Cardiovascular Deconditioning and Exercise
Cardiovascular deconditioning are changes in function or structure of the heart and blood vessels in response to a space flight or reduced gravity environment, including weightlessness and radiation exposure, that may result in impaired or altered responses at rest or during stress. Exercise includes physical activity to prevent deconditioning during space flight or reduced gravity as well as the physical work required to perform work inside and outside of the spacecraft.
Human physiological responses are well designed to operate in Earth’s gravitational environment in which we exist, yet standing up on Earth imposes a substantial challenge to the cardiovascular system because the heart is located above about 75% of the total blood volume in the body. Upon standing, the increase in the hydrostatic pressure gradient acting along the length of the body reduces the amount of blood returning to the heart by 500–1000 mL, which triggers a complex reflex response designed to maintain blood flow to the brain. A reduction in pressure and volume in the arteries and veins of the upper body results in both fast and slow acting processes that increase the strength and speed of heart beats, vasoconstrict blood vessels to maintain blood pressure, and start a cascade of hormonal events to maintain blood volume.
Orthostatic intolerance is the inability to control blood pressure to maintain adequate cerebral perfusion during upright posture and is a well-documented risk that occurs following space flight. Postlanding OI has been a recognized consequence of space flight since early in the space program, with astronauts demonstrating elevated heart rates, decreased blood pressure, and signs or symptoms of presyncope, which included lightheadedness, dizziness, and confusion in the hours immediately after landing. Overall, after landing, one in five Space Shuttle astronauts were unable to tolerate 10 min of quiet upright standing (Lee et al. 1999; Meck et al. 2001), although this was reported to be as high as 64% in one study (Buckey et al. 1996b). However, the frequency of presyncopal symptoms is substantially increased to >60% after long-duration missions to the Mir Space Station and the ISS (Meck et al. 2001; Lee et al. 2015).
Despite years of cardiovascular research during and following short- and long-duration space flight, the mechanisms responsible for postflight OI on landing day are not fully understood. Thus, the ability to predict which astronauts are at a greater risk for developing presyncope is limited. During space flight, the headward fluid shift and subsequent reduction in blood volume leads to remodeling of cardiac and blood vessel structures and function (see section “Physiological Adaptations to Space Flight” below) which has a significant impact on both OI, as well as exercise and work capacity. Factors which appear to be related to space flight-induced OI on landing day include decreased plasma volume, an inability to vasoconstrict peripheral vasculature, cardiac atrophy, reduced cardiac compliance, and smaller stroke volume. Additional factors contributing to OI include flight duration and sex, as OI incidence is greater after long-duration than after short-duration space flight (Meck et al. 2001; Lee et al. 2015) and greater in women than in men (Waters et al. 2002). Countermeasures to OI (see section “Countermeasures” below) include inflight exercise to minimize cardiovascular and general deconditioning, lower body negative pressure to stimulate cardiovascular responses to simulated orthostatic stress, fluid loading to replace plasma volume at the end of the mission, lower body compression garments to prevent venous blood pooling in the legs and abdomen during re-entry and landing, and suit cooling to prevent thermal stress. After the first 24 h following landing from both short- and long-duration space flight, exposure to Earth’s gravity, particularly while seated and standing, diminishes the incidence of OI, although complete recovery to the preflight condition is related to mission length. Recovery of orthostatic responses appears to be largely complete by 3 days after Apollo and Space Shuttle landings (Hoffler and Johnson 1975; Waters et al. 2002) but may require a week or more after Skylab and ISS missions (Johnson et al. 1977; Lee et al. 2015).
When crewmembers are attended by support personnel soon after landing, as is the nominal case, the consequences of OI can be controlled by maintaining the crewmember in a recumbent position, assisting them when ambulation is required, administering oral and intravenous fluids to replace plasma volume loss, and preventing significant elevations in core and skin temperatures which would exacerbate hypotension. However, when support personnel are not immediately available in the event of an off-nominal landing when assistance may be delayed by several hours (Pettit 2010), OI may still be a concern. What role OI will play in recovery from a water landing for future landings on Earth or during exploration missions to Mars or the Moon has yet to be determined. However, there were no reports of OI on the Moon during the Apollo missions.
Reduced Exercise and Work Capacity
The ability to perform strenuous work or to work for long periods of time is influenced by the capacity of the cardiovascular system to deliver oxygen and key nutrients to working muscles and remove metabolic waste products. Weightlessness clearly reduces daily metabolic workload, but an astronaut’s physical fitness must be maintained during and after space flight in order to accomplish mission critical tasks and respond to emergency situations (Moore et al. 2010), especially during re-exposure to gravity upon landing.
Early in the US/NASA space program, decreased inflight and postflight maximum exercise capacity, or maximal aerobic capacity, was inferred from elevated heart rates in response to submaximal exercise (Moore et al. 2010) and likely resulted from the limited ability to perform exercise in the small spacecraft. In contrast, when astronauts participated in regular exercise during Skylab missions (28–84 days), submaximal exercise heart rates were unchanged during space flight. However, immediately after landing, submaximal heart rate was elevated in Skylab astronauts during upright cycle ergometry suggesting some deconditioning had occurred. Submaximal heart rates during these exercise tests recovered to preflight levels over the course of 30 days. During early ISS missions, submaximal exercise heart rates were elevated during the first 30 days of space flight, but over the course of the mission, as astronauts continued to perform regular exercise, some recovery occurred (Moore et al. 2010, 2015). Similar to Skylab astronauts, during the immediate postflight period submaximal exercise heart rates were elevated but generally were not different than preflight after 30–45 days of reconditioning. Comparable responses to submaximal exercise have been reported in Russian crewmembers during ISS missions. Heart rates of cosmonauts exercising on a cycle ergometer at the same absolute work rates were higher early inflight compared to preflight, but the heart rate response to exercise decreased as the mission progressed (Popov et al. 2004).
Heart rate response to submaximal exercise has obvious limitations for identifying changes in maximal aerobic capacity, particularly for an individual crewmember (Moore et al. 2010). During Space Shuttle missions (<16 days), crewmembers performed exercise tests to maximal exertion. In these subjects, maximal aerobic capacity and the maximal work rate that could be achieved on a cycle ergometer was not reduced compared to the preflight condition (Levine et al. 1996; Moore et al. 2001). In contrast, maximal aerobic capacity was reduced within the first month of long-duration missions in ISS astronauts (Moore et al. 2014). While the difference between the time inflight when the Shuttle and ISS crewmembers performed these tests seems small, two other factors may explain differences between these observations. First, maximal aerobic capacity of the Space Shuttle astronauts was less than ISS astronauts (2.71 vs. 3.16 L/min, respectively); results from bed rest studies indicate that exercise deconditioning is greater in those who start with a higher maximal aerobic capacity (Lee et al. 2010). Second, time allotment for exercise during the first 2 weeks of an ISS mission may be constrained as the arriving crew becomes familiar with the required daily on-orbit operations so that little or no inflight exercise is performed (Moore et al. 2010).
On landing day after space flight both Shuttle and ISS astronauts have a reduced maximal aerobic capacity relative to preflight, and recovery does not occur as quickly as the recovery of OI. Maximal aerobic capacity does not recover to preflight levels for up to 2 weeks following Space Shuttle missions (Levine et al. 1996; Moore et al. 2001; Trappe et al. 2006) and 4 weeks after ISS missions (Moore et al. 2014). A similar relation between duration of cardiovascular unloading and the length of time required to recover maximal aerobic capacity has been observed following bed rest studies (Lee et al. 2010). However, Shuttle astronauts did not participate in a structured reconditioning program after landing, while ISS astronauts were prescribed a daily reconditioning program scheduled to last at least 45 days. While it is assumed that the rate of recovery after space flight would be improved with structured reconditioning program, this has not been specifically tested.
Factors which likely contribute to decreased maximal aerobic capacity include decreased plasma (Leach et al. 1996) and blood volume (Alfrey et al. 1996), lower stroke volumes and maximal cardiac output (Levine et al. 1996; Capelli et al. 2006), reduced cardiac mass and function (Perhonen et al. 2001a), decreased or altered ability to constrict vascular beds of inactive tissue to divert blood flow towards active muscle, and/or altered skeletal muscle phenotype and function (Adams et al. 2003). The initial decline in maximal aerobic capacity during short duration bed rest studies (<30 days) without countermeasures appears to be linear and largely related to the reduction in plasma volume (Convertino 1996). Conversely, during longer bed rest studies (up to 90 days), the reduction occurs in a nonlinear, asymptotic fashion with an apparent increasing influence from cardiac atrophy and altered peripheral function (Capelli et al. 2006). The magnitude of the influence from different, and likely interacting, factors on maximal aerobic capacity shifts as the duration of bed rest increases when countermeasures are not performed (Ade et al. 2015). The importance of these respective factors during space flight has not been studied but is likely modified depending upon the exercise countermeasures employed.
Maximal aerobic capacity is one parameter suggestive of decreased exercise performance during and after space flight, but additional factors might impair the ability for an astronaut or cosmonaut to perform work, including reduced anaerobic threshold and impaired thermoregulation. In ground-based studies, the onset of blood lactate accumulation and maximal work rate of steady-state exercise that can be sustained without increasing blood lactate accumulation are more strongly related to the ability to perform work for an extended period of time than maximal aerobic capacity (Coyle 1999). Even after brief exposure to bed rest, blood lactate is higher during submaximal exercise, especially in more fit subjects, and the blood lactate threshold is decreased (Williams and Convertino 1988; Smorawiński et al. 2001). While limited space flight data exist regarding thermoregulation, calculated sweating rates were reduced in Skylab astronauts, presumably due to reduced sweat drippage because of lack of gravity and resulting sweat film formation on the skin (Leach et al. 1978). Elevated core temperature has been reported in astronauts during Space Shuttle re-entry and landing despite the use of liquid cooling garments (Rimmer et al. 1999), and two cosmonauts experienced higher core temperatures, as well as altered sweating rates and skin vasodilation, during submaximal exercise after a long-duration Mir mission despite their participation in inflight exercise countermeasures (Fortney et al. 1998).
Physiological Adaptations to Space Flight
When astronauts enter weightlessness in space, the cardiovascular system no longer needs to actively help return blood from the lower part of the body to the heart. Rather, the head-to-toe fluid pressure gradient is removed and fluid redistributes evenly across the body. This leads to a reduction in plasma volume (PV) of ~10–15%, after the first few days in space which also occurs in subjects exposed to 6° head-down tilt bed rest, a space flight analog. Plasma volume losses in bed rest subjects occur because the headward fluid shift increases pressure in cardiopulmonary and carotid baroreceptors which is sensed as too much blood volume and leads to diuresis. Conversely, during space flight, the loss of PV is likely not due to diuresis, but instead total body water remains unchanged and fluid is redistributed out of the vasculature. A key difference between bed rest and space flight is that during space flight removal of the gravitational vector unloads all body tissue, which changes the balance of forces acting on the microvasculature to favor net fluid filtration out of the vasculature and into the extravascular space. Data collected during short-duration space flight suggest that this increased capillary filtration likely leads to increased intracellular fluid volume (Leach et al. 1996). Research currently being conducted on ISS crew members will determine if further changes occur in fluid compartmentalization during long-duration space flight. Plasma volume remains low throughout the duration of space flight or bed rest and recovers within 1–2 days of astronauts or subjects resuming upright mobility in a gravitational environment (Platts et al. 2009b).
The loss of PV was originally believed to be the primary factor contributing to postflight OI, but three pieces of evidence suggest additional cardiovascular changes occur during prolonged exposure to weightlessness that contribute to the development of OI upon return to a gravitational environment. First, restoration of PV alone does not prevent OI (Shibata et al. 2010). Second, despite stable PV after the initial adjustment period in weightlessness, there is an increased incidence of OI following long-duration space flight (~80%) compared to short-duration space flight (~20%) (Meck et al. 2001). Finally, following both space flight and bed rest, the drop in PV is not different between those who do and do not experiencing presyncope. These factors led to investigations of the heart, vasculature, and autonomic system to determine what other cardiovascular alterations occur during weightlessness that increase the risk of OI upon landing.
Central Venous Pressure/Venous Return
In order for the cardiovascular system to successfully maintain arterial pressure, sufficient blood flow must return from the body for the heart to pump back out. This blood return to the heart, called venous return, can be affected by two factors during weightlessness: (1) loss of the hydrostatic pressure column causes a headward redistribution of fluid and potentially increases flow from the lower body and decreasing flow draining from above the heart and (2) expansion of the lungs and thoracic cage causes a negative pressure around the heart and great vessels. Initially, it was hypothesized that headward fluid shift would increase central venous pressure relative to the supine position based on bed rest data. A fluid-filled catheter advanced into an intrathroacic vein has provided direct measures of central venous pressure prior to and during the first few hours of space flight on three occasions (Buckey et al. 1996a; Foldager et al. 1996). These rare but important data indicate that, contrary to the original hypothesis, central venous pressure actually decreases relative to seated upright on the ground and falls close to that of being supine. These data are also supported by similar results during brief periods of weightlessness in parabolic flight (Foldager et al. 1996). However, because of the expansion of the lungs and ribcage, there was an even greater fall in pressure surrounding the heart and great vessels such that transmural central venous pressure is elevated (Videbaek and Norsk 1997). An increase in transmural central venous pressure will increase venous return and increase cardiac output. Despite the fall in PV in weightlessness, gravitational unloading of the body causes an expansion of cardiac chambers and vessels which, when combined with the headward fluid shift, increases venous return, leading to an increased stroke volume and cardiac output. In response to this increase in cardiac output, heart rate slows (Fritsch-Yelle et al. 1994; Norsk et al. 2015) and vasorelaxation of peripheral vasculature occurs to decrease blood flow resistance throughout the body. This increase in venous return and resulting increase in cardiac output occurs rapidly and has been confirmed during brief 20-s periods of weightlessness in parabolic flight (Norsk et al. 2006). When these measurements were collected ~1 week into space flight, during which losses in PV had stabilized, there was still an increase in cardiac output and decrease in vascular resistance, but to a lesser degree than during parabolic flight (22% vs. 29%, respectively) (Norsk et al. 2006). While these physiological responses are appropriate for acute adjustments in blood pressure, chronic expansion of heart chambers and vascular dilation during space flight may lead to remodeling and functional changes of these structures. Consequently, during long-duration space flight, chronic vasorelaxation of small arteries, combined with the unweighting of the skeletal muscle surrounding the vessels, may cause functional changes that impair appropriate vasoconstriction. Thus, following space flight when this impaired cardiovascular system is challenged during upright posture in a gravitational environment, it is unable to appropriately maintain arterial pressure. The increased incidence of OI following long-duration space flight may reflect impaired arterial function and the inability for adequate vasoconstriction of peripheral vasculature, leading to venous pooling, decreased venous return, and a fall in systemic arterial pressure.
Dysfunction of arterial vasoconstriction following space flight has been postulated to be a significant factor contributing to OI. Following BR arteries in the lower leg show a reduction in intimal media thickness suggesting vascular remodeling and a loss of smooth muscle. Because of the thinner vessel, a greater amount of nitric oxide released by the endothelium reaches vascular smooth muscle and thus amplifies vasorelaxation. During the 16-day Neurolab Mission, a series of studies indicated that the sympathetic system is augmented during space flight (Cox et al. 2002); muscle sympathetic nerve activity and plasma noradrenaline spillover and clearance are elevated during baseline periods and during a stimulus of lower body negative pressure (Ertl et al. 2002). When crew members return from flight and the cardiovascular system was stressed due to head-up tilt, stroke volume was lower and heart rate and muscle sympathetic nerve activity were higher but appropriate for the imposed hemodynamic challenge (Levine et al. 2002). Additionally, subjects with the least decrement in vasoconstriction following 60 days of head-down bed rest, as assessed by leg and splanchnic flow volume relative to cerebral flow volume, were more protected from OI than those with large decrements (Arbeille et al. 2008). Thus, despite normal functioning autonomic outflow, it appears changes occur in the ability of arteries to respond to the sympathetic stimuli.
Animal models of space flight provide opportunities to study cellular and molecular mechanisms contributing to postflight vascular dysfunction, including changes in arterial resistance vessels. The hindlimb unloading (HU) model suspends rats by their tails to unload their hindlimbs and causes many of the similar cardiovascular changes that occur due to weightlessness, including headward fluid shift, PV loss, and decreased orthostatic tolerance, among others (Zhang 2013). Functional changes of the arterioles are not uniform across all vascular beds. Vasoconstrictor responsiveness is different between slow and fast twitch fibers and fore- and hind-limb muscular arteries. These differences in vasoconstriction and resulting vascular dysfunction likely result from remodeling of vessels. Arteries harvested from the lower body of tail-suspended rats have a reduced vasoconstrictor responsiveness, suggesting smooth muscle contractile dysfunction, and have decreased vascular media thickness and cross sectional area (Zhang 2001). Conversely, arteries from the upper body have shown the opposite changes: increased cross sectional area and greater smooth muscle cell layers. Lower body (mesenteric) and upper body (middle cerebral) arteries have divergent changes in ion channels that promote vasoconstriction. Activation and protein expression of K+ channels (KV) is smaller in cerebral vascular smooth muscle cells, effectively enhancing vasoconstriction. In contrast, larger K+ currents causing a more negative membrane potential and thus reduced vasoconstriction occur in mesenteric vascular smooth muscle cells. Similar increases in L-type voltage-dependent Ca2+ channels (CaL) and Ca2+-activated K+ channels (BKCa) in cerebral vasculature smooth muscle cells enhances membrane depolarization. Finally, ion channels on the sarcoplasmic reticulum inside the smooth muscle cell which regulate calcium release and thus contribute to vasoconstriction reveal a similar pattern where mesenteric arteries are not as sensitive to releasing calcium, and sensitivity to calcium release is upregulated in cerebral arteries. These and other data suggest that the redistribution of transmural pressure along the vessel walls due to removal of the hydrostatic pressure column leads to cellular remodeling and consequently vascular functional changes.
The heart is responsive to changes in pressure and volume loading as well as cardiac work. Normal ambulatory subjects on the ground who initiate a regular exercise program may experience mild to moderate eccentric cardiac hypertrophy (increase in myocardial mass with an increase in cardiac chamber size), while decreased activity, particular with bed rest, results in eccentric cardiac atrophy (decreased in chamber size and myocardial mass). Given that plasma and blood volume decreases, hydrostatic pressure gradients are eliminated, and physical work is reduced during space flight, lower ventricular volumes and cardiac remodeling are expected outcomes when countermeasures are not performed.
Early radiological studies in Mercury, Gemini, Apollo, and Skylab astronauts were suggestive of decreased cardiac size (Nicogossian et al. 1976; Henry et al. 1977). For example, the cardiothoracic ratio, calculated as the ratio of the maximal horizontal cardiac diameter to the maximal horizontal thoracic diameter (inner edge of ribs) from a posterior-anterior chest X-ray, was reduced in 24 of 30 Apollo astronauts, with an average decrease of 5%, from pre- to postflight (Hoffler and Johnson 1975). However, this technique lacked the ability to distinguish between changes in cardiac volumes and myocardial mass. Later M-mode ultrasound studies of the Skylab 4 crew after 84 days of space flight showed decrease in calculated ventricular volume and mass in two of the three astronauts, despite the performance of vigorous exercise throughout the mission (Henry et al. 1977). More recently 2D echocardiography of Space Shuttle and Mir Space Station astronauts confirmed that space flight reduced end-diastolic and end-systolic volumes as well as lower resting stroke volume on landing day (Bungo et al. 1987; Arbeille et al. 2001; Martin et al. 2002). However, while these ultrasound methodologies were considered to be state-of-the-art at the time when the data were collected, the assumptions required to calculate ventricular volumes and total ventricular mass were not consistently accurate. Current technology allows for more complete characterization of the cardiac volume, shape, and mass through the use of 3D echocardiography and magnetic resonance imaging, which has been applied to the study of cardiac mass and volumes after space flight. Left ventricular mass measured using MRI decreased from pre- to postflight in three of four Space Shuttle astronauts when measures were obtained within 12 h after landing; the average decrease was ~12% after just 10 days of space flight (Perhonen et al. 2001a). Although two astronauts participated in short (~10 min) bouts of submaximal exercise on three different days, in general these astronauts did not participate in regular exercise countermeasures. Unfortunately, similar data are not yet available during and following long-duration ISS missions.
Data collected during bed rest as an analog of the space flight-induced cardiac adaptations suggest that the reductions in ventricular volumes are relatively rapid, with remodeling following in a progressive manner as the duration of unloading progresses. Although the immediate response to the initiation of bed rest (moving from standing to the supine posture) is an increase in stroke volume and a decrease in heart rate, over the first 24 h of bed rest stroke volume is reduced and heart rate stabilizes as there is a concomitant decrease in plasma volume (Nixon et al. 1979; Gaffney et al. 1985; Levine et al. 1997; Arbeille et al. 2001). Thereafter, while end diastolic and end systolic left ventricular volumes are reduced within the first 2 weeks of bed rest, reductions in left ventricular mass may not be evident until later (Levine et al. 1997; Perhonen et al. 2001a; Shibata et al. 2010; Hastings et al. 2012; Carrick-Ranson et al. 2013). That is, cardiac atrophy progresses as bed rest duration increases (~1%/week) (Perhonen et al. 2001a; Dorfman et al. 2007; Carrick-Ranson et al. 2013) but can be prevented through the application of exercise countermeasures during bed rest (Dorfman et al. 2007; Shibata et al. 2010; Hastings et al. 2012; Carrick-Ranson et al. 2013).
The most evident functional outcome of reduced ventricular volume and mass is a decrease in stroke volume, which has been linked to post-bed rest and post-space flight orthostatic intolerance (Atkov et al. 1987; Buckey et al. 1996b; Levine et al. 1997) and decreased maximal aerobic capacity (Atkov et al. 1987; Levine et al. 1996; Capelli et al. 2006; Carrick-Ranson et al. 2013). It is generally agreed, however, that systolic function is not compromised during bed rest and space flight (Carrick-Ranson et al. 2013), as indicated by a maintenance of ejection fraction (Arbeille et al. 2001; Platts et al. 2009a) and no change in the relation between end-diastolic volume and stroke volume (Henry et al. 1977; Levine et al. 1997). Rather, impaired diastolic function contributes to a larger degree to the reduction in stroke volume at rest, with orthostatic stress, and during exercise. Decreased early ventricular filling (E wave), for example, likely results (Carrick-Ranson et al. 2013) from reduced left ventricular compliance (Levine et al. 1997; Perhonen et al. 2001b) and reduced diastolic suction (Dorfman et al. 2008).
Pressure sensors in the heart and carotid artery sense changes in blood pressure and provide feedback to the brain if pressure begins to fall so appropriate cardiovascular adjustments can be initiated. Signals from both the parasympathetic and sympathetic system are directed to the heart and to blood vessels to adjust for changes in arterial pressure. Thus, space flight has the potential to affect the parasympathetic and sympathetic responses to changes in blood pressure as well as the target organs, such as the heart and vasculature.
The NEUROLAB mission of STS-90 set out to measure basic autonomic function and how this changed due to space flight. For the first time, muscle sympathetic nerve activity was measured as a direct assessment of sympathetic activity, and norepinephrine spillover and clearance gave insight into norepinephrine kinetics. Compared to supine control, short-duration space flight decreased parasympathetic activity and increased sympathetic activity, which is in opposition to the “vasorelaxation” discussed above. However, this likely reflects differences in the posture used for the control conditions (seated, standing, supine) and now it is believed that autonomic function lies somewhere between that of seated and supine positions on Earth. Indirect measures of sympathetic activity have been made during both short- and long-duration space flight using power spectral analysis of heart rate variability, but few statistical differences have been reported. This may in part reflect differences in control positions (seated, supine, standing) and breathing patterns (spontaneous vs. paced), but it also may be that with the small sample of astronauts completing each experiment, statistical changes are difficult to achieve (Mandsager et al. 2015). Overall, our current understanding is that the autonomic system responds normally due to space flight stressors, and changes in end-organ function underlie the observed physiological adaptations.
In addition to systemic vascular dysfunction, a few investigations have also focused on changes induced by space flight specific to the cerebral vasculature (Blaber et al. 2013). On Earth, the gravitational vector that draws fluid towards the feet creates a pressure gradient such that an arterial pressure of 100 mm Hg at the heart translates to ~200 mm Hg at the feet but only 70 mm Hg at the brain. Because of the headward fluid shift and removal of the hydrostatic pressure gradient during space flight, the cerebral circulation constantly faces a higher pressure than normally occurs on Earth. Cerebral autoregulation (CA) describes the local adjustments by cerebral vessels to maintain a constant cerebral blood flow across a wide range of cerebral blood perfusion pressures (Lassen 1959). However, the increased perfusion pressure to the cerebrovasculature may cause changes in the functioning of autoregulation. Cerebral blood flow velocity measured in crew members during long-duration space flight did not change relative to preflight levels (Iwasaki et al. 2007). Following short-duration space flight cerebrovascular autoregulation was impaired in those astronauts that developed OI (Blaber et al. 2011) and to variable degrees between subjects following long-duration space flight (Zuj et al. 2012). Cerebral arteries harvested from mice flown on STS-135 had lower vasoconstrictor responsiveness and greater distensibility than control mice kept on the Earth (Taylor et al. 2013). If similar changes occur in crewmembers when cerebral perfusion pressure falls during upright posture, the vasoconstrictor response may not sufficiently maintain cerebral blood flow, leading to OI. Because space flight may increase perfusion pressure of the cerebral vasculature, patients with chronic hypertension on Earth may represent an analog population for identifying cerebral vasculature changes that may be occurring during space flight. These patients have an upward shift of cerebrovascular autoregulation, potentially predisposing these patients to cerebral hypotension and syncope (Strandgaard 1976). In other words, the low end of perfusion pressure at which the cerebral vasculature can maintain blood flow is increased. Thus, after space flight, a fall in perfusion pressure below this point will result in a fall in blood flow and syncope. This is an intriguing potential common feature and is consistent with data suggesting impaired autoregulation following space flight in crew members with OI. Future work should focus on determining if long-duration space flight leads to chronic changes in cerebrovascular function that directly increases the risk of OI upon return to a gravitational environment.
Effect of Sex on Cardiovascular Adaptations
The first woman to fly in space was cosmonaut Valentina Tereshkova, who launched aboard Vostok 6 on June 16, 1963, flying for a total of 71 h. The first US/NASA female astronaut was Sally Ride, who launched aboard the Space Shuttle Challenger (STS-7) on June 18, 1983, completing a 6-day mission. Since that time, the number of women who have compromised NASA’s astronauts corps has increased, with 22% of the corps being women in 2001 (Harm et al. 2001), and four of eight selected in NASA’s most recent astronaut selection were women. Given that it is likely women will continue to participate in space flight missions including exploration missions, the influence of sex on cardiovascular adaptations to space flight should be considered. However, since proportionately so few women have flown in space, there are limited data to fully understand differences based on sex. Data from short-duration space flight suggest the incidence of postflight OI is greater in women than in men. In one study of Space Shuttle astronauts, all five women studied became presyncopal during a 10-min orthostatic test on landing day while only 20% of the 30 men became presyncopal (Waters et al. 2002). Additionally, women in this study lost more plasma volume (−20%) than men (−7%). In an earlier study, 70% (five of seven) of female Space Shuttle astronauts became presyncopal during a 10-min stand test on landing day compared to 14 of the male astronauts. There are no comparable data yet available to compare the incidence of OI in men and women after long-duration space flight. Similarly, there is insufficient space flight data to test the effects of gender on other cardiovascular adaptations to space flight, such as cardiac atrophy and maximal aerobic capacity. Despite limited measures of left ventricular mass and function during bed rest, one 60-day bed rest study reported that the rate of left ventricular atrophy did not appear to be different than that observed in men in other bed rest studies (Dorfman et al. 2007). Although maximal aerobic capacity is generally lower in women than in men before bed rest, the relative decrease (%) appears roughly equal between both sexes (Lee et al. 2010). However, assuming that women astronauts have a lower maximal aerobic capacity before launch, women may be at an increased risk of not being able to complete some mission critical tasks that require a higher level of absolute oxygen consumption (Harm et al. 2001).
Prevention of cardiovascular deconditioning has become an important focus of space flight countermeasures to ensure crew health and safety. During the mission, crewmembers must maintain the ability to perform physical tasks required both inside and outside of the vehicle or habitat (Moore et al. 2010), including the ability to respond to emergencies (Bishop et al. 1999). While some aspects of physical work will be less demanding during weightlessness, the stress on the cardiovascular system would be elevated in a deconditioned astronaut, particularly upon return to gravity (Bishop et al. 1999). Additionally, the crewmembers will be required to act autonomously without the assistance of ground personnel during interplanetary travel or in the event of off-nominal landings upon return to Earth (Pettit 2010). An astronaut who cannot perform strenuous work due to reduced aerobic capacity or OI will increase the risk to their crewmates who assist that individual. Thus, countermeasures are directed towards the prevention of physiological adaptations (e.g., cardiac atrophy, diminished vasoconstriction) that result in reduced cardiovascular function (e.g., reduced stroke volume during orthostatic stress and exercise) and would significantly impact operational performance.
Exercise has been the mainstay of countermeasures to prevent cardiovascular deconditioning since early in the space flight program (Moore et al. 2010), with varying levels of effectiveness depending upon hardware availability (Kozlovskaya and Grigoriev 2004), constraints imposed by the space vehicle (e.g., cabin space to house countermeasure equipment), crew scheduling, and adherence by the crew to exercise prescriptions (Hayes et al. 2013). Countermeasure exercise programs implemented by the US/NASA and the Soviet/Russian space programs utilize different specific exercise regimens, and hardware has varied. Countermeasure programs employed by other space agencies have adopted various aspects of the US/NASA and Soviet/Russian programs and, partially due to relatively small amount of space flight experience, are evolving (Loehr et al. 2015).
In the history of the US/NASA space program, small capsule size during the Mercury, Gemini, and Apollo programs prohibited the implementation an extensive exercise countermeasure system. Although limited in duration and intensity, the inflight exercise tests (e.g., 30 s of pulling on bungee cords while measuring heart rate) during these missions suggested that cardiovascular responses to mild to moderate exercise were not significantly impaired during these short duration missions (Moore et al. 2010). However, elevated heart rate during postflight exercise tests and signs of OI during stand tests on landing day were suggestive of the need for inflight exercise countermeasures. An extensive exercise countermeasure program was employed during the three Skylab missions, with more exercise modalities and increased exercise duration implemented as the length of successive missions increased (Skylab 2: 28 days; Skylab 3: 59 days; Skylab 4: 84 days). During the Space Shuttle program when interior vehicle space was limited, generally only one exercise countermeasure device was flown on each mission. A cycle ergometer was most often flown, but Shuttle astronauts also used different versions of treadmills and rowing ergometers. The Space Shuttle flight crew (commander, pilot, and flight engineer) was scheduled to exercise 3 days/week while on-orbit while the remaining crewmembers were scheduled to exercise at least twice per week. The largest study to examine exercise habits of Space Shuttle astronauts found regular participation (>3/week) of moderate intense exercise (>70% age-predicted maximal heart rate) prevented or attenuated the tachycardic response during upright exercise (Hayes et al. 2013) and standing (Lee et al. 1999) on landing day.
More frequent and more intense exercise, including resistive exercise, has been performed by all astronauts and cosmonauts during long-duration stays on space stations (e.g., Skylab, Mir, ISS). Current exercise countermeasure hardware on the ISS including treadmills, cycle ergometers, and a resistive exercise device (Moore et al. 2010; Loehr et al. 2011). Crewmembers are allotted ~2.5 h/day for exercise, including time for hardware set-up and tear down and personal hygiene. In US/NASA astronauts, aerobic exercise (treadmill or cycle ergometry) generally is performed for 30 min/session, 6 days/week. Resistive exercise is usually performed for 30–45 min/session, 6 days/week, with an emphasis on the lower body musculature that experiences the greatest loss during space flight. Versions of the treadmill and resistive exercise device used during early ISS missions lacked the capacity to provide high intensity exercise (Moore et al. 2010) and have been replaced with more robust hardware (Smith et al. 2012). Consequently, ISS astronauts have engaged more intense exercise sessions and anecdotal reports suggest that this has improved the overall condition of astronauts during and after space flight. Results from bed rest studies suggest that regular vigorous aerobic and resistive exercise will reduce or prevent some aspects of cardiovascular (Dorfman et al. 2007; Schneider et al. 2009) and musculoskeletal deconditioning (Adams et al. 2003; Alkner and Tesch 2004; Trappe et al. 2007), but countermeasures without an orthostatic-stress component will not prevent post-space flight OI (Lee et al. 1999, 2015; Meck et al. 2001). However, regular performance of intense exercise, particularly in astronauts who are less fit before space flight, appears to prevent significant losses and may actually, in some cases, increase maximal aerobic capacity (Moore et al. 2014) and left ventricular mass and function (Abdullah et al. 2013).
Similarly, in the Soviet/Russian space flight program exercise countermeasure performance largely has not been possible in the small Soyuz space capsules (Kozlovskaya et al. 2010). The countermeasure program, developed based upon results from a series of studies in space flight analogs, was first employed on the Soviet Salyut space station in the 1970s and has been refined through the years by later experiences on the Mir Space Station. Cosmonauts exercised using a treadmill, a cycle ergometer, and heavy load bungee cords on the Mir Space Station. A full body suit with bungee cords sewn in (Penguin Suit) could be worn to provide axial loading throughout the day. Russian crewmembers on ISS continue to perform treadmill and cycle ergometer exercise in the Russian segment of the vehicle but also use the resistive exercise device provided by NASA. In contrast to the US/NASA system of exercise countermeasures in which crewmembers exercise for 6 days of resistive and aerobic exercise and then have 1 day of active rest, the current Russian cosmonauts’ exercise countermeasures are organized into microcycles consisting of three consecutive days of physical training and then have 1 day of active recovery (Kozlovskaya and Grigoriev 2004; Kozlovskaya et al. 2010). In the Russian program, exercise is prescribed to be performed in two separate 1-h sessions each day, with the intensity of the exercise countermeasures increasing throughout the mission.
While results from small studies (n < 15) are promising, there is no large-scale database from which to judge the overall effectiveness of countermeasures performed during space flight to protect cardiovascular outcomes. All astronauts and cosmonauts participate in countermeasures since space flight analog data have documented the benefits of countermeasures and therefore asking crewmembers not to perform countermeasures is considered unethical. Having crewmembers refrain from performing countermeasures, even for research, would be equivalent to withholding medication with known benefit. Further, a significantly deconditioned crewmember could increase the likelihood that the crewmember could not perform mission critical tasks, which could endanger the success of the mission and the health and wellbeing of other astronauts. Additionally, while adherence to countermeasures varies across crewmembers and assessing outcomes across a large number of astronauts and cosmonauts might normally provide information about the relation between level of countermeasure participation and crew health, most space flight studies have an insufficient number of subjects with a limited range in countermeasure adherence or limited or no documentation of countermeasure participation to determine what level of countermeasure participation is required. Two recent retrospective analyses have documented reduced orthostatic tolerance (Lee et al. 2015) and estimated maximal oxygen uptake (Moore et al. 2015) in astronauts participating in early ISS missions, but there was no consistent logging of exercise countermeasures.
During re-entry and landing, development of OI could result in catastrophic vehicle damage or loss and poses a serious threat to crew safety. Throughout much of the space exploration history, crewmembers in the spacecraft have been placed in a recumbent or semi-recumbent position relative to the resultant acceleration vector to minimize the effects of acceleration vectors on the potential for hypotension and loss of consciousness, although this was not the case during the Space Shuttle program when astronauts were seated upright (Sawin et al. 1999). To combat pooling of blood in the abdominal region and the legs, crewmembers wore an inflatable lower body compression garment, called an “antigravity” suit (G-suit suit), during Shuttle landings. Today, all cosmonauts and astronauts wear a similar garment, the Russian Kentavr compression garment (Platts et al. 2009b), when returning from the ISS in the Soyuz capsule.
End of mission countermeasures are routinely employed to mitigate OI, including fluid loading to restore plasma volume, compression garments to prevent blood pooling in the lower body, and body cooling to prevent heat-induced vasodilation. The specifics of these countermeasures have varied across space programs and vehicles. During the Space Shuttle program, NASA instructed astronauts to consume at least 1 L of isotonic fluid, either as water with salt tablets or chicken consumé, within an hour of vehicle re-entry to increase plasma volume (Bungo et al. 1985). Additionally, Shuttle astronauts wore an inflatable lower body compression garment, called an antigravity suit, to prevent blood pooling in the legs and abdomen and to promote venous return (Perez et al. 2003; Platts et al. 2009b). Finally, astronauts wore long-sleeved CapileneTM shirt and pants with plastic tubing through which cooled water was circulated, called the liquid cooling garment, as a means to prevent heat-induced vasodilation and consequent orthostatic intolerance (Wilson et al. 2002; Perez et al. 2003). During the Soviet and Russian space programs, and currently employed by individuals returning on the Soyuz space craft, cosmonauts gradually increase salt and fluid intake in the days before landing to increase plasma volume (Kozlovskaya et al. 2010), wear an individually fitted lower body compression garment called a Kentavr (Vil-Viliams et al. 1998; Platts et al. 2009b), and receive air cooling in the Sokol suit worn during re-entry and landing. Cosmonauts also are exposed to increasing levels and durations of lower body negative pressure, using a garment called the Chibis, over the last few weeks of space flight as a means to re-introduce the cardiovascular system to fluid shifts in the body which are similar to those experienced while standing in normal gravity (Kozlovskaya et al. 2010).
Future countermeasures which have been tested using the space flight analog of bed rest include artificial gravity (Stenger et al. 2007), artificial gravity plus exercise (Katayama et al. 2004), lower body negative pressure plus exercise (Dorfman et al. 2007; Watenpaugh et al. 2007; Schneider et al. 2009), and enhanced fluid loading (Shibata et al. 2010; Jeong et al. 2012; Hastings et al. 2012). Each of these modalities has demonstrated promise, but challenges unique to implementing these countermeasures have prevented implementation during space flight (Lee et al. 2010). For example, continuous application of artificial gravity throughout the duration of a mission will likely require whole vehicle rotation, which imposes specific requirements on vehicle design. Current concepts for countermeasures such as short-arm centrifugation for artificial gravity or treadmill exercise combined with lower body negative pressure require significant space in the vehicle. This may be particularly problematic in the current models for space exploration to Mars, its moons, and asteroids when the interior of the space vehicle is expected to be small relative to the amount of hardware, food, and other supplies that will be transported to and from these far-off destinations to support crew activities and health.
Artificial gravity (AG) by centrifugation has been widely discussed as a whole body countermeasure to space flight deconditioning, and possible future vehicle designs involve rotation of the whole vehicle, or a part of the vehicle, or have a module with an onboard centrifuge. By spinning the vehicle, or an onboard centrifuge, Gz forces can be created, recreating a hydrostatic gradient similar to that experienced on Earth. An onboard centrifuge is the most technically feasible method of creating artificial gravity for future missions and has been the most widely tested modality. Artificial gravity via centrifugation has the potential to preserve plasma volume and baroreflex function (Iwasaki et al. 2001), aerobic capacity (Katayama et al. 2004; Stenger et al. 2012), and orthostatic intolerance in ambulatory (Evans et al. 2004; Stenger et al. 2007) and deconditioned individuals (Stenger et al. 2012; Evans et al. 2015). While the idea of AG as a countermeasure dates back to the 1960s (White et al. 1966), the ideal combination of AG magnitude, frequency, and duration has yet to be determined.
Lower Body Negative Pressure
While artificial gravity can successfully restore a hydrostatic gradient across the length of the body similar to normal gravity on Earth, lower body negative pressure produces many effects on the cardiovascular system that are similar to upright standing and exercise by inducing a fluid shift towards the legs and abdomen. The subject’s lower body is enclosed in a chamber, closed at the waist using a flexible seal, and air is pumped out of the chamber, decompressing the lower body. This results in a level of central hypovolemia that is proportional to the amount of lower body decompression, stimulating baroreceptors to increase heart rate and vascular tone in order to maintain arterial blood pressure. The Russian countermeasure system includes the regular application of lower body negative pressure using the Chibis suit but is currently only utilized during the last few weeks of a long-duration mission. Shorter and lower levels of lower body negative pressure are applied in the first week of applying the countermeasure, and these are increased as the end of the mission approaches (Kozlovskaya et al. 2010). At the end of the mission, cosmonauts may be exposed to up to 20 min of lower body negative pressure with up to −45 mmHg of lower body decompression, a level that produces similar cardiovascular responses to standing in normal gravity (Wolthuis et al. 1974). During Chibis exposures, cosmonauts are also encouraged to move their legs to simulate walking at a rate of 10–12 steps/min. During the Space Shuttle program, NASA astronauts tested a 4-h exposure to −30 mmHg of lower body negative pressure as a countermeasure to OI based upon successful results from a bed rest study (Hyatt and West 1977). Results from the Space Shuttle study suggested that this prolonged LBNP exposure temporarily reversed the deconditioning effects of short-duration space flight if employed 24 h, but not 48 h before landing (Charles et al. 2014). Prolonged LBNP exposure may protect against OI by restoring plasma volume and autonomic control of the cardiovascular system to prefight levels.
The effectiveness of a lower body negative pressure countermeasure might be enhanced by combining it with a bout of exercise (Vernikos et al. 1996). Lower body negative pressure coupled with concurrent exercise during short duration bed rest is as effective as upright exercise for reducing OI (Watenpaugh et al. 1994) and protecting submaximal exercise response and was more effective in restoring plasma volume (Lee et al. 1997). Later studies indicated that regular performance of an interval exercise protocol on a treadmill during up to 60 days of bed rest maintained maximal aerobic capacity (Watenpaugh et al. 2000; Lee et al. 2007; Schneider et al. 2009) and attenuated OI (Schneider et al. 2002; Watenpaugh et al. 2007; Guinet et al. 2009). Like artificial gravity, combining lower body negative pressure with exercise into one countermeasure session is an efficient manner to positively impact multiple physiological systems (e.g., bone, muscle), in addition to its impacts on cardiovascular function (Hargens et al. 2002).
Early bed rest studies suggested that excessive consumption of salt and fluid could be used to quickly return plasma volume to prespace flight levels. Space Shuttle astronauts consumed various amounts of salt and fluid prior to re-entry and demonstrated improved cardiovascular responses to standing on landing day (Bungo et al. 1985). In nine astronauts who did not participate in the fluid loading protocol, heart rate was 110 bpm after 5 min of quiet standing compared to 84 bpm in 17 astronauts who ingested 1 L of water and eight salt tablets beginning approximately 2 h before re-entry. In contrast, Russian cosmonauts attempt to replace space flight-induced plasma volume loss by consuming 0.9 g of sodium chloride and 300 mL of water during lower body negative pressure Chibis sessions in the last few weeks at the end of the mission (Kozlovskaya et al. 1995) and increasing salt intake with meals over the last several days before landing. Reportedly cosmonauts who participate in this form of end-of-mission fluid loading better tolerate the workloads associated with the final phase of the space flight mission and the postflight reconditioning program (Kozlovskaya et al. 2010).
While exercise countermeasures are a well-accepted component of the space flight countermeasures to prevent cardiovascular deconditioning, recent bed rest studies have demonstrated the importance of fluid loading specifically to protect against OI. Bed rest subjects maintained upright maximal aerobic capacity by performing 90 min of daily supine cycling during 18 days of bed rest (Shibata et al. 2010) or rowing 6 days/week with bi-weekly resistive exercise during 35 days of bed rest (Hastings et al. 2012), but OI did not improve. Only when subjects participated in end-of-bed rest fluid loading was tolerance to a ramped lower body negative pressure protocol to presyncope maintained. Subjects received either an infusion of Dextran to restore plasma volume and left ventricular filling pressure on the last day or 0.1 mg of oral fludrocortisone to retain fluid over the last 2 days of bed rest.
Orthostatic intolerance during re-entry and immediately postflight has been the primary cardiovascular risk of space flight for the last several decades. The current countermeasure suite of inflight exercise, prelanding fluid loading, and cooling and compression garments during re-entry and postlanding are successful in preventing postflight orthostatic intolerance after Shuttle- and ISS-length missions. As NASA’s prepares for exploration class missions exceeding 2–3 years in length, it is unclear what the prolonged exposure to the space flight environment will be on the cardiovascular system. Even if part of that mission is spent on the 3/8 gravity (relative to Earth) environment of Mars, it is possible that the level of deconditioning will be sufficiently severe such that current countermeasures are ineffective in protecting against orthostatic intolerance when returning to Earth gravity. Furthermore, the synergistic effects of the spaceflight environment, including radiation, sleep loss, and associated mental stress, altered diet and exercise habits, and oxidative and inflammatory stress may increase the risk of cardiovascular disease. It is well known that increased oxidative damage and inflammation can accelerate the development of atherosclerosis (Madamanchi et al. 2005; Vogiatzi et al. 2009; Ahmadi et al. 2010), and there is related evidence from spaceflight of increased arterial stiffness (Tuday et al. 2007). Adding circulatory disease to the NASA cancer risk assessment model (NSCR-2012) for a Mars-length mission, the risk of exposure-induced death is increased by 40% (Cucinotta et al. 2013) with Life Loss Expectancy of 9–10 years (Cucinotta 2014). The synergistic effect of these combined spaceflight stressors is currently unknown and will be the topic of future cardiovascular research related to spaceflight.
- Abdullah S, Hastings J, Shibata S et al (2013) Effects of prolonged space flight on cardiac structure and function (Abstract). Circulation 128:A18672Google Scholar
- Atkov OY, Bednenko VS, Fomina GA (1987) Ultrasound techniques in space medicine. Aviat Space Environ Med 58:A69–A73Google Scholar
- Bishop PA, Lee SM, Conza NE et al (1999) Carbon dioxide accumulation, walking performance, and metabolic cost in the NASA launch and entry suit. Aviat Space Environ Med 70:656–665Google Scholar
- Bungo MW, Charles JB, Johnson PC Jr (1985) Cardiovascular deconditioning during space flight and the use of saline as a countermeasure to orthostatic intolerance. Aviat Space Environ Med 56:985–990Google Scholar
- Charles JB, Campbell MR, Stenger MB, Lee SMC (2014) Standing without gravity: the use of lower body negative pressure for research and reconditioning during spaceflight. Aviat Space Environ Med 85(3):238, 2014. (85th Annual Meeting of the Aerospace Medical Association, San Diego, CA. May 11–15, 2014.)Google Scholar
- Convertino VA (1996) Exercise and adaptation to microgravity environments. In: Fregly MJ, Blatteis CM (eds) Section 4: Environmental physiology. Oxford University Press, New York, pp 815–844Google Scholar
- Evans JM, Stenger MB, Moore FB et al (2004) Centrifuge training increases presyncopal orthostatic tolerance in ambulatory men. Aviat Space Environ Med 75:850–858Google Scholar
- Fortney SM, Mikhaylov V, Lee SM et al (1998) Body temperature and thermoregulation during submaximal exercise after 115-day spaceflight. Aviat Space Environ Med 69:137–141Google Scholar
- Hargens AR, Groppo ER, Lee SMC et al (2002) The gravity of LBNP exercise: preliminary lessons learned from identical twins in bed for 30 days. J Gravit Physiol 9:P59–P62Google Scholar
- Hayes JC, Guilliams ME, Lee SMC et al (2013) Exercise: developing countermeasure systems for optimizing astronaut performance in space. In: Risin D, Stepaniak PC (eds) Biomedical results of the Space Shuttle Program, NASA/SP-2013-607. US Government Printing Office, Washington, DC, pp 289–314Google Scholar
- Henry W, Epstein SE, Griffith JM et al (1977) Effect of prolonged space flight on cardiac function and dimensions. Biomedical results from Skylab. Scientific and Technical Information Office, National Aeronautics and Space Administration: for sale by the Supt. of Docs., U.S. Govt. Print. Off, Washington, DC, pp 366–371Google Scholar
- Hoffler GW, Johnson RL (1975) Apollo flight crew cardiovascular evaluations. Biomedical results of Apollo. Scientific and Technical Information Office, National Aeronautics and Space Administration, Washington, DC, pp 227–264Google Scholar
- Hyatt KH, West DA (1977) Reversal of bedrest-induced orthostatic intolerance by lower body negative pressure and saline. Aviat Space Environ Med 48:120–124Google Scholar
- Johnson RL, Hoffler GW, Nicogossian AE et al (1977) Lower body negative pressure: third manned Skylab mission. Biomedical results from Skylab. Scientific and Technical Information Office, National Aeronautics and Space Administration: for sale by the Supt. of Docs., U.S. Govt. Print. Off, Washington, DC, pp 284–312Google Scholar
- Katayama K, Sato K, Akima H et al (2004) Acceleration with exercise during head-down bed rest preserves upright exercise responses. Aviat Space Environ Med 75:1029–1035Google Scholar
- Madamanchi NR, Vendrov A, Runge MS (2005) Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 25:29–38. https://doi.org/10.1161/01.ATV.0000150649.39934.13CrossRefGoogle Scholar
- Martin DS, South DA, Wood ML et al (2002) Comparison of echocardiographic changes after short- and long-duration spaceflight. Aviat Space Environ Med 73:532–536Google Scholar
- Nicogossian A, Hoffler GW, Johnson RL, Gowen RJ (1976) Determination of cardiac size following space missions of different durations: the second manned Skylab mission. Aviat Space Environ Med 47:362–365Google Scholar
- Norsk P, Damgaard M, Petersen L et al (2006) Vasorelaxation in space. Hypertension 47:69–73. https://doi.org/10.1161/01.HYP.0000194332.98674.57CrossRefGoogle Scholar
- Perez SA, Charles JB, Fortner GW et al (2003) Cardiovascular effects of anti-G suit and cooling garment during space shuttle re-entry and landing. Aviat Space Environ Med 74:753–757Google Scholar
- Pettit D (2010) Mars landing on Earth: an astronaut’s perspective. J Cosmol 12:3529–3536Google Scholar
- Popov DV, Khusnutdinova DR, Shenkman BS et al (2004) Dynamics of physical performance during long-duration space flight (first results of “Countermeasure” experiment). J Gravit Physiol 11:P231–P232Google Scholar
- Sawin CF, Taylor GR, Smith WL (eds) (1999) Extended duration orbiter medical project final report, 1989–1995, NASA/SP-1999-534. National Aeronautics and Space Administration, HoustonGoogle Scholar
- Schneider SM, Watenpaugh DE, Lee SMC et al (2002) Lower-body negative-pressure exercise and bed-rest-mediated orthostatic intolerance. Med Sci Sports Exerc 34:1446–1453. https://doi.org/10.1249/01.MSS.0000027761.31366.06CrossRefGoogle Scholar
- Taylor CR, Hanna M, Behnke BJ et al (2013) Spaceflight-induced alterations in cerebral artery vasoconstrictor, mechanical, and structural properties: implications for elevated cerebral perfusion and intracranial pressure. FASEB J 27:2282–2292. https://doi.org/10.1096/fj.12-222687CrossRefGoogle Scholar
- Vernikos J, Ludwig DA, Ertl AC et al (1996) Effect of standing or walking on physiological changes induced by head down bed rest: implications for spaceflight. Aviat Space Environ Med 67:1069–1079Google Scholar
- Vil-Viliams IF, Kotovskaya AR, Gavrilova LN et al (1998) Human +Gx tolerance with the use of anti-G suits during descent from orbit of the Soyuz space vehicles. J Gravit Physiol 5:P129–P130Google Scholar
- Vogiatzi G, Tousoulis D, Stefanadis C (2009) The role of oxidative stress in atherosclerosis. Hell J Cardiol 50:402–409Google Scholar
- Watenpaugh DE, Fortney SM, Ballard RE et al (1994) Lower body negative pressure exercise during bed rest maintains orthostatic tolerance. FASEB J 8:A261Google Scholar
- White P, Nyberg J, Finney L, White W (1966) Influence of periodic centrifugation on cardiovascular functions of man during bed rest. Douglas Aircraft, Co., Inc., San MonicaGoogle Scholar
- Williams DA, Convertino VA (1988) Circulating lactate and FFA during exercise: effect of reduction in plasma volume following exposure to simulated microgravity. Aviat Space Environ Med 59:1042–1046Google Scholar