Effects of 14 Days Head-down Tilt Bed Rest on Autonomic Response

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1 International Journal of Bioelectromagnetism Vol. 12, No. 3, pp , Effects of 14 Days Head-down Tilt Bed Rest on Autonomic Response Manuela Ferrario a, Federico Aletti a, Enrico Tam b, Michela Cautero c, Carlo Capelli c, Maria G. Signorini a and G. Baselli a a Department of Bioengineering, Politecnico di Milano, Milan, Italy b Department of Human and General Physiology, Università di Bologna, Bologna, Italy c Department of Motor and Sport Sciences, Università di Verona, Verona, Italy Correspondence: M Ferrario, Department of Bioengineering, Politecnico di Milano, P.zza Leonardo da Vinci 32, Milano, Italy. manuela.ferrario@polimi.it, phone , fax Abstract. Cardiovascular responses to orthostatic stress induced by tilt maneuver were measured in seven subjects, before and after a 14 days head-down tilt bed rest (HDTBR). The response of the autonomic nervous system was evaluated through the analysis of the heart rate (HRV) and arterial blood pressure (ABP) variability. Spectral components, entropy indices and the Lempel Ziv Complexity were measured on the HRV and ABP variability signals. After HDTBR, a significant increase of the HF component in the diastolic arterial pressure was reported (rest: 81 ± 55 mmhg 2 ; tilt 313 ± 179 mmhg 2 ), accompanied by a significant decrease of the LZC (rest: 0.72± 0.07; tilt: 0.63±0.08). On the contrary, a significant decrease of the HF component in the RR series was obtained (rest: 174 ± 57 ms 2 ; tilt: 76 ± 28 ms 2 ), accompanied by a significant increase of LZC (rest: 0.64 ± 0.10; tilt: 0.77 ± 0.05). The results obtained suggested that different compensatory mechanisms act on the complexity of heart rate and pressure in the response to cardiovascular deconditioning. Keywords: Head-down tilt bed rest, tilting maneuver, entropy estimators, Lempel Ziv Complexity, Heart rate variability 1. Introduction Prolonged bed rest is one of the most common experimental protocol used to induce cardiovascular deconditioning (CD), i.e. a condition characterized by the impairment of the cardiovascular regulatory responses [Convertino et al., 1982, Capelli et al., 2008]. The withdrawal of the orthostatic stress brings about several cardiovascular adaptations to the supine posture that are essentially triggered by the decrease of the plasma volume. In fact, the sudden shift of the blood towards the thorax and head initiates a complex neuro-humoral response leading to increased natriuresis and renal water loss [Norsk 2000]. In addition, the drop of vascular hydrostatic pressure in the lower limb leads to a net fluid reabsorption that results in peripheral hemo-dilution and increases volume expansion, eventually corrected by kidney diuresis. In this study we investigated the cardiovascular (CV) adaptation to a 14 days head down tilt bed rest (HDTBR), through the analysis of heart rate variability (HRV) and arterial blood pressure (ABP) variability, in order to evaluate the responses of the autonomic nervous system and of the vascular regulatory mechanisms to CD. In order to challenge the main mechanisms of CV regulation before and after HDTBR, a tilt maneuver was applied since it is recognized as a standardized, physiological, and clinically relevant stimulus for testing cardiovascular regulation response. In the case of tilt test after bed rest, the potential alterations in the maintaining of blood pressure by neural controller and local vascular responses are supposed to result from the bed rest-induced CD. Afterwards, we performed also a complexity analysis on the HRV and ABP signals since physiologic complexity is related to the adaptive capacity of the organism, which requires an integrative and multiscale functionality, and altered states may be associated with a loss of original information content [Goldberger et al., 2002]. 102

2 The measured signals carry complementary information on the status of the CV system: HRV carries valuable information about the autonomic regulation of the heart rhythm, whereas ABP variability can bring additional knowledge as to vascular responses, either induced by baroreflex control of peripheral resistances, sympathetic vasomotor tone control or autoregulation of blood flow to tissues, which is responsive to mechanical, chemical and metabolic stimuli. In particular, diastolic arterial pressure (DAP) has been shown to be related to total peripheral resistance [Bourgeois et al., 1974; Mukkamala et al., 2006] and its control. A noticeable component of the overall information conveyed in its variability has been proposed as an index of the systemic effect of peripheral autoregulation [Aletti et al., 2009]. The aims of this study are thus twofold: 1) to measure the autonomic response to tilt after HDTBR 2) to verify whether complexity indices can add information about the mechanism of CD or whether they are simply correlated with the cardiac autonomic modulation. 2. Material and Methods Protocol and Subjects Seven young, healthy subjects (age 24 years ± 3.5; weight 78 kg ± 7.7; height 182 cm ± 5.6), all non-smokers, were enrolled in a 14 days HDTBR protocol for which they signed the informed consent. Before the beginning of the bed rest period and on day 15 of the protocol, a tilt test was performed. The study was approved by the ethical committee of the School of Medicine of the University of Udine. During the 14-day bed rest the subjects were monitored constantly and were strictly confined to bed in the -6 head down position. Each subject had abstained from caffeine for 24h before the pre-hdtbr test and no caffeine was allowed during HDTBR period. For each tilt test, baseline measurements were collected after the subjects had rested quietly for few minutes following instrumentation. Subsequently the subjects were passively tilted up to the orthostatic position. Blood pressure (Portapress; TPD Biomedical Instrumentation, Amsterdam, The Netherlands) and ECG (BioPac systems Inc., Santa Barbara, CA) were continuously recorded for at least 3 minutes before and after the tilting maneuver, in supine position and in orthostatic position respectively. Sampling frequency of the recordings were 100 Hz Preprocessing and Data Analysis Artifact free stationary segments were selected for Rest and Tilt with a duration of approximately 3 minutes. Beat-by-beat series of RR intervals, systolic (SAP) and diastolic arterial pressure (DAP) were obtained. Time series were then derived from the beat-by-beat series after resampling at 2Hz. The RR time series were successively corrected by adopting an adaptive filtering procedure [Wessel et al., 2000]. For each signal, the mean value and the standard deviation were computed. Autoregressive (AR) spectral analysis was performed as well and the power in the very low frequency (VLF, Hz), low frequency (LF, Hz) and high frequency (HF, Hz) bands, the LF/HF ratio, the normalized LF and HF power were computed [Task Force, 1996]. The cardiac baroreceptor reflex sensitivity (BRS) was assessed by cross-spectrum analysis, i.e. as the average gain of the transfer function between SAP and RR in the range where the coherence is high ( 0.5) in either LF (α LF ) and HF band (α HF ) [Porta et al., 2000]. Finally, we analyzed the regularity of the different signals, by computing the Approximate Entropy (ApEn) [10] and the Sample entropy (SampEn) [11], and we estimated the information content through the Lempel Ziv complexity (LZC), assessed with different coding procedures [Lempel and Ziv, 1976]. The rest and tilt epochs, both before and after HDTBR, were compared by means of paired t-test and paired Wilcoxon signed rank test. The two resting conditions and the two upright conditions were compared as well, in order to verify not only the response to the orthostatic stress before and after HDTBR, but also the potential effects of HDTBR on the same postural condition. The significance was considered when the index passed both tests with a P-value< Lempel Ziv Complexity and Coding Procedure The measure of complexity introduced by Lempel and Ziv assesses the so-called algorithmic complexity, which is defined according to the Information Theory as the minimum quantity of information needed to define a binary string. In case of random strings, the algorithmic complexity is the length of the string itself. In fact any compression effort will produce an information loss. The LZC quantifies the rate of new patterns arising with the temporal evolution of the signal. The algorithm to 103

3 assess LZC is fully described in [Ferrario et al., 2007]. As suggested in [Kaspar and Shuster, 1987], we adopted the measure of complexity normalized by a factor depending on the sequence length. This permits to compare the complexity values of two strings different in length. In order to estimate the LZC for a biological signal, it is necessary to transform the time series into symbolic sequences. In this work we considered two different approaches. As suggested in [Yang et al., 2003], the most straightforward procedure is to use the simple increase/decrease of the signal. The second approach we applied is based on moving thresholds. Given a signal {x n }, the encoding rule adopted for the binary alphabet is the following: we assign 0 if x n x n-1 +p x n-1, and 1 if x n >x n-1 +p x n-1. The rule for the ternary alphabet is: 2 if x n-1 -p x n-1 x n x n-1 +p x n-1, 0 if x n <x n-1 -p x n-1 and 1 if x n >x n-1 +p x n-1. The factor p is a fixed percentage: the current value is then classified as stationary if it lies in a p range around the previous sample. This procedure is proposed to limit the effect of additive noise and to exclude the dependence on signal quantization. For these analyses we adopted the encoding parameter p=0.001 both for the binary LZC(2,p) and ternary coding LZC(3,p). The second approach adopts the following coding rule: given a time series {x n }, the average value is computed on a time window of N samples and then the current sample x n is encoded with 1 if x n >avg, with 0 if x n avg. In case of a ternary coding, the minimum and maximum values of the signal are estimated on a time window of N samples and then the range [min, max] is divided in order to obtain 3 regions of the same amplitude A. The current sample is encoded with 0 if x n min+a, with 1 if min+a<x n max-a and with 2 if x n >max-a. The time window considered for these analyses was N=120 samples long, for both the binary LZCm(2) and ternary coding LZCm(3). 3. Results 3.1. RR variability Table I shows the values obtained from time domain, spectral and complexity analyses performed on RR time series. HR increased from 69.0 ± 7.0 bpm to 81.3 ± 8.0 bpm before bed rest and from 7 ± 8.7 bpm to 89.8±1 bpm after bed rest. Both before HDTBR and after HDTBR, the tilt test produced an increase in the LF/HF ratio (significant only in the pre- bed rest condition), consistently with the sympathetic stimulus provided by the tilting maneuver and, as expected, accompanied by an inhibition of the vagal tone. Before HDTBR, the values of all the entropy estimators resulted significantly reduced, and the LZCm(2) significantly decreased as well. Furthermore, the rest tilt test performed after HDTBR produced a significant decrease of ApEn(2,0.15) and an increase of LZC(3,0.001). As regard the comparisons between the single epochs, no significant differences were found between the two rest conditions. On the contrary, by comparing the RR indices at the upright position, the normalized LF component showed a significant decrease after HDTBR with respect to the values obtained before the protocol SAP variability and BRS No significant differences were found in SAP variability time series from the comparison between rest and tilt epochs before HDTBR. After HDTBR, we reported instead a significant increase of the HF component (rest: 335 ± 153 mmhg 2 ; tilt: 1300 ± 666 mmhg 2 ), a significant increase of the total power LF+HF (rest: 1534 ± 553 mmhg 2 ; tilt: 5437 ± 4130 mmhg 2 ) and, like for the RR time series, a decrease of ApEn(2,0.15) (rest: 1±0.08; tilt: 0.74± 0.08). The tilting maneuver has produced a significant reduction of the BRS gain in the HF band both before and after HDTBR. No significant differences in SAP indices were noticed by comparing the single epochs, neither at rest nor at upright position. The BRS gain estimated in the HF band at upright position showed instead a significant reduction after HDTBR with respect to the values obtained before the bed rest period DAP variability The tilt test performed before HDTBR produced a significant increase of DAP mean value (rest: 57.5 ± 12.8 mmhg; tilt: 71.6±10.0 mmhg) and of its total power LF+HF (rest: 548± 582 mmhg 2 ; tilt: 1869±1340 mmhg 2 ). We obtained a significant reduction of the ApEn(2,0.15) (rest: 3 ±0.09; tilt: 0.78 ± 0.09) and LZC(2,0.001) (rest: 1.07± 0.045; tilt: 0.96± 0.09). The tilt maneuver performed after HDTBR produced again a significant increase of DAP mean value (rest: 46.3 ± 6.6 mmhg; tilt: 62.1 ± 8.2 mmhg) and the reduction of ApEn(2,0.15) (rest: 2± 0.06; tilt: 0.75±0.08). In addition we obtained a decrease of the LZC(3,0.001) (rest: 0.72± 0.07; tilt: 0.63±0.08). As reported for SAP, we 104

4 obtained a significant increase of the HF component (rest: 81.1 ± 55.0 mmhg 2 ; tilt ± mmhg 2 ). No significant differences were observed by comparing the single epochs at rest condition. On the contrary, we obtained a significant reduction in the LF/HF ratio at upright position (before HDTBR: 10.3 ± 6.9; after HDTBR: 6.1± 5.0). On the contrary, ApEn(2,0.15) significantly decreased in both conditions (before and after HDTBR) and it seemed thus to simply emphasize the outcome of the sympathetic response elicited by the tilt maneuver. Table 1. Values obtained from the RR time series (mean ± std). The indices which produced significant differences by passing from rest to tilt condition are showed in bold (P-value<0.05). Before HDTBR After HDTBR LF (ms 2 ) 952 ± ± ± ± 464 HF (ms 2 ) 283 ± ± ± ± 28 LF% 55.6 ± ± ± ± 16.1 HF% 20.2 ± ± ± ± LF/HF 3.68 ± ± ± ± ApEn(2,0.15) 0.97 ± ± ± ± 0.04 SampEn(2,0.15) 1.45 ± ± ± ± ApEn(2,0.2) 0.97 ± ± ± ± 0.10 SampEn(2,0.2) 1.19 ± ± ± ± 0.22 LZC(3,0.001) 0.61 ± ± ± ± 0.05 LZC(2,0.001) 6 ± ± ± ± 0.05 LZCm(2) 0.68 ± ± ± ± 0.15 LZCm(3) 0.61 ± ± ± ± 0.12 BRS α LF 9.47 ± ± ± ± 1.73 BRS α HF ± ± ± ± LZC(3,0.001) ms HF ApEn(2,0.15) LZC(3,0.001) 600 HF 1 ApEn(2,0.15) mmhg Figure 1. The figures illustrate the values of ApEn(2,0.15), HF component, and LZC(3,0.001) obtained after HDTBR for each subject. In the upper panels are shown the values computed on RR time series, in the lower ones on DAP time series. 105

5 4. Discussion The trends shown by the LF, HF and LF/HF indices of RR time series suggested that the response to the sympathetic stimulus provided by the tilt maneuver was maintained after bed rest. The absence of significant variations, between the two resting conditions and the reduction of the normalized LF component in upright position after HDTBR, could suggest that the effect of the CD became apparent at the onset of the orthostatic stimulus, whereas in supine position the variations were not noticeable. This observation was consistent with the reduction in the HF component of the BRS gain. This indicated a blunted vagal baroreflex as the possible reason for the reduced HF of the RR [Cooke et al., 1999; Pagani et al., 1987]. On the other hand, DAP LF/HF was lower in upright position after bed rest. This result may point in the direction of different compensatory mechanisms acting on heart rate and pressure in response to CD. This feature was also revealed by the different trends showed by the LZC indices (Figure 1). Thus, HR and DAP appear driven by different mechanisms in their re-organization in response to the orthostatic stimulus after HDTBR. As regard the entropy and complexity indices, the LZC computed with a coding procedure based on moving thresholds was not able to find significant differences in the HDTBR protocol, except LZCm(2), which resulted lower after the tilt maneuver before bed rest. However, it showed a significant correlation with the entropy estimators, e.g. the Pearson coefficient estimated with ApEn(2,0.15), at rest condition, was ρ= The LZC estimated with a coding procedure based on the increase/decrease of the signal enhanced information about the small oscillations of the signal: in this way interesting findings were obtained in the changes in the DAP and RR variability after bed rest. On the contrary, ApEn(2,0.15) significantly decreased in both signals and in both conditions (before and after HDTBR) and it seemed thus to simply emphasize the outcome of the sympathetic response elicited by the tilt maneuver. 5. Conclusions The preliminary results presented in this paper suggested that the integration of information relevant to the modulation of the cardiac rhythm and to the arterial tree could shed light on the compensatory mechanisms elicited by CD. A combined use of non linear techniques and classical, linear methods for the identification of pressure variability components could complete these findings. Acknowledgements This research was supported by the Italian Space Agency (ASI) under the DCMC Project. References Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, Circulation; 93(5): , Aletti F, Bassani T, Lucini D, Pagani M, Baselli G, Multivariate decomposition of arterial blood pressure variability for the assessment of arterial control of circulation, IEEE Trans Biomed Eng, 56(7): , Bourgeois MJ, Gilbert BK, Donald DE, Wood EH, Characteristics of aortic diastolic pressure decay with application to the continuous monitoring of changes in peripheral vascular resistance, Circulation Research, 35(1): 56-66, Capelli C, Antonutto G, Cautero M, Tam E, Ferretti G, Metabolic and cardiovascular responses during sub-maximal exercise in humans after 14 days of head-down tilt bed rest and inactivity, Eur J Appl Physiol. 104(5): , Convertino VA, Goldwater DJ, Sandler H, Effect of orthostatic stress on exercise performance after bedrest, Aviation Space Enviromental Medicine, 53(7): 652-7, Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL, Human responses to upright tilt: a window on central autonomic integration, The Journal of Physiology, 517: , Ferrario M, Signorini MG, Magenes G, Comparison between Fetal Heart Rate standard parameters and complexity indexes for the identification of severe Intra Uterine Growth Restriction, Methods of Information in Medicine, 46: , Goldberger AL, Amaral LA, Hausdorff JM, Ivanov PCh, Peng CK, Stanley HE, Fractal dynamics in physiology: Alterations with disease and aging, Proceedings of the National Academy of Sciences of the USA, 99 (suppl. 1): , Kaspar F and Schuster HG, Easily calculable measure for the complexity of spatiotemporal patterns, Physical Review A, 36(2): , Lempel A and Ziv J, On the complexity of finite sequences, IEEE Transaction on Information Theory, 22(1): 75-81,

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