representative recording in Fig. 1. Data from all subjects showed that, from 100 to 60 s before onset of syncope, LF amplitude of MSNA variability started to decrease (Fig. 4). In contrast, magnitudes of MSNA (burst rate and total activity) and HF amplitude of MSNA variability remained elevated above 0° supine levels (Fig. 4; P < 0.05). AP (systolic, diastolic, and mean) started to decrease, but pulse pressure did not change (Fig. 2). LF amplitude of mean AP variability started to decrease, whereas HF amplitude of the variability remained increased above 0° supine levels (Fig. 3; P < 0.05). R-R interval and HF amplitude of R-R interval variability remained decreased below 0° supine levels (Fig. 5; P < 0.05). Respiratory rate was nearly constant at 15 cycles/min. Instantaneous frequencies in LF and HF bands of all variables remained fixed at 0.09 and 0.25 Hz, respectively (Figs. 2–5).
From 60 s before to onset of syncope, AP (systolic, diastolic, and mean) further decreased (Fig. 2). Pulse pressure decreased in the last 20 s (Fig. 2). LF amplitude of MSNA variability further decreased (Fig. 4). Magnitudes of MSNA (burst rate and total activity) decreased markedly (Fig. 4), as seen in the representative recording in Fig. 1. HF amplitude of MSNA variability decreased (Fig. 4). LF amplitude of mean AP variability further decreased, whereas HF amplitude of the variability remained elevated above 0° supine levels (Fig. 3; P < 0.05). R-R interval and LF and HF components of R-R interval variability greatly increased (Fig. 5). Respiratory rate was nearly constant at 15 cycles/min. Instantaneous frequencies for LF and HF bands of all variables remained fixed at 0.09 and 0.25 Hz, respectively (Fig. 2–5).
Coherence function. In the LF band, MSNA exhibited coherence with the R-R interval and AP during 0° supine rest and significantly stronger coherence during HUT in syncopal and nonsyncopal subjects (Table 1). In the HF band, MSNA exhibited coherence with the R-R interval, AP, and respiration during 0° supine rest and coherence did not change during HUT in syncopal and nonsyncopal subjects (Table 1).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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As far as we are aware, the present study is the first that addresses the time course of changes in MSNA oscillation in development of orthostatic neurally mediated syncope. The change in MSNA oscillation consisted of two stages. The first stage (from 100 to 60 s before onset of syncope) is marked by a decrease in LF oscillation of MSNA at the initial development of orthostatic neurally mediated syncope, when AP starts to decrease. MSNA and heart rate remain elevated above horizontally supine levels. The second stage (from 60 s before to onset of syncope) is characterized by the total disappearance of MSNA oscillation during further development of orthostatic neurally mediated syncope, when AP further decreases to the level at syncope. Sympathetic withdrawal and bradycardia occur, consistent with earlier studies (16–18).
Increase in LF oscillations of AP and MSNA in normotensive HUT. In agreement with previous studies (1, 5), when AP was well maintained, early HUT increased the amplitude of LF oscillation of MSNA and caused mirrored changes in the amplitude of LF oscillation of mean AP (Figs. 3 and 4). In addition, a high coherence between the two in the LF band was observed during HUT, consistent with results of an earlier study (5). These findings indicate that HUT induces a common LF oscillatory pattern in the variability of sympathetic discharge and AP (5).
Possible mechanism for the increase in LF oscillations of mean AP and MSNA: baroreflex-loop theory. Two mechanisms have been speculated to generate LF oscillation of mean AP and MSNA in normotensive HUT. The first mechanism is the baroreflex-loop theory (2, 6). First, we examined how the baroreflex-loop system may explain generation of LF oscillation of AP and MSNA. Figure 6A shows a block diagram of the arterial baroreflex system. The total arc baroreflex is a negative-feedback control system that senses AP by baroreceptors and regulates AP. The total arc baroreflex system consists of the neural arc transfer function (HN), saturation function (sat), and peripheral arc transfer function (HP; Fig. 6A) (12). HN, coupled with saturation, represents central processing from baroreceptor pressure to SNA, whereas HP represents processing from SNA to systemic AP. According to our previous studies, we used derivative and high-cut filter characteristics with a pure delay to model HN and the second-order low-pass filter with a pure delay to model HP (see APPENDIX; Fig. 6, B and C) (12). The saturation function simulates the upper and lower saturation of SNA. Because the total arc baroreflex transfer function is a multiplication of these subsystem transfer functions, it approximates a first-order low-pass filter with a pure delay, consistent with previous studies (see APPENDIX; Fig. 6, B and C) (10).
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radians. The phase in the total arc transfer function is delayed as the frequency increases and reaches –2 radians at a given frequency, which we define as f0 (Fig. 7). We also define the gain at f0 as G0 (Fig. 7). The total arc low-pass filter has the following important characteristics: at G0 > 1, closing the feedback loop generates oscillations of AP and SNA at f0, whereas at G0 < 1, closing the loop does not generate the oscillation. Because LF oscillation of AP and SNA is not significant in the supine position, G0 may be <1 (Fig. 6, B and D). If G0 remains unchanged in HUT, the closed-loop baroreflex system will increase SNA in response to tilt-induced pressure perturbation by gravity but will not produce oscillation of AP and SNA (Fig. 6, C and D). However, if G0 increases to >1 in HUT, the closed-loop baroreflex system will generate LF oscillations of AP and SNA (Fig. 6, C and D). Therefore, we raise the possibility that HUT increases G0, resulting in generation of LF oscillations of AP and SNA.
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Furthermore, we can propose how the baroreflex system generates LF oscillations. Interestingly, our data showed that frequency of the LF component of AP and MSNA variability was constant in supine rest and HUT (Figs. 3 and 4). This indicates that f0 remains unchanged during HUT. Accordingly, the possible increase in G0 during HUT may be the result of an increase in total baroreflex transfer gain. Such an increase in total arc gain may be caused by an increase in HN, but not HP, gain (Fig. 6B). This occurs because HUT shifts body fluid toward the lower body, including the third space, and may result in deterioration of the peripheral transduction from SNA to AP.
Possible mechanism for increase in LF oscillations of AP and MSNA: pacemaker oscillator theory. The second mechanism that has been speculated to generate LF oscillation of AP and MSNA is the pacemaker oscillator theory (1). This theory is supported by earlier studies in dogs showing that LF oscillation of SNA persisted even after baroreceptor afferent activity was abolished by spinal section and bilateral vagotomy (11) and that LF oscillation was preserved even after baroreceptor pressure fluctuations were abolished by a pressure-stabilizing device (22). Such evidence supports the concept that the LF pacemaker oscillator generates LF oscillation of MSNA.
Next, we attempted to apply the pacemaker oscillator theory to explain LF oscillation of AP and MSNA. We added elements of the pacemaker oscillator theory to the baroreflex-feedback-loop model and modeled the pacemaker oscillator as a 0.1-Hz sine wave in a block diagram (Fig. 8A). The numerical simulation indicates that increasing the amplitude of SNA pacemaker oscillation will increase amplitudes of LF oscillations of MSNA and AP (Fig. 8C), while the baroreflex system remains constant (Fig. 8B). Therefore, it is possible that HUT activates the pacemaker oscillator, resulting in enhancement of LF oscillations of MSNA and AP. Details of the mechanism responsible for activation of the pacemaker oscillator are unclear.
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The first possible explanation is a decrease in neural arc baroreflex transfer gain. A recent finding suggests that the total and neural arc baroreflex gains largely decrease during tilt-induced syncope (19). Our numerical simulation indicates that decreasing HN gain will attenuate the total arc baroreflex transfer function gain and attenuate G0 to <1 (Fig. 9A). As a result, the baroreflex system could not sustain LF oscillations of AP and SNA (Fig. 9C). Although an increase in pure delay of the total baroreflex system theoretically decreases G0 and suppresses LF oscillations, it might not relate to the decrease in G0, because our data showed that the frequencies of LF components of AP and MSNA variability were constant during development of tilt-induced syncope. A possible decrease in the baroreflex subsystem transfer gain may also explain the hypotension and sympathetic withdrawal in addition to reductions of LF oscillations (Fig. 9C), except withdrawal of MSNA lags behind decreases of AP and LF oscillations of AP and MSNA (from 100 to 60 s before onset of syncope).
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Respiratory HF component of MSNA variability. As reported earlier (1), the respiratory HF oscillation of MSNA increased during early HUT, when AP was maintained. Several mechanisms may contribute to this increase. 1) It is likely that downward displacement of the diaphragm reduces inspiratory intrathoracic pressure and inspiratory left ventricular stroke volumes (1, 7). This increases the respiratory HF fluctuation of AP and would increase the respiratory HF oscillation of MSNA via the baroreflex neural arc, in particular, its dynamic high-pass characteristics of HN (10, 12). If the HN gain increases during HUT, increases in HF oscillation of MSNA and AP may be further enhanced. 2) Because early HUT decreases the respiratory HF fluctuation of the R-R interval, which is known to decrease the respiratory HF fluctuation of AP (25), it would increase the HF fluctuation of AP (1). 3) Because HUT induces hyperpnea during normotensive HUT (13), the respiratory-related oscillation of MSNA might be increased. Unfortunately, because numerical data are not available for the transfer characteristics involved in these possible explanations, we cannot simulate how these possibilities generate the respiratory HF oscillations.
This study investigated respiratory HF oscillation of MSNA during tilt-induced syncope. We found that HF oscillation of MSNA decreased just before onset of tilt-induced syncope. We cannot determine the mechanism(s) for this observation but propose the following explanations. The first possibility is that the baroreflex neural arc gain decreases during the progression of tilt-induced syncope, resulting in a decrease of the respiratory HF oscillation of MSNA. This can explain our finding that HF oscillation of MSNA decreased whereas HF oscillation of AP remained elevated during tilt-induced syncope, because the peripheral arc low-pass filter characteristics (12) would limit the reduction of HF oscillation of AP and keep HF oscillation of AP elevated. The second possibility is that tidal volume decreases during development of tilt-induced syncope. When tidal volume decreases, the lung will be less inflated. Consequently, MSNA will be less suppressed by lung inflation, reducing respiratory modulation of MSNA.
Our results indicate a decrease in MSNA and an increase in cardiac vagal nerve activity in development of tilt-induced syncope. In contrast to HF amplitude of MSNA variability, HF amplitude of R-R interval variability increased markedly just before onset of orthostatic syncope, consistent with earlier reports (4). This finding indicates an excitation of cardiac vagal outflow to the heart. In addition, LF amplitude of R-R interval variability also increased just before onset of syncope, in agreement with a previous study (13). This might also be explained by excitation of vagal, but not sympathetic, nerve activity, because MSNA and heart rate decrease in this stage.
Limitations. This study has several limitations. 1) We studied healthy subjects with no recent history of spontaneous syncope. Therefore, it is difficult to generalize our findings to patients with recurrent and chronic orthostatic hypotension (3, 17, 18). 2) We did not measure tidal volume, arterial PCO2, and pH, which may affect MSNA and AP and their fluctuations. 3) We measured AP wave changes during HUT by noninvasive photoplethysmography. Nevertheless, the photoplethysmographic pressure waveform correlated very well with invasive intra-arterial pressure during tilt (21). 4) Because the baroreflex transfer functions of total, neural, and peripheral arcs have not been determined in humans, we used the characteristics of transfer function derived from animal studies (rabbits) (10, 12) in numerical simulations of AP, MSNA, and their oscillations. 5) Our model used in the numerical simulation focused on baroreflex-loop and pacemaker theories governing SNA and did not incorporate vagal nerve activity into the model.
In conclusion, LF oscillation of MSNA decreases at the initial development of orthostatic neurally mediated syncope, before sympathetic withdrawal, bradycardia, and severe hypotension, to the level of syncope.
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APPENDIX |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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 | (A1) |
where f and j represent frequency (in Hz) and imaginary units, respectively; KN is static gain (in AU/mmHg), fc1 and fc2 (fc1 < fc2) are corner frequencies (in Hz) for derivative and high-cut characteristics, respectively, and L is a pure delay (in s), which would represent the sum of delays in the synaptic transmission at the baroreflex central pathways and the sympathetic ganglion. The dynamic gain increases from fc1 to fc2 and decreases above fc2. We set fc1, fc2, and L at 0.1, 0.8, and 0.2, respectively, in all simulations in Figs. 6, 8, 9, and 10. We set KN appropriately in each simulation (Figs. 6, 8, 9, and 10).
In addition, the transfer function of the baroreflex peripheral arc (SNA to systemic AP) approximates the second-order low-pass filter with a lag time in rabbits (12). Therefore, we model the peripheral arc transfer function (Hp) as follows
 | (A2) |
where KP is static gain (in mmHg/AU), fN and 
represent natural frequency (in Hz) and damping ratio, respectively, and L is a pure delay (in s), which would represent the sum of delays in the synaptic transmission at the neuroeffector junction and the intracellular signal transduction in the effector organs. We set KP, fN, , and L at 1.3, 0.07, 1.4 and 2.4, respectively, in all simulations in Figs. 6, 8, 9, and 10 by modifying these parameter values observed in rabbits (12) to simulate AP oscillation at 0.1 Hz in humans.
Consequently, the transfer function of the total arc baroreflex system (baroreceptor pressure to systemic AP) in our model (Fig. 6A) approximates the first-order low-pass filter with a pure delay (10) as follows
 | (A3) |
where KT is static gain (in mmHg/mmHg), fc is corner frequency (in Hz), and L is pure delay (in s) of the total arc system. The "sat" function in Figs. 6A and 8A is a saturation function that determines minimum (–50 AU) and maximum SNA (50 AU).
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXGRANTSREFERENCES |
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) and nonsyncopal (
) subjects during 6 min of supine rest (averaged every 2 min) and during 410 s before completion of HUT test or onset of syncope in HUT posture (averaged every 20 s). Line 1 and line 2, 100 and 60 s, respectively, before completion of HUT test or onset of syncope in HUT test. Pulse pressure in both groups is lower throughout HUT test than in supine posture (P < 0.05). *P < 0.05, syncopal vs. nonsyncopal. #P < 0.05 vs. mean for the first 100 s of HUT. Error bars, SE.
