- Journal Details
- Format
- Journal
- eISSN
- 2332-7774
- First Published
- 30 Jan 2019
- Publication timeframe
- 2 times per year
- Languages
- English
Astronauts experience arterial blood pressure (ABP) variations, decrements in bone density, cardiovascular degradation, and neurocognitive deconditioning during long-term space missions (Schneider, 2016). In order to prevent these physiological changes, efficient countermeasures applicable during human spaceflight are needed (Clement et al., 2015; Richter et al., 2017; Tanaka et al., 2017; Linnarsson et al., 2015; Waki et al., 2005). Various countermeasures have been investigated during space missions in recent years. Lower body negative pressure devices, exercises with bungee cords, modified bicycles, self-propelled centrifuge devices, and fixed treadmills have been assessed and used to counteract negative physiological responses (Clement and Bukley, 2007). However, all countermeasures mentioned require a significant amount of crew time and still appear to be inefficient in counteracting the degradation of physiological structures. The application of artificial gravity (AG) generated by, for example, a short arm human centrifuge (SAHC) is under intense scientific investigation (Chouker et al., 2013; Clement and Pavy-Le Traon, 2004; Dern et al., 2014; Evans et al., 2015; Goswami et al., 2015; Linnarsson et al., 2015; Zhang et al., 2017). Centrifugation in a sitting or supine position generates a centrifugal force, which simulates the gravity-induced physiological effects, similar to standing. In addition to the implementation of SAHC in microgravity environments, these devices could be installed on planetary destinations, such as Mars or the Moon, where gravity is only a fraction of Earth's gravity. Additionally, the application of AG generated by a SAHC is also thought to be beneficial in the fields of competitive sports (Barr et al., 2015), rehabilitation, and therapy for immobilized persons (Pavy-Le Traon et al., 2007). Besides possible positive effects on the musculoskeletal system, there are also possible beneficial effects of AG on the cardiovascular system (Migeotte et al., 2009), which are considered to be as effective as exercise to counteract physiological deconditioning during spaceflight (Clement and Bukley, 2007).
The primary aim of this study was to determine the effects of various AG protocols on the cardiovascular system in order to determine (1) if AG at a tolerable level stimulates an increase in ABP and heart rate (HR), similar to what would be expected during a moderate bout of exercise, and (2) if different protocols, intermittent AG vs. continuous AG, might have a different impact on the above mentioned parameters.
The activation of the cardiovascular system has a modulating effect on the release of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1) (Knaepen et al., 2010; Rojas Vega et al., 2010; Schiffer et al., 2009), which all play key roles in the signaling pathways of neurogenesis (BDNF), synaptogenesis (BDNF, IGF-1), and angiogenesis (IGF-1, VEGF) (Lista and Sorrentino, 2010). The second aim of this study was to determine the effect of AG on the release of these proteins. Based on the assumption of cardiovascular system activation, we hypothesized that BDNF, VEGF, and IGF-1 would increase after exposure to AG.
The third aim of this study was to further investigate blood volume redistribution following different levels of AG (Schneider et al., 2013). It was hypothesized that AG generated by a SAHC would decrease cerebral oxygenation, increase cerebral deoxygenation, and increase peripheral intravascular pooling, which can be assessed using near infrared spectroscopy (NIRS). Although alterations in hemodynamics have been assessed in previous studies, the relationship between the gradient in the centrifugal force generated by a SAHC, and oxygenation of various tissues, such as the brain, during continuous and intermittent application of AG has been under-investigated.
Ten healthy males (29.57± 6.61 years, 183.21± 5.11 cm, 82.14± 7.24 kg) participated in this study. Participants had a varied experience with AG and hypergravity. All participants underwent a preliminary medical screening performed by medical personnel at the Institute of Aerospace Medicine/German Aerospace Centre (DLR), Cologne, Germany, and all gave their written consent to participate in the study. None of the participants reported taking any medication during the study. Before the centrifugation at the SAHC, the participants were informed about the experimental protocol and the risks of centrifugation (nausea, syncope, tachycardia, dizziness, etc.). All experimental procedures were performed according to national legislation and the Declaration of Helsinki; methods were performed in accordance with relevant regulations and guidelines and were approved by the Medical Council – North Rhine (Ärztekammer Nordrhein, Düsseldorf, Germany).
The study was conducted at the Institute of Aerospace Medicine at the German Aerospace Centre in Cologne, Germany, which granted access to the SAHC, which is owned and operated by the European Space Agency (ESA). On experimental days, participants arrived two hours before centrifugation. Two different AG protocols were performed with a time lag of at least 48 hours between each. Participants were exposed to AG in a supine position and exposure to the two protocols was randomized. To avoid influencing hemodynamic parameters, participants were instructed not to flex their leg muscles during AG. The Gz-load was measured at foot level. The “continuous” AG protocol is illustrated in Figure 1A; it commenced with a phase of 1 Gz, 2 Gz, and 3 Gz for 120 s each (incremental phase 1), followed by a continuous phase of 2 Gz for 30 min, and ended with a phase of 1 Gz, 2 Gz, and 3 Gz for 120 s each (incremental phase 2; Figure 1A). For detailed analysis, the phase of continuous Gz-load was divided into six time segments. In contrast, the intermittent protocol is illustrated in Figure 1B, and included a phase of intermittent Gz-load of 2 Gz and approximately 0.0279 Gz (baseline rotation of 5 rounds per minute (RPM)) for 180 s. The intermittent sequence was performed five times, and started and ended with a phase of 1 Gz, 2 Gz, and 3 Gz for 120 s each (Figure 1B). If participants showed abnormal vital signs and/or syncope, a physician would determine whether to terminate the protocol. This was based upon cardiovascular parameters, such as cardiac arrhythmias, including increased HR > 80% of maximal HR (220-age) for more than 10 s, decreased HR < 50% of initial HR, or continuous decrease of HR or ABP for more than 15 s below initial values. Additionally, audio and video surveillance, as well as a “panic button,” were available for the participant's safety during the experiment. Baseline measurement was performed during baseline rotation at 5 RPM before incremental phase 1 with the participant in a supine position, eyes closed and no one except the participant in the centrifuge room.
Figure 1
Experimental protocol of continuous (A) or intermittent (B) application of artificial gravity (AG). Panel (A) displays the results generated by a short arm centrifuge, illustrating periods of baseline measurement and all Gz accelerations (at 5 RPM, 1 Gz, 2 Gz, and 3 Gz), including the duration of each Gz acceleration (1′, 2′, and 30′). Panel B displays the results generated by a short arm centrifuge, illustrating periods of baseline measurement and all Gz accelerations (at 5 RPM, 1 Gz, 2 Gz, and 3 Gz), including the duration of each Gz acceleration (1′, 2′, 3′, and 30′). ′ indicates minutes.
Electrocardiogram electrodes and a blood pressure (BP) cuff dedicated to the portable medical surveillance system (Intelivue XDS, Philips, Amsterdam, Netherlands), as well as a continuous BP device (Finometer, Portapress/TVO, Amsterdam, Netherlands), were used to monitor and record cardiovascular parameters and the vital signs of the participant. BP was continuously assessed at the participant's index finger and calculations were performed to obtain a value valid at heart level. Changes in oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb) in the underlying tissue were recorded using a four-channel NIRS system (Oxymon MKIII, Artinis, Amsterdam, Netherlands) at the prefrontal cortex (PFC), the
BDNF, VEGF, and IGF-1 were measured from blood samples taken through a permanent venous catheter, which was inserted into each participant's left arm by a physician two hours prior to acceleration and was kept open by a 0.9% saline dilution. Immediately before the centrifugation started, and after the end of the centrifugation, 10 ml of EDTA blood was drawn in pre-chilled vacutainers®. Blood samples were centrifuged at 5000 RPM for 10 min after collection in a cooled centrifuge. The plasma was divided into fractions, first stored at −20°C for 8 h, and later frozen at −80°C until final analysis.
In order to quantify the serum prolactin and cortisol concentrations, an in vitro test using quantitative sandwich enzyme immunoassays (Elisa, R&D Systems, USA) was conducted. Monoclonal antibodies specific for human BDNF, IGF-1, and VEGF were pre-coated onto a microplate. The standards and samples were pipetted into the wells and BDNF, IGF-1, or VEGF present in the sample were bound by the immobilized antibodies. After washing away any unbound substances, an enzyme-linked polyclonal antibody specific for human BDNF, IGF-1, or VEGF was added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution was added to the wells and the color developed in proportion to the amount of proteins bound in the initial step. When the color development stopped, the intensity of the color was measured.
Before further analysis, all data were tested for normal distribution using a one sample Kolmogorov-Smirnov test. For O2Hb and HHb, an ANOVA test with the inter-individual factor PROTOCOL (continuous, intermittent) and the intra-individual factor TIME (course of different Gz levels and baseline, see Figure 1) was calculated for the three measurement points at the PFC, the
O2Hb and HHb in the prefrontal cortex, the
Whereas HR increased with increasing gravity levels (F(13, 130)=20.34 p<.001), ABP only increased during the initial 2G and 3G phases (F(13, 130)=1.89, p<.05). Post-hoc analyses showing significant changes to baseline conditions are displayed in Figure 2 (left).
Figure 2
Analysis of oxygenated blood (O2Hb) and deoxygenated blood (HHb) in response to either continuous or intermittent artificial gravity (AG) application. Means and confidence intervals (95%) for O2Hb and HHb concentrations in the prefrontal cortex (PFC) are shown in the graphs on the top row, for the
O2Hb and HHB values at the PFC,
We did not observe any changes in BDNF (F(1, 10)=2.13, p=.17), IGF-1 (F(1, 9)=.00, p=.98), or VEGF (F(1, 10)=.18, p=.68) values from pre to post centrifugation in either protocol. These results are presented in Table 1.
Brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1(IGF-1), and vascular endothelial growth factor (VEGF) values pre and post interventions.
| AG constant [pg/ml] | AG intermittent [pg/ml] | |||
|---|---|---|---|---|
| Pre | Post | Pre | Post | |
| BDNF | 12212,66±8716,77 | 10028,43±10637,02 | 9912,01±10748,13 | 12195,94±11949,15 |
| IGF-1 | 139,31±68,64 | 144,48±74,03 | 137,99±60,75 | 143,53±69,55 |
| VEGF | 174,77±146,25 | 159,61±169,65 | 186,29±166,47 | 180,22±181,45 |
Data is presented as mean ± standard deviation.
One aim of this study was to describe the hemodynamic and tissue oxygenation responses to continuous and intermittent periods of AG compared to what would be expected during a moderate bout of exercise. This study was conducted in a SAHC, with the aim of investigating the use of AG as a potential countermeasure to physiological deconditioning during long-duration human spaceflight. The results suggest that both the continuous and the intermittent AG protocols induced an increase in
During the intermittent protocol, there were rapid and large increases in O2Hb at the PFC and the biceps during the periods of reduced centrifugal forces in the head-to-toe axis. Consistent with the earlier interpretation, this likely reflects a transient restoration of the pressure gradient towards the upper body, and an increase in blood flow to the head and arms. In some cases, this increase in O2Hb exceeded baseline values, particularly at the PFC, which may represent a reactive hyperaemia response to the periods of AG. These transient increases in O2Hb (and flow) might also be mediated by central hemodynamic changes, whereby an abrupt increase in venous return to the right atria with a reduction in gravity (0 G) contributes to an increase in stroke volume and driving pressure for blood flow. The observed reduction in HR during the periods of 0 G to levels below baseline might partly be a compensatory response to maintain cardiac output. Interestingly, these periods of normal gravity and restored upper-body blood flow during the intermittent protocol were associated with a slight (p<.05) attenuation of rise in HHb, particularly at the
We recently suggested (Schneider et al., 2013) that a reduction in gravity allows more oxygenated blood with each pulse wave to be directed to the low-resistance vessels of the head. This leads to a significant increment in O2Hb concentration. In contrast to that, the HHb concentration decreases only slightly, since no additional gravitational forces are pulling blood out of the brain, and the oxygen consumption of the brain remains stable throughout the application of AG (Schneider et al., 2013).
The absence of a significant change in BP during the application of AG was somewhat unexpected given the typical alterations in autonomic activity with changes in gravitational force (Linnarsson et al., 2015; Migeotte et al., 2009). The stable BP might be an adaptation, such that there is a sequestration of blood in capacitance veins in the lower peripheral extremities, demonstrated using computer-based simulations by Summers and colleagues (Summers et al., 2010). Alternatively, a gradual venous pooling in the peripheral extremities might cause a reflex myogenic constriction, including the blood vessels in the index finger, which could have an impact on the continuous assessment of BP.
Although AG at a tolerable level (<2 Gz) is related to an increase in HR, this increase is far below what is experienced during moderate exercise. At this level of AG, no changes in ABP were detected. The positive effect of exercise on cardiovascular health is based on the physiological stress caused by exercise. Our data suggests that moderate doses of AG at or below 2 Gz are not sufficient to create a relevant physiological stressor for cardiovascular training. The same is true for the release of neurotrophic factors, which are not affected by either of the AG protocols (Table 1). Several studies on the effects of exercise on the release of neurotrophic factors showed that only high intensity exercise is related to an increase in neurotrophic factors (Rojas Vega et al., 2006). As shown by Schiffer et al. (2011) using lactate infusion, the driving factor for a release of neurotrophic factors seems to be lactate, which in young healthy persons, is released only at exercise intensities that induce a HR of 180-age (Hollmann et al., 2012; McArdle et al., 2015).
With respect to the data in the present study, much higher values of AG=3 Gz (Figure 2) seem necessary to increase HR to a level similar to moderate physical activity, which is around 180-age. Nevertheless, this level is barely tolerated by the individual, at least not for a long duration. In order to promote vascular adaptations that offset the negative effects of spaceflight, an intermittent protocol with Gz=3 Gz would be a better choice compared to a constant protocol; intermittent AG might lead to increases in blood flow and shear stress, which would in turn promote maintenance or improvement of vascular function (e.g., endothelial function), or even vascular adaptations such as an increase in vessel size.
It should be acknowledged that the study is missing measures of central hemodynamics and blood flow. NIRS has the advantage of being applicable in extreme situations, but interpretation of findings needs to be validated by, for example, a Doppler Ultrasound. This would also clarify possible interference of scalp and/or skull perfusion and blood flow at the PFC. A recent study by Ogawa et al. (2016) showed a decrease in cerebral blood flow velocity when exposed to artificial gravity, similar to the O2Hb values in the PFC described in the present study.
Figure 1
Figure 2
Brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1(IGF-1), and vascular endothelial growth factor (VEGF) values pre and post interventions.
| AG constant [pg/ml] | AG intermittent [pg/ml] | |||
|---|---|---|---|---|
| Pre | Post | Pre | Post | |
| BDNF | 12212,66±8716,77 | 10028,43±10637,02 | 9912,01±10748,13 | 12195,94±11949,15 |
| IGF-1 | 139,31±68,64 | 144,48±74,03 | 137,99±60,75 | 143,53±69,55 |
| VEGF | 174,77±146,25 | 159,61±169,65 | 186,29±166,47 | 180,22±181,45 |
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