60 d头低位卧床实验间中药对心血管控制的影响

作者：刘杰昕 李勇枝 Bart Verheyden 刘向昕 陈章煌 陈善广 谢琼 André E Aubert.    作者单位：航天医学与医学工程,2009,22(6):391～398

【摘要】  目的 本研究旨在通过头低位卧床60 d试验，探讨中草药方剂太空养心丸（Tai Kong Yang Xin Prescription）对心血管自主神经功能控制及动脉压力反射功能的影响。方法 14名健康志愿者，随机分为对照组（7名）和中草药治疗组（7名）。在卧床试验前、中、后，对志愿者的心血管变异性和动脉压力反射敏感度进行了详细评估。结果 所有志愿者的心率都随卧床期的延长而逐步升高，并且在卧床后恢复期的第12天仍未恢复到卧床前的基础水平；平均动脉压也在卧床试验过程中逐渐升高，但在卧床结束后的第12天缓慢恢复到卧床前的水平；压力反射敏感度和呼吸性窦性心律不齐在卧床试验中明显下降，且在卧床结束后的恢复期仍保持很低水平；动脉收缩压的低频功率在卧床试验开始后升高，该值在整个卧床期及卧床后的恢复期均保持着较高的水平。虽然上述变化在对照组和中草药治疗组中没有显著性差异，并且两组的压力反射最佳延迟时间在卧床后均明显增加，但是在卧床期结束后的第12天，压力反射最佳延迟时间只在中草药治疗组中出现了部分的恢复。结论 本研究首次探讨了太空养心丸对人体心脏自主神经功能影响的评价。研究结果表明该方剂对志愿者在模拟失重试验结束后的动脉压力反射最佳延迟时间的恢复有明显的帮助。

【关键词】  头低位卧床实验 心血管变异性 自主神经系统 中草药

　　Cardiovascular Control during 60 d Headdown Bed Rest: Chinese Herbal Medicine as a Countermeasure

　　LIU Jiexin,LI Yongzhi, Bart Verheyden,LIU  Xiangxin,CHEN Zhanghuang,CHEN Shanguang,XIE Qiong, André E Aubert

　　(1.Laboratory of Experimental Cardiology, University Hospital Gasthuisberg, K. U. Leuven, Belgium;2.China Astronaut Training and Research Center, Beijing, PR of China)

　　Abstract:Objective  To investigate the effect of CHM (Tai Kong Yang Xin Prescription) during 60 d headdown bed rest(HDBR), on cardiovascular autonomic control and arterial baroreflex function. Methods  Fourteen male healthy volunteers were randomly allocated to control group (n=7) and CHM group (n=7). Cardiovascular variability and baroreflex sensitivity (BRS) were assessed before, during and after HDBR. Results  In all subjects, there was a progressive rise in heart rate, which remained higher until 12 d of recovery. Mean arterial pressure gradually increased until day 56 of HDBR and then returned to baseline after 12 d of recovery. BRS and respiratory sinus arrhythmia decreased during HDBR and remained suppressed until 12 d of recovery. Lowfrequency power of systolic arterial pressure increased during HDBR and remained elevated during the recovery. These responses were not different between control and CHM groups. Although the optimal time delays (Tau) of BRS showed a shift towards higher values after 56 d of HDBR in both groups, there seems to be a partial recovery after 12 d of recovery in the CHM group only. Conclusion  As used in this setup, CHM have shown an effect on the Tau, in faster recovery toward prebed rest values.

　　Key words: headdown bed rest, cardiovascular variability, autonomic nervous system, Chinese herbal medicine

　　During spaceflight, the lack of gravitational  stress is associated with adaptation in cardiovascular structure and neurohumoral control circuits［16］. Due to many limitations related to real human spaceflight(high cost, limited access, small number of subjects, limited crew time...), as an alternative,Corresponding author:LIU Jiexin  liu.jiexin@med.kuleuven.beheaddown bed rest (HDBR) is often applied to investigate physiological adaptations to microgravity.
   
　　During HDBR, there is a shift in body fluids from the lower to the upper part, resulting in an increased thoracic plasma volume during the first hours of HDBR［78］. A decrease in plasma volume may occur after a couple of days, which has been reported restoring the central blood volume to baseline levels［911］. Arterial baroreflex function is chronically unchallenged during HDBR, which may result in decreased baroreflex sensitivity (BRS), probably due to deconditioning of the autonomic nervous system［9, 1214］. Moreover, many published data suggests that, as a microgravity simulation model, the effects of HDBR are very similar to what happens after spaceflight as well, i.e. postural tachycardia with a variable degree of orthostatic intolerance［15］. Decreased orthostatic function after spaceflight or bed rest seems to be related to excessive reductions in stroke volume (SV)［1618］, possibly due to hypovolemia［19］. In addition, in a study of Eckberg et al, they found decreased stroke volume after space mission was combined with a higher sympathetic outflow［20］, which might imply that the effects of spaceflight or bed rest deconditioning on autonomic control are most likely related to the changes in baroreceptor input, due to changes in hemodynamic, i.e. stroke volume. However, the exact mechanisms are still poorly understood.

　　Traditional Chinese medicine has been developed based on theories formulated through millennia of observation and practical experience［21］. It considers the processes of human body are interrelated, in balance (Yin and Yang) and in constant interaction with the environment. From this point of view diseases are due to an imbalance. One of the most important treatments of Traditional Chinese Medicine is the application of Chinese herbs which will be coined Chinese herbal medicine (CHM). As a form of noninvasive therapeutic intervention, herbal medicines may contain some biochemical agents, and might avoid the toxicity of some chemically composed drugs.
   
　　A previous animal microgravity simulation study using CHM (Tai Kong Yang Xin prescription) in the tail suspended rats［22］ shows that stroke volume decreased less after 5 d in the treated animals. Therefore in this study, we tested the hypothesis that CHM will increase orthostatic function after HDBR, i.e. it can be helpful in protecting cardiovascular control system from the deconditioning induced by prolonged HDBR. The purpose of this study is to investigate the effect of CHM, used as a countermeasure during 60 d HDBR, on cardiovascular autonomic control and arterial baroreflex function at rest among Chinese subjects.

　　Cardiovascular Control during 60 d HDBR: Chinese Medicine as a Countermeasuren= 7) and Chinese herbal medicine (CHM) group (n= 7). Subjects in the control group were given a placebo, consisting of amylum, saccharine and pigment, during HDBR; while subjects in the CHM group were given CHM (Tai Kong Yang Xin Prescription) during HDBR. All subjects spent 90 d in the Bed Rest Study Lab in China Astronaut Training and Research Center (CATRC): 15 d pretest period, 60 d -6° headdown bed rest period and 15 d recovery period. All subjects were in excellent health, without any history of chronic or recent acute illness. None of them participated in regular athletics. Dietary intake was: 2 600～2 800 kcal/d of which 90～100 g/d protein, 85～95 g/d fat and 390～430 g/d carbohydrate. Medication, smoking, alcohol and caffeinecontaining drinks were not allowed during the whole study. Each subject was thoroughly briefed on the experimental procedures prior to giving written consent. The protocol was approved by the Medical Committee of CATRC.

　　Study protocol

　　Data collection was performed before (day10), during (day 2, 7, 21, 41, 56) and after (day R+6, R+12) bed rest. Recording took place in the morning before 12:00 in a temperaturecontrolled room at 24 ℃.

　　The protocol started with the subjects resting quietly in the supine position with comfortable uncontrolled respiration for 10 min baseline recording. Then, they were instructed to pace their breathing to an audio stimulus. Controlled breathing was held for 3 min, and was performed in succession in which respiratory sequences were evenly spaced in time at a preset rate of 12 breaths/min or 0.2 Hz. On the first day of bed rest, after showering and breakfast, the subjects moved from standing upright to head down position. During the bed rest the subjects were allowed once a day to use the bathroom for defecation only (about 5 min). During their free time subjects could watch TV, listen to music or read books or newspapers.
   
　　Chinese herbal medicine

　　Tai Kong Yang Xin Prescription, a Chinese herb formulae composed with about 10 Chinese herbs was used in this study as a countermeasure. The main parts of Tai Kong Yang Xin Prescription are Radix Ginseng (containing saponins),C.A. May and Angelica Sinensis (Oliv.) Diels. It was provided as pills of 6 g and given 3 times a day orally.

　　The formula prescription (patent pending) was developed and provided by CARTC for astronaut use and microgravity simulation study.

　　Data acquisition and analysis

　　Noninvasive beattobeat blood pressure was measured with an infrared finger photoplethysmograph (Finometer Blood Pressure Monitor, TNOTPD Biomedical Instrumentation, Amsterdam, the Netherlands), using a brachial return to flowcalibration in the supine position before each measurement. The measured signal was analog to digital converted at 200 Hz, and stored on a harddisk for offline analysis. Systolic and diastolic arterial pressures were derived from the arterial pressure waveform. Mean arterial pressure (MAP) was the true integral of the arterial pressure wave over one beat divided by the corresponding beat interval.
Pulse pressure (PP) was defined as the difference between systolic and diastolic pressure. Heart rate (HR) was computed from ECG recording and expressed as beats per minute.
   
　　During the paced breathing protocol (3min period), beattobeat systolic arterial pressure(SAP) and RR interval (RRI) time series were constructed for frequency analysis. First, two linear filters (SD filter and 20% mean values) were applied to correct for data points outside a limit interval［23］. The resulting beattobeat haemodynamic time series were interpolated using a cubicspline approximation and were resampled at 2 Hz to construct equidistant time series. A sliding window of 128 s (256 samples) was applied with 16 s increments. This process resulted in four segments of data in each time series. The DC component was removed by subtracting the mean value, and a Hanning window was applied. A nonparametric ‘run test’ of means and mean square values was used to validate the stationarity of data within 5% of the confidence limits［23］. In the resulting time windows, power spectral density was averaged using Fast Fourier transform. The spectral resolution for all estimates equaled 0.0078 Hz. Respiratory powers were expressed as the area under the spectrum from 0.18 to 0.22 Hz and used as a marker of respiratory sinus arrhythmia (RSA). A second spontaneous rhythm occurring over an approximate 10s cycle and resulting in a lowfrequency band (0.04～0.15 Hz) was obtained as well for SAP variability［24］. Power spectral units for RRI and SAP fluctuations were squared amplitudes.
   
　　During 10 min baseline recording  timedomain analysis of spontaneous baroreflex sensitivity (BRS) was performed using the crosscorrelation method［25］. The SAP and RRI time series were resampled at 1 Hz. In a 10s window, the correlation and regression slope between SAP and RRI were computed. Delays of 0 to 5s increments in RRI were computed, and the delay with the highest positive coefficient of correlation was selected (Tau). The slope between SAP and RRI was recorded as a BRS estimate if the correlation was significant at P= 0.01.The number of significant BRS estimates was also calculated and expressed per minute.

　　 Statistical analysis

　　Statistical analysis was performed with SPSS 13.0 for Windows (Scientific Packages for Social Sciences, Chicago, IL, USA). Data are given as x±s, unless stated otherwise. Spectral data were logarithmically transformed to approximate normal distributions. Hemodynamic measurements, spectral and baroreflex indices were analyzed across conditions using multivariate repeatedmeasures ANOVA with the experimental sessions (before, during and after bedrest) as within subject factor and experimental conditions (control group vs. CHM group) as between subject factor. The interaction term in the model was used to assess significant differences between groups across experimental conditions. Simple contrast analysis was conducted in case of significant betweengroup interactions to evaluate changes within both groups at each time point as compared to baseline. Possible differences in Tau (optimal time delay of BRS) between conditions were assessed using Chisquare test. P< 0.05 were considered statistically significant. Exact pvalues below 0.10 are given; otherwise p values are indicated as not significant (NS).
 
　　Results

　　All subjects completed the whole study. Baseline characteristics in the two groups are shown in Table 1. No significant differences were observed between groups for age, weight, height and BMI, as well as for the hemodynamic, spectral and baroreflex data.

　　Evolution of body weight throughout the HDBR study for the two groups is shown in Table 2. No change over time was observed in both groups. Water intake and urine output data during HDBR are shown in Table 3. In contrast to water intake, which did not change systematically over time, a significant increase in urine output was observed from day 30～45 of HDBR in both experimental groups.

　　Circulatory control during and after HDBR

　　Fig. 1 shows the changes in circulatory control before, during and after HDBR in the control and CHM groups separately. None of the circulatory patterns differed significantly between groups (no significant interaction effects) and no significant betweengroup differences were observed at any timepoint. On average in all subjects of both groups, there was a progressive rise in HR until day 56 of HDBR (from 71±12 beats/min before HDBR to 78±6 beats/min at day 56, P=0.050). HR remained significantly higher until day 12 of recovery. Respiration frequency decreased during HDBR  (from 16±3 min-1 before HDBR to 14±2 min-1 at day 56, P=0.008) and returned to baseline during  the recovery. MAP increased gradually until day 56 of HDBR (from 80±5 mmHg before HDBR to 91±8 mmHg at day 56, P<0.001) and then returned to baseline after 12 d of recovery. Both BRS and RSA decreased during HDBR (BRS: from 16.3±11.2 ms/mmHg before HDBR to 9.3±2.9 ms/mmHg at day 56,P=0.021; RSA: from 345±423 ms2 before HDBR to 181±162 ms2,P=0.065) and remained suppressed until 12 d of recovery. The num ber of significant baroreflex estimates per minute   decreased from the 2nd day of HDBR (from 11.7±4.3 min-1 before HDBR to 9.0±2.4 min-1 at day 2,P=0.014) and then gradually recovered to baseline after 56 d of HDBR. Lowfrequency power of　RESP (respiration frequency), RSA (respiratory sinus arrhythmia) and LF power of BPV in the two groups (right panel);PRE: before bed rest; HDBR: during bed rest; POST: after bed rest; Before bed rest = 10 day before bed rest; D 2 = the 2nd day of bed rest; D 7 = the 7th day of bed rest; D 21 = the 21st day of bed rest; D 41 = the 41st of the bed rest; D 56 = the 56th day of bed rest; R+6 = the 6th day during recovery and R+12 = the 12th during recovery;*P< 0.05,as compared to before bed rest; +P< 0.1,as compared to before bed rest　SAP increased during HDBR (from 5.1±3.7 ms2 before HDBR to 10.5±5.1 ms2 at day 2, P=0.007) and then tended to be higher until day 56.Also during recovery, the low frequency power of SAP remained higher as compared to baseline (11.5±7.6 ms2 at day 6 of recovery, P=0.012 compared to baseline). Table 1  Baseline characteristics in the two groups(略)Table 2  Changes in body weight during HDBR(略)Table 3  Changes of water intake and urine output during HDBR(略)

　　Discussion

　　The purpose of this HDBR study was to assess the effect of CHM on cardiovascular and respiratory control during a longduration microgravity simulation of 60 d HDBR. The main finding of our study suggested that the influence of CHM as a countermeasure seemed to be limited. A novel technique was used to determine BRS allowing the assessment of three complementary aspects of arterial baroreflex  function: 1) BRS, which provided qualitative information; 2) number of BRS estimates, which provided quantitative information and 3) Tau, which provided temporal information on cardiac baroreflex control. An influence was shown on the distribution of temporal information of optimal time delay with aFig. 2  Distribution of optimal time delay Tau (s) of each baroreflex estimation before bed rest, at the end of bed rest and at the 12th day during recovery

　　Control = control group; CHM = Chinese herbal medicine group

　　faster return to prebed rest values in the CHM group.

　　 The mean energy intake was in line with previous HDBR studies as for example Kamiya et al［26］. To the contrary as was often seen in astronauts who lost weight during space flight, the weight of all subjects did not change. In HDBR studies, most likely a transition from muscle mass to body fat occurred, that could also store more liquid resulting in a redistribution of cellular and extracellular liquids［11, 15］. The mechanism of increased urine output after 30 d of HDBR remained to be explained. A possibility included the HenryGauer reflex accounting for the thoracic fluid shift elicited by HDBR［27］. The compensatory loss of intravascular water and sodium through a series of neural, humoral and direct hydraulic mechanisms might also explain our finding of a shift toward lower vagal modulation and a higher sympathetic dominance in cardiovascular control by the end of HDBR (increase in HR, MAP, LF power of SAP, Tau and decrease in BRS and RSA).
   
　　Effects of CHM as a countermeasure

　　As a noninvasive approach, the processes of the human body to be interrelated and in balance (Yin and Yang), as well as in constant interaction with the environment were considered with Traditional Chinese Medicine. The optimum health resulted from living harmoniously, which could be translated into Western Medicine as a homeostatic balance and optimal food intake; and a holistic (systemic) approach considering the body as an interconnected system was used. From this point of view, CHM claimed the diminished orthostatic tolerance after spaceflight was due to the extra consume of “Qi”, the imbalance between “Qi” and “blood”, and the damage of the “heart” and “kidney”. Mi et al reported that after 28 d of tail suspension, Tai Kong Yang Xin Prescription increased left ventricular diastolic diameter (LVDD), left ventricular diastolic volume (LVDV) and SV in rats, and suggested Tai Kong Yang Xin Prescription might protect heart pump function in rats after simulated microgravity［11, 22, 27］. But unfortunately, the results of our study did not fully support that CHM could be helpful in protecting the cardiovascular control system from deconditioning during prolonged HDBR by maintaining stroke volume, because no significant differences were observed between the two groups either in the hemodynamic parameters or in the autonomic control during HDBR, except for the optimal time delay (Tau). Accurate absolute values of stroke volume and cardiac output might be examined with echocardiogram to be needed as references in a future study.

　　 Effects of CHM on tau distribution

　　 In our findings, it was suggested that the influence of CHM in the setting of bed rest deconditioning was limited to a partial recovery of the distribution in cardiac baroreflex optimal time delay toward lower values after 12 d of recovery. The exact mechanism underlying this partial recovery remained lack. Following speculations might hold. Firstly, dynamic baroreflex control of HR acted through the “fast” (vagal) pathways and “slow” (sympathetic) pathways. A zero s time delay could be expected for vagal control of heart rate, while increasing time lags resulted from combined effects of vagal and sympathetic influences on baroreflex regulation of cardiac cycle length［28］. Hence, the increase in tau at day 56 of HDBR could be interpreted as a shift toward more sympathetic influence on cardiac modulation, also supported by other findings, i.e. higher HR, higher MAP, higher LF power of SAP, lower BRS and lower RSA. Alternatively, the faster recovery in tau after 12 d might be an indication of a faster recovery in sympathovagal balance. This however was not supported by other neural indices of cardiovascular regulation, rendering the tau distribution a more sensitive index of sympthovagal RRI modulation.

　　An alternative explanation for the larger Tau values at day 56 of HDBR might be an increased time interval for processing afferent baroreceptor signals within the central nervous system. In this respect, Gulli et al［29］ documented an increased baroreflex lag in syncopal patients with poor orthostatic tolerance. The reduction in RRItoSAP lag might then lead to instability and inadequate blood pressure control. In our study, Tau was observed to be partially recovered in the CHM group only (not in the control group) after 12 d recovery. Thus, Chinese herbal medicine might play a certain role in the response time of the central nervous system during recovery from HDBR deconditioning. However this remained to be confirmed by further studies, adapting the formula and dosage.

　　Comparison to spaceflight

　　No doubt, HDBR has proven its usefulness as a simulation model in the past 20 years, not only for the physiological study on the ground, but also for developing countermeasures to be used during spaceflight［15］. In agreement with previous studies［9, 1314, 3031］, our study shows a reduced BRS during and after HDBR. These results after HDBR were in line with a decreased BRS after real spaceflight［3234］. However, the gradual decrease in BRS during HDBR was in sharp contrast to recent reports of a preserved［35］ of even increased［36］ BRS in space. Therefore, a similar decrease in BRS after HDBR and spaceflight may be due to different mechanisms: immobilization with inactivity in HDBR and lack of gravity stimulation with inactivity in space missions. In both conditions, inactivity appeared to play a substantial role. Indeed, the present finding of a lower breathing frequency during HDBR corresponded to previous findings of a slower respiration rate in astronauts in space［3739］, which could be ascribed to a reduction in metabolic rate.

　　Besides, HR and MAP were reported to be well maintained during prolonged exposure to microgravity in space［3940］, while current HDBR findings demonstrated a progressive increase in both HR and MAP. A reasonable interpretation of these differences could be that, as a groundbased simulation model, HDBR does not eliminate the influence of gravity. Contrary to our finding of a gradual increase in MAP during HDBR as well in the control group as in the CHM group, Kamyia et al［41］ found no change in MAP after 60 d of HDBR. Although no definitive explanation could be given for this different behavior in MAP at this time, in light of the observed increase in sympathetic dominance in both studies, an increase in MAP also appeared logical.

　　Conclusion

　　From our study, it is found a shift toward lower vagal modulation and higher sympathetic dominance in cardiovascular neural control by the end of HDBR. Tai Kong Yang Xin Prescription, as used in this setup, has some effects on the distribution of optimal time delay in faster recovery to prebed rest values.
   
　　Acknowledgements

　　We thank the subjects who participated to this bed rest study. Special acknowledgement must also be made to the efforts of the China Astronaut Training and Research Center in supporting this study. This work was funded by granting from the Belgian Federal Office of Scientific Affairs, BelgianChina cooperation. Bart Verheyden is supported as a postdoctoral researcher from ESAPRODEX grants from the Belgian Federal Office of Scientific Affairs. Jiexin Liu is supported from bilateral agreements BelgiumChina from the Belgian Federal Office of Scientific Affairs.
 

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