INTRODUCTION

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MICROGRAVITY PROVOKES AUTONOMIC changes that may contribute to orthostatic intolerance when astronauts return to Earth (8). After space missions, astronauts' heart rates may increase inordinately with standing, their arterial pressures may decline, and they may even experience frank syncope. It is likely that several mechanisms contribute to these changes. Returning astronauts have blood volume reductions of 10-15% (5), impaired vagal baroreceptor-cardiac reflex responses (13, 16), and inadequate increases in total peripheral resistance during standing (4). Autonomic impairment has been documented after space missions lasting only 4-5 (13) and 8-14 days (16). Autonomic abnormalities persisted for 10 days after 4- to 5-day missions (13) but had disappeared 3 days after 8- to 14-day missions (16). It is not clear how long autonomic dysfunction persists after brief space missions. Differences in the rate of readaptation to Earth's gravitational field after missions of different durations suggest that changes of autonomic mechanisms may depend on the duration of exposure to microgravity.

As the focus of manned space exploration shifts from brief to prolonged missions in low earth orbits and to exploration of neighboring planets, understanding the effects of long-duration space travel on human physiology assumes great importance. We studied autonomic cardiovascular control mechanisms in three cosmonauts exposed to 9 mo of microgravity aboard the Russian space station Mir. On the basis of earlier research (13, 16), we expected that microgravity would reduce vagal-cardiac neural outflow and vagal baroreceptor-cardiac reflex responses. Therefore, in this project, we tested the hypothesis that the magnitude of autonomic changes and the time course of their recovery would be proportional to the duration of exposure to microgravity. Our data suggest that autonomic changes develop early but do not necessarily progress as the duration of exposure to microgravity increases. We found that the most dramatic changes occurred soon after landing and that some autonomic abnormalities persisted for 2 wk after return to Earth.

	METHODS

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Subjects. We studied three male Russian cosmonauts, ages 36, 45, and 47 yr, before, during, and after 9 mo aboard the Russian space station Mir, as part of NASA's Phase-1B American/Russian collaboration (Mir-23 and Mir-25 missions). We obtained measurements 14 days before launch; on in-flight days 18, 120, 140, and 180; and on postflight days 1 and 14. Our protocol was approved by the Johnson Space Center Human Research Policies and Procedures Committee (Houston, TX), The Institute for Biomedical Problems (Moscow, Russia), the Human Research Committees of the Hunter Holmes McGuire Department of Veterans Affairs Medical Center, the Medical College of Virginia at Virginia Commonwealth University, and The University of Texas Southwestern Medical Center.

Measurements. We recorded the electrocardiogram and estimated beat-by-beat arterial pressure with finger photoplethysmography (Portapres, TNO, Amsterdam, The Netherlands). We measured end-tidal CO₂ at the mouth (GASMAP, Marquette, Milwaukee, WI) before and after each mission. Respiratory flow was measured by a Fleisch pneumotachograph (M956, Medikro Oy, Kuopio, Finland) that was part of an electronic module placed in an IBM ThinkPad (Model 750C, Armonk, NY). Nasal airflow was prevented with a nose clip, and cosmonauts breathed via a mouthpiece and a two-way respiratory valve (Hans Rudolph, Kansas City, MO). The electrocardiogram, arterial pressure, and end-tidal CO₂ were recorded directly to optical disk (Medex, Pancosmos, Munich, Germany). Respiratory flow was recorded on the laptop harddrive and time-stamped to data stored on the Medex system through an RS232 data cable.

Protocol. Cosmonauts were supine during all pre- and postflight measurements. The laptop computer with the Medikro insert was positioned above and in front of the cosmonaut, at a distance of ~0.4 m, so that he could view the screen comfortably. Breathing protocols were performed in succession and were driven by software that guided the cosmonauts to perform the experiment on themselves in space. Once the controlled breathing protocol was initiated, cosmonauts were prompted by the computer to breathe spontaneously for 5 min. After this initial baseline period, the cosmonauts performed a 12-min stepwise breathing protocol, consisting of six different breathing frequencies of 2 min each (at 0.3, 0.25, 0.2, 0.15, 0.1, and 0.05 Hz), followed by fixed-rate breathing for 5 min (0.25 Hz) and random-rate breathing for 6 min (between 0.05 and 0.3 Hz). Our laboratory has recently shown that it is not necessary to calculate and control inspired volumes during identical controlled-frequency breathing protocols (6). In the present investigation, respiratory frequency, but not inspired volume, was strictly controlled.

Data analysis. We analyzed all results with custom software written to accommodate the merged and synchronized data from the Medikro and Medex acquisition systems. We calculated power spectra as follows: the nonequidistant R-R interval (electrocardiogram; sampled at 500 Hz) and systolic pressure (Portapres; sampled at 200 Hz) time series were spline interpolated (linear), resampled at 5.0 Hz, and passed through a low-pass filter with a cut-off frequency of 0.5 Hz. Data sets comprising 60 s, sliding every 10 s, were trend eliminated (linear regression), windowed (Hanning method), and fast Fourier transformed. Power was expressed as the area under the spectrum over the frequency range of interest [low frequency (0.04-0.15 Hz); respiratory frequency (0.15-0.4 Hz); and total (0.04-0.4 Hz) spectral power (3)]. We calculated the squared coherence between systolic pressures and R-R intervals by dividing their cross-spectral densities by the product of the individual power spectral densities and calculated the transfer function by dividing the cross-spectra of the two signals by the power spectra of the input signal, systolic pressure (29).

	RESULTS

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This research was plagued by problems. Three days after the flight day 18 session during the Mir-23 mission, an oxygen canister caught fire aboard the space station. Ensuing and other unrelated but serious complications prohibited cosmonaut 1 from performing this experiment in space beyond flight day 18. During flight day 140 of the Mir-25 mission, data were corrupted for cosmonaut 2. On about flight day 190, cosmonaut 2 began taking the beta-blocker, atenolol, for undisclosed medical reasons. On the day after this mission ended, this cosmonaut also was prohibited from performing the experiment. Fourteen days after landing, however, cosmonaut 2 was allowed to perform the experiment, and at that time he was taking no medications. Therefore, our data set comprises measurements from three cosmonauts studied 2 wk before launch and 2 wk after landing; two cosmonauts studied on flight days 120 and 180 and 1 day after landing; one cosmonaut studied on flight day 18; and one cosmonaut studied on flight day 140.

Although the cosmonauts we studied were not medically trained, they were able to collect data on themselves and each other using the Medex/Medikro laptop-based data acquisition system. Figure 1 depicts data from one cosmonaut recorded during fixed-frequency breathing at 0.25 Hz. The cosmonauts were able to track their respiratory rates with the visual targets closely. Respiratory rates during each breathing protocol before, during, and after flight were similar.

View larger version (31K): [in this window] [in a new window]   Fig. 1.   A representative tracing of original in-flight data from one cosmonaut.

Baseline measurements. We compared in-flight and postflight measurements with measurements made 14 days before launch. Although we report many of our observations, we comment only on those that seem to reflect trends. Table 1 lists measurements obtained during 5 min of uncontrolled spontaneous breathing. R-R intervals changed in-flight but with no consistent pattern. Arterial pressures also changed in-flight with no consistent pattern but were elevated in all cosmonauts in postflight recordings.

Controlled-frequency breathing. Figure 2 depicts R-R interval and systolic pressure spectral powers during 0.25 Hz (15 breaths/min) breathing for one cosmonaut. In this cosmonaut, R-R interval spectral powers at low end-respiratory frequencies were substantially lower, and systolic pressure spectral power at the breathing frequency was moderately higher postflight than during the preflight recording session. R-R interval standard deviations during 0.25-Hz breathing were decreased in all cosmonauts in the majority of experimental sessions, as shown in Fig. 3.

View larger version (20K): [in this window] [in a new window]   Fig. 2.   R wave-to-R wave (R-R) interval and systolic pressure spectral power during fixed-frequency breathing (0.25 Hz; 5 min) in one cosmonaut 14 days before launch and 1 day after landing.

View larger version (12K): [in this window] [in a new window]   Fig. 3.   R-R interval standard deviations during 0.25-Hz breathing for each session and cosmonaut. , Cosmonaut 1; , cosmonaut 2; , cosmonaut 3.

View larger version (18K): [in this window] [in a new window]   Fig. 4.   Total (0.04-0.4 Hz) R-R interval and systolic pressure spectral power at each breathing frequency during the stepwise-frequency protocol 14 days after return to Earth. Values are means ± SD; n = 3.

Vagal baroreflex gain. We estimated vagal baroreceptor-cardiac reflex gain two ways. First, we analyzed three or more increasing systolic pressure and R-R interval sequences with linear regression during uncontrolled breathing. The slopes of ascending baroreflex sequences were diminished during all in- and postflight sessions compared with preflight measurements. Baroreflex slopes averaged 26.6 preflight and 15.0 ms/mmHg 14 days after landing (Table 1). Second, we estimated baroreflex gain at low frequencies from the transfer function between systolic pressure and R-R interval spectral powers when the squared coherence was greater than 0.50 (see METHODS). During 0.1-Hz breathing, the transfer function was less in-flight for two of the three cosmonauts and unchanged in one. One day after landing, the transfer function was 8.0 and 5.6 ms/mmHg (preflight values: 19.4 and 9.0), in cosmonauts 1 and 3. Fourteen days after landing, the transfer function averaged 6.8 ms/mmHg in all three cosmonauts (average preflight value: 18.1).

View larger version (27K): [in this window] [in a new window]   Fig. 5.   Coherence (top) and transfer function magnitude (bottom) from one cosmonaut during random-frequency breathing.

View larger version (13K): [in this window] [in a new window]   Fig. 6.   Transfer function magnitude during random-frequency breathing from all cosmonauts during each experimental session. , Cosmonaut 1; , cosmonaut 2; , cosmonaut 3.

	DISCUSSION

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We used a simple breathing algorithm to perturb autonomic cardiovascular function in three Russian cosmonauts before, during, and after 9-mo sojourns in the Russian space station Mir. Our observations on the effects of very-long-duration microgravity exposure are unique: we report what may be the first registrations of beat-by-beat arterial pressure from space and the first study in which controlled breathing was used as an intervention to study autonomic function in space. The principal conclusions from this work are that long-duration microgravity exposure diminishes human vagal cardiac efferent neural outflow and vagal baroreflex gain and that these changes persist for at least 2 wk after return to Earth.

R-R interval fluctuations. Microgravity decreased R-R interval standard deviations in all cosmonauts (Fig. 3) and decreased respiratory frequency R-R interval spectral power in two cosmonauts. These findings are consistent with results published earlier. Goldberger and co-workers (18) reported analyses of Holter recordings made in six Russian cosmonauts who were in microgravity for 131, 175, and 179 days and documented reduced R-R interval standard deviations. Fritsch-Yelle et al. (17) also reported reduced R-R interval standard deviations derived from Holter recordings. Goldberger's group (18) also reported unchanged respiratory-frequency R-R interval spectral power. In Goldberger's study, however, breathing frequency was neither measured nor controlled. We report R-R interval spectral power at the measured breathing frequency and document reductions from preflight values.

Vagal baroreflex responses. We also documented reduced vagal baroreflex gain, as reflected by three or more beat sequences of increasing systolic pressures and R-R intervals (15, 26) and systolic pressure-R-R interval transfer functions during random-frequency breathing (2). These findings are consistent with observations made during (Ref. 14, and J. F. Cox et al., unpublished data) and before and after short-duration space missions (13, 16, 25). Reduced vagal baroreflex gain and reduced vagal-cardiac nerve traffic may be causally related, because arterial baroreceptor activity is a strong determinant of vagal-cardiac neural outflow (9, 23). In unanesthetized cats, sinoaortic denervation greatly reduces R-R interval fluctuations at all frequencies (7).

Limitations. The most important limitations are the small number of cosmonauts studied and the fact that different numbers of cosmonauts were studied at different times during the missions. We estimated arterial pressure changes with finger photoplethysmography; although photoplethysmograms do not track absolute arterial pressure changes exactly, the correlations are quite good (20). Also, we used respiratory sinus arrhythmia as an index of vagal-cardiac nerve traffic (21); this usage is accepted but is not perfect (22). (There is no published report of directly measured human vagal-cardiac nerve activity.)