Subjects

This study was conducted during three scientific ESA-Soyuz missions (Odissea, Cervantes, and Delta: 10–11 day missions provided by the European Space Agency [ESA]) and two Chinese Shenzhou missions (Shenzhou 6 & 7: 3–5 day spaceflights), provided by the Chinese Space Agency. Five male European astronauts (age, 40–52 years; height, 169–185 cm; weight, 67–90 kg), and five male Chinese astronauts (age, 40–42 years; height, 168–172 cm; weight, 62–70 kg) were studied before and after spaceflight. The baseline characteristics of the astronauts are shown in Table 1.

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Table 1. General characteristics of the European and Chinese astronauts.

https://doi.org/10.1371/journal.pone.0120920.t001

All subjects were in excellent health, without any history of chronic or recent acute illnesses. During these short duration flights, no routine physical exercise program was performed as a counter-measure. Each subject was thoroughly briefed on the experimental procedures prior to giving written consent. Medications, cigarette smoking, and alcohol- and caffeine-containing drinks were not permitted during the study in the pre-and post-flight stages.

Study protocol

The study protocol has been extensively described in the papers by Verheyden et al [6,15,16]. In the following paragraphs a short version is described. Pre-flight data was collected from all astronauts 21–30 days before launch (pre-flight); post-flight data was collected 1, 4, and 10 days after return to Earth (R+1, R+4, and R+10, respectively). All tests on the European astronauts were carried out in the Medical Building of the Gagarin Cosmonaut Training Center (Moscow, Russia), and all tests on the Chinese astronauts were carried out in the China Astronaut Training and Research Center (CATRC; Beijing, PR of China).

Dedicated software was used allowing standardization of each test procedure [17]. All recordings were measured in a temperature-controlled room (24°C) in the morning before 12:00 h, starting with the subjects resting quietly in the supine position with comfortable spontaneous respiration for 10 min (baseline). Then, the subjects were instructed to pace their breathing to an audio/visual stimulus. Paced breathing was maintained 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⁻¹ or 0.2 Hz. This was followed by a standing pattern, which included 10 min of spontaneous breathing while standing (baseline) and 3 min of paced breathing recording of 12 breaths min⁻¹ or 0.2 Hz in the standing position.

The experimental protocol was approved by the Medical Ethical Committee of the University Hospital Gasthuisberg (K.U. Leuven, Belgium) and the Medical Ethical Committees of the ESA and CATRC.

Data acquisition and analysis

The analytic methods have been described in detail in previous works [15,16,18,19]. In brief:

The following parameters were recorded:

• the ECG (Medtronic 9690; Minneapolis, MN, USA)
• beat-to-beat finger arterial BP (Portapres Model-2; FMS, Amsterdam, The Netherlands
• Brachial arterial BP (STBP-780’ Colin, Komaki, Japan) was measured three times in each positione

After peak detection on the ECG, an R-R interval (RRI) time series was obtained.

The HR was computed from the ECG recording. Systolic arterial (SAP) and diastolic arterial pressures (DAP) were derived from the arterial pressure waveform. The mean arterial pressure (MAP) was calculated as the true integral of the pressure wave over one beat, divided by the corresponding beat interval.

During the 10-min baseline recording, time-domain analysis of spontaneous baroreflex sensitivity (BRS) was performed using the cross-correlation method [20]. Two complementary aspects of arterial baroreflex function were assessed: 1) BRS, which provides qualitative information; and 2) number of BRS estimates, which provides quantitative information.

During the 3-min paced breathing protocol, beat-to-beat SAP and the RRI time series were constructed for frequency analysis[21]. using Fast Fourier transform. 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 the resulting low-frequency band (0.04–0.15 Hz) was obtained as well for SAP variability [16]. Power spectral units for RRI and SAP fluctuations were squared amplitudes.

Statistical analysis

Software for statistical analysis was SPSS (version 13.0 for Windows; Scientific Packages for Social Sciences, Inc., Chicago, IL, USA). Data are given as the mean ± SD. The bias between brachial and finger MAP readings was estimated by calculating the mean difference and the standard deviation of individual differences over different recording sessions [22]. Normal distributions were approximated for spectral data by logarithmic transformations. Postural differences in all parameters before and after spaceflight were evaluated by paired t-tests. Parameters were analyzed across sessions using multivariate repeated-measures ANOVA; the non-parametric Wilcoxon text was used to evaluate changes at each time point as compared to baseline. The differences between the two groups in the same position were compared using independent samples t-tests.

Pre- and post-flight standing and supine data were used to assess functional operational curves by means of linear regression analysis with 95% confidence intervals. Graphical analysis was followed by hypothesis testing (univariate analysis of variance) to compare pre-flight data to post-flight standing and supine reference values with multiple contrast analysis at a 0.05 significance level. P-values <0.05 were considered statistically significant.

Baseline autonomic characteristics

As introduced in our previous work, the dynamic relationships between qualitative components of vagal-cardiac modulation and the mean RRI as a reference were used to assess the re-adaptation to gravity after return to Earth (Fig. 2). This type of analysis is warranted because the mean RRI has been identified as a major determinant of overall HR variability [15,23]. Similarly, the effectiveness of cardiac baroreflex modulation in driving the sinoatrial node during recovery was investigated as a function of the dynamic input–output relationship (Fig. 2, lower part) [15].

The present data indicate that autonomic modulation appears different between European and Chinese astronauts before exposure to microgravity. Pre-flight standing vagal modulation and sympathetic nervous activity were significantly higher in European astronauts than Chinese astronauts, despite a comparable baseline HR and arterial pressure. This phenomenon is difficult to explain with the present limited data derived from a small number of subjects; however, the possible explanations include the following: 1. different personal characteristics with different genetic diversities between different races [24–27]; 2. differences in body habitus between Chinese and Europeans populations [15,28–31]; 3. selection of astronauts (the Chinese were selected from fighter pilots only, while the Europeans were selected from a mix of scientists and pilots); 4. training methods [32–34] (none of the astronauts on these short-duration missions submitted to counter-measures during spaceflight); and 5. nutrition [35].

The only difference we identified between European and Chinese astronauts in baseline characteristics was the significant difference in height; however, little data are available that suggest standing results in higher vagal modulation and nervous sympathetic activity in taller people, possibly related to larger intravascular hydrostatic pressure gradients [36]).

Post-flight orthostatic tachycardia

Standing upright immediately after spaceflight is difficult for most astronauts. In many previous studies from NASA, ESA, and Russia, post-flight orthostatic tachycardia has been commonly reported, while HR has remained stable in the supine position compared to pre-flight [1,16,37]. This finding was thought to be due to a post-flight sympathetic dominance of HR control indicated by a significant decrease in high-frequency power of heart rate variability (HRV) compared to pre-flight values [1] and increased levels of noradrenaline [38–41], as well as increased human muscle sympathetic nerve activity [42–44] after spaceflight.

In the current study we noted orthostatic tachycardia in all five European astronauts on R+1, but only two of five Chinese astronauts showed an increase in HR after the space mission (Fig. 1, upper part). Although the flight durations were slightly different between the European and Chinese astronauts, flight duration is unlikely to be a determinant for post-flight orthostatic tachycardia [45] because the effects of microgravity are felt immediately [1,6]. In agreement with the results of Verheyden et al. [16], we observed a reduction in RSA after spaceflight in the European astronauts in the supine and standing positions, which indicated a post-flight vagal cardiac neural deficit; however, no vagal cardiac depression was observed in the Chinese astronauts in the supine or standing position. This result is also difficult to explain and needs to be investigated further.

Cardiac baroreflex function after spaceflight remains to be elucidated. In several previous studies, it was reported that the hypotensive buffering of baroreflex response was affected [13,46], while the hypertensive buffering remained intact [40]. Nevertheless, the spontaneous baroreflex, including both hypotensive and hypertensive buffering, as measured by Sigaudo-Roussel et al. [47], did not show significant differences after spaceflight during standing. In agreement with Sigaudo-Roussel et al. [47], we found that the baroreflex sensitivity was well-maintained after spaceflight in all subjects.

Similar to the post-spaceflight orthostatic tachycardia, patients with postural orthostatic tachycardia syndrome (POTS) have problems maintaining consciousness when changing position. In a study published in 2010, Fu et al. [48] found that despite intact autonomic function in POTS patients, marked tachycardia during orthostasis was attributable to a small heart coupled with reduced blood volume, while exercise training improved or even cured this syndrome in most patients. This finding implies that cardiac size and volume might be important determinants underlying post-spaceflight orthostatic tachycardia; however, weight loss was similar in both groups after landing.

It has been reported that respiratory frequency decreases in space [49–51], which might be related to the reduction in lung volume [50], tidal volume, pulmonary ventilation, and metabolic rate [49]. In a long-duration space mission study, Baevsky et al. [51] observed that the respiratory rate decreased to values close to 6 breaths per minute in some cosmonauts after 5 months in space; the respiratory rate rapidly recovered or even exceeded the baseline values after return to Earth. In the current study, we did not find any significant changes in respiratory rate after spaceflight in European [52] or Chinese astronauts. This finding implies that physiologic deconditioning due to microgravity in pulmonary function may recover rapidly, which might not be the basis for post-spaceflight orthostatic tachycardia.

There is also substantial evidence from the literature that initial adaptations of fluid regulation and neural cardiovascular mechanisms in space occur more rapidly than over a 5-day period. The following cardiovascular events have been reported to take place immediately after entering weightlessness. First, the acute mechanical consequences of microgravity lead to prompt cardiac distention [53]. Increased cardiac filling early in-flight is confirmed by an elevated stroke volume and cardiac output [49,54]. The higher stroke volume and cardiac output triggers a fast depressor reflex that decreases the HR and BP at once [54]. Second, right atrial stretching enhances the secretion of atrial natriuretic peptide [55], leading to increased vascular permeability, which together with increased transmural pressure, facilitates extravasation of fluid and sodium [56]. In addition, the expanded central blood volume is sensed as a ‘fluid-volume overload’ and might inhibit the renin–angiotensin system [57]. Third, it should be noted that some plasma volume loss may already precede launch because astronauts commonly experience ≥2 h in a supine legs-elevated posture prior to launch [58]. Also, space motion sickness and diminished fluid intake in the first days of microgravity exposure may contribute to an early plasma volume loss [59].

All of the above cardiovascular effects of microgravity take place rapidly within 1–3 days in space [60]. Di Rienzo et al. [61] showed that HR baroreflex sensitivity and markers of cardiac vagal modulation tend to be increased during the first hours of spaceflight and return to baseline in subsequent flight phases. Most likely, the dynamic adaption of integrative cardiovascular neural control takes place more rapidly, following the pattern of fluid volume regulation, i.e., within 1–3 days in space.